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Sample records for r-2 anticonvulsant activity

  1. Primary amino acid derivatives: substitution of the 4'-N'-benzylamide site in (R)-N'-benzyl 2-amino-3-methylbutanamide, (R)-N'-benzyl 2-amino-3,3-dimethylbutanamide, and (R)-N'-benzyl 2-amino-3-methoxypropionamide provides potent anticonvulsants with pain-attenuating properties.

    Science.gov (United States)

    King, Amber M; Salomé, Christophe; Salomé-Grosjean, Elise; De Ryck, Marc; Kaminski, Rafal; Valade, Anne; Stables, James P; Kohn, Harold

    2011-10-13

    Recently, we reported that select N'-benzyl 2-substituted 2-amino acetamides (primary amino acid derivatives (PAADs)) exhibited pronounced activities in established whole animal anticonvulsant (i.e., maximal electroshock seizure (MES)) and neuropathic pain (i.e., formalin) models. The anticonvulsant activities of C(2)-hydrocarbon N'-benzyl 2-amino acetamides (MES ED(50) = 13-21 mg/kg) exceeded those of phenobarbital (ED(50) = 22 mg/kg). Two additional studies defining the structure-activity relationship of PAADs are presented in this issue of the journal. In this study, we demonstrated that the anticonvulsant activities of (R)-N'-benzyl 2-amino-3-methylbutanamide and (R)-N'-benzyl 2-amino-3,3-dimethylbutanamide were sensitive to substituents at the 4'-N'-benzylamide site; electron-withdrawing groups retained activity, electron-donating groups led to a loss of activity, and incorporating either a 3-fluorobenzyloxy or 3-fluorophenoxymethyl group using a rationally designed multiple ligand approach improved activity. Additionally, we showed that substituents at the 4'-N'-benzylamide site of (R)-N'-benzyl 2-amino-3-methoxypropionamide also improved anticonvulsant activity, with the 3-fluorophenoxymethyl group providing the largest (∼4-fold) increase in activity (ED(50) = 8.9 mg/kg), a value that surpassed phenytoin (ED(50) = 9.5 mg/kg). Collectively, the pharmacological findings provided new information that C(2)-hydrocarbon PAADs represent a novel class of anticonvulsants.

  2. Anticonvulsant activity of a mGlu(4alpha) receptor selective agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid.

    Science.gov (United States)

    Chapman, A G; Talebi, A; Yip, P K; Meldrum, B S

    2001-07-20

    The metabotropic Group III agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (ACPT-1), selective for the mGlu(4alpha) receptor, suppresses sound-induced seizures in DBA/2 mice following its intracerebroventricular (i.c.v.) administration (ED(50) 5.6 [2.9-10.7], nmol i.c.v., 15 min, clonic phase) and in genetically epilepsy-prone (GEP) rats following focal administration into the inferior colliculus (ED(50) 0.08 [0.01-0.50], nmol, 60 min, clonic phase). ACPT-1 also protects against clonic seizures induced in DBA/2 mice by the Group I agonist, (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG) (ED(50) 0.60 [0.29-1.2], nmol i.c.v.) and by the Group III antagonist, (RS)-alpha-methylserine-O-phosphate (MSOP) (ED(50) 49.3 [37.9-64.1], nmol i.c.v.). Another Group III agonist, (RS)-4-phosphonophenyl-glycine (PPG), preferentially activating the mGlu(8) receptor, previously shown to protect against sound-induced seizures in DBA/2 mice and GEP rats, also protects against seizures induced in DBA/2 by 3,5-DHPG (ED(50) 3.7 [2.4-5.7], nmol i.c.v.) and by the Group III antagonist, MSOP (ED(50) 40.2 [21.0-77.0], nmol i.c.v.). At very high doses (500 nmol i.c.v. and above), Group III antagonists have pro-convulsant and convulsant activity. The anticonvulsant protection against sound-induced seizures in DBA/2 mice provided by a fully protective dose (20 nmol, i.c.v.) of the mGlu(4) receptor agonist ACPT-1, is partially reversed by the co-administration of the Group III antagonists, MSOP, (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) or (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4), in the 20-50 nmol dose range. At doses of 50-200 nmol, MPPG and MAP4 cause further reversal of the ACPT-1 anticonvulsant protection, while the MSOP effect on ACPT-1 protection is abolished at higher doses. In contrast, the anticonvulsant protection against sound-induced seizures in DBA/2 mice provided by a fully protective dose (20 nmol, i.c.v.) of the mGlu(8) receptor agonist PPG, is not

  3. Anticonvulsant activity of B2, an adenosine analog, on chemical convulsant-induced seizures.

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    Min Li

    Full Text Available Epilepsy is a chronic neurological disorder characterized by recurrent seizures. However, approximately one-third of epilepsy patients still suffer from uncontrolled seizures. Effective treatments for epilepsy are yet to be developed. N (6-(3-methoxyl-4-hydroxybenzyl adenine riboside (B2 is a N(6-substitued adenosine analog. Here we describe an investigation of the effects and mechanisms of B2 on chemical convulsant-induced seizures. Seizures were induced in mice by administration of 4-aminopyridine (4-AP, pentylenetetrazol (PTZ, picrotoxin, kainite acid (KA, or strychnine. B2 has a dose-related anticonvulsant effect in these chemical-induced seizure models. The protective effects of B2 include increased latency of seizure onset, decreased seizure occurrence, shorter seizure duration and reduced mortality rate. Radioligand binding and cAMP accumulation assays indicated that B2 might be a functional ligand for both adenosine A1 and A2A receptors. Furthermore, DPCPX, a selective A1 receptor antagonist, but not SCH58261, a selective A2A receptor antagonist, blocked the anticonvulsant effect of B2 on PTZ-induced seizure. c-Fos is a cellular marker for neuronal activity. Immunohistochemical and western blot analyses indicated that B2 significantly reversed PTZ-induced c-Fos expression in the hippocampus. Together, these results indicate that B2 has significant anticonvulsant effects. The anticonvulsant effects of B2 may be attributed to adenosine A1 receptor activation and reduced neuronal excitability in the hippocampus. These observations also support that the use of adenosine receptor agonist may be a promising approach for the treatment of epilepsy.

  4. Substituted N-(biphenyl-4'-yl)methyl (R)-2-acetamido-3-methoxypropionamides: potent anticonvulsants that affect frequency (use) dependence and slow inactivation of sodium channels.

    Science.gov (United States)

    Lee, Hyosung; Park, Ki Duk; Torregrosa, Robert; Yang, Xiao-Fang; Dustrude, Erik T; Wang, Yuying; Wilson, Sarah M; Barbosa, Cindy; Xiao, Yucheng; Cummins, Theodore R; Khanna, Rajesh; Kohn, Harold

    2014-07-24

    We prepared 13 derivatives of N-(biphenyl-4'-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound's whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI=TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.

  5. Anticonvulsant activity of 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose isolated from leaves of Mangifera indica.

    Science.gov (United States)

    Viswanatha, G L; Mohan, C G; Shylaja, H; Yuvaraj, H C; Sunil, V

    2013-07-01

    The present study was aimed to evaluate the anticonvulsant activity of 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose (PGG) isolated from methanolic leaf extracts of Mangifera indica in mice. Anticonvulsant activity of PGG was evaluated against pentylenetetrazole (PTZ)-induced and maximal electroshock (MES)-induced convulsions in mice. Additionally, locomotor activity and GABA levels in the brain were estimated to explore the possible CNS-depressant activity and mechanism behind the anticonvulsant activity, respectively. In these studies, PGG (2.5, 5, and 10 mg/kg, intraperitoneal (i.p.)) showed significant and dose-dependent inhibition of PTZ and MES-induced convulsions. Furthermore, PGG administration showed significant decrease in the locomotor activity as an indication of its CNS-depressant property; also, PGG has significantly increased the GABA levels in the cerebellum and whole brain other than the cerebellum. In conclusion, PGG isolated from M. indica showed potent anticonvulsant activity, and possible mechanism may be due to enhanced GABA levels in the brain.

  6. Anticonvulsant Activity of Extracts of Plectranthus barbatus Leaves in Mice

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    Luciana Cristina Borges Fernandes

    2012-01-01

    Full Text Available Plectranthus barbatus is a medicinal plant used to treat a wide range of disorders including seizure. However, the anticonvulsant activity of this plant has not been studied in depth. We therefore sought to evaluate the anticonvulsant activity of a hydroalcoholic extract of P. barbatus leaves on seizures induced by strychnine sulphate (2.0 mg/kg and pilocarpine (600 mg/kg in mice. The extract was administered orally at 1, 10, 30, and 100 mg/kg. We report that the P. barbatus extract had marked anticonvulsant activity against strychnine-induced convulsions, but was quite ineffective against pilocarpine-induced convulsions. Further experiments will be required to identify the active molecules(s and their mechanism(s of action.

  7. Synthesis and anticonvulsant activity of certain chalcone based pyrazoline compounds

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    Sudhakara Rao Gerapati

    2015-09-01

    Full Text Available Convulsions are involuntary, violent, spasmodic and prolonged contractions of skeletal muscles. That means a patient may have epilepsy without convulsions and vice versa. Epilepsy is a common neurological abnormality affecting about 1% of the world population. The primary objectives of these synthesized compounds are to suppress seizures and provide neuroprotection by minimizing the effects from seizure attacks. Here some of the chalcones and chalcone based various pyrazolines were evaluated for anticonvulsant activity. Their structures have been elucidated on the basis of elemental analyses and spectroscopic studies (IR, 1H-NMR & Mass spectroscopy. A preliminary evaluation of the prepared compounds has indicated that some of them exhibit moderate to significant anticonvulsant activity compared to a diazepam standard1-3.  All compounds were tested for their anticonvulsant activity using maximal electroshock induced convulsions (MES in mice at a dose level of 4 mg/kg.b.w. The compounds  Ph1, Ph2 , Py2 ,Py3 and Py4 have shown  to  good anticonvulsant activity when doses are administered as 25mg/ kg.b.w  , reduced the phases of seizures severity and  found to be active and also  increased survival rate. Remaining compounds are less efficacious.

  8. Age and activation determines the anticonvulsant effect of ifenprodil in rats

    Czech Academy of Sciences Publication Activity Database

    Mareš, Pavel

    2014-01-01

    Roč. 387, č. 8 (2014), s. 753-761 ISSN 0028-1298 R&D Projects: GA ČR(CZ) GBP304/12/G069 Institutional support: RVO:67985823 Keywords : NMDA receptors * NR2B subunit * anticonvulsant action * ontogeny * rat Subject RIV: FH - Neurology Impact factor: 2.471, year: 2014

  9. Anticonvulsant activity of bioflavonoid gossypin

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    Srinivasan Duraisamy

    2009-06-01

    Full Text Available The anticonvulsant activity of gossypin was investigated by studying the effects on seizures induced by pentelentetrazole, strychnine and maximal electroshock convulsive methods in mice. Gossypin (10 and 20 mg/kg significantly reduced the duration of convulsion in tonic seizure induced by pentelenetetrazole (95 mg/kg, intraperitoneally. Gossypin (20 mg/kg p.o significantly reduced the tonic extensor convulsion induced by strychnine and maximum electroshock-induced convulsions. The data obtained suggest that gossypin have anticonvulsant property and may probably be affecting both GABA aminergic and glycine inhibitory mechanism.

  10. Anticonvulsant activity of bioflavonoid gossypin

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    Duraisami Rasilingam

    2009-03-01

    Full Text Available The anticonvulsant activity of gossypin was investigated by studying the effects on seizures induced by pentelentetrazole, strychnine and maximal electroshock convulsive methods in mice. Gossypin (10 and 20 mg/kg significantly reduced the duration of convulsion in tonic seizure induced by pentelenetetrazole (95 mg/kg, intraperitoneally. Gossypin (20 mg/kg p.o significantly reduced the tonic extensor convulsion induced by strychnine and maximum electroshock-induced convulsions. The data obtained suggest that gossypin have anticonvulsant property and may probably be affecting both GABA aminergic and glycine inhibitory mechanism.

  11. Group III mGlu receptor agonists potentiate the anticonvulsant effect of AMPA and NMDA receptor block.

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    De Sarro, Giovambattista; Chimirri, Alba; Meldrum, Brian S

    2002-09-06

    We report the anticonvulsant action in DBA/2 mice of two mGlu Group III receptor agonists: (R,S)-4-phosphonophenylglycine, (R,S)-PPG, a compound with moderate mGlu8 selectivity, and of (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid, ACPT-1, a selective agonist for mGlu4alpha receptors. Both compounds, given intracerebroventricularly at doses which did not show marked anticonvulsant activity, produced a consistent shift to the left of the dose-response curves (i.e. enhanced the anticonvulsant properties) of 1-(4'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one hydrochloride, CFM-2, a noncompetitive AMPA receptor antagonist, and 3-((+/-)-2-carboxypiperazin-4-yl)-1-phosphonic acid, CPPene, a competitive NMDA receptor antagonist, in DBA/2 mice. In addition, (R,S)-PPG and ACPT-1 administered intracerebroventricularly prolonged the time course of the anticonvulsant properties of CFM-2 (33 micromol/kg, i.p.) and CPPene (3.3 micromol/kg, i.p.) administered intraperitoneally. We conclude that modest reduction of synaptic glutamate release by activation of Group III metabotropic receptors potentiates the anticonvulsant effect of AMPA and NMDA receptor blockade. Copyright 2002 Elsevier Science B.V.

  12. Anticonvulsant effect of AMP by direct activation of adenosine A1 receptor.

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    Muzzi, Mirko; Coppi, Elisabetta; Pugliese, Anna Maria; Chiarugi, Alberto

    2013-12-01

    Purinergic neurotransmission mediated by adenosine (Ado) type 1 receptors (A1Rs) plays pivotal roles in negative modulation of epileptic seizures, and Ado is thought to be a key endogenous anticonvulsant. Recent evidence, however, indicates that AMP, the metabolic precursor of Ado, also activate A1Rs. Here, we evaluated the antiepileptic effects of AMP adopting in vitro and in vivo models of epilepsy. We report that AMP reversed the increase in population spike (PS) amplitude and the decrease in PS latency induced by a Mg(2+)-free extracellular solution in CA1 neurons of mouse hippocampal slices. The AMP effects were inhibited by the A1R antagonist DPCPX, but not prevented by inhibiting conversion of AMP into Ado, indicating that AMP inhibited per se sustained hippocampal excitatory neurotransmission by directly activating A1Rs. AMP also reduced seizure severity and mortality in a model of audiogenic convulsion. Of note, the anticonvulsant effects of AMP were potentiated by preventing its conversion into Ado and inhibited by DPCPX. When tested in a model of kainate-induced seizure, AMP prolonged latency of convulsions but had no effects on seizure severity and mortality. Data provide the first evidence that AMP is an endogenous anticonvulsant acting at A1Rs. © 2013.

  13. Study of Convolvulus pluricaulis for antioxidant and anticonvulsant activity.

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    Verma, Sristi; Sinha, Reema; Kumar, Puspendra; Amin, Faizal; Jain, Jainendra; Tanwar, Shivani

    2012-03-01

    Convolvulus pluricaulis Choisy is a perennial wild herb commonly found on sandy & rocky areas under xerophytic conditions in northern India. It is a reputed drug of ayurveda and reported to posses antioxidant, brain tonic, nervine tonic, laxative and has been used in anxiety, neurosis, epilepsy, insomnia, burning sensation, oedema and urinary disorders. In the present study, methanolic extract of whole plant of Convolvulus pluricaulis Choisy was evaluated for antioxidant activity by using 1, 1-diphenyl-2-picryl- hydrazyl (DPPH) free radical scavenging model and anticonvulsant activity by using maximal electroshock seizure model. In antioxidant activity, ascorbic acid was used as standard agent while results of anticonvulsant studies were compared with phenytoin. Results of antioxidant activity have demonstrated significant free radical scavenging effect for methanolic extract of Convolvulus pluricaulis Choisy. IC50 value of methanolic extract was observed as 41.00μg/ml as compared to 2.03μg/ml of ascorbic acid. Methanolic extract of C. pluricaulis was evaluated for anticonvulsant activity at 250, 500 and 1000mg/kg. Experimental results have shown that at the dose of 500 and 1000mg/kg, C. pluricaulis didn't abolish the hind limb extension, but reduced the mean recovery time from convulsion.

  14. Anticonvulsant activity of extracts from six Cameroonian plants ...

    African Journals Online (AJOL)

    Epilepsy remains one of the leading public health problems that affects about 50 million people worldwide, thus stressing the need for new anticonvulsant drug. This study was designed to evaluate the anticonvulsant activity against Penty lenetetrazole induced–convulsion in mice. Plants were extracted by maceration with ...

  15. Synthesis and anticonvulsant activity of Schiff’s bases of 3-{[2-({(E-[(substituted phenyl] methylidene} amino ethyl] amino} quinoxalin-2(1H-one

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    Ratnadeep V. Ghadage

    2011-06-01

    Full Text Available In an effort to develop potent anticonvulsant agents, we have synthesized some novel schiff’s bases of 3-{[2-({(E-[substituted phenyl] methylidene} amino ethyl] amino} quinoxalin-2(1H-one and evaluated for in vivo anticonvulsant activity. All the compounds were characterized by IR, 1H NMR data. This activity was carried out on pentylenetetrazole-induced seizure model. Compounds (IIIb and (IIIc Showed maximum time for straub tail and clonic convulsions. That means they possess good activity compared with standard. Animals treated with compounds (IIIb and (IIIe were recovered from this activity.

  16. Small Molecule Anticonvulsant Agents with Potent In Vitro Neuroprotection

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    Smith, Garry R.; Zhang, Yan; Du, Yanming; Kondaveeti, Sandeep K.; Zdilla, Michael J.; Reitz, Allen B.

    2012-01-01

    Severe seizure activity is associated with recurring cycles of excitotoxicity and oxidative stress that result in progressive neuronal damage and death. Intervention to halt these pathological processes is a compelling disease-modifying strategy for the treatment of seizure disorders. In the present study, a core small molecule with anticonvulsant activity has been structurally optimized for neuroprotection. Phenotypic screening of rat hippocampal cultures with nutrient medium depleted of antioxidants was utilized as a disease model. Increased cell death and decreased neuronal viability produced by acute treatment with glutamate or hydrogen peroxide were prevented by our novel molecules. The neuroprotection associated with this chemical series has marked structure activity relationships that focus on modification of the benzylic position of a 2-phenyl-2-hydroxyethyl sulfamide core structure. Complete separation between anticonvulsant activity and neuroprotective action was dependent on substitution at the benzylic carbon. Chiral selectivity was evident in that the S-enantiomer of the benzylic hydroxy group had neither neuroprotective nor anticonvulsant activity, while the R-enantiomer of the lead compound had full neuroprotective action at ≤40 nM and antiseizure activity in three animal models. These studies indicate that potent, multifunctional neuroprotective anticonvulsants are feasible within a single molecular entity. PMID:22535312

  17. Synthesis and anticonvulsant activity of some 2-pyrazolines derived from chalcones

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    Nagihan Beyhan

    2017-05-01

    All compounds were tested for their anticonvulsant activity using pentylenetetrazole induced seizure (PTZ and maximal electroshock seizure (MES tests in mice at a dose level of 50 mg/kg. Among the 2-pyrazoline-1-carbothioamide derivatives, 5-(2,6-dichlorophenyl-3-(thiophen-2-yl-4,5-dihydro-1H-pyrazole-1-carbothioamide (2e reduced grade-5 seizure activity and also increased survival rate in PTZ test. In MES test, 5-(4-methoxyphenyl-3-[4-(methylsulphonylphenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide(2g has not only decreased seizure severity, but also increased survival rate. Among the 2-pyrazoline-1-carboxamide derivatives, 3-(5-bromothiophen-2-yl-N-(4-chlorophenyl-5-(2,6-dichlorophenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (3d having 5-bromothiophen and 2,6-dichlorophenyl moieties and N-(4-chlorophenyl-5-(2,6-dichlorophenyl-3-(5-chlorothiophen-2-yl-4,5-dihydro-1H-pyrazole-1-carboxamide (3e having 5-chlorothiophen and 2,6-dichlorophenyl moieties showed remarkable activities in PTZ test. Among all tested derivatives, compound 3d was found to be the most active one and reduced grade-5 seizure severity and also increased survival rate.

  18. Anticonvulsant and reproductive toxicological studies of the imidazole-based histamine H3R antagonist 2-18 in mice

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    Bastaki SM

    2018-01-01

    Full Text Available Salim M Bastaki,1 Yousef M Abdulrazzaq,2 Mohamed Shafiullah,1 Małgorzata Więcek,3 Katarzyna Kieć-Kononowicz,3 Bassem Sadek1 1Department of Pharmacology and Therapeutics, College of Medicine and Health Science, United Arab Emirates University, Al Ain, 2Department of Medical Education, Dubai Health Authority, Dubai, UAE; 3Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna, Kraków, Poland Abstract: The imidazole-based H3R antagonist 2-18 with high in vitro H3R antagonist affinity, excellent in vitro selectivity profile, and high in vivo H3R antagonist potency was tested for its anticonvulsant effect in maximal electroshock (MES-induced convulsions in mice having valproic acid (VPA as a reference antiepileptic drug (AED. Additionally, H3R antagonist 2-18 was evaluated for its reproductive toxicity in the same animal species. The results show that acute systemic administration (intraperitoneal; i.p. of H3R antagonist 2-18 (7.5, 15, 30, and 60 mg/kg, i.p. significantly and dose dependently protected male as well as female mice against MES-induced convulsion. The protective action observed for H3R antagonist 2-18 in both mice sexes was comparable to that of VPA and was reversed when mice were pretreated with the selective H3R agonist (R-alpha-methylhistamine (RAMH, 10 mg/kg, i.p.. Moreover, the results show that acute systemic administration of single (7.5, 15, 30, or 60 mg/kg, i.p. or multiple doses (15×3 mg/kg, i.p. of H3R antagonist 2-18 on gestation day (GD 8 or 13 did not affect the maternal body weight of mice when compared with the control group. Furthermore, no significant differences were observed in the average number of implantations and resorptions between the control and H3R antagonist 2-18-treated group at the early stages of gestation and the organogenesis period. However, oral treatment with H3R antagonist 2-18 (15 mg/kg on GD 8 induced a reduced number of

  19. Correlation of [14C]muscimol concentration in rat brain with anticonvulsant activity

    International Nuclear Information System (INIS)

    Matthews, W.D.; Intoccia, A.P.; Osborne, V.L.; McCafferty, G.P.

    1981-01-01

    Muscimol, an in vivo and in vitro GABA agonist, has anticonvulsant activity against bicuculline-induced seizures when given systemically to rats. To determine whether parent compound or a metabolite possessed the anticonvulsant activity, experiments were performed with [ 14 C]muscimol. Anticonvulsant activity was determined by the percent of animals protected against tonic forelimb extension induced by bicuculline. Brain and urine were analyzed for unchanged [ 14 C]muscimol by thin-layer chromatography. The time course of anticonvulsant activity and [ 14 C]muscimol concentration in brain after intravenous injection were similar. Peak brain concentration of [ 14 C]muscimol and maximal protection against bicuculline-induced seizures occurred simultaneously. These data suggest that intravenously administered [ 14 C]muscimol rapidly penetrates brain tissue and parent compound is responsible for antagonism of bicuculline-induced convulsions. (Auth.)

  20. Role of neurosteroids in the anticonvulsant activity of midazolam.

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    Dhir, Ashish; Rogawski, Michael A

    2012-04-01

    Midazolam is a short-acting benzodiazepine that is widely used as an i.v. sedative and anticonvulsant. Besides interacting with the benzodiazepine site associated with GABA(A) receptors, some benzodiazepines act as agonists of translocator protein (18 kDa) (TSPO) to enhance the synthesis of steroids, including neurosteroids with positive modulatory actions on GABA(A) receptors. We sought to determine if neurosteroidogenesis induced by midazolam contributes to its anticonvulsant action. Mice were pretreated with neurosteroid synthesis inhibitors and potentiators followed by midazolam or clonazepam, a weak TSPO ligand. Anticonvulsant activity was assessed with the i.v. pentylenetetrazol (PTZ) threshold test. Midazolam (500-5000 µg·kg(-1) , i.p.) caused a dose-dependent increase in seizure threshold. Pretreatment with the neurosteroid synthesis inhibitors finasteride, a 5α-reductase inhibitor, and a functional TSPO antagonist PK 11195, reduced the anticonvulsant action of midazolam. The anticonvulsant action of midazolam was enhanced by the neurosteroidogenic drug metyrapone, an 11β-hydroxylase inhibitor. In contrast, the anticonvulsant action of clonazepam (100 µg·kg(-1) ) was reduced by finasteride but not by PK 11195, indicating a possible contribution of neurosteroids unrelated to TSPO. Enhanced endogenous neurosteroid synthesis, possibly mediated by an interaction with TSPO, contributed to the anticonvulsant action of midazolam. Enhanced neurosteroidogenesis may also be a factor in the actions of other benzodiazepines, even those that only weakly interact with TSPO. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  1. Anticonvulsant activity of Granisetron in Albino mice

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    Sathisha Aithal

    2015-05-01

    Full Text Available The objective of this study was to investigate the anticonvulsant activity of  5-HT3 antagonist, granisetron in albino mice. In this study granisetron (0.5mg/kg, i.p. was administered 30 minutes prior to application of electroshock (60mA, 02.seconds or administration of pentylenetetrazole. Granisetron significantly reduced the duration of tonic hind limb extension in maximum electroshock seizure (MES test. In pentylenetetrazole (PTZ test, granisetron delayed the onset and the decreased the duration of convulsions compared to control group. The percentage of animals protected in MES and PTZ  models were 66 and 83 respectively. The results showed that granisetron at dose of 0.5mg possess anticonvulsant activity in both MES and PTZ models.

  2. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

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    Sadek B

    2016-11-01

    Full Text Available Bassem Sadek,1 Ali Saad,1 Johannes Stephan Schwed,2,3 Lilia Weizel,2 Miriam Walter,2 Holger Stark2,3 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany; 3Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Düsseldorf, Germany Abstract: Phenytoin (PHT, valproic acid, and modern antiepileptic drugs (AEDs, eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%–80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S-2-(4-(3-(piperidin-1-ylpropoxybenzylaminopropanamide (1. In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R-2-(4-(3-(piperidin-1-ylpropoxybenzylaminopropaneamide (2 and analogs thereof, in maximum electroshock (MES-, pentylenetetrazole (PTZ-, and strychnine (STR-induced convulsion models in rats having PHT and valproic acid (VPA as reference AEDs. Unlike the S-enantiomer (1, the results show that animals pretreated intraperitoneally (ip with the R-enantiomer 2 (10 mg/kg were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R-enantiomer (3

  3. Synthesis, potential anticonvulsant and antidepressant effects of 2-(5-methyl-2,3-dioxoindolin-1-ylacetamide derivatives

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    Xinghua Zhen

    2015-07-01

    Full Text Available A new series of 2-(5-methyl-2,3-dioxoindolin-1-ylacetamide derivatives were synthesized and evaluated for their anticonvulsive activity in a pentylenetetrazole (PTZ-evoked convulsion model and antidepressant activity in the forced swimming test (FST model. Eleven synthesized compounds were found to be protective against PTZ-induced seizure and showed the anticonvulsant activity. In addition, four of the synthesized compounds (4l, 4m, 4p and 4q showed potent antidepressant-like activity. Among these compounds, compound 4l was found to have the most potent antidepressant-like activity, and significantly reduced the duration of immobility time at 100 mg/kg dose level when compared to the vehicle control, which is similar to the reference drug fluoxetine.

  4. Anticonvulsant activity of the ethanolic extract of Punica granatum L. seed.

    Science.gov (United States)

    Mehrzadi, Saeed; Sadr, Samir; Hosseinzadeh, Azam; Gholamine, Babak; Shahbazi, Ali; FallahHuseini, Hasan; Ghaznavi, Habib

    2015-06-01

    Various morphological parts of pomegranate (Punica granatum L.) have extensively been used in the folk medicine to treat an array of human ailments. The aim of the present study is to demonstrate the anticonvulsant potential of the ethanolic extract of P. granatum L. seed in chemoconvulsant-induced seizures in mice. The anticonvulsant activity of the ethanolic extract was investigated in strychnine (STR)-induced and pentylenetetrazole (PTZ)-induced seizure models in mice. Diazepam was used as reference anticonvulsant drug. Ethanolic extract (150, 300, and 600 mg/kg per os, p.o.), diazepam (1 mg/kg intraperitoneally, i.p.), and distilled water (10 ml/kg, i.p.) were administered before induction of seizures by PTZ (60 mg/kg, i.p.) or STR (2.5 mg/kg, i.p.). The latent time before the onset of convulsions, the duration of convulsions, the percentage of seizure protection, and mortality rate were recorded. The seed ethanolic extract did not show any toxicity and did not protect the animals against seizures but demonstrated a significant increase in seizure latency at 300 and 600 mg/kg in both STR and PTZ seizure models (P < 0.001). It also showed a significant reduction in seizure duration at 300 mg/kg (P < 0.05) and 600 mg/kg (P < 0.001) in the STR seizure model and 600 mg/kg (P < 0.01) in the PTZ seizure model compared with the control group. Ethanol extract has dose-dependent anticonvulsant activity against STR- and PTZ-induced seizures. This activity might be due to its saponins, flavonoids, triterpenes, and alkaloids ingredients.

  5. Seizures induced in immature rats by homocysteic acid and the associated brain damage are prevented by group II metabotropic glutamate receptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate.

    Science.gov (United States)

    Folbergrová, Jaroslava; Druga, Rastislav; Otáhal, Jakub; Haugvicová, Renata; Mares, Pavel; Kubová, Hana

    2005-04-01

    The present study has examined the anticonvulsant and neuroprotective effect of group II metabotropic glutamate receptor (mGluR) agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) in the model of seizures induced in immature 12-day-old rats by bilateral intracerebroventricular infusion of dl-homocysteic acid (DL-HCA, 600 nmol/side). For biochemical analyses, rat pups were sacrificed during generalized clonic-tonic seizures, approximately 45-50 min after infusion. Comparable time intervals were used for sacrificing the pups which had received 2R,4R-APDC. Low doses of 2R,4R-APDC (0.05 nmol/side) provided a pronounced anticonvulsant effect which was abolished by pretreatment with a selective group II mGluR antagonist LY341495. Generalized clonic-tonic seizures were completely suppressed and cortical energy metabolite changes which normally accompany these seizures were either normalized (decrease of glucose and glycogen) or markedly reduced (an accumulation of lactate). EEG recordings support the marked anticonvulsant effect of 2R,4R-APDC, nevertheless, this was only partial. In spite of the absence of obvious motor phenomena, isolated spikes or even short periods of partial ictal activity could be observed. Isolated spikes could also be seen in some animals after application of 2R,4R-APDC alone, reflecting most likely subclinical proconvulsant activity of this agonist. The neuroprotective effect of 2R,4R-APDC was evaluated after 24 h and 6 days of survival following DL-HCA-induced seizures. Massive neuronal degeneration, as revealed by Fluoro-Jade B staining, was observed in a number of brain regions following infusion of DL-HCA alone (seizure group), whereas 2R,4R-APDC pretreatment provided substantial neuroprotection. The present findings support the possibility that group II mGluRs are a promising target for a novel approach to treating epilepsy.

  6. [Effect of psychotropic drugs on activity of anticonvulsants in maximal electroshock test].

    Science.gov (United States)

    Alikina, N A; Tregubov, A L; Kotegov, V P

    2010-08-01

    The effect ofpsychotropic drugs on the pharmacological properties of anticonvulsants was studied on white mice under maximal electroshock (ME) test conditions. Changes in the anticonvulsant effect of phenobarbital, diphenin, carbamazepine, hexamidine were traced upon their joint administration with psychotropic drugs, including piracetam, aminalon, amitriptyline, imizine, levomepromazine, and lithium oxybutyrate. An important result of research is the fact, that in no one of combinations the basic pharmacological effect of anticonvulsants was decreased. Based on the results of experiments, the most rational combinations of anticonvulsants with psychotropic preparations were revealed as manifested in the ME test. As criterion of rational combination was the increase in the activity of anticonvulsants and reduction of their toxicity in combination or at least invariance of this parameter. Rational combinations include (i) phenobarbital with piracetam, amitriptyline, levomepromazine, and lithium oxybutyrate; (ii) carbamazepine with piracetam; and (iii) hexamidine with amitriptyline, levomepromazine and imizine.

  7. Molecular Docking and Anticonvulsant Activity of Newly Synthesized Quinazoline Derivatives

    Directory of Open Access Journals (Sweden)

    Hatem A. Abuelizz

    2017-06-01

    Full Text Available A new series of quinazoline-4(3H-ones are evaluated for anticonvulsant activity. After intraperitoneal (ip injection to albino mice at a dose of 100 mg/kg body weight, synthesized quinazolin-4(3H-ones (1–24 were examined in the maximal electroshock (MES induced seizures and subcutaneous pentylenetetrazole (scPTZ induced seizure models in mice. The Rotarod method was applied to determine the neurotoxicity. Most of the compounds displayed anticonvulsant activity in the scPTZ screen at a dose range of 0.204–0.376 mmol/mL. Out of twenty-four, compounds 8, 13 and 19 proved to be the most active with a remarkable protection (100% against PTZ induced convulsions and four times more potent activity than ethosuximide. The structure-activity relationship concluded valuable pharmacophoric information, which was confirmed by the molecular docking studies using the target enzyme human carbon anhydrase II (HCA II. The studied quinazoline analogues suggested that the butyl substitution at position 3 has a significant effect on preventing the spread of seizure discharge and on raising the seizure threshold. However, benzyl substitution at position 3 has shown a strong anticonvulsant activity but with less seizure prevention compared to the butyl substitution.

  8. Cav2.3 (R-Type Calcium Channels are Critical for Mediating Anticonvulsive and Neuroprotective Properties of Lamotrigine In Vivo

    Directory of Open Access Journals (Sweden)

    Maxine Dibué-Adjei

    2017-11-01

    Full Text Available Background/Aims: Lamotrigine (LTG is a popular modern antiepileptic drug (AED, however, its mechanism of action has yet to be fully understood, as it is known to modulate many members of several ion channel families. In heterologous systems, LTG inhibits Cav2.3 (R-type calcium currents, which contribute to kainic-acid- (KA induced epilepsy in vivo. To gain insight into the role of R-type currents in LTG drug action in vivo, we compared the effects of LTG to topiramate and lacosamide in Cav2.3-deficient mice and controls on KA-induced seizures. Methods: Behavioral seizure rating and quantitative electrocorticography were performed after injection of 20 mg/kg [and 30 mg/kg] KA. One hour before KA injection, mice were pretreated with either 30 mg/kg LTG, 50 mg/kg topiramate (TPM or 30 mg/kg lacosamide (LSM. Results: Ablation of Cav2.3 reduced total seizure scores by 28.6% (p=0.0012 and pretreatment with LTG reduced seizure activity of control mice by 23.2% (p=0.02. In Cav2.3-deficient mice LTG pretreatment increased seizure activity by 22.1% (p=0.018 and increased the percentage of degenerated CA1 pyramidal neurons (p=0.02. All three tested AEDs reduced seizure activity in control mice, however only the non-calcium channel modulating AED, LSM had an anticonvulsive effect in Cav2.3-deficient mice. Furthermore LTG altered electrocorticographic parameters differently in the two genotypes, decreasing relative power of ictal spikes in control mice compared to Cav2.3-defcient mice. Conclusion: These findings give first in vivo evidence for an essential role for Cav2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Cav2.3-deficient mice resulting in increased neurotoxicity in the CA1 region. This paradoxical mechanism, possibly reflecting rebound hyperexcitation of pyramidal CA1 neurons after increased inhibition, may be key in understanding LTG-induced seizure

  9. Anti-Convulsant Activity of Boerhaavia diffusa: Plausible Role of Calcium Channel Antagonism

    Directory of Open Access Journals (Sweden)

    Mandeep Kaur

    2011-01-01

    Full Text Available “Ethnopharmacological” use of roots of Boerhaavia diffusa (B. diffusa in the treatment of epilepsy in Nigerian folk medicine and reports showing the presence of a calcium channel antagonistic compound “liriodendrin” in its roots, led us to undertake the present study. The study was designed to investigate the methanolic root extract of B. diffusa and its different fractions including liriodendrin-rich fraction for exploring the possible role of liriodendrin in its anti-convulsant activity. Air-dried roots of B. diffusa were extracted with methanol by cold maceration. The methanol soluble fraction of extract thus obtained was successively extracted to obtain liriodendrin-rich fraction and two side fractions, that is, chloroform fraction and phenolic compound fraction. Anti-convulsant activity of methanolic extract (1000, 1500 and 2000 mg kg-1, intraperitoneally (i.p. and its different fractions, that is, liriodendrin-rich fraction (10, 20 and 40 mg kg-1, i.p., chloroform fraction (20 mg kg-1, i.p. and phenolic compound fraction (1 mg kg-1, i.p. were studied in pentylenetetrazol (PTZ-induced seizures (75 mg kg-1, i.p.. The crude methanolic extract of B. diffusa and only its liriodendrin-rich fraction showed a dose-dependent protection against PTZ-induced convulsions. The liriodendrin-rich fraction also showed significant protection against seizures induced by BAY k-8644. These findings reiterated the anti-convulsant activity of methanolic extract of B. diffusa roots. Furthermore, it can be concluded that the observed anti-convulsant activity was due to its calcium channel antagonistic action as this activity was retained only in the liodendrin-rich fraction, which has additionally been confirmed by significant anti-convulsant activity of liriodendrin-rich fraction in BAY k-8644-induced seizures.

  10. Anticonvulsant activity of Bacopa monniera in rodents

    Directory of Open Access Journals (Sweden)

    Darpan Kaushik

    2009-12-01

    Full Text Available Bacopa monnieri (L, belonging to the Scrophulariaceae family and commonly known as Brahmi, is well known in India for its CNS activity but its neuropharmacological effect has not yet been explored. In the present study, the antiepileptic effects of the plant were investigated. The ethanolic extract of Bacopa monniera was tested for anticonvulsant activity in albino rats, using different convulsive models. The ethanolic extract of leaves produced significant anticonvulsant activity for all the different models studied. The present study shows a probable mechanism of action similar to that of benzodiazepines (GABA agonist. Thus, these results emphasize the need to diversify by using alternative therapeutic approaches pertaining to herbal medicine, where a single easily available plant may provide solutions to several therapeutic challenges, as observed in the anticonvulsant action of ethanolic extract of B. monniera.Bacopa monniera, da família Scrophulariaceae, e comumente denominada Brahmi, é bem conhecida na Índia por sua atividade no Sistema Nervoso Central, mas seu efeito neurofarmacológico não foi, ainda, explorado. No presente estudo, investigaram-se os efeitos antiepilépticos da planta. O extrato etanólico da Bacopa monniera foi testado quanto à atividade anticonvulsivante em ratos albinos, utilizando-se diferentes modelos de convulsão. O extrato etanólico das folhas produziu atividade anticonvulsivante significativa para todos os diferentes modelos estudados. O presente estudo mostra provável mecanismo de ação semelhante ao dos benzodiazepínicos (agonista do GABA. Assim sendo, esses resultados enfatizam a necessidade de diversificar, utilizando-se abordagens terapêuticas alternativas da medicina natural, em que uma planta facilmente disponível pode fornecer soluções para vários desafios terapêuticos, como o observado na ação anticonvulsivante do extrato etanólico de Bacopa monniera.

  11. Coumarin incorporated triazoles: a new class of anticonvulsants.

    Science.gov (United States)

    Bhat, Mashooq A; Al-Omar, Mohammed A

    2011-01-01

    A series of coumarin incorporated 1,2,4- triazole compounds (1-14) were evaluated for their possible anticonvulsant and neurotoxic properties, log P values, pharmacophoric mapping and three dimensional structure analysis. Compound (6) with para-fluoro substitution showed significant anticonvulsant activity.

  12. Anticonvulsants.

    Science.gov (United States)

    Hillebrand, Marc; Young, John L.

    1994-01-01

    Anticonvulsants have gained recognition for their beneficial effect in the treatment of aggressive behavior, particularly carbamazepine. Empirical studies of the effectiveness of anticonvulsants in decreasing aggression are reviewed and evaluated, and cost-benefit factors related to the use of anticonvulsants are evaluated. A protocol for the…

  13. A new class of anticonvulsants possessing 6 Hz psychomotor seizure test activity: 2-(1H-benzotriazol-1-yl)-N'-[substituted] acetohydrazides.

    Science.gov (United States)

    Kumar, Praveen; Tripathi, Laxmi

    2012-05-01

    A series of 2-(1H-Benzotriazol-1-yl)-N'-[substituted]acetohydrazides were designed & synthesized keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and neurotoxicity. The new compounds were characterized using FT-IR, 1H NMR, mass spectral data and elemental analysis. The anticonvulsant activity of the titled compounds was assessed using the 6 Hz psychomotor seizure test. The neurotoxicity was assessed using the rotorod method. The most active compound of the series was N'-[4-(1,3-Benzodioxol-5-yloxy)benzylidene]-2-(1H-benzotriazol-1-yl)acetohydrazide (BTA 9), which showed good activity with 75 % protection (3/4, 0.5 h) at a dose of 100 mg/kg in mice. All the compounds exhibited no neurotoxicity. A computational study was carried out for calculation of pharmacophore pattern and prediction of pharmacokinetic properties. Titled compounds have also exhibited good binding properties with epilepsy molecular targets such as glutamate, GABA (A) delta, GABA (A) alpha-1 receptors and Na/H exchanger, in Lamarckian genetic algorithm based flexible docking studies.

  14. [The original nootropic and neuroprotective drug noopept potentiates the anticonvulsant activity of valproate in mice].

    Science.gov (United States)

    Kravchenko, E V; Ponteleeva, I V; Trofimov, S S; Lapa, V I; Ostrovskaia, R U; Voronina, T A

    2009-01-01

    The influence of the original dipeptide drug noopept, known to possess nootrope, neuroprotector, and anxiolytic properties, on the anticonvulsant activity of the antiepileptic drug valproate has been studied on the model of corazole-induced convulsions in mice. Neither a single administration of noopept (0.5 mg/kg, i.p.) nor its repeated introduction in 10 or 35 days enhanced the convulsant effect of corazole, which is evidence that noopept alone does not possess anticonvulsant properties. Prolonged (five weeks) preliminary administration of noopept enhanced the anticonvulsant activity of valproate. This result justifies the joint chronic administration of noopept in combination with valproate in order to potentiate the anticonvulsant effect of the latter drug. In addition, the administration of noopept favorably influences the cognitive functions and suppresses the development of neurodegenerative processes.

  15. Design, synthesis and anticonvulsant activity evaluation of 7-substituted-4H-[1,2,4]triazino[3,4-alpha]phthalazin-4-one derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Xian-Yu; Quan, Zhe-Shan [Yanbian Univ., Yanji, Jilin (China). Key Lab. of Organism Functional Factors of the Changbai Mountain; Yanbian Univ., Yanji, Jilin (China). Coll. of Pharmacy; Guan, Li-Ping; Zhang, Lei; Wei, Cheng-Xi; Piao, Hu-Ri [Yanbian Univ., Yanji, Jilin (China). Key Lab. of Organism Functional Factors of the Changbai Mountain

    2009-07-01

    In this study, a novel series of 7-substituted-4H-[1,2,4]triazino[3,4-a]phthalazin-4-one derivatives was synthesized as potential anticonvulsant agents. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test, and their neurotoxicities were evaluated by the rotarod neurotoxicity test. The pharmacological results showed that 7-hexyloxy-4H-[1,2,4]triazino[3,4-alpha]phthalazin-4-one 4e was the most potent with median effective dose (ED{sub 50}) value of 6.6 mg kg-1, median toxicity dose (TD{sub 50}) of 39.4 mg kg{sup -1}, providing a protective index (PI=TD{sub 50} /ED{sub 50}) value of 6.0. (author)

  16. Anticonvulsant activity of DNS II fraction in the acute seizure models.

    Science.gov (United States)

    Raza, Muhammad Liaquat; Zeeshan, Mohammad; Ahmad, Manzoor; Shaheen, Farzana; Simjee, Shabana U

    2010-04-21

    Delphinium nordhagenii belongs to family Ranunculaceae, it is widely found in tropical areas of Pakistan. Other species of Delphinium are reported as anticonvulsant and are traditionally used in the treatment of epilepsy. Delphinium nordhagenii is used by local healer in Pakistan but never used for scientific investigation as anticonvulsant. Thus, Delphinium nordhagenii was subjected to bioassay-guided fractionation and the most active fraction, i.e. DNS II acetone was chosen for further testing in the acute seizure models of epilepsy to study the antiepileptic potential in male mice. Different doses (60, 65 and 70mg/kg, i.p.) of DNS II acetone fraction of Delphinium nordhagenii was administered 30min prior the chemoconvulsant's injection in the male mice. Convulsive doses of chemoconvulsants (pentylenetetrazole 90mg/kg, s.c. and picrotoxin 3.15mg/kg, s.c.) were used. The mice were observed 45-90min for the presence of seizures. Moreover, four different doses of DNS II (60, 65, 70 and 100mg/kg, i.p.) were tested in the MES test. The DNS II acetone fraction of Delphinium nordhagenii has exhibited the anticonvulsant actions by preventing the seizures against PTZ- and picrotoxin-induced seizure as well as 100% seizure protection in MES test. The results are comparable with standard AEDs (diazepam 7.5mg/kg, i.p. and phenytoin 20mg/kg, i.p.). These findings suggest that the Delphinium nordhagenii possesses the anticonvulsant activity. Further analysis is needed to confirm the structure and target the extended activity profile. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  17. Synthesis, Anticonvulsant, Sedative and Anxiolytic Activities of Novel Annulated Pyrrolo[1,4]benzodiazepines

    Directory of Open Access Journals (Sweden)

    Kumaraswamy Sorra

    2014-09-01

    Full Text Available Four new pentacyclic benzodiazepine derivatives (PBDTs 13–16 were synthesized by conventional thermal heating and microwave-assisted intramolecular cyclocondensation. Their anticonvulsant, sedative and anxiolytic activities were evaluated by drug-induced convulsion models, a pentobarbital-induced hypnotic model and an elevated plus maze in mice. PBDT 13, a triazolopyrrolo[2,1-c][1,4]benzodiazepin-8-one fused with a thiadiazolone ring, exhibited the best anticonvulsant, sedative and anxiolytic effects in our tests. There was no significant difference in potency between PBDT 13 and diazepam, and we proposed that the action mechanism of PBDT 13 could be similar to that of diazepam via benzodiazepine receptors.

  18. Practical synthesis, anticonvulsant, and antimicrobial activity of N-allyl and N-propargyl di(indolyl)indolin-2-ones.

    Science.gov (United States)

    Praveen, Chandrasekaran; Ayyanar, Asairajan; Perumal, Paramasivan Thirumalai

    2011-07-01

    An operation friendly protocol for the synthesis of novel di(indolyl)indolin-2-ones via Cu(OTf)(2) catalyzed bis-addition of N-allyl and N-propargyl indole with isatin was developed. This methodology allowed us to achieve the products in excellent yields without requiring purification technique like column chromatography. All the synthesized compounds were evaluated for their in vivo anticonvulsant activity against maximal electroshock test. Six compounds showed maximum activity compared to the standard drug phenytoin. The scope of the new molecules as antimicrobial agents were tested against two bacterial strains (Staphylococcus aureus and Escherichia coli) and one fungal strain (Candida albicans). Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. Anticonvulsants and thyroid function.

    Science.gov (United States)

    Yeo, P P; Bates, D; Howe, J G; Ratcliffe, W A; Schardt, C W; Heath, A; Evered, D C

    1978-01-01

    Serum total and free thyroid hormone concentrations were estimated in 42 patients with epilepsy taking anticonvulsants (phenytoin, phenobarbitone, and carbamazepine either singly or in combination). There was a significant reduction in total thyroxine (TT4), free thyroxine (FT4), and free triiodothyronine (FT3) in the treated group compared with controls. Free hormone concentrations were lower than total hormone concentrations, suggesting that increased clearance of thyroid hormones occurs in patients receiving anticonvulsants. Detailed analysis indicated that phenytoin had a significant depressant effect on TT4, FT4, FT3, and reverse T3 (rT3). Phenobarbitone and carbamazepine had no significant main effects, but there were significant interactions between phenytoin and carbamazepine for TT4 and FT4. phenobarbitone and carbamazepine for FT3, and phenytoin and phenobarbitone for rT3. PMID:656820

  20. Schiff Bases of Benzothiazol-2-ylamine and Thiazolo[5,4-b] pyridin-2-ylamine as Anticonvulsants: Synthesis, Characterization and Toxicity Profiling.

    Science.gov (United States)

    Shukla, Rashmi; Singh, Ajeet P; Sonar, Pankaj K; Mishra, Mudita; Saraf, Shailendra K

    2016-01-01

    Schiff bases have a broad spectrum of biological activities like antiinflammatory, analgesic, antimicrobial, anticonvulsant, antitubercular, anticancer, antioxidant, anthelmintic and so forth. Thus, after a thorough perusal of literature, it was decided to conjugate benzothiazol-2-ylamine/thiazolo [5, 4-b] pyridin-2-ylamine with aromatic and heteroaromatic aldehydes to get a series of Schiff bases. Synthesis, characterization, in-silico toxicity profiling and anticonvulsant activity of the Schiff bases of Benzothiazol-2-ylamine and Thiazolo [5, 4-b] pyridin-2-ylamine. Aniline/4-aminopyridine was converted to the corresponding thiourea derivatives, which were cyclized to obtain benzothiazol-2-ylamine/thiazolo [5, 4-b] pyridin-2-ylamine. Finally, these were condensed with various aromatic and heteroaromatic aldehydes to obtain Schiff bases of benzothiazol-2-ylamine and thiazolo [5, 4-b] pyridin-2-ylamine. The synthesized compounds were characterized and screened for their anticonvulsant activity using maximal electroshock (MES) test and isoniazid (INH) induced convulsions test. In-silico toxicity profiling of all the synthesized compounds was done through "Lazar" and "Osiris" properties explorer. Majority of the compounds were more potent against MES induced convulsions than INH induced convulsions. Schiff bases of benzothiazol-2-ylamine were more effective than thiazolo [5, 4-b] pyridin-2-ylamine against MES induced convulsions. The compound benzothiazol-2-yl-(1H-indol-2-ylmethylene)-amine (VI) was the most potent member of the series against both types of convulsions. Compound VI exhibited the most significant activity profile in both the models. The compounds did not exhibit any carcinogenicity or acute toxicity in the in-silico studies. Thus, it may be concluded that the Schiff bases of benzothiazol-2-ylamine exhibit the potential to be promising and non-toxic anticonvulsant agents.

  1. Sedative and Anticonvulsant Activities of the Ethanol Root Extract of ...

    African Journals Online (AJOL)

    Purpose: To investigate the sedative, hypnotic and anticonvulsant activities of the ethanol extract of the roots of the Flemingia chappar (ERFC) on the central nervous system (CNS) of mice. Methods: The ..... Higher extract doses (400 and.

  2. Synthesis and Evaluation of the Anticonvulsant Activities of 4-(2-(Alkylthiobenzo[d]oxazol-5-yl-2,4-dihydro-3H-1,2,4-triazol-3-ones

    Directory of Open Access Journals (Sweden)

    Ming-Xia Song

    2018-03-01

    Full Text Available In this study, a novel series of 4-(2-(alkylthiobenzo[d]oxazol-5-yl-2,4-dihydro-3H-1,2,4-triazol-3-ones (4a–m was designed and synthesized. The anticonvulsant activities of these compounds were evaluated by using the maximal electroshock seizure (MES and subcutaneous pentylenetetrazole (scPTZ seizure models in mice. The neurotoxicity of these compounds was evaluated using the rotarod neurotoxicity test. The majority of compounds showed anti-MES activities at 100 or 300 mg/kg. Compound 4g was considered to be the most promising, based on its potency against MES- and PTZ-induced seizures with ED50 values of 23.7 and 18.9 mg/kg, respectively. The TD50 value of 4g was 284.0 mg/kg, which resulted in a higher protective index (PI = TD50/ED50 value than that of carbamazepine and valproate. In an ELISA test, compound 4g significantly increased the γ-aminobutyric acid (GABA content in mouse brain. In addition, pretreatment with thiosemicarbazide (an inhibitor of the GABA synthesizing enzyme significantly decreased the activity of 4g in the MES model, which suggests that the mechanism through which compound 4g elicits its anticonvulsive action is at least in part through increasing the GABA level in the brain.

  3. Anticonvulsive evaluation of THIP in the murine pentylenetetrazole kindling model

    DEFF Research Database (Denmark)

    Simonsen, Charlotte; Boddum, Kim; von Schoubye, Nadia L

    2017-01-01

    . Evaluation of THIP as a potential anticonvulsant has given contradictory results in different animal models and for this reason, we reevaluated the anticonvulsive properties of THIP in the murine pentylenetetrazole (PTZ) kindling model. As loss of δ-GABAA R in the dentate gyrus has been associated...... the observed upregulation of δ-GABAA Rs. Even in the demonstrated presence of functional δ-GABAA Rs, THIP (0.5-4 mg/kg) showed no anticonvulsive effect in the PTZ kindling model using a comprehensive in vivo evaluation of the anticonvulsive properties....

  4. Anticonvulsants for tinnitus.

    Science.gov (United States)

    Hoekstra, Carlijn El; Rynja, Sybren P; van Zanten, Gijsbert A; Rovers, Maroeska M

    2011-07-06

    Tinnitus is the perception of sound or noise in the absence of an external or internal acoustic stimulation. It is a common and potentially distressing symptom for which no adequate therapy exists. To assess the effectiveness of anticonvulsants in patients with chronic tinnitus. We searched the Cochrane Ear, Nose and Throat Disorders Group Specialised Register, CENTRAL (2010, Issue 2), MEDLINE, EMBASE, bibliographies and additional sources for published and unpublished trials. The date of the most recent search was 26 May 2010. We selected randomised controlled trials in patients with chronic tinnitus comparing orally administered anticonvulsants with placebo. The primary outcome was improvement in tinnitus measured with validated questionnaires. Secondary outcomes were improvement in tinnitus measured with self-assessment scores, improvement in global well-being or accompanying symptoms, and adverse drug effects. Three authors assessed risk of bias and extracted data independently. Seven trials (453 patients) were included in this review. These studies investigated four different anticonvulsants: gabapentin, carbamazepine, lamotrigine and flunarizine. The risk of bias of most studies was 'high' or 'unclear'. Three studies included a validated questionnaire (primary outcome). None of them showed a significant positive effect of anticonvulsants. One study showed a significant negative effect of gabapentin compared to placebo with an increase in Tinnitus Questionnaire (TQ) score of 18.4 points (standardised mean difference (SMD) 0.82, 95% confidence interval (CI) 0.07 to 1.58). A second study showed a positive, non-significant effect of gabapentin with a difference compared to placebo of 2.4 points on the Tinnitus Handicap Inventory (THI) (SMD -0.11, 95% CI -0.48 to 0.25). When the data from these two studies are pooled no effect of gabapentin is found (SMD 0.07, 95% CI -0.26 to 0.40). A third study reported no differences on the THI after treatment with gabapentin

  5. Anticonvulsant use after formulary status change for brand-name second-generation anticonvulsants.

    Science.gov (United States)

    Patel, Hemal; Toe, Diana C; Burke, Shawn; Rasu, Rafia S

    2010-08-01

    Anticonvulsant medications are commonly used for off-label indications. However, managed care organizations can restrict utilization of medication to indicated uses only. To evaluate the pattern of off-label use of second-generation anticonvulsants after implementing a formulary change. We did a retrospective analysis of an administrative pharmacy claims database for a managed care plan with more than 1 million members continuously enrolled during 2004-2005. The study evaluated off-label use and explored pharmacy utilization patterns (by physician specialty, region, plan type, age, sex, copayment) across the study population following the formulary change. A total of 10,185 patients had at least 1 pharmacy claim (total of 137,638 claims) for a second-generation anticonvulsant during the study period. Most members were female (68%), and 4.9% were anticonvulsants prescribed for off-label use in 2004 and 2005, respectively (P = .162). The off-label usage pattern varied for individual anticonvulsants in 2004 and 2005 (P anticonvulsants for off-label uses, followed by neurologists (9.4%), psychiatrists (2.8%), and other (46.5%). The coverage change resulted in cost savings for the plan of $0.16 per member per month. The off-label usage pattern varied for individual anticonvulsants in 2004 and 2005. Future considerations for controlling off-label use may include requiring prior authorization and provider education.

  6. Synthesis and evaluation of 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-yl)methyl]benzonitrile derivatives as potential anticonvulsants.

    Science.gov (United States)

    Madaiah, Malavalli; Prashanth, Maralekere K; Revanasiddappa, Hosakere D; Veeresh, Bantal

    2013-03-01

    New 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-yl)methyl]benzonitrile derivatives 8-37 were synthesized and their pharmacological activities were determined with the objective to better understand their structure-activity relationship (SAR) for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) test. Compounds 11, 18, 31, and 32 showed significant and protective effect on seizure, when compared with the standard drug valproate. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug. From this study, it is quite apparent that there are at least three parameters for the activity of anticonvulsant drugs, that is, a lipophilic domain, a hydrophobic center, and a two-electron donor. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Screening of the anticonvulsant activity of some plants from Fabaceae family in experimental seizure models in mice

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    S Sardari

    2011-10-01

    Full Text Available "n  Background and purpose of the study: Fabaceae is the third largest family of flowering plants. Lack of essential oils in the plants of this family can be an advantage in search for safe and effective medicines. In this study the anticonvulsant effect of the leaves of Albizzia julibrissin, Acacia juliflora, Acacia nubica and aerial parts of Astragalus obtusifolius was evaluated in pentylenetetrazole (PTZ and maximal electroshock (MES seizure tests. "n  Methods: The hydroalcoholic extracts of the plants were obtained by percolation. Different doses of the extracts were injected to the mice intraperitoneally (i.p. and occurrence of clonic seizures induced by PTZ (60 mg/kg, i.p. or tonic seizures induced by MES (50 mA, 50Hz, 1sec were monitored up to 30 min after administration. Acute toxicity of the extracts was also assessed. The safe and effective extract was then fractionated by dichloromethane and anticonvulsant activity of the fractions was determined. Finally, the constituents of the extract and the fractions were screened by thin layer chromatography. "n  Results: Among the extracts, only A. obtusifolius extract showed low toxicity and protective effect against clonic seizures with ED50 value of 3.97 g/kg. Fractionation of the extract led to increase in anticonvulsant activity and ED50 value of 2.86 g/kg was obtained for the aqueous fraction. Phytochemical screening revealed the presence of alkaloids, flavonoids, anthrones and saponins in the aqueous fraction. "n  Major conclusion: The presence of anticonvulsant compounds in A. obtusifolius suggests further activity-guided fractionation and analytical studies to find out the potential of this plant as a source of anticonvulsant agent.

  8. Evaluation of anticonvulsant activity of ethanolic leaves extract of Desmodium triflorum in mice

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    Girish Gowda

    2012-01-01

    Full Text Available The present investigation was aimed to study an anticonvulsant activity of ethanolic extract of Desmodium triflorum (L. DC., Fabaceae, in mice. Animal models of epilepsy namely the pentylenetetrazole (PTZ, isoniazid or isonicotinic hydrazide (INH and maximal electroshock induced convulsion (MES were used to evaluate the anticonvulsant effects of the extracts. The biochemical estimation was done by measuring the lipid peroxidation and reduced glutathione (GSH. In the PTZ induced convulsion, ethanolic extract of D. triflorum (EEDT 400 mg/kg significant delayed the onset of convulsion, reduced the duration of convulsion and reduced mortality. Similarly a dose of 800 mg/kg of EDDT significantly delayed the onset of convulsion, reduced the duration of convulsion and showed 33.33% protection in mice against INH induced convulsion. Further no mortality was found. Both the doses reduced hind limb tonic extension (HLTE phase of MES induced convulsion in mice. The pretreated EEDT showed significant inhibition of lipid peroxidation and increases the reduced glutathione level in mice brain tissue. The results revealed that D. triflorum possesses a significant dose dependent anticonvulsant activity.

  9. Evaluation of anticonvulsant activity of ethanolic leaves extract of Desmodium triflorum in mice

    Directory of Open Access Journals (Sweden)

    Girish Gowda

    2012-06-01

    Full Text Available The present investigation was aimed to study an anticonvulsant activity of ethanolic extract of Desmodium triflorum (L. DC., Fabaceae, in mice. Animal models of epilepsy namely the pentylenetetrazole (PTZ, isoniazid or isonicotinic hydrazide (INH and maximal electroshock induced convulsion (MES were used to evaluate the anticonvulsant effects of the extracts. The biochemical estimation was done by measuring the lipid peroxidation and reduced glutathione (GSH. In the PTZ induced convulsion, ethanolic extract of D. triflorum (EEDT 400 mg/kg significant delayed the onset of convulsion, reduced the duration of convulsion and reduced mortality. Similarly a dose of 800 mg/kg of EDDT significantly delayed the onset of convulsion, reduced the duration of convulsion and showed 33.33% protection in mice against INH induced convulsion. Further no mortality was found. Both the doses reduced hind limb tonic extension (HLTE phase of MES induced convulsion in mice. The pretreated EEDT showed significant inhibition of lipid peroxidation and increases the reduced glutathione level in mice brain tissue. The results revealed that D. triflorum possesses a significant dose dependent anticonvulsant activity.

  10. Lysine and pipecolic acid and some of their derivatives show anticonvulsant activity, and stimulation of benzodiazepine receptor activity

    International Nuclear Information System (INIS)

    Chang, Yung-Feng; Gao, Xue-Min

    1989-01-01

    Benzodiazepines are one of the most widely prescribed drugs in the treatment of anxiety, epilepsy and muscle tension. The natural products lysine and pipecolic acid known to be present in the animal, plant and microorganism, have been shown to be anticonvulsant against pentetrazol (PTZ)-induced seizures in mice. Methyl and ethyl esters of L-lysine and the N-isopropanol derivative of pipecolic acid appear to increase the anticonvulsant potency of the parent compounds, presumably due to their increase in hydrophobicity. Lysine and pipecolic acid showed significant stimulation of specific [ 3 H]flunitrazepam (FZ) binding to mouse brain membranes. This stimulation was enhanced by chloride ions and stereospecific with L-isomer having higher effect. The dose-dependent anticonvulsant activity of lysine and pipecolic acid, and their stimulation of [ 3 H]FZ binding appear to be correlated. The antiepileptic activity lysine, pipecolic acid and their derivatives therefore may be mediated through the γ-aminobutyric acid-benzodiazepine receptor complex

  11. Studies on anticonvulsant agents. Achievements and prospects

    International Nuclear Information System (INIS)

    Pandey, Sh; Shukla, Sh; Pandey, D; Srivastava, R S

    2011-01-01

    The data published over the past 15 years on the search for newer anticonvulsant drugs are generalized. Pyrrolidinedione, quinazolinone, xanthone, hydrazine and thiadiazole derivatives manifesting anticonvulsant activity in model in vivo tests in rodents are considered.

  12. Studies on anticonvulsant agents. Achievements and prospects

    Energy Technology Data Exchange (ETDEWEB)

    Pandey, Sh; Shukla, Sh; Pandey, D; Srivastava, R S

    2011-02-28

    The data published over the past 15 years on the search for newer anticonvulsant drugs are generalized. Pyrrolidinedione, quinazolinone, xanthone, hydrazine and thiadiazole derivatives manifesting anticonvulsant activity in model in vivo tests in rodents are considered.

  13. In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures.

    Science.gov (United States)

    Gharibi Loron, Ali; Sardari, Soroush; Narenjkar, Jamshid; Sayyah, Mohammad

    2017-01-01

    Resistance to antiepileptic drugs and the intolerability in 20-30% of the patients raises demand for developing new drugs with improved efficacy and safety. Acceptable anticonvulsant activity, good tolerability, and inexpensiveness of docosahexaenoic acid (DHA) make it as a good candidate for designing and development of the new anticonvulsant medications. Ten DHA-based molecules were screened based on in silico screening of DHA-like molecules by root-mean-square deviation of atomic positions, the biological activity score of Professional Association for SQL Server, and structural requirements suggested by pharmacophore design. Anticonvulsant activity was tested against clonic seizures induced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) and tonic seizures induced by maximal electroshock (MES, 50 mA, 50 Hz, 1 ms duration) by intracerebroventricular (i.c.v.) injection of the screened compounds to mice. Among screened compounds, 4-Phenylbutyric acid, 4-Biphenylacetic acid, phenylacetic acid, and 2-Phenylbutyric acid showed significant protective activity in pentylenetetrazole test with ED50 values of 4, 5, 78, and 70 mM, respectively. In MES test, shikimic acid and 4-tert-Butylcyclo-hexanecarboxylic acid showed significant activity with ED50 values 29 and 637 mM, respectively. Effective compounds had no mortality in mice up to the maximum i.c.v. injectable dose of 1 mM. Common electrochemical features and three-dimensional spatial structures of the effective compounds suggest the involvement of the anticonvulsant mechanisms similar to the parent compound DHA.

  14. Design, synthesis, molecular docking and anticonvulsant evaluation of novel 6-iodo-2-phenyl-3-substituted-quinazolin-4(3H-ones

    Directory of Open Access Journals (Sweden)

    Mohamed-Kamal Ibrahim

    2015-12-01

    Full Text Available A new series of 6-iodo-2-phenyl-3-substituted-quinazolin-4(3H-one (5–12a–b derivatives were synthesized, evaluated for their anticonvulsant activity against pentylenetetrazole (PTZ-induced seizures and maximal electroshock test and compared with the reference drugs phenobarbital sodium and methaqualone. The neurotoxicity was assessed using rotarod test. The molecular docking was performed for all the synthesized compounds to assess their binding affinities to GABA-A receptor in order to rationalize their anticonvulsant activities in a qualitative way. The data obtained from the molecular modeling were correlated with those obtained from the biological screening. Compounds 9a, 9b, 12a and 7a showed the highest anticonvulsant activities of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test when compared with the reference drugs. The obtained results proved that the most active compounds could be a useful model for future design, adaptation and investigation to construct more active analogs.

  15. Natural products as potential anticonvulsants: caffeoylquinic acids.

    Science.gov (United States)

    Kim, Hyo Geun; Oh, Myung Sook

    2012-03-01

    Current anticonvulsant therapies are generally directed at symptomatic treatment by suppressing excitability within the brain. Consequently, they have adverse effects such as cognitive impairment, dependence, and abuse. The need for more effective and less toxic anticonvulsants has generated renewed interest in natural products for the treatment of convulsions. Caffeoylquinic acids (CQs) are naturally occurring phenolic acids that are distributed widely in plants. There has been increasing interest in the biological activities of CQs in diseases of the central nervous system. In this issue, Nugroho et al. give evidence for the anticonvulsive effect of a CQ-rich extract from Aster glehni Franchet et Sckmidt. They optimized the extract solvent conditions, resulting in high levels of CQs and peroxynitrite-scavenging activity. Then, they investigated the sedative and anticonvulsive effects in pentobarbital- and pentylenetetrazole-induced models in mice. The CQ-rich extract significantly inhibited tonic convulsions as assessed by onset time, tonic extent, and mortality. They suggested that the CQ-rich extract from A. glehni has potential for treating convulsions. This report provides preclinical data which may be used for the development of anticonvulsants from natural products.

  16. ANTICONVULSANT AND ANTIEPILEPTIC ACTIONS OF 2-DEOXY-DGLUCOSE IN EPILEPSY MODELS

    Science.gov (United States)

    Stafstrom, Carl E.; Ockuly, Jeffrey C.; Murphree, Lauren; Valley, Matthew T.; Roopra, Avtar; Sutula, Thomas P.

    2009-01-01

    Objective Conventional anticonvulsants reduce neuronal excitability through effects on ion channels and synaptic function. Anticonvulsant mechanisms of the ketogenic diet remain incompletely understood. Since carbohydrates are restricted in patients on the ketogenic diet, we evaluated the effects of limiting carbohydrate availability by reducing glycolysis using the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in experimental models of seizures and epilepsy. Methods Acute anticonvulsant actions of 2DG were assessed in vitro in rat hippocampal slices perfused with 7.5mM [K+]o, 4-aminopyridine (4-AP), or bicuculline and in vivo against seizures evoked by 6 Hz stimulation in mice, audiogenic stimulation in Fring’s mice, and maximal electroshock and subcutaneous Metrazol in rats. Chronic antiepileptic effects of 2DG were evaluated in rats kindled from olfactory bulb or perforant path. Results 2DG (10mM) reduced interictal epileptiform bursts induced by high [K+]o, 4-AP and bicuculline, and electrographic seizures induced by high [K+]o in CA3 of hippocampus. 2DG reduced seizures evoked by 6 Hz stimulation in mice (ED50 = 79.7 mg/kg) and audiogenic stimulation in Fring’s mice (ED50 = 206.4 mg/kg). 2DG exerted chronic antiepileptic action by increasing afterdischarge thresholds in perforant path (but not olfactory bulb) kindling and caused a 2-fold slowing in progression of kindled seizures at both stimulation sites. 2DG did not protect against maximal electroshock or Metrazol seizures. Interpretation The glycolytic inhibitor 2DG exerts acute anticonvulsant and chronic antiepileptic actions and has a novel pattern of effectiveness in preclinical screening models. These results identify metabolic regulation as a potential therapeutic target for seizure suppression and modification of epileptogenesis. PMID:19399874

  17. Comparative Anticonvulsant Study of Epoxycarvone Stereoisomers

    Directory of Open Access Journals (Sweden)

    Paula Regina Rodrigues Salgado

    2015-10-01

    Full Text Available Stereoisomers of the monoterpene epoxycarvone (EC, namely (+-cis-EC, (−-cis-EC, (+-trans-EC, and (−-trans-EC, were comparatively evaluated for anticonvulsant activity in specific methodologies. In the pentylenetetrazole (PTZ-induced anticonvulsant test, all of the stereoisomers (at 300 mg/kg increased the latency to seizure onset, and afforded 100% protection against the death of the animals. In the maximal electroshock-induced seizures (MES test, prevention of tonic seizures was also verified for all of the isomers tested. However, the isomeric forms (+ and (−-trans-EC showed 25% and 12.5% inhibition of convulsions, respectively. In the pilocarpine-induced seizures test, all stereoisomers demonstrated an anticonvulsant profile, yet the stereoisomers (+ and (−-trans-EC (at 300 mg/kg showed a more pronounced effect. A strychnine-induced anticonvulsant test was performed, and none of the stereoisomers significantly increased the latency to onset of convulsions; the stereoisomers probably do not act in this pathway. However, the stereoisomers (+-cis-EC and (+-trans-EC greatly increased the latency to death of the animals, thus presenting some protection. The four EC stereoisomers show promise for anticonvulsant activity, an effect emphasized in the isomers (+-cis-EC, (+-trans-EC, and (−-trans-EC for certain parameters of the tested methodologies. These results serve as support for further research and development of antiepileptic drugs from monoterpenes.

  18. Novel, broad-spectrum anticonvulsants containing a sulfamide group: pharmacological properties of (S)-N-[(6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112).

    Science.gov (United States)

    McComsey, David F; Smith-Swintosky, Virginia L; Parker, Michael H; Brenneman, Douglas E; Malatynska, Ewa; White, H Steve; Klein, Brian D; Wilcox, Karen S; Milewski, Michael E; Herb, Mark; Finley, Michael F A; Liu, Yi; Lubin, Mary Lou; Qin, Ning; Reitz, Allen B; Maryanoff, Bruce E

    2013-11-27

    Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such "neurostabilizers" have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4-9, 10a-i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures. Mechanistically, 4 inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels and was effective as a K(+) channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies.

  19. Design and synthesis of new of 3-(benzo[d]isoxazol-3-yl)-1-substituted pyrrolidine-2, 5-dione derivatives as anticonvulsants.

    Science.gov (United States)

    Malik, Sachin; Ahuja, Priya; Sahu, Kapendra; Khan, Suroor Ahmad

    2014-09-12

    A series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2, 5-dione (7a-7d, 8a-8d, 9a-9c) have been prepared and evaluated for their anticonvulsant activities. Preliminary anticonvulsant activity was performed using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests after intraperitoneal (ip) injection into mice, which are the most widely employed models for early identification of anticonvulsant candidate. The acute neurological toxicity (NT) was determined applying rotorod test. The quantitative evaluation after oral administration in rats showed that the most active was 3-(benzo[d]isoxazol-3-yl)-1-(4-fluorophenyl) pyrrolidine-2, 5-dione (8a) with ED50 values of 14.90 mg/kg. Similarly the most potent in scPTZ was 3-(benzo[d]isoxazol-3-yl)-1-cyclohexylpyrrolidine-2, 5-dione (7d) with ED50 values of 42.30 mg/kg. These molecules were more potent and less neurotoxic than phenytoin and ethosuximide which were used as reference antiepileptic drugs. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  20. Novel Hybrid Anticonvulsants Derived from Pyrrolidine-2,5-dione Scaffold with Broad Spectrum of Activity in the Preclinical Studies.

    Science.gov (United States)

    Kaminski, Krzysztof

    2017-01-01

    The multifunctional ligands application is an emerging approach in drug delivery, mainly in the treatment of diseases with complex pathology, such as Alzheimer's, cancer, and epilepsy. Using this method many biomolecules with different properties are combined to form a single unit that can provide a complex broad spectrum activity. Thus, a new type of hybrid anticonvulsants based on the pyrrolidine-2,5-dione frame are detailed with the aim of acquiring more effective antiepileptic drugs (AED) that could suppress various human convulsions. These hybrid molecules attach to the chemical particles of clinically relevant AEDs such as ethosuximide, levetiracetam, and lacosamide. As a result of this hybridization process the compounds obtained were effective in three most important animal epilepsy models, namely the maximal electroshock seizure (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-Hertz (6 Hz) model in mice. These substances displayed wider spectrum of protection, more potent efficacy, and better safety profile than the aforementioned AEDs. Several compounds were also active in the formalin model of persistent pain in mice. The in vitro ligand binding studies have proved that the most conceivable molecular mechanism of anticonvulsant and antinociceptive action was the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Anticonvulsants for alcohol withdrawal.

    Science.gov (United States)

    Minozzi, Silvia; Amato, Laura; Vecchi, Simona; Davoli, Marina

    2010-03-17

    Alcohol abuse and dependence represents a most serious health problem worldwide with major social, interpersonal and legal interpolations. Besides benzodiazepines, anticonvulsants are often used for the treatment of alcohol withdrawal symptoms. Anticonvulsants drugs are indicated for the treatment of alcohol withdrawal syndrome, alone or in combination with benzodiazepine treatments. In spite of the wide use, the exact role of the anticonvulsants for the treatment of alcohol withdrawal has not yet bee adequately assessed. To evaluate the effectiveness and safety of anticonvulsants in the treatment of alcohol withdrawal. We searched Cochrane Drugs and Alcohol Group' Register of Trials (December 2009), PubMed, EMBASE, CINAHL (1966 to December 2009), EconLIT (1969 to December 2009). Parallel searches on web sites of health technology assessment and related agencies, and their databases. Randomized controlled trials (RCTs) examining the effectiveness, safety and overall risk-benefit of anticonvulsants in comparison with a placebo or other pharmacological treatment. All patients were included regardless of age, gender, nationality, and outpatient or inpatient therapy. Two authors independently screened and extracted data from studies. Fifty-six studies, with a total of 4076 participants, met the inclusion criteria. Comparing anticonvulsants with placebo, no statistically significant differences for the six outcomes considered.Comparing anticonvulsant versus other drug, 19 outcomes considered, results favour anticonvulsants only in the comparison carbamazepine versus benzodiazepine (oxazepam and lorazepam) for alcohol withdrawal symptoms (CIWA-Ar score): 3 studies, 262 participants, MD -1.04 (-1.89 to -0.20), none of the other comparisons reached statistical significance.Comparing different anticonvulsants no statistically significant differences in the two outcomes considered.Comparing anticonvulsants plus other drugs versus other drugs (3 outcomes considered), results

  2. Anticonvulsant Activity of Argyreia speciosa in Mice.

    Science.gov (United States)

    Vyawahare, N S; Bodhankar, S L

    2009-03-01

    Argyreia speciosa commonly known as Vridha daraka in Sanskrit is one of the important plants used in indigenous system of medicine. The root is regarded as an alternative tonic and useful in the diseases of nervous system. To confirm the veracity of aforementioned claim, we have evaluated the anticonvulsant effect of the extract. In this investigation, the mice were pretreated with different doses of Argyreia speciosa extract (100, 200, 400 mg/kg) for 10 days and then, they were subjected to either pentylenetetrazole (80 mg/kg) or maximal electroshock seizures (50 mA, 0.2 s) treatment. The hydroalcoholic extract of Argyreia speciosa at the dose of 200 and 400 mg/kg significantly delayed the latency to the onset of first clonus as well as onset of death in unprotected mice and exhibited protection in 16.66% and 33.33% of pentylenetetrazole treated mice respectively. Whereas in case of maximal electroshock-seizures, the dose of 200 and 400 mg/kg significantly reduced the duration of hind limb extension and both the doses were statistically found to be equipotent. The reference standards, clonazepam (0.1 mg/kg) and phenytoin (20 mg/kg) provided complete protection. Thus, present study revealed anticonvulsant effect of Argyreia speciosa against pentylenetetrazole- and maximal electroshock-induced convulsions in mice.

  3. Design, synthesis and evaluation of benzofuran-acetamide scaffold as potential anticonvulsant agent

    Directory of Open Access Journals (Sweden)

    Shakya Ashok K.

    2016-09-01

    Full Text Available A series of N-(2-(benzoyl/4-chlorobenzoyl-benzofuran- 3-yl-2-(substituted-acetamide derivatives (4a-l, 5a-l was synthesized in good yield. All synthesized compounds were in agreement with elemental and spectral data. The anticonvulsant activity of all synthesized compounds was assessed against the maximal electroshock induced seizures (MES model in mice. Neurotoxicity was evaluated using the rotarod method. The majority of compounds exhibited anticonvulsant activity at a dose of 30 mg kg-1 body mass during 0.5-4 h, indicating their ability to prevent seizure spread at low doses. Relative to phenytoin, [N-(2-(4-chlorobenzoylbenzofuran-3-yl-2-(cyclohexyl( methyl amino-acetamide] (5i and [N-(2-(4-chlorobenzoylbenzofuran-3-yl-2-(4-methylpiperidin-1- yl-acetamide] (5c demonstrated comparable relative anticonvulsant potency of 0.74 and 0.72, respectively, whereas [(N-(2-(4-chlorobenzoylbenzofuran-3-yl-2-(4-(furan-2-carbonyl-piperazin-1-yl-acetamide] (5f exhibited the lowest relative potency of 0.16. The ALD50 of tested compounds ranged from 1.604 to 1.675 mmol kg-1 body mass. The ED50 of synthesized compounds ranged from 0.055 to 0.259 mmol kg-1 (~23.4 to 127.6 mg kg-1 body mass. The pharmacophore mapping of the examined compounds on standard drugs (phenobarbital, phenytoin, ralitolin and carbamazepine strongly suggests that these compounds may exert their anticonvulsant activity via the same established mechanism as that of known drugs.

  4. The anticonvulsant retigabine suppresses neuronal Kv2-mediated currents

    DEFF Research Database (Denmark)

    Stas, Jeroen I; Bocksteins, Elke; Jensen, Camilla S

    2016-01-01

    Enhancement of neuronal M-currents, generated through KV7.2-KV7.5 channels, has gained much interest for its potential in developing treatments for hyperexcitability-related disorders such as epilepsy. Retigabine, a KV7 channel opener, has proven to be an effective anticonvulsant and has recently...

  5. CM 40907: a structurally novel anticonvulsant in mice, rats and baboons

    International Nuclear Information System (INIS)

    Chambon, J.P.; Brochard, J.; Hallot, A.; Heaulme, M.; Brodin, R.; Roncucci, R.; Biziere, K.

    1985-01-01

    CM 40907 [3-(4-hydroxypiperidyl)-6-(2'-chlorophenyl)-pyridazine] is a chemically original compound which possesses the pharmacological properties of a potent, p.o. active anticonvulsant. The anticonvulsant activity of CM 40907 was examined in mice, rats and photosensitive Papio-papio baboons and compared to that of phenobarbital, diphenylhydantoin, carbamazepine, sodium valproate and ethosuximide. In mice, CM 40907 antagonized electroconvulsive shock and chemically induced seizures with an overall potency comparable to that of carbamazepine and a therapeutic ratio (ED50 rotorod/ED50 electroshock) superior to that of ethosuximide, sodium valproate, phenobarbital and carbamazepine. In the rat CM 40907 suppressed completed kindled amygdaloid seizures and was approximately as active as phenobarbital. In naturally photosensitive Senegalese Papio-papio baboons CM 40907 antagonized myoclonus and cortical paroxysmal discharges. In this model CM 40907 was approximately one-fourth as potent as phenobarbital, twice as potent as carbamazepine and 6 times more potent than sodium valproate. In mice CM 40907, at anticonvulsant doses, increased the affinity of [ 3 H]flunitrazepam for its central receptor site. Based on these results it is postulated that CM 40907 is a potent and relatively nonsedative anticonvulsant and may be of therapeutic benefit in epileptic disorders

  6. Anticonvulsant activity of methanolic extract from Kalanchoe pinnata Lam. stems and roots in mice: A comparison to diazepam.

    Science.gov (United States)

    Mora-Pérez, A; Hernández-Medel, M del R

    2016-04-01

    In ancient and current traditional medicine in México, extracts from the leaves or whole plant of 'life leaf' (Kalanchoe pinnata [K. pinnata]Lam) have been used to treat an entity known locally as 'yellow epilepsy' (alferecía amarilla) when it is accompanied by seizures. However, the anticonvulsive activity of its stems and roots remains unexplored The anticonvulsant activity of the methanolic root extract (MER) or stem (MES) of K. pinnata Lam. was evaluated in a pentylenetetrazol-induced seizure model in Balb/C mice, and effects were compared to those of diazepam. The stem extract fractions that produced anticonvulsant activity were subsequently evaluated using the pentylenetetrazol -induced seizure model. We observed increased latency of tonic-clonic seizures that was inversely proportional to the dose of MRE, with a similar impact on the lethal effects of pentylenetetrazol. Different doses of the MSE showed a dose-dependent increase in latency to myoclonus, clonus, and tonic-clonic seizures, acting similarly to diazepam and offering 100% protection against the lethal effects of pentylenetetrazol. Fractioning MSE decreased its effectiveness, but when fractions were mixed with fractions of chloroform and ethyl acetate, anticonvulsive activity was restored. The preliminary phytochemical analysis identified alkaloids and sterols in MRE, and sterols and terpenes in MSE CONCLUSIONS: The anticonvulsant activity of K. pinnata Lam. decreases with increased doses of MRE, whereas the effect of MSE is dose-dependent and preserved in the mixture chloroform and ethyl acetate. We suggest that the metabolites responsible for these effects are sterols in MRE, and sterols and terpenes in MSE. Copyright © 2015 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  7. Neurosteroids exhibit anticonvulsant action in immature rats

    Czech Academy of Sciences Publication Activity Database

    Mareš, Pavel

    2005-01-01

    Roč. 46, č. S8 (2005), s. 115-116 ISSN 0013-9580. [Joint Annual Meeting of the American Epilepsy Society and American Clinical Neurophysiology Society. 02.12.2005-06.12.2005, Washington, DC] R&D Projects: GA AV ČR(CZ) IBS5011007 Institutional research plan: CEZ:AV0Z50110509 Keywords : neurosteroids * anticonvulsants * immature rats Subject RIV: ED - Physiology

  8. Anticonvulsants for alcohol dependence.

    Science.gov (United States)

    Pani, Pier Paolo; Trogu, Emanuela; Pacini, Matteo; Maremmani, Icro

    2014-02-13

    anticonvulsants reduced drinks/drinking days (11 studies, 1126 participants, mean difference (MD) -1.49, 95% Cl -2.32 to -0.65) and heavy drinking (12 studies, 1129 participants, standardised mean difference (SMD) -0.35, 95% Cl -0.51 to -0.19). Moreover, withdrawal for medical reasons (12 studies, 1410 participants, RR 1.22, 95% Cl 0.58 to 2.56, moderate-quality evidence) showed no evidence of difference, but for specific adverse effects (nine studies, 1164 participants), two of 18 adverse event outcomes favoured placebo. The direction of results was confirmed by subgroup analyses for topiramate and partially for gabapentin and valproate.Anticonvulsants versus naltrexone: No evidence of difference was shown in dropout rates (five studies, 528 participants, RR 0.74, 95% CI 0.52 to 1.06), severe relapse rates (four studies, 427 participants, RR 0.69, 95% Cl 0.44 to 1.07) and continuous abstinence rates (five studies, 528 participants, RR 1.21, 95% Cl 0.99 to 1.49); anticonvulsants were associated with fewer heavy drinking days (three studies, 308 participants, MD -5.21, 95% Cl -8.58 to -1.83), more days to severe relapse (three studies, 244 participants, MD 11.88, 95% Cl 3.29 to 20.46) and lower withdrawal for medical reasons (three studies, 245 participants, RR 0.13, 95% Cl 0.03 to 0.58). At the current stage of research, randomised evidence supporting the clinical use of anticonvulsants to treat alcohol dependence is insufficient. Results are conditioned by heterogeneity and by the low number and quality of studies comparing anticonvulsants with other medications. The uncertainty associated with these results leaves to clinicians the need to balance possible benefits/risks of treatment with anticonvulsants versus other medications as supported by evidence of efficacy.

  9. Metabolic stability of new anticonvulsants in body fluids and organ homogenates.

    Science.gov (United States)

    Marszałek, Dorota; Goldnik, Anna; Pluciński, Franciszek; Mazurek, Aleksander P; Jakubiak, Anna; Lis, Ewa; Tazbir, Piotr; Koziorowska, Agnieszka

    2012-01-01

    The stability as a function of time of compounds with established anticonvulsant activity: picolinic acid benzylamide (Pic-BZA), picolinic acid 2-fluorobenzylamide (Pic-2-F-BZA), picolinic acid 3-fluorobenzylamide (Pic-3-F-BZA), picolinic acid 4-fluorobenzylamide (Pic-4-F-BZA) and picolinic acid 2-methylbenzylamide (Pic-2-Me-BZA) in body fluids and homogenates of body organs were determined after incubation. It was found that they decompose relatively rapidly in liver and kidney and are stable against enzymes present in body fluids and some organs. These results are consistent with the bond strength expressed as total energy of amide bonds (calculated by quantum chemical methods) in the studied anticonvulsants. The calculated values of the amide bond energy are: 199.4 kcal/mol, 200.2 kcal/mol, 207.5 kcal/mol, 208.4 kcal/mol and 198.2 kcal/mol, respectively. The strength of the amide bonds in the studied anticonvulsants correctly reflects their stability in liver or kidney.

  10. GABA-A Receptor Modulation and Anticonvulsant, Anxiolytic, and Antidepressant Activities of Constituents from Artemisia indica Linn

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    Imran Khan

    2016-01-01

    Full Text Available Artemisia indica, also known as “Mugwort,” has been widely used in traditional medicines. However, few studies have investigated the effects of nonvolatile components of Artemisia indica on central nervous system’s function. Fractionation of Artemisia indica led to the isolation of carnosol, ursolic acid, and oleanolic acid which were evaluated for their effects on GABA-A receptors in electrophysiological studies in Xenopus oocytes and were subsequently investigated in mouse models of acute toxicity, convulsions (pentylenetetrazole induced seizures, depression (tail suspension and forced swim tests, and anxiety (elevated plus maze and light/dark box paradigms. Carnosol, ursolic acid, and oleanolic acid were found to be positive modulators of α1β2γ2L GABA-A receptors and the modulation was antagonized by flumazenil. Carnosol, ursolic acid, and oleanolic acid were found to be devoid of any signs of acute toxicity (50–200 mg/kg but elicited anticonvulsant, antidepressant, and anxiolytic activities. Thus carnosol, ursolic acid, and oleanolic acid demonstrated CNS activity in mouse models of anticonvulsant, antidepressant, and anxiolysis. The anxiolytic activity of all three compounds was ameliorated by flumazenil suggesting a mode of action via the benzodiazepine binding site of GABA-A receptors.

  11. Triazole incorporated thiazoles as a new class of anticonvulsants: design, synthesis and in vivo screening.

    Science.gov (United States)

    Siddiqui, Nadeem; Ahsan, Waquar

    2010-04-01

    Various 3-[4-(substituted phenyl)-1,3-thiazol-2-ylamino]-4-(substituted phenyl)-4,5-dihydro-1H-1,2,4-triazole-5-thiones (7a-t) were designed keeping in view the structural requirements suggested in the pharmacophore model for anticonvulsant activity. Thiazole and triazole moieties being anticonvulsants were clubbed together to get the titled compounds and their in vivo anticonvulsant screening were performed by two most adopted seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). Two compounds 7d and 7f showed significant anticonvulsant activity in both the screens with ED(50) values 23.9 mg/kg and 13.4 mg/kg respectively in MES screen and 178.6 mg/kg and 81.6 mg/kg respectively in scPTZ test. They displayed a wide margin of safety with Protective index (PI), median hypnotic dose (HD(50)) and median lethal dose (LD(50)) much higher than the standard drugs. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

  12. NEW DERIVATIVES OF 2-R1-N-(5-R-1,3,4-THIADIAZOL-2-YL-BENZOLSULFONAMIDES: SYNTHESIS, PHYSICOCHEMICAL PROPERTIES AND BIOLOGICAL ACTIVITY PREDICTION

    Directory of Open Access Journals (Sweden)

    Sych I.V.

    2015-12-01

    Full Text Available Introduction: The analysis of modern literature, including overseas one, showed that a lot of the scientific researches is devoted to finding and creating biologically active compounds on base 1,3,4-thiadiazole. Derivatives of 1,3,4-thiadiazole are the large group of heterocyclic compounds with high rates of antimicrobial, antituberculosis, antidiabetic, antineoplastic and anticonvulsant activity. Material and methods: The purpose of this study was the expansion of sulfone derivatives substituted nitrogen-containing heterocyclic systems through the synthesis of 2-R1-N (5-R-1,3,4-thiadiazol-2-ilbenzolsulfonamides and prediction their pharmacological activity for future planning pharmacological screening. Synthesis of semi-products 2-amino-5-R-1,3,4-thiadiazoles was carried out by cyclization thiosemicarbazide and substituted derivatives of carboxylic acids in the presence of concentrated sulfuric acid. The synthesis of target compounds 2-R1-N(5-R-1,3,4-thiadiazol-2-ylbenzolsulfon-amides was carried out by N-acylation of 2-amino-5R-1,3,4-thiadiazole substituted benzolsul-fochlorides in the presence of anhydrous pyridine. The reaction proceeds by the classic SN2-mechanism. The resulting compounds are white crystalline substances, soluble in alcohol, chloroform and acetone, difficult to dissolve in water. Yields of obtained compounds was satisfactory (76-84%. The purity of the obtained compounds was determined by TLC. The structure of the obtained compounds was proved by elemental analysis, IR methods and 1H NMR spectroscopy. NMR 1H spectra were recorded at Bruker WM spectrometer (200 MHz; solvent DMSO-d6; chemical shifts were in ppm, internal standard (TMS (tetramethylsilane was used. The prognosis of biological activity for obtained compounds were carried out using the program PASS (Prediction of Activity Spectra for Substances in order to plan the further pharmacological screening. The program PASS predicts more than 500 kinds of biological

  13. Preliminary Screening of a Classical Ayurvedic Formulation for Anticonvulsant Activity.

    Science.gov (United States)

    Dhar, Arnab; Maurya, Santosh Kumar; Mishra, Ashish; Singh, Gireesh Kumar; Singh, Manoj Kumar; Seth, Ankit

    2016-01-01

    Epilepsy is a serious and complex central nervous system disorder associated with recurrent episodes of convulsive seizures due to the imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmitters level in the brain. The available treatments are neither competent to control the seizures nor prevent progress of disease. Since ages, Herbal medicines have remained important sources of medicines in many parts of world which is evidenced through their uses in traditional systems of medicine i.e. Ayurveda, Siddha, Unani, Homeopathy and Chinese etc. A polyherbal formulation (containing Terminalia chebula Retz., Asparagus racemosus Willd., Embelia ribes Burm. F, Acorus calamus L., Tinospora cordifolia (Willd.) Miers, Convolvulus pluricaulis Choisy, Saussurea lappa C.B.Clarke, Achyranthes aspera L.) is mentioned in Ayurvedic classics Bhaiṣajya Ratnāvali . The aim of the study was to evaluate the anticonvulsant activity of the formulation in Maximum electroshock and Pentylenetetrazole induced convulsions in rats. In the present study, a polyherbal formulation was developed as directed by classical text and evaluated for the anticonvulsant activity using Maximal Electroshock Shock (MES) and Pentylenetetrazole (PTZ) induced convulsions in rats. Statistical comparison was done by one way ANOVA followed by the Tukey's multiple comparison test. The obtained results showed that the PHF had a protective role on epilepsy. Treatment with PHF significantly improves antioxidant enzymes activities of superoxide dismutase (SOD) and glutathione (GSH) levels significantly as compared to controls. PHF also significantly decreased malonaldialdehyde (MDA) levels in the brain. Moreover, it also attenuated the PTZ-induced increase in the activity of GABA-T in the rat brain. These findings suggest that PHF might have possible efficacy in the treatment of epilepsy.

  14. BTS 72664-- a novel CNS drug with potential anticonvulsant, neuroprotective, and antimigraine properties.

    Science.gov (United States)

    Smith, S L; Thompson, K S; Sargent, B J; Heal, D J

    2001-01-01

    BTS 72664, (R)-7-[1-(4-chlorophenoxy)]ethyl]-1,2,4-triazolo(1,5-alpha)pyrimidine, was identified as a drug development candidate from a research program designed to discover novel, broad-spectrum, non-sedative anticonvulsant drugs. BTS 72664 antagonized bicuculline (BIC)- and maximal electroshock (MES)-induced convulsions with ED(50) values of 1.9 and 47.5 mg/kg p.o., respectively. In rodents, it has a wide spectrum of activity preventing seizures induced by picrotoxin, pentylenetetrazol, i.c.v. 4-aminopyridine or NMDA, and audiogenic seizures in DBA-2 mice and GEPR-9 rats. BTS 72664 was also effective in preventing convulsions in amygdala-kindled rats The lack of sedative potential was predicted on the basis of wide separation between ED(50) in anticonvulsant models and TD(50) for motor impairment in mice in rotating rod and inverted horizontal grid tests. BTS 72664 is likely to produce its anticonvulsant effect by enhancing chloride currents through picrotoxin-sensitive chloride channels, and by weak inhibition of Na(+) and NMDA channels. It does not act, however, at the benzodiazepine binding site. In addition to its potential use in the treatment of epilepsy BTS 72664 may be useful in the treatment of stroke. At 50 mg/kg p.o. x 4, given to rats at 12 hourly intervals, starting at 15 min after permanent occlusion of middle cerebral artery (MCA), it reduced cerebral infarct size by 31% (measured at 2 days after insult) and accelerated recovery in a functional behavioral model. BTS 72664 prevented increases in extraneuronal concentrations of glutamate, glycine and serine brain levels induced by a cortical insult to rats (cf. cortical spreading depression). It may, therefore, have also antimigraine activity.

  15. The gamma-aminobutyric acid uptake inhibitor, tiagabine, is anticonvulsant in two animal models of reflex epilepsy.

    Science.gov (United States)

    Smith, S E; Parvez, N S; Chapman, A G; Meldrum, B S

    1995-02-06

    The effects of i.p. administration of the gamma-aminobutyric acid (GABA) uptake inhibitors R(-)N-(4,4-di(3-methylthien-2-yl)-but-3-enyl) nipecotic acid hydrochloride (tiagabine; molecular weight 412.0), (1-(2-(((diphenylmethylene)-amino)oxy)ethyl)-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride (NNC-711; molecular weight 386.9), and (+/-)-nipecotic acid (molecular weight 128.2) are compared with those of carbamazepine (molecular weight 236.3) on sound-induced seizures and locomotor performance in genetically epilepsy-prone (GEP) rats. The ED50 value against clonic seizures (in mumol kg-1 at the time of maximal anticonvulsant effect) for tiagabine was 23 (0.5 h), and for NNC-711 was 72 (1 h), and for carbamazepine was 98 (2 h). (+/-)-Nipecotic acid (0.4-15.6 mmol kg-1) was not anticonvulsant. High doses of NNC-711 (207-310 mumol kg-1) and of (+/-)-nipecotic acid (39-78 mmol kg-1) induced ataxia and myoclonic seizures 0.25-1 h. Tiagabine and carbamazepine did not induce myoclonic seizures and had similar therapeutic indices (locomotor deficit ED50/anticonvulsant ED50) ranging from 0.4 to 1.9. In Papio papio, we observed a reduction in photically induced myoclonic seizures with tiagabine (2.4 mumol kg-1 i.v.) accompanied with neurological impairment. Tiagabine has comparable anticonvulsant action to carbamazepine in rats and has anticonvulsant effects in non-human primates supporting the potential use of inhibitors of GABA uptake as therapy for epilepsy.

  16. [Anticonvulsant hypersensitivity syndrome and lamotrigine-associated anticonvulsant hypersensitivity syndrome].

    Science.gov (United States)

    Taillia, H; Alla, P; Fournier, B; Bounolleau, P; Ouologem, M; Ricard, D; Sallansonnet-Froment, M; de Greslan, T; Renard, J-L

    2009-10-01

    Anticonvulsant hypersensitivity syndrome (AHS) is defined by the association of high fever, cutaneous rash and multiorgan-system abnormalities (incidence, one in 1000 to one in 10,000 exposures). Fatal complications are described in 10%. This reaction usually develops 1 to 12 weeks after initiation of an aromatic anticonvulsant. Drug rash with eosinophilia and systemic symptoms (DRESS) can be discussed as differential diagnosis. Several hypotheses have been put forward to explain the pathogenesis of AHS. These include accumulation of toxic metabolites, antibody production and viral infection. The one based on toxic metabolites has found the greatest acceptance due to the fact that it can be proven by an in vitro test, the lymphocyte toxicity assay. In vivo, skin biopsies show characteristic findings of erythema multiform or typical leucocytoclastic angitis. The patch-test is positive in 80% of the cases. Lamotrigine-associated anticonvulsant hypersensitivity syndrome (LASH) is rare and was described in 1998. We report two new cases demonstrating the two particular configurations of apparition of LASH found in the 14 cases from the review of literature (Pubmed: anticonvulsant hypersensitivity syndrome - lamotrigine): high doses of lamotrigine (or lamotrigine in very young or old patients), and lamotrigine associated with another anti-epileptic (phenobarbital or sodium valproate). We discuss the links between DRESS after lamotrigine and LASH as illustrated in a new case.

  17. Anticonvulsant activity of the fractionated extract of Crinum jagus bulbs in experimental animals

    Directory of Open Access Journals (Sweden)

    Azikiwe CCA

    2012-05-01

    Full Text Available Objective: To investigate the anticonvulsant activity of the bulbs of Crinum jagus in experimental animals. Methods: The uprooted bulbs were air dried for a week and ground into creamy-paste. 200g of paste was macerated each in 2 litres of water, ethanol and petroleum ether and filtered after 48 h. The obtained filtrates were each evaporated at the appropriate temperature to solid residue. The residues were further fractionated with successive changes of petroleum ether, ethyl acetate and n-butanol into a pooled filtrate which was further evaporated to dry solid brown-paste. Phytochemistry was carried out based on Treas and Evans method of 1987. The acute toxicity study (LD50 was carried based on Lorke ’s 1983 method. Convulsion was induced using maximum electric shock (MEST, pentylenetetrazole(PTZ, strychnine and Picrotoxin in the appropriate animal models. Seizures onset time and death time were used as successful induction of convulsion while prolongations of these features were taken as anticonvulsant activity. Results where possible, were statistically analyzed using SPSS-16.0 version. Results: The LD 50 was got at 1118.003mg/kg (IP in mice using Lorke ’s 1983 method. Fractionated extract of Crinum jagus exhibited dose dependent antiseizure against MEST induced seizure (P<0.001 and comparable to that of phenytoin, a standard anti generalized tonic-clonic seizure. There were also observable antiseizure activity of the fractionated extracts against PTZ, strychnine and Picrotoxin induced seizure and comparable to their standard corresponding antiseizures. Conclusions: We conclude that the bulbs of Crinum jagus possess proven broad spectrum antiseizure and perhaps antiepileptogenic activity thus justifies its use in traditional medicine. Clinical trial in man is recommended.

  18. Preliminary Screening of a Classical Ayurvedic Formulation for Anticonvulsant Activity

    Directory of Open Access Journals (Sweden)

    Arnab Dhar

    2016-01-01

    Full Text Available Background: Epilepsy is a serious and complex central nervous system disorder associated with recurrent episodes of convulsive seizures due to the imbalance between excitatory (glutamatergic and inhibitory (GABAergic neurotransmitters level in the brain. The available treatments are neither competent to control the seizures nor prevent progress of disease. Since ages, Herbal medicines have remained important sources of medicines in many parts of world which is evidenced through their uses in traditional systems of medicine i.e. Ayurveda, Siddha, Unani, Homeopathy and Chinese etc. Aim: A polyherbal formulation (containing Terminalia chebula Retz., Asparagus racemosus Willd., Embelia ribes Burm. F, Acorus calamus L., Tinospora cordifolia (Willd. Miers, Convolvulus pluricaulis Choisy, Saussurea lappa C.B.Clarke, Achyranthes aspera L. is mentioned in Ayurvedic classics Bhaiṣajya Ratnāvali. The aim of the study was to evaluate the anticonvulsant activity of the formulation in Maximum electroshock and Pentylenetetrazole induced convulsions in rats. Materials and Methods: In the present study, a polyherbal formulation was developed as directed by classical text and evaluated for the anticonvulsant activity using Maximal Electroshock Shock (MES and Pentylenetetrazole (PTZ induced convulsions in rats. Statistical comparison was done by one way ANOVA followed by the Tukey's multiple comparison test. Results: The obtained results showed that the PHF had a protective role on epilepsy. Treatment with PHF significantly improves antioxidant enzymes activities of superoxide dismutase (SOD and glutathione (GSH levels significantly as compared to controls. PHF also significantly decreased malonaldialdehyde (MDA levels in the brain. Moreover, it also attenuated the PTZ-induced increase in the activity of GABA-T in the rat brain. Conclusion: These findings suggest that PHF might have possible efficacy in the treatment of epilepsy.

  19. Evaluation of Analgesic, Anticonvulsant and Hypnotic activities of ...

    African Journals Online (AJOL)

    AqPs (100-400mg/kg i.p.) also demonstrated a protective effect against strychnine-induced convulsion. The extract potentiated the hypnotic effect of hexobarbitone following i.p. injection at the dose levels studied. The results suggested that AqPs possesses potential analgesic, anticonvulsive and hypnotic properties.

  20. Staged anticonvulsant screening for chronic epilepsy.

    Science.gov (United States)

    Berdichevsky, Yevgeny; Saponjian, Yero; Park, Kyung-Il; Roach, Bonnie; Pouliot, Wendy; Lu, Kimberly; Swiercz, Waldemar; Dudek, F Edward; Staley, Kevin J

    2016-12-01

    Current anticonvulsant screening programs are based on seizures evoked in normal animals. One-third of epileptic patients do not respond to the anticonvulsants discovered with these models. We evaluated a tiered program based on chronic epilepsy and spontaneous seizures, with compounds advancing from high-throughput in vitro models to low-throughput in vivo models. Epileptogenesis in organotypic hippocampal slice cultures was quantified by lactate production and lactate dehydrogenase release into culture media as rapid assays for seizure-like activity and cell death, respectively. Compounds that reduced these biochemical measures were retested with in vitro electrophysiological confirmation (i.e., second stage). The third stage involved crossover testing in the kainate model of chronic epilepsy, with blinded analysis of spontaneous seizures after continuous electrographic recordings. We screened 407 compound-concentration combinations. The cyclooxygenase inhibitor, celecoxib, had no effect on seizures evoked in normal brain tissue but demonstrated robust antiseizure activity in all tested models of chronic epilepsy. The use of organotypic hippocampal cultures, where epileptogenesis occurs on a compressed time scale, and where seizure-like activity and seizure-induced cell death can be easily quantified with biomarker assays, allowed us to circumvent the throughput limitations of in vivo chronic epilepsy models. Ability to rapidly screen compounds in a chronic model of epilepsy allowed us to find an anticonvulsant that would be missed by screening in acute models.

  1. The potential anticonvulsant activity of the ethanolic extracts of Achillea nobilis and Momordica charantia in rats

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    Gamal A. Soliman

    2016-06-01

    Full Text Available Context: Currently available antiepileptic drugs have debilitating adverse effects. Natural products and plants already used in traditional medicine can be a good place to start in the search for safer and more effective options. Aims: To investigate the anticonvulsant potential of Achillea nobilis and Momordica charantia extracts in maximal electroshock (MES, as well as pentylenetetrazole (PTZ- and strychnine nitrate (STN- induced seizure models in rats. Methods: For each model, eight groups of 21-day-old male Albino rats were used. The 1st group was kept as control, 2nd as standard (diazepam, 7.5 mg/kg; 3rd – 5th treated with A. nobilis (100, 200 and 300 mg/kg; and 6th – 8th administered M. charantia (100, 200 and 300 mg/kg. After 30 min, rats were exposed to a shock of 150 mA by a convulsiometer, via ear electrodes for 2 s (in MES test or sc injection of PTZ (85 mg/kg or STN (2.5 mg/kg. Results: A. nobilis and M. charantia extracts (200 and 300 mg/kg demonstrated dose-dependent anticonvulsant effect against MES-induced seizures. In the PTZ induced convulsion, A. nobilis and M. charantia (200 and 300 mg/kg significantly slowed the commencement of convulsions and minimized the duration of seizures. A. nobilis (300 mg/kg showed 60% protection in rats against STN induced seizures. In contrast, A. nobilis (100 and 200 mg/kg and M. charantia (100, 200 and 300 mg/kg showed no significant protection against STN-induced seizures in rats. Conclusions: The results of the present study suggest that both extracts exhibited marked anticonvulsant activities.

  2. Anticonvulsants for cocaine dependence.

    Science.gov (United States)

    Minozzi, Silvia; Cinquini, Michela; Amato, Laura; Davoli, Marina; Farrell, Michael F; Pani, Pier Paolo; Vecchi, Simona

    2015-04-17

    Cocaine dependence is a major public health problem that is characterised by recidivism and a host of medical and psychosocial complications. Although effective pharmacotherapy is available for alcohol and heroin dependence, none is currently available for cocaine dependence, despite two decades of clinical trials primarily involving antidepressant, anticonvulsivant and dopaminergic medications. Extensive consideration has been given to optimal pharmacological approaches to the treatment of individuals with cocaine dependence, and both dopamine antagonists and agonists have been considered. Anticonvulsants have been candidates for use in the treatment of addiction based on the hypothesis that seizure kindling-like mechanisms contribute to addiction. To evaluate the efficacy and safety of anticonvulsants for individuals with cocaine dependence. We searched the Cochrane Drugs and Alcohol Group Trials Register (June 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 6), MEDLINE (1966 to June 2014), EMBASE (1988 to June 2014), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to June 2014), Web of Science (1991 to June 2014) and the reference lists of eligible articles. All randomised controlled trials and controlled clinical trials that focus on the use of anticonvulsant medications to treat individuals with cocaine dependence. We used the standard methodological procedures expected by The Cochrane Collaboration. We included a total of 20 studies with 2068 participants. We studied the anticonvulsant drugs carbamazepine, gabapentin, lamotrigine, phenytoin, tiagabine, topiramate and vigabatrin. All studies compared anticonvulsants versus placebo. Only one study had one arm by which the anticonvulsant was compared with the antidepressant desipramine. Upon comparison of anticonvulsant versus placebo, we found no significant differences for any of the efficacy and safety measures. Dropouts: risk ratio (RR) 0.95, 95

  3. Synthesis and Pharmacological Evaluation of Novel Benzenesulfonamide Derivatives as Potential Anticonvulsant Agents

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    Zhiming Wang

    2015-09-01

    Full Text Available A novel series of benzenesulfonamide derivatives containing 4-aminobenzenesul-fonamide and α-amides branched valproic acid or 2,2-dimethylcyclopropanecarboxylic acid moieties were synthesized and screened for their anticonvulsant activities in mice maximal electroshock seizure (MES and subcutaneous pentylenetetrazole (scPTZ test. The activity experimental study showed that 2,2-dipropyl-N1-(4-sulfamoylphenylmalonamide (18b had the lowest median effective dose (ED50 of 16.36 mg/kg in MES test, and 2,2-dimethyl-N-(4-sulfamoylphenylcyclopropane-1,1-dicarboxamide (12c had the lowest ED50 of 22.50 mg/kg in scPTZ test, which resulted in the protective indexe (PI of 24.8 and 20.4, respectively. These promising data suggest the new compounds have good potential as new class of anticonvulsant agents with high effectiveness and low toxicity for the treatment of epilepsy.

  4. The efficacy of anticonvulsants on orofacial pain: a systematic review.

    Science.gov (United States)

    Martin, Wilhelmus J J M; Forouzanfar, Tymour

    2011-05-01

    Controversy exists about the effectiveness of anticonvulsants for the management of orofacial pain disorders. To ascertain appropriate therapies, a systematic review was conducted of existing randomized controlled trials. Trials were identified from PubMed, Cochrane, and Ovid Medline databases from 1962 through March 2010, from references in retrieved reports, and from references in review articles. Eight useful trials were identified for this review. Six studies were randomized placebo-controlled trials and 2 studies were randomized active-controlled. Two independent investigators reviewed these articles by using a 15-item checklist. Four studies were classified as "high quality." However, heterogeneity of the trials and the small sample sizes precluded the drawing of firm conclusions about the efficacy of the interventions studied on orofacial pain patients. There is limited to moderate evidence supporting the efficacy of commonly used anticonvulsants for treatment of patients with orofacial pain disorders. More randomized controlled trials are needed on the efficacy of anticonvulsants. Copyright © 2011 Mosby, Inc. All rights reserved.

  5. Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats

    Science.gov (United States)

    Todorovic, Slobodan M; Rastogi, A J; Jevtovic-Todorovic, Vesna

    2003-01-01

    Anticonvulsant agents are commonly used to treat neuropathic pain conditions because of their effects on voltage- and ligand-gated channels in central pain pathways. However, their interaction with ion channels in peripheral pain pathways is poorly understood. Therefore, we studied the potential analgesic effects of commonly used anticonvulsant agents in peripheral nociception. We injected anticonvulsants intradermally into peripheral receptive fields of sensory neurons in the hindpaws of adult rats, and studied pain perception using the model of acute thermal nociception. Commonly used anticonvulsants such as voltage-gated Na+ channel blockers, phenytoin and carbamazepine, and voltage-gated Ca2+ channel blockers, gabapentin and ethosuximide, induced dose-dependent analgesia in the injected paw, with ED50 values of 0.30, 0.32 and 8, 410 μg per 100 μl, respectively. Thermal nociceptive responses were not affected in the contralateral, noninjected paws, indicating a lack of systemic effects with doses of anticonvulsants that elicited local analgesia. Hill slope coefficients for the tested anticonvulsants indicate that the dose–response curve was less steep for gabapentin than for phenytoin, carbamazepine and ethosuximide. Our data strongly suggest that cellular targets like voltage-gated Na+ and Ca2+ channels, similar to those that mediate the effects of anticonvulsant agents in the CNS, may exist in the peripheral nerve endings of rat sensory neurons. Thus, peripherally applied anticonvulsants that block voltage-gated Na+ and Ca2+ channels may be useful analgesics. PMID:12970103

  6. New benzo[d]thiazol-2-yl-aminoacetamides as potential anticonvulsants: synthesis, activity and prediction of molecular properties.

    Science.gov (United States)

    Ali, Ruhi; Siddiqui, Nadeem

    2015-04-01

    A series of N-(substituted-2-oxo-4-phenylazetidin-1-yl)-2-((6-substitutedbenzo[d]thiazol-2-yl)amino)acetamide derivatives were synthesized using pharmacophoric features with aromatic hydrophobic aryl ring (A), NH-C=O as hydrogen bonding domain, the nitrogen atom as electron donor (D), and phenyl as distal aryl ring (C). The synthesized molecules were initially screened for anticonvulsant activity using the maximal electroshock seizure (MES) test and the subcutaneous pentylenetetrazole test in albino mice. An acute neurotoxicity study on the synthesized molecules was also carried out using the rotarod test. The results of these tests revealed that two compounds, 5b and 5q, showed promising activity with ED50 values of 15.4 and 18.6 mg/kg and protective indices of 20.7 and 34.9 in the MES test, respectively, which are found to be approximately fourfold higher than those of the standard drugs phenytoin (6.9) and carbamazepine (8.1). These molecules may act as lead of the designed scheme. The pharmacokinetic profiles of all the synthesized compounds were estimated using Molinspiration software. None of the compounds violated Lipinski's "rule of five". The possible structure-activity relationship was discussed. In conclusion, this manuscript shows that the developed model has a highly prognostic power for the further investigation of better benzothiazole derivatives for future discovery and development. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. THE APPLICATION OF PASS-COMPUTER PROGRAMME AND MOLECULAR DOCKING FOR THE SEARCH OF NEW ANTICONVULSANTS

    Directory of Open Access Journals (Sweden)

    Perekhoda L.O.

    2014-12-01

    anticonvulsant activity of 1,2,3(1,2,4triazole, 1,3,4- oxa(thiadiazole we investigated the mechanisms of action that involve the interaction of the ligand NMDA-, GAMKA- or glutamate receptors and GABA-AT ligandenzyme. We have perfomed docking research for our structures and for known anticonvulsants using the Fast Dock method, in which both protein and ligand are rigid (Software SCIGRESS; Fujitsu, Fukuoka, Japan. We have evaluated affinity of the investigated structures with molecules biotargets: GABAA receptor protein (PDB code 1GNU, glutamate receptor protein Glu-1 (PDB code 1EWK, GluN1 NMDA receptor protein (PDB code 3Q41 and protein enzyme GABA-AT (PDB code 1OHW. Results and discussion. As a result, we have obtained the values of scoring functions Consensus, which enabled to evaluate affinity compounds and biological anticonvulsant targets and identify 11 perspective groups of compounds (number of compounds 190 that can selectively inhibit NMDA, a GABA - or glutamate receptors and GABA aminotransferase enzyme in comparison with known anticonvulsant drugs. The number of active groups of the results PASS prediction according to the obtained results is 10 (the number of compounds 168. It should be noted that result of docking research coincided with the results of PASS prediction for eight groups of compounds. Conclusion 1. Eleven groups of compounds derivatives of 1,2,3(1,2,4 -triazols, 1,3,4-oxadiazoles and 1,3,4- thiadiazoles was selected for further screening as perspective anticonvulsants; 2. GABA-ergic mode of action for 8 groups of derivatives and glutamatergic mode of action for 3 groups of derivatives five-membered di(threeazaheterocycle was predicted

  8. Acne and anticonvulsants.

    Science.gov (United States)

    Greenwood, R; Fenwick, P B; Cunliffe, W J

    1983-01-01

    The severity of acne and rate of excretion of sebum were assessed in 243 patients with epilepsy taking various anticonvulsants who were in hospital long term and in matched controls derived from a normal population of 2176 people. Neither the prevalence of acne nor the sebum excretion rate significantly increased in the patients compared with the controls or in patients taking phenytoin compared with those not. It is concluded that anticonvulsant treatment does not cause acne. PMID:6227369

  9. Opioid receptor mediated anticonvulsant effect of pentazocine.

    Science.gov (United States)

    Khanna, N; Khosla, R; Kohli, J

    1998-01-01

    Intraperitoneal (i.p.) administration of (+/-) pentazocine (10, 30 & 50 mg/kg), a Sigma opioid agonist, resulted in a dose dependent anticonvulsant action against maximal electroshock seizures in mice. This anticonvulsant effect of pentazocine was not antagonized by both the doses of naloxone (1 and 10 mg/kg) suggesting thereby that its anticonvulsant action is probably mediated by Sigma opiate binding sites. Its anticonvulsant effect was potentiated by both the anticonvulsant drugs viz. diazepam and diphenylhydantoin. Morphine, mu opioid agonist, on the other hand, failed to protect the animals against maximal electroshock seizures when it was given in doses of 10-40 mg/kg body wt.

  10. [Ketamine--anticonvulsive and proconvulsive actions].

    Science.gov (United States)

    Kugler, J; Doenicke, A

    1994-11-01

    Animal experimentation has revealed that ketamine has anticonvulsive properties. Changes in the EEG have also been reported in animals; these have been designated non-convulsive generalized electrographic seizures because of their similarities to epileptiform potentials, even though there are no recognizable signs of seizures. The cataleptic condition of the cats in which these changes were observed led to the conclusion that ketamine could cause petit mal seizures, which took the course of petit mal status. Ketamine was therefore also seen as a dangerous anaesthetic agent predisposing to convulsions, the use of which could lead to status epilepticus and irreversible brain damage. These conflicts of opinion should be resolved, as they are based on various misconceptions. (1) The terminology used for epilepsy by specialized clinicians is not always correctly applied in the context of animal experimentation. (2) The activation of epileptiform potentials in the EEG of animals cannot be interpreted as a reliable sign of epileptogenic efficiency in humans. (3) Too little regard is paid to the different actions of anaesthetic agents in various sites of the brain, at different doses and with different routes of administration. (4) The statistical significance and biological relevance of the study results are inadequate because the numbers of observations are too small. Epileptologists regret the insufficiency of animal models as paradigma for the study of efficiency of antiepileptic drugs in humans. The degree by which extensor spasms in the front paw of Gerbils of rats induced by pentylentetrazol or electric current are reduced after application of an anticonvulsive drug is no reliable measure of its anticonvulsive effect in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Evaluation of anticonvulsant, antimicrobial and hemolytic activity of Aitchisonia rosea

    Directory of Open Access Journals (Sweden)

    Shahid Rasool

    2015-12-01

    Full Text Available The purpose of this study was to evaluate the anticonvulsant, antimicrobial and hemolytic effect of Aitchisonia rosea. The anticonvulsant effect was studied at doses 400 and 800 mg/kg against pentylenetetrazole, strychnine and picrotoxin-induced seizures in albino mice. The antimicrobial assay was conducted by disc diffusion method and minimum inhibitory concentration. Hemolytic effect was analyzed by reported method. Phenolic compounds present in the n-butanol fraction of the plant were estimated by HPLC. The plant showed maximum response against drug-induced convulsions and provided protection to animals at both doses. It also showed maximum zone of inhibition and highly significant MIC against all bacterial and fungal strains. The plant protected the RBCs from hemolysis. The highest amount of phenolics found was caffeic acid (7.5 ± 0.04.

  12. Evaluation of anticonvulsant activity of methanol leaf extract of ...

    African Journals Online (AJOL)

    Hymenocardia acida is a plant used in African folkloric medicine in the treatment of headache, rheumatic pain, sickle cell crisis, malaria, epilepsy and cancer. This study was aimed at investigating the anticonvulsant potential of the methanol leaf extract of H. acida (MLEHA) in chicks and mice. Preliminary phytochemical ...

  13. Menthone aryl acid hydrazones: a new class of anticonvulsants.

    Science.gov (United States)

    Jain, Jainendra; Kumar, Y; Sinha, Reema; Kumar, Rajeev; Stables, James

    2011-01-01

    A series of ten compounds (Compounds J(1)-J(10)) of (±) 3-menthone aryl acid hydrazone was synthesized and characterized by thin layer chromatography and spectral analysis. Synthesized compounds were evaluated for anticonvulsant activity after intraperitoneal (i.p) administration to mice by maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure method and minimal clonic seizure test. Minimal motor impairment was also determined for these compounds. Results obtained showed that four compounds out of ten afforded significant protection in the minimal clonic seizure screen at 6 Hz. Compound J(6), 4-Chloro-N-(2-isopropyl-5-methylcyclohexylidene) benzohydrazide was found to be the most active compound with MES ED(50) of 16.1 mg/kg and protective index (pI) of greater than 20, indicating that (±) 3-menthone aryl acid hydrazone possesses better and safer anticonvulsant properties than other reported menthone derivatives viz. menthone Schiff bases, menthone semicarbazides and thiosemicarbazides.

  14. National trends in pediatric use of anticonvulsants.

    Science.gov (United States)

    Tran, Allen R; Zito, Julie M; Safer, Daniel J; Hundley, Sarah D

    2012-11-01

    This research study aimed to assess national trends in pediatric use of anticonvulsants for seizures and psychiatric disorders. In a cross-sectional design, data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey were analyzed. Outpatient visit information for youths (ages 0-17 years) was grouped by year for 1996-1997, 2000-2001, 2004-2005, and 2008-2009. Six of the most common anticonvulsant drugs used for psychiatric conditions were examined. Psychiatric diagnoses and seizure or convulsion diagnoses were identified with ICD-9-CM codes. The primary outcome measure was percentage prevalence of visits for anticonvulsants that included a psychiatric diagnosis as a proportion of total youth visits for an anticonvulsant. Total, diagnosis-stratified, and drug-specific visits, as well as visits for concomitant anticonvulsants and psychotropics, were analyzed. As a proportion of total youth visits for anticonvulsants, visits with a psychiatric diagnosis increased 1.7 fold (panticonvulsant use significantly increased, from .33% to .68% of total youth visits in the 14-year period. There were significant increases in anticonvulsant use to treat pediatric bipolar disorder and disruptive behavior disorders. Visits noting divalproex decreased while visits noting lamotrigine increased among visits involving a psychiatric diagnosis. The concomitant use of stimulants and anticonvulsants significantly increased in visits noting a psychiatric diagnosis. Whereas anticonvulsant use for seizure disorders across the 14-year period was stable, the use of these drugs for psychiatric conditions rose to a dominant position. The growth of concomitant and off-label use to treat behavioral disorders raises questions about effectiveness and safety in community populations of youths.

  15. Anticonvulsant properties of the total alkaloid fraction of Rauvolfia ligustrina Roem. et Schult. in male mice

    Directory of Open Access Journals (Sweden)

    Lucindo J. Quintans-Júnior

    Full Text Available Rauvolfia ligustrina Roem et. Schult (Apocynaceae, commonly known as "paratudo" and "arrebenta-boi" is a small tree found in Brazilian Northeastern. Previous studies have demonstrated depressant and anticonvulsant properties of the ethanol extract of Rauvolfia ligustrina. The aim of the present study was the determination of the lethal dose 50% (LD50 and the effects of total alkaloid fraction (TAF of the aerial parts of R. ligustrina in animal models of convulsion. It was found that the acute toxicity of TAF was 127.8 (112.5-145.2 mg/kg (i.p. in mice. TAF (20 mg/kg, ip significantly increased (p < 0.05 the latencies of clonic seizures induced by pentylenetetrazol (PTZ and picrotoxin (PIC. However, TAF did not protect the animals in maximal electroshock (MES induced seizures. These results suggest that TAF of R. ligustrina possesses anticonvulsant properties.

  16. Is bioavailability altered in generic versus brand anticonvulsants?

    Science.gov (United States)

    Jankovic, Slobodan M; Ignjatovic Ristic, Dragana

    2015-03-01

    Therapeutic window of anticonvulsants is not a wide one, with phenytoin being one extreme, which can be classified as a narrow therapeutic index drug, since its ratio between the least toxic and the least effective concentration is less than twofold. In order to obtain marketing authorization, a generic anticonvulsant should demonstrate relative bioequivalence with its brand-name counterpart. However, although bioequivalent, generic anticonvulsants still do not have the same bioavailability as brand-name drugs, which may lead to larger fluctuations of steady-state plasma concentrations, and sometimes to loss of seizure control if a patient is switched from brand-name to generic or from generic to generic anticonvulsant. Generic anticonvulsants are effective, safe and affordable drugs for treatment of epilepsy, and patients could be successfully treated with them from the very beginning. It is switching from brand-name to generic anticonvulsant or from one generic anticonvulsant to another that should be avoided in clinical practice, since subtle differences in bioavailability may disturb optimal degree of seizure control to which the patient was previously successfully titrated.

  17. Anticonvulsants for fibromyalgia.

    Science.gov (United States)

    Üçeyler, Nurcan; Sommer, Claudia; Walitt, Brian; Häuser, Winfried

    2013-10-16

    pregabalin use than with a placebo (risk ratio (RR) 1.59; 95% confidence interval (CI) 1.33 to 1.90; number needed to treat for an additional beneficial outcome (NNTB) 12; 95% CI 9 to 21). The number of people who reported being 'much' or 'very much' improved was higher with pregabalin than with placebo (RR 1.38; 95% CI 1.23 to 1.55; NNTB 9; 95% CI 7 to 15). Pregabalin did not substantially reduce fatigue (SMD -0.17; 95% CI -0.25 to -0.09; 2.7% absolute improvement on a 1 to 50 scale) compared with placebo. Pregabalin had a small benefit over placebo in reducing sleep problems by 6.2% fewer points on a scale of 0 to 100 (standardised mean difference (SMD) -0.35; 95% CI -0.43 to -0.27). The dropout rate due to adverse events was higher with pregabalin use than with placebo use (RR 1.68; 95% CI 1.36 to 2.07; number needed to treat for an additional harmful outcome (NNTH) 13; 95% CI 9 to 23). There was no significant difference in serious adverse events between pregabalin and placebo use (RR 1.03; 95% CI 0.71 to 1.49). Dizziness was reported as an adverse event more frequently with pregabalin use than with placebo use (RR 3.77; 95% CI 3.06 to 4.63; NNTH 4; 95% CI 3 to 5). The anticonvulsant, pregabalin, demonstrated a small benefit over placebo in reducing pain and sleep problems. Pregabalin use was shown not to substantially reduce fatigue compared with placebo. Study dropout rates due to adverse events were higher with pregabalin use compared with placebo. Dizziness was a particularly frequent adverse event seen with pregabalin use. At the time of writing this review, pregabalin is the only anticonvulsant drug approved for treating FM in the US and in 25 other non-European countries. However, pregabalin has not been approved for treating FM in Europe. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM.

  18. Behavioral and electroencephalographic evaluation of the anticonvulsive activity of Moringa oleifera leaf non-polar extracts and one metabolite in PTZ-induced seizures.

    Science.gov (United States)

    González-Trujano, María Eva; Martínez-González, Claudia Lizbeth; Flores-Carrillo, Maricela; Luna-Nophal, Sara Ibeth; Contreras-Murillo, Gerardo; Magdaleno-Madrigal, Víctor Manuel

    2018-01-15

    Moringa oleifera Lamarck is a species that has long been used in high demand in folk medicine, including for the treatment of epilepsy. Nevertheless, scientific studies demonstrating its anticonvulsant properties and the nature of the bioactive constituents are lacking. The aim of this study was to evaluate the anticonvulsant activities of the Moringa oleifera leaves in non-polar vs. polar extracts using behavioral and electroencephalographic (EEG) analyses in rodents. First, PTZ (80 mg/kg, i.p.)-induced tonic-clonic seizures were assayed via a dose-response (100, 200 and 300 mg/kg, i.p.) evaluation in mice. Then, a dosage of the extracts (100 or 300 mg/kg) and one metabolite (30 mg/kg, i.p.) was selected to evaluate its effect on PTZ (35 mg/kg, i.p.)-induced EEG paroxystic activities in rats compared to the effects of ethosuximide (reference anticonvulsant drug, 100 mg/kg, i.p.). Latent onset of the first paroxystic spike, first seizure and frequency as well as seizure severity, were determined using Racine's scale. Moringa oleifera ethanol and hexane extracts produced a delay in the seizure latency in mice and rats; this effect was improved in the presence of the hexane extract containing the active metabolite hexadecanoic acid. The anticonvulsant effects were corroborated in the spectral analysis by the potency of the EEG due to a reduction in the spike frequency and amplitude, as well as in the duration and severity of the seizures. The effects of the hexane extract resembled those observed in the reference antiepileptic drug ethosuximide. Moringa oleifera leaves possess anticonvulsant activities due to the complementary of the non-polar and polar constituents. However, the non-polar constituents appear to exert an important influence via the partial participation of fatty acids, providing evidence of the effects of this plant in epilepsy therapy. Copyright © 2017. Published by Elsevier GmbH.

  19. Synthesis, anti-inflammatory, analgesic and anticonvulsant activities of some new 4,6-dimethoxy-5-(heterocyclesbenzofuran starting from naturally occurring visnagin

    Directory of Open Access Journals (Sweden)

    E.R. El-Sawy

    2014-12-01

    Full Text Available Novel 3-(4,6-dimethoxybenzofuran-5-yl-1-phenyl-1H-pyrazole-4-carboxaldehyde (3 and 3-chloro-3-(4,6-dimethoxybenzofuran-5-ylpropenal (4 were prepared via Vilsmeier–Haack reaction of 1-(4,6-dimethoxybenzofuran-5-ylethanone (1 and its hydrazone derivative 2. Reaction of compound 4 with some hydrazine derivatives, namely hydrazine hydrate, phenylhydrazine and benzylhydrazine hydrochloride led to the formation of pyrazole derivatives 5–8, respectively. On the other hand, reaction of compound 4 with thiourea, urea or guanidine gave the pyrimidine derivatives 9–11, respectively. Reaction of amino compound 11 with acetic anhydride, benzoyl chloride and benzenesulphonyl chloride yielded N-substituted pyrimidine derivatives 12–14, respectively. Reaction of diazonium salt of compound 11 with sodium azide afforded azidopyrimidine derivative 15, which upon reaction with ethyl acetoacetate gave 1,2,3-triazole derivative 16. Acid catalyzed reaction of 11 with p-nitrobenzaldehyde gave Schiff base 17, which cyclized upon reaction with thioglycolic acid or chloroacetyl chloride to give thiazolidin-4-one 18 and azetidin-2-one 19, respectively. The newly synthesized compounds were tested for their anti-inflammatory, analgesic and anticonvulsant activities. Depending on the obtained results, the newly synthesized compounds possess significant anti-inflammatory, analgesic and anticonvulsant activities.

  20. Search for new potential anticonvulsants with anxiolytic and antidepressant properties among derivatives of 4,4-diphenylpyrrolidin-2-one.

    Science.gov (United States)

    Malawska, Katarzyna; Rak, Aleksandra; Gryzło, Beata; Sałat, Kinga; Michałowska, Małgorzata; Żmudzka, Elżbieta; Lodarski, Krzysztof; Malawska, Barbara; Kulig, Katarzyna

    2017-02-01

    The aim of this study was to synthesize a series of new N-Mannich bases derived from 4,4-diphenylpyrrolidin-2-one having differently substituted 4-phenylpiperazines as potential anticonvulsant agents with additional (beneficial) pharmacological properties. The target compounds 8-12 were prepared in one step from the 4-substituted phenylpiperazines, paraformaldehyde, and synthesized 4,4-diphenylpyrrolodin-2-one (7) by a Mannich-type reaction. The obtained compounds were assessed and tested for their anticonvulsant activity in two screening mouse models of seizures, i.e., the maximal electroshock (MES) test and in the subcutaneous pentylenetetrazole (scPTZ) test. The effect of these compounds on animals' motor coordination was measured in the rotarod test. A selected 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one (8) was evaluated in vivo for its anxiolytic- and antidepressant-like properties. Its impact on animals' locomotor activity was also evaluated. Compound 8 showed protection (25%) in the MES and in the scPTZ tests at the dose of 100mg/kg and was not neurotoxic. In the four-plate test, compound 8 at the dose of 30mg/kg showed a statistically significant (p<0.05) anxiolytic-like activity. In the forced swim test, it reduced the immobility time by 24.3% (significant at p<0.05), which indicates its potential antidepressant-like properties. In the locomotor activity test, compound 8 significantly reduced animals' locomotor activity by 79.9%. The results obtained make a new derivative of 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one (8) a promising lead structure for further development. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

  1. The anticonvulsant action of the galanin receptor agonist NAX-5055 involves modulation of both excitatory- and inhibitory neurotransmission

    DEFF Research Database (Denmark)

    Walls, Anne B; Flynn, Sean P; West, Peter J

    2016-01-01

    -based anti-convulsant drugs was prompted. Based on this, a rationally designed GalR1 preferring galanin analogue, NAX-5055, was synthesized. This compound demonstrates anti-convulsant actions in several animal models of epilepsy. However, the alterations at the cellular level leading to this anti......-convulsant action of NAX-5055 are not known. Here we investigate the action of NAX-5055 at the cellular level by determining its effects on excitatory and inhibitory neurotransmission, i.e. vesicular release of glutamate and GABA, respectively, in cerebellar, neocortical and hippocampal preparations. In addition...

  2. Design, synthesis and evaluation of dialkyl 4-(benzo[d][1,3]dioxol-6-yl)-1,4-dihydro-2,6-dimethyl-1-substituted pyridine-3,5-dicarboxylates as potential anticonvulsants and their molecular properties prediction.

    Science.gov (United States)

    Prasanthi, G; Prasad, K V S R G; Bharathi, K

    2013-08-01

    The present study is on the development of dialkyl 4-(benzo[d][1,3]dioxol-6-yl)-1,4-dihydro-2,6-dimethyl-1-substituted pyridine-3,5-dicarboxylate derivatives as isosteric analogues of isradipine and nifedipine, by the replacement of benzofurazanyl and 2-nitrophenyl groups respectively with benzo[d][1,3]dioxo-6-yl group, as potential anticonvulsants. Fivfteen new derivatives (8a-8o) were synthesized and tested for anticonvulsant activity using maximal electroshock and subcutaneous pentylenetetrazole induced seizure methods. Compound 8f possessing free NH group in 1,4-dihydropyridine ring, diethyl ester functionality at the positions 3 and 5 showed significant anticonvulsant and antioxidant activities. This was also supported by molecular properties prediction data. Selected compounds were evaluated for antinociceptive activity in capsaicin induced nociception assay at 10 mg/kg body weight, but displayed no significant activity at the tested dose. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  3. Anticonvulsant action of gamma-irradiated diazepam with correlation to certain brain amino acids and electrocorticogram activity in experimental animals

    International Nuclear Information System (INIS)

    Saad, S.F.; Roushdy, H.M.; Hassan, S.H.M.; Elkashef, H.S.; Mahdy, A.M.; Elsayeh, B.M.

    1994-01-01

    The effect of sterilization by gamma irradiation (215 KGy) of diazepam on is anticonvulsant action, on norma and depleted cerebral gamma aminobutyric acid (GABA), on glutamic acid, as well as electrocorticogram activity (ECOG) was determined in the experimental animals. For the evaluation of the anticonvulsant action of either diazepam (D) or irradiated diazepam (ID), pentyl ene tetrazole seizure test, was used and the protective dose 50 (PD50) was determined in adult male mice. GABA, the main central inhibitory transmitter which is implicated in the mechanism of the anticonvulsant action of D and its precursor glutamic acid, were electrophoretically separated and spectrophotometrical evaluated. Moreover, brain electrical activity was recorded using an electroencephalograph apparatus. Although the PD50 of ID as well the effect on normal brain cerebral GABA and glutamic acids did not differ significantly from that of D, yet there was certain variabilities. Thus, the effect of D was about 4 times more potent than the ID on elevating depleted cerebral GABA. Also, electrocorticogram records demonstrated that D produced a slight inhibition while ID induced a decrease in B rhythm with remarkable in the amplitude of ECOG waves. The same pattern of effects were obtained when D or ID were used in combination with INH (250 mg kg-1). 1 tab. 1 fig

  4. Action of bicyclic isoxazole GABA analogues on GABA transporters and its relation to anticonvulsant activity

    DEFF Research Database (Denmark)

    Bolvig, T; Larsson, O M; Pickering, D S

    1999-01-01

    The inhibitory action of bicyclic isoxazole gamma-aminobutyric acid (GABA) analogues and their 4,4-diphenyl-3-butenyl (DPB) substituted derivatives has been investigated in cortical neurones and astrocytes as well as in human embryonic kidney (HEK 293) cells transiently expressing either mouse GA...... anticonvulsant activity, lack of proconvulsant activity and the ability of THPO to increase extracellular GABA concentration, indicate that these bicyclic isoxazole GABA analogues and their DPB derivatives may be useful lead structures in future search for new antiepileptic drugs....

  5. 1-[(2-arylthiazol-4-yl)methyl]azoles as a new class of anticonvulsants: design, synthesis, in vivo screening, and in silico drug-like properties.

    Science.gov (United States)

    Ahangar, Nematollah; Ayati, Adile; Alipour, Eskandar; Pashapour, Arsalan; Foroumadi, Alireza; Emami, Saeed

    2011-11-01

    A series of novel thiazole incorporated (arylalkyl)azoles were synthesized and screened for their anticonvulsant properties using maximal electroshock and pentylenetetrazole models in mice. Among target compounds, 1-[(2-(4-chlorophenyl)thiazol-4-yl)methyl]-1H-imidazole (compound 4b), 1-[(2-phenylthiazol-4-yl)methyl]-1H-1,2,4-tria-zole (8a), and its 4-chlorophenyl analog (compound 8b) were able to display noticeable anticonvulsant activity in both pentylenetetrazole and maximal electroshock tests with percentage protection range of 33-100%. A computational study was carried out for prediction of pharmacokinetics properties and drug-likeness. The structure-activity relationship and in silico drug relevant properties (molecular weight, topological polar surface area, clog P, hydrogen bond donors, hydrogen bond acceptors, and log BB) confirmed that the compounds were within the range set by Lipinski's rule-of-five, and possessing favorable physicochemical properties for acting as CNS-drugs, making them potentially promising agents for epilepsy therapy. © 2011 John Wiley & Sons A/S.

  6. Synthesis, characterization and screening for antidepressant and anticonvulsant activity of 4,5-dihydropyrazole bearing indole derivatives

    Directory of Open Access Journals (Sweden)

    Pravin O. Patil

    2016-07-01

    Full Text Available In the present study, a series of new substituted 5-(1H-Indol-3-yl-3-(phenyl-4,5-dihydropyrazoline derivatives (2a–m have been synthesized with good yield by microwave assisted synthesis. The compounds synthesized were screened for antidepressant and anticonvulsant potentialities in mice by a forced swim test and subcutaneous pentylenetetrazole (scPTZ test, respectively. Neuro-toxicities were determined by rotarod test in albino mice. The structures of all new compounds were confirmed by IR, 1H NMR, mass spectral data, and microanalyses. The results revealed that compounds 2b, 2e and 2k were found to be potent antidepressant molecules of the series, at 20 mg/kg dose level when compared with the reference drugs imipramine and fluoxetine. Whereas, compounds 2c and 2d were found to be potent anticonvulsant molecules of this series, when compared with the reference drug diazepam. None of the synthesized compounds showed neurotoxicity.

  7. Trends in resource utilization and prescription of anticonvulsants for patients with active epilepsy in Germany.

    Science.gov (United States)

    Strzelczyk, Adam; Haag, Anja; Reese, Jens P; Nickolay, Tanja; Oertel, Wolfgang H; Dodel, Richard; Knake, Susanne; Rosenow, Felix; Hamer, Hajo M

    2013-06-01

    This study evaluated trends in the resource use of patients with active epilepsy over a 5-year period at an outpatient clinic of a German epilepsy center. Two cross-sectional cohorts of consecutive adults with active epilepsy were evaluated over a 3-month period in 2003 and 2008. Data on socioeconomic status, course of epilepsy, as well as direct and indirect costs were recorded using validated patient questionnaires. We enrolled 101 patients in 2003 and 151 patients in 2008. In both cohorts, 76% of the patients suffered from focal epilepsy, and the majority was on antiepileptic drug (AED) polytherapy (mean AED number: 1.7 (2003), 1.8 (2008)). We calculated epilepsy-specific costs of € 2955 in 2003 and € 3532 in 2008 per 3 months per patient. Direct medical costs were mainly due to anticonvulsants in 2003 (59.4% of total direct costs, 34.0% in 2008) and to hospitalization in 2008 (46.9% of total direct costs, 27.7% in 2003). The proportion of enzyme-inducing anticonvulsants and 'old' AEDs decreased between 2003 and 2008. Indirect costs of € 1689 and € 1847 were mainly due to early retirement (48.4%; 46.0% of total indirect costs in 2003; 2008), unemployment (26.1%; 24.2%), and days off due to seizures (25.5%; 29.8%). This study showed a shift in distribution of direct cost components with increased hospital costs as well as a cost-neutral increase in the prescription of 'newer' AEDs. The amount and distribution of indirect cost components remained unchanged. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients

    Science.gov (United States)

    GIACCONE, M.; BARTOLI, A.; GATTI, G.; MARCHISELLI, R.; PISANI, F.; LATELLA, M.A.; PERUCCA, E.

    1996-01-01

    1To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500 mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine. 2Compared with controls, epileptic patients showed markedly shorter ethosuximide half-lives (29.0±7.8 vs 53.7±14.3 h, means±s.d., Panticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity. 4The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients. PMID:8799524

  9. Anticonvulsant and neuroprotective effects of Rosa damascena hydro-alcoholic extract on rat hippocampus

    Directory of Open Access Journals (Sweden)

    Mansour Homayoun

    2015-04-01

    Full Text Available Objective: Previously, analgesic, hypnotic, and anticonvulsant effects have been suggested for Rosa damascena (R. damascena. In the present study, possible anti-seizure and neuro-protective effects of hydro-alcoholic extract of R. damascena has been investigated after inducing seizures in rats by pentylenetetrazole (PTZ. Materials and Methods: The rats were divided to five groups: (1 Control: received saline, (2 PTZ: 100 mg/kg, i.p., (3 PTZ-Extract 50 mg/kg(PTZ-Ext 50, (4 PTZ- Extract 100 mg/kg(PTZ-Ext 100, and (5 PTZ- Extract 200 mg/kg(PTZ-Ext 200 groups which were treated with 50, 100, and 200 mg/kg respectively of hydro-alcoholic extract of R. damascena for one week before PTZ injection. The animals were examined for electrocorticography (ECoG recording and finally, the brains were removed for histological study. Results: The hydro-alcoholic extract of R. damascena significantly prolonged the latency of seizure attacks and reduced the frequency and amplitude of epileptiform burst discharges induced by PTZ injection. Moreover, all three doses of the extract significantly inhibited production of dark neurons in different regions of the hippocampus in the mentioned animal model. Conclusion: The present study showed that the hydro-alcoholic extract of R. damascena has anticonvulsant and neuroprotective effects. More investigations are needed to be done in order to better understand the responsible compound(s as well as the possible mechanism(s.

  10. Anticonvulsant effect of the ethanol extract of Caesalpiniapulcherrima (L. Sw., Fabaceae, leaves

    Directory of Open Access Journals (Sweden)

    Dinesh Kumar

    2010-08-01

    Full Text Available In this study, ethanol extract of Caesalpinia pulcherrima (L. Sw., Fabaceae, leaves (CPEE was investigated for anticonvulsant effect against maximal electroshock (MES and pentylenetetrazole (PTZ induced seizures in rats and mice at dose levels 200 and 400 mg/kg, i.p. respectively. Diazepam (3 mg/kg, i.p. was used as a standard anticonvulsant drug for comparison. CPEE was found to be safe up to the dose of 4000 mg/kg in mice, when administered intraperitoneally. The extract at 400 mg/kg dose produced significant (p<0.01 anticonvulsant effect w.r.t. control against PTZ-induced clonic seizures. In MES-induced seizure model, there were no significant alterations in the onset as well as duration of hind limb extension seizures as compared to control at a dose of 200 mg/kg when administered intraperitoneally. However, the extract (CPEE, 400 mg/kg i.p. significantly (p<0.01 delayed the onset as well as decreased the duration of hind limb extension seizures (HLES as compared to control. However, the extract, CPEE, percentage protection of the animals was increased at higher dose (200 mg/kg in both the models. The results of the study suggest that ethanol extract of Caesalpinia pulcherrima (L. Sw. leaves possess anticonvulsant effect.

  11. Lactation studies of anticonvulsants: a quality review.

    Science.gov (United States)

    van der Meer, Douwe H; Wieringa, Andre; Wegner, Ilse; Wilffert, Bob; Ter Horst, Peter G J

    2015-04-01

    The aim of this review was to investigate the quality of the current literature on the transfer of anticonvulsants to breast milk to provide an overview of which anticonvulsants are in need of further research. We reviewed the quality of the available lactation studies for 19 anticonvulsants against the guidelines of the Food and Drug Administration (FDA) and the International Lactation Consultant Association (ILCA). Except for one study on lamotrigine and one case report on gabapentin, no study on anticonvulsants had both the absolute infant dose (AID) and milk to plasma ratio (M : P) correctly assessed. Only one study on carbamazepine, phenytoin and vigabatrin was found that correctly assessed the AID. The main cause for this low number is the lack of essential details in published studies, since 25 of 62 studies were case reports, letters or abstracts. Other major shortcomings were the lack of information on sampling methods, the number of samples in a particular dose interval as well as the low number of study participants. The quality of the current literature on the transfer of anticonvulsants to breast milk is low, except for lamotrigine, which makes it hard to draw conclusions about the safety of the use of anticonvulsants during the lactation period. Therefore, further research is needed. © 2014 The British Pharmacological Society.

  12. Anticonvulsant use in elderly patients in long-term care units.

    LENUS (Irish Health Repository)

    Timmons, S

    2012-02-03

    BACKGROUND: Elderly patients in long-term care units are frailer than their community-dwelling peers and may be more at risk from toxic side-effects of anticonvulsant medication at standard doses. AIM: To examine the prescribing of anticonvulsants to patients in elderly care units. METHODS: Drug prescription sheets and case notes were reviewed. Serum anticonvulsant concentration, renal and liver profiles and albumin level were measured. RESULTS: Anticonvulsants were prescribed to twice as many male as female patients (32 vs 14%; p<0.03) and to 33% of those younger than 80 years of age versus 10% of those aged 80 years or older (p<0.0002). No patient had significant hypoalbuminaemia and routine measurement of serum anticonvulsant concentration did not indicate an alteration of dosage. CONCLUSIONS: Anticonvulsants appear to be well tolerated in these patients. The younger age of those receiving anticonvulsants is inadequately explained by the characteristics of the patient cohort and may reflect a shift towards a younger age in patients requiring anticonvulsants due to increased mortality in this group.

  13. Sudden unexpected death in epilepsy following resective epilepsy surgery in two patients withdrawn from anticonvulsants.

    Science.gov (United States)

    Mansouri, Alireza; Alhadid, Kenda; Valiante, Taufik A

    2015-09-01

    We report sudden unexpected death in epilepsy (SUDEP) following resective epilepsy surgery in two patients who had been documented as seizure free. One patient had been weaned off of anticonvulsants and was leading a normal life. The other patient had discontinued only one anticonvulsant but had recently started working night shifts. Following resective epilepsy surgery, one of the major objectives among patients, caregivers, and the healthcare team is to safely wean patients off anticonvulsant medications. The main concern regarding anticonvulsant withdrawal is seizure recurrence. While SUDEP following surgical resection has been reported, to our knowledge, there have been no confirmed cases in patients who have been seizure free. Considering the patients reported here, and given that there are no concrete guidelines for the safe withdrawal of anticonvulsants following epilepsy surgery, the discontinuation of anticonvulsants should be considered carefully and must be accompanied by close monitoring and counseling of patients regarding activities that lower seizure threshold, even after successful epilepsy surgery. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Synthesis and pharmacological investigation of 2-(4-dimethylaminophenyl)-3,5-disubstituted thiazolidin-4-ones as anticonvulsants.

    Science.gov (United States)

    Senthilraja, Manavalan; Alagarsamy, Veerachamy

    2012-10-01

    A new series of 2-(4-dimethylaminophenyl)-3-substituted thiazolidin-4-one-5-yl-acetyl acetamides/benzamides were synthesized by the nucleophilic substitution of 3-substituted-2-(4-dimethylaminophenyl)-thiazolidin-4-one-5-yl-acetylchloride with acetamide and benzamide. The starting material 3-substituted-2-(4-dimethylaminophenyl)-thiazolidin-4-one-5-yl-acetylchloride was synthesized from 3-substituted-2-(4-dimethylaminophenyl)-thiazolidin-4-one-5-yl-acetic acid, which in turn was prepared by one-pot reaction of amino component, p-dimethylamino benzaldehyde and mercapto succinic acid. The title compounds were investigated for their anticonvulsant activities; among the test compounds, compound 2-(4-dimethylaminophenyl)-3-phenylamino-thiazolidine-4-one-5-yl-acetylbenzamide (14) emerged as the most active compound of the series and as moderately more potent than the reference standard diazepam. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Skeletal mass in patients receiving chronic anticonvulsant therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zanzi, I.; Roginsky, M.S.; Rosen, A.; Cohn, S.H.

    1981-01-01

    The technique of in vivo total body neutron activation analysis was used to measure total body calcium (TBCa), a sensitive and precise index of skeletal mass, expressed as the Ca ratio (TBCa observed/TBCa predicted). 23 unselected, ambulatory, noninstitutionalized, adult epileptic patients under long-term anticonvulsant therapy were studied. Ca ratio was normal in 20 of the patients, low in only 2 and borderline in 1 patient. Plasma alkaline phosphatase values were elevated in half the subjects. Plasma Ca (uncorrected) was in the normal range in all. Serum 25-hydroxvitamin D (25-OHD) was low in 67% of the subjects, but only 1 patient had a value below 5 ng/ml. There was no correlation between the Ca ratio and the alkaline phosphatase or 25-OHD values. No radiographic or other evidences of osteomalacia were observed. This study does not support the notion of a prevalence of osteopenia in ambulatory, noninstitutionalized, adult epileptic patients receiving chronic anticonvulsant therapy in this geographical area despite the frequent findings of biochemical abnormalities.

  16. The effectiveness of anticonvulsants in psychiatric disorders

    Science.gov (United States)

    Grunze, Heinz C. R.

    2008-01-01

    Anticonvulsant drugs are widely used in psychiatric indications. These include mainly alcohol and benzodiazepine withdrawal syndromes, panic and anxiety disorders, dementia, schizophrenia, affective disorders, bipolar affective disorders in particular, and, to some extent, personality disorders, A further area in which neurology and psychiatry overlap is pain conditions, in which some anticonvulsants, and also typical psychiatric medications such as antidepressants, are helpful. From the beginning of their psychiatric use, anticonvulsants have also been used to ameliorate specific symptoms of psychiatric disorders independently of their causality and underlying illness, eg, aggression, and, more recently, cognitive impairment, as seen in affective disorders and schizophrenia. With new anticonvulsants currently under development, it is likely that their use in psychiatry will further increase, and that psychiatrists need to learn about their differential efficacy and safety profiles to the same extent as do neurologists. PMID:18472486

  17. The mTOR inhibitor rapamycin has limited acute anticonvulsant effects in mice.

    Directory of Open Access Journals (Sweden)

    Adam L Hartman

    Full Text Available The mammalian target of rapamycin (mTOR pathway integrates signals from different nutrient sources, including amino acids and glucose. Compounds that inhibit mTOR kinase activity such as rapamycin and everolimus can suppress seizures in some chronic animal models and in patients with tuberous sclerosis. However, it is not known whether mTOR inhibitors exert acute anticonvulsant effects in addition to their longer term antiepileptogenic effects. To gain insights into how rapamycin suppresses seizures, we investigated the anticonvulsant activity of rapamycin using acute seizure tests in mice.Following intraperitoneal injection of rapamycin, normal four-week-old male NIH Swiss mice were evaluated for susceptibility to a battery of acute seizure tests similar to those currently used to screen potential therapeutics by the US NIH Anticonvulsant Screening Program. To assess the short term effects of rapamycin, mice were seizure tested in ≤ 6 hours of a single dose of rapamycin, and for longer term effects of rapamycin, mice were tested after 3 or more daily doses of rapamycin.The only seizure test where short-term rapamycin treatment protected mice was against tonic hindlimb extension in the MES threshold test, though this protection waned with longer rapamycin treatment. Longer term rapamycin treatment protected against kainic acid-induced seizure activity, but only at late times after seizure onset. Rapamycin was not protective in the 6 Hz or PTZ seizure tests after short or longer rapamycin treatment times. In contrast to other metabolism-based therapies that protect in acute seizure tests, rapamycin has limited acute anticonvulsant effects in normal mice.The efficacy of rapamycin as an acute anticonvulsant agent may be limited. Furthermore, the combined pattern of acute seizure test results places rapamycin in a third category distinct from both fasting and the ketogenic diet, and which is more similar to drugs acting on sodium channels.

  18. Anticonvulsive effect of paeoniflorin on experimental febrile seizures in immature rats: possible application for febrile seizures in children.

    Directory of Open Access Journals (Sweden)

    Hitomi Hino

    Full Text Available Febrile seizures (FS is the most common convulsive disorder in children, but there have been no clinical and experimental studies of the possible treatment of FS with herbal medicines, which are widely used in Asian countries. Paeoniflorin (PF is a major bioactive component of Radix Paeoniae alba, and PF-containing herbal medicines have been used for neuromuscular, neuropsychiatric, and neurodegenerative disorders. In this study, we analyzed the anticonvulsive effect of PF and Keishikashakuyaku-to (KS; a PF-containing herbal medicine for hyperthermia-induced seizures in immature rats as a model of human FS. When immature (P5 male rats were administered PF or KS for 10 days, hyperthermia-induced seizures were significantly suppressed compared to control rats. In cultured hippocampal neurons, PF suppressed glutamate-induced elevation of intracellular Ca(2+ ([Ca(2+](i, glutamate receptor-mediated membrane depolarization, and glutamate-induced neuronal death. In addition, PF partially suppressed the elevation in [Ca(2+](i induced by activation of the metabotropic glutamate receptor 5 (mGluR5, but not that mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA or N-methyl-D-aspartate (NMDA receptors. However, PF did not affect production or release of γ-aminobutyric acid (GABA in hippocampal neurons. These results suggest that PF or PF-containing herbal medicines exert anticonvulsive effects at least in part by preventing mGluR5-dependent [Ca(2+](i elevations. Thus, it could be a possible candidate for the treatment of FS in children.

  19. Prenatal exposure to anticonvulsants and psychosexual development

    NARCIS (Netherlands)

    Dessens, A. B.; Cohen-Kettenis, P. T.; Mellenbergh, G. J.; vd Poll, N.; Koppe, J. G.; Boer, K.

    1999-01-01

    Animal studies have shown that prenatal exposure to the anticonvulsant drugs phenobarbital and phenytoin alters steroid hormone levels which consequently leads to disturbed sexual differentiation. In this study, possible sequelae of prenatal exposure to these anticonvulsants on gender development in

  20. Antiausterity activity of arctigenin enantiomers: importance of (2R,3R)-absolute configuration.

    Science.gov (United States)

    Awale, Suresh; Kato, Mamoru; Dibwe, Dya Fita; Li, Feng; Miyoshi, Chika; Esumi, Hiroyasu; Kadota, Shigetoshi; Tezuka, Yasuhiro

    2014-01-01

    From a MeOH extract of powdered roots of Wikstroemia indica, six dibenzyl-gamma-butyrolactone-type lignans with (2S,3S)-absolute configuration [(+)-arctigenin (1), (+)-matairesinol (2), (+)-trachelogenin (3), (+)-nortrachelogenin (4), (+)-hinokinin (5), and (+)-kusunokinin (6)] were isolated, whereas three dibenzyl-gamma-butyrolactone-type lignans with (2R,3R)-absolute configuration [(-)-arctigenin (1*), (-)-matairesinol (2*), (-)-trachelogenin (3*)] were isolated from Trachelospermum asiaticum. The in vitro preferential cytotoxic activity of the nine compounds was evaluated against human pancreatic PANC-1 cancer cells in nutrient-deprived medium (NDM), but none of the six lignans (1-6) with (2S,3S)-absolute configuration showed preferential cytotoxicity. On the other hand, three lignans (1*-3*) with (2R,3R)-absolute configuration exhibited preferential cytotoxicity in a concentration-dependent manner with PC50 values of 0.54, 6.82, and 5.85 microM, respectively. Furthermore, the effect of (-)- and (+)-arctigenin was evaluated against the activation of Akt, which is a key process in the tolerance to nutrition starvation. Interestingly, only (-)-arctigenin (1*) strongly suppressed the activation of Akt. These results indicate that the (2R,3R)-absolute configuration of (-)-enantiomers should be required for the preferential cytotoxicity through the inhibition of Akt activation.

  1. Application of Green Chemistry Principle in Synthesis of Phenytoin and Its Biogical Evaluation as Anticonvulsant Agents

    Directory of Open Access Journals (Sweden)

    Abhijit Kadam

    2011-01-01

    Full Text Available Phenytoin (5,5'-dipenylimidazolidine-2,4-dione is the prime example of anticonvulsant agent. According to reported procedure, it is synthesized by condensation of benzil and urea in presence of base (30% w/v NaOH using ethanol as solvent which itself acts as CNS stimulant. Removal of solvent after synthesis is most difficult and non-assured process. In case of phenytoin transformation in polymorphism plays an important role when solvent other than water is used. About 30% extra cost is calculated if solvent other than water is used. Therefore by application of green chemistry principle phenytoin was synthesized by condensation of benzil and urea in presence of base (30% NaOH and water as green solvent. This compound was characterized on the basis of its spectral (IR, 1H NMR data and evaluated for anticonvulsant activity using MES induced and PTZ induced seizure models in Swiss albino mice. Significant anticonvulsant activity was found by using 25 mg/kg and 50 mg/kg of phenytoin compared with standard phenytoin at 25 mg/kg dose.

  2. Anticonvulsant-induced rickets and nephrocalcinosis

    Science.gov (United States)

    Lau, Keith K; Papneja, Koyelle

    2012-01-01

    Reported here is the case of a severely disabled young girl who developed Fanconi syndrome secondary to long-term valproic acid administration, ultimately leading to hypophosphatemic rickets. Although nephrocalcinosis is not a common feature in patients with proximal tubulopathy, the patient presented also with this condition, and the concomitant use of another anticonvulsant might have potentiated this condition. The purpose of this report is to increase awareness among healthcare providers of such rare but significant complications associated with anticonvulsants. PMID:22665570

  3. Anticonvulsant profile of a balanced ketogenic diet in acute mouse seizure models.

    Science.gov (United States)

    Samala, Ramakrishna; Willis, Sarah; Borges, Karin

    2008-10-01

    Anticonvulsant effects of the ketogenic diet (KD) have been reported in the mouse, although previous studies did not control for intake of vitamins, minerals and antioxidants. The aim of this study was to examine the effects of balanced ketogenic and control diets in acute mouse seizure models. The behavior in four mouse seizure models, plasma d-beta-hydroxybutyrate (d-BHB) and glucose levels were determined after feeding control diet, 4:1 and 6:1 KDs with matched vitamins, minerals and antioxidants. Feeding 4:1 and 6:1 KDs ad lib to 3-week-old (adolescent) mice resulted in 1.2-2.2mM d-BHB in plasma, but did not consistently change glucose levels. The 6:1 KD reproducibly elevated the CC50 (current that initiates seizures in 50% mice tested) in the 6-Hz model after 14 days of feeding to adolescent CD1 mice. Higher plasma d-BHB levels correlated with anticonvulsant effects. Despite ketosis, no consistent anticonvulsant effects of KDs were found in the fluorothyl or pentylenetetrazole CD1 mouse models. The 4:1 KD was neither anticonvulsant nor neuroprotective in hippocampus in the C3H mouse kainate model. Taken together, the KD's anticonvulsant effect was limited to the 6-Hz model, required chronic feeding with 6:1 fat content, and was independent from lowering plasma glucose.

  4. Preclinical anticonvulsant and neuroprotective profile of 8319, a non-competitive NMDA antagonist

    International Nuclear Information System (INIS)

    Fielding, S.; Wilker, J.C.; Chernack, J.; Ramirez, V.; Wilmot, C.A.; Martin, L.L.; Payack, J.F.; Cornfeldt, M.L.; Rudolphi, K.A.; Rush, D.K.

    1990-01-01

    8319, ((+-)-2-Amino-N-ethyl-alpha-(3-methyl-2-thienyl)benzeneethanamine 2HCl), is a novel compound with the profile of a non-competitive NMDA antagonist. The compound displaced [3H] TCP with high affinity (IC50 = 43 nM), but was inactive at the NMDA, benzodiazepine and GABA sites; in vivo, 8319 showed good efficacy as an anticonvulsant and potential neuroprotective agent. It blocked seizures induced by NMDLA, supramaximal electroshock, pentylenetetrazol (PTZ), picrotoxin, and thiosemicarbazide with ED50's of 1-20 mg/kg ip. As a neuroprotective agent, 8319 (30-100 mg/kg sc) prevented the death of dorsal hippocampal pyramidal cells induced by direct injection of 20 nmol NMDA. At 15 mg/kg ip, the compound was also effective against hippocampal neuronal necrosis induced via bilateral occlusion of the carotid arteries in gerbils. In summary, 8319 is a noncompetitive NMDA antagonist with good anticonvulsant activity and may possess neuroprotective properties useful in the treatment of brain ischemia

  5. Lactation studies of anticonvulsants : A quality review

    NARCIS (Netherlands)

    van der Meer, Douwe H.; Wieringa, Andre; Wegner, Ilse; Wilffert, Bob; Ter Horst, Peter G.J.

    2015-01-01

    AIM: The aim of this review was to investigate the quality of the current literature on the transfer of anticonvulsants to breast milk to provide an overview of which anticonvulsants are in need of further research. METHODS: We reviewed the quality of the available lactation studies for 19

  6. Amino acid neurotransmitters and new approaches to anticonvulsant drug action.

    Science.gov (United States)

    Meldrum, B

    1984-01-01

    Amino acids provide the most universal and important inhibitory (gamma-aminobutyric acid (GABA), glycine) and excitatory (glutamate, aspartate, cysteic acid, cysteine sulphinic acid) neurotransmitters in the brain. An anticonvulsant action may be produced (1) by enhancing inhibitory (GABAergic) processes, and (2) by diminishing excitatory transmission. Possible pharmacological mechanisms for enhancing GABA-mediated inhibition include (1) GABA agonist action, (2) GABA prodrugs, (3) drugs facilitating GABA release from terminals, (4) inhibition of GABA-transaminase, (5) allosteric enhancement of the efficacy of GABA at the receptor complex, (6) direction action on the chloride ionophore, and (7) inhibition of GABA reuptake. Examples of these approaches include the use of irreversible GABA-transaminase inhibitors, such as gamma-vinyl GABA, and the development of anticonvulsant beta-carbolines that interact with the "benzodiazepine receptor." Pharmacological mechanisms for diminishing excitatory transmission include (1) enzyme inhibitors that decrease the maximal rate of synthesis of glutamate or aspartate, (2) drugs that decrease the synaptic release of glutamate or aspartate, and (3) drugs that block the post-synaptic action of excitatory amino acids. Compounds that selectively antagonise excitation due to dicarboxylic amino acids have recently been developed. Those that selectively block excitation produced by N-methyl-D-aspartate (and aspartate) have proved to be potent anticonvulsants in many animal models of epilepsy. This provides a novel approach to the design of anticonvulsant drugs.

  7. Staged anticonvulsant screening for chronic epilepsy

    OpenAIRE

    Berdichevsky, Yevgeny; Saponjian, Yero; Park, Kyung‐Il; Roach, Bonnie; Pouliot, Wendy; Lu, Kimberly; Swiercz, Waldemar; Dudek, F. Edward; Staley, Kevin J.

    2016-01-01

    Abstract Objective: Current anticonvulsant screening programs are based on seizures evoked in normal animals. One‐third of epileptic patients do not respond to the anticonvulsants discovered with these models. We evaluated a tiered program based on chronic epilepsy and spontaneous seizures, with compounds advancing from high‐throughput in vitro models to low‐throughput in vivo models. Methods: Epileptogenesis in organotypic hippocampal slice cultures was quantified by lactate production and l...

  8. Activity of the anticonvulsant lacosamide in experimental and human epilepsy via selective effects on slow Na+ channel inactivation.

    Science.gov (United States)

    Holtkamp, Dominik; Opitz, Thoralf; Niespodziany, Isabelle; Wolff, Christian; Beck, Heinz

    2017-01-01

    In human epilepsy, pharmacoresistance to antiepileptic drug therapy is a major problem affecting ~30% of patients with epilepsy. Many classical antiepileptic drugs target voltage-gated sodium channels, and their potent activity in inhibiting high-frequency firing has been attributed to their strong use-dependent blocking action. In chronic epilepsy, a loss of use-dependent block has emerged as a potential cellular mechanism of pharmacoresistance for anticonvulsants acting on voltage-gated sodium channels. The anticonvulsant drug lacosamide (LCM) also targets sodium channels, but has been shown to preferentially affect sodium channel slow inactivation processes, in contrast to most other anticonvulsants. We used whole-cell voltage clamp recordings in acutely isolated cells to investigate the effects of LCM on transient Na + currents. Furthermore, we used whole-cell current clamp recordings to assess effects on repetitive action potential firing in hippocampal slices. We show here that LCM exerts its effects primarily via shifting the slow inactivation voltage dependence to more hyperpolarized potentials in hippocampal dentate granule cells from control and epileptic rats, and from patients with epilepsy. It is important to note that this activity of LCM was maintained in chronic experimental and human epilepsy. Furthermore, we demonstrate that the efficacy of LCM in inhibiting high-frequency firing is undiminished in chronic experimental and human epilepsy. Taken together, these results show that LCM exhibits maintained efficacy in chronic epilepsy, in contrast to conventional use-dependent sodium channel blockers such as carbamazepine. They also establish that targeting slow inactivation may be a promising strategy for overcoming target mechanisms of pharmacoresistance. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  9. In silico validation and structure activity relationship study of a series of pyridine-3-carbohydrazide derivatives as potential anticonvulsants in generalized and partial seizures.

    Science.gov (United States)

    Sinha, Reema; Sara, Udai Vir Singh; Khosa, Ratan Lal; Stables, James; Jain, Jainendra

    2013-06-01

    A series of twelve compounds (Compounds RNH1-RNH12) of acid hydrazones of pyridine-3-carbohydrazide or nicotinic acid hydrazide was synthesized and evaluated for anticonvulsant activity by MES, scPTZ, minimal clonic seizure and corneal kindling seizure test. Neurotoxicity was also determined for these compounds by rotarod test. Results showed that halogen substitution at meta and para position of phenyl ring exhibited better protection than ortho substitution. Compounds RNH4 and RNH12, were found to be the active analogs displaying 6Hz ED50 of 75.4 and 14.77 mg/kg while the corresponding MES ED50 values were 113.4 and 29.3 mg/kg respectively. In addition, compound RNH12 also showed scPTZ ED50 of 54.2 mg/kg. In the series, compound RNH12 with trifluoromethoxy substituted phenyl ring was the most potent analog exhibiting protection in all four animal models of epilepsy. Molecular docking study has also shown significant binding interactions of these two compounds with 1OHV, 2A1H and 1PBQ receptors. Thus, N-[(meta or para halogen substituted) benzylidene] pyridine-3-carbohydrazides could be used as lead compounds in anticonvulsant drug design and discovery.

  10. Role of nitric oxide in additive anticonvulsant effects of agmatine and morphine.

    Science.gov (United States)

    Payandemehr, Borna; Rahimian, Reza; Bahremand, Arash; Ebrahimi, Ali; Saadat, Seyedehpariya; Moghaddas, Peiman; Fadakar, Kaveh; Derakhshanian, Hoda; Dehpour, Ahmad Reza

    2013-06-13

    The anticonvulsant effects of agmatine, an endogenous polyamine and a metabolite of l-arginine, have been shown in various experimental seizure models. Agmatine also potentiates the anti-seizure activity of morphine. The present study aimed to investigate a possible involvement of nitric oxide (NO) pathway in the protection by agmatine and morphine co-administration against pentylenetetrazole (PTZ) -induced seizure in male mice. To this end, the thresholds for the clonic seizures induced by the intravenous administration of PTZ, a GABA antagonist, were assessed. Intraperitoneal administration of morphine at lower dose (1mg/kg) increased the seizure threshold. Also intraperitoneal administration of agmatine (5 and 10mg/kg) increased the seizure threshold significantly. Combination of subeffective doses of morphine and agmatine led to potent anticonvulsant effects. Non-effective doses of morphine (0.1 and 0.5mg/kg) were able to induce anticonvulsant effects in mice pretreated with agmatine (3mg/kg). Concomitant administration of either the non-selective nitric oxide synthase (NOS) inhibitor L-NAME (1, 5mg/kg, i.p.) or the selective NOS inhibitor 7-NI (15, 30mg/kg, i.p.), with an ineffective combination of morphine (0.1mg/kg) plus agmatine (1mg/kg) produced significant anticonvulsant impacts. Moreover, the NO precursor, l-arginine (30, 60mg/kg, i.p.), inhibited the anticonvulsant action of agmatine (3mg/kg) plus morphine (0.5mg/kg) co-administration. Our results indicate that pretreatment of animals with agmatine enhances the anticonvulsant effects of morphine via a mechanism which may involve the NO pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. A Review of the Effect of Anticonvulsant Medications on Bone Mineral Density and Fracture Risk

    Science.gov (United States)

    Lee, Richard H.; Lyles, Kenneth W.; Colón-Emeric, Cathleen

    2011-01-01

    Background Osteoporosis and seizure disorders are common diagnoses in older adults and often occur concomitantly. Objective The goal of this review was to discuss the current hypothesis for the pathogenesis of anticonvulsant-induced bone density loss and the evidence regarding the risk for osteoporosis and fractures in older individuals. Methods A review of the literature was performed, searching in MEDLINE and CINAHL for articles published between 1990 and October 2009 with the following search terms: anticonvulsant OR antiepileptic; AND osteoporosis OR bone density OR fracture OR absorptiometry, photon. Studies within the pediatric population, cross-sectional studies, and studies whose results were published in a language other than English were excluded. Results A search of the published literature yielded >300 results, of which 24 met the inclusion and exclusion criteria and were included in this review. Hepatic enzyme induction by certain anticonvulsant medications appears to contribute to increased metabolism of 25-hydroxyvitamin D to inactive metabolites, which results in metabolic bone disease. There is increasing evidence that anticonvulsant use is associated with a higher risk of osteoporosis and clinical fractures, especially among older agents such as phenobarbital, carbamazepine, phenytoin, and valproate. Several observational studies suggest a class effect among anticonvulsant agents, associated with clinically significant reductions in bone mineral density and fracture risk. The use of anticonvulsant medications increases the odds of fracture by 1.2 to 2.4 times. However, only 2 large-scale observational studies have specifically examined the risk among those aged >65 years. This review also identified a randomized controlled trial whose results suggest that supplementation with high-dose vitamin D may be associated with increased bone mineral density in patients taking anticonvulsant medications. However, no randomized controlled trials

  12. Anticonvulsants and suicide attempts in bipolar I disorders.

    Science.gov (United States)

    Bellivier, F; Belzeaux, R; Scott, J; Courtet, P; Golmard, J-L; Azorin, J-M

    2017-05-01

    To identify risk factors for suicide attempts (SA) in individuals commencing treatment for a manic or mixed episode. A total of 3390 manic or mixed cases with bipolar disorder (BD) type I recruited from 14 European countries were included in a prospective, 2-year observational study. Poisson regression models were used to identify individual and treatment factors associated with new SA events. Two multivariate models were built, stratified for the presence or absence of prior SA. A total of 302 SA were recorded prospectively; the peak incidence was 0-12 weeks after commencing treatment. In cases with a prior history of SA, risk of SA repetition was associated with younger age of first manic episode (P = 0.03), rapid cycling (P anticonvulsant at study entry (P anticonvulsant at study entry (P = 0.002). The introduction of anticonvulsants for a recent-onset manic or mixed episode may be associated with an increased risk of SA. Further BD studies must determine whether this link is causal. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes.

    Science.gov (United States)

    Miller, J. A.; Richter, J. A.

    1985-01-01

    The effects of several anticonvulsant drugs on sodium-dependent high affinity choline uptake (HACU) in mouse hippocampal synaptosomes was investigated. HACU was measured in vitro after in vivo administration of the drug to mice. HACU was inhibited by drugs which have in common the ability to facilitate gamma-aminobutyric acid (GABA) transmission, pentobarbitone, phenobarbitone, barbitone, diazepam, chloridiazepoxide, and valproic acid. Dose-response relationships were determined for these drugs and the drugs' potencies at inhibiting HACU correlated well with their anticonvulsant potencies. Clonazepam, ethosuximide, carbamazepine, and barbituric acid had no effect on HACU in the doses used while phenytoin and trimethadione stimulated HACU. These results suggest that certain anticonvulsants may elicit a part of their anticonvulsant activity by modulating cholinergic neurones. This effect may be mediated through a GABA mechanism. PMID:3978310

  14. Anticonvulsant, anxiolytic and discriminative effects of the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX).

    Science.gov (United States)

    Swedberg, M D; Jacobsen, P; Honoré, T

    1995-09-01

    The anticonvulsant effects of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), phencyclidine (PCP) and diazepam against audiogenic seizures in DBA/2 mice and against seizures induced by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in NMRI mice were compared. Motor impairment was assessed in a rotarod apparatus in DBA/2 as well as NMRI mice. At 30 min after i.p. administration, NBQX was as effective as PCP and diazepam in protecting against audiogenic seizures and had a therapeutic ratio slightly higher than diazepam's and 7-fold higher than PCP's. Whereas diazepam was fully effective, NBQX and PCP were both ineffective against seizures induced by DMCM 30 min after i.p. administration. The anticonvulsant potential and motor-impairing effects of NBQX were evaluated further by the i.p. and the i.v. routes at different time points after administration. At all pretreatment intervals, NBQX protected against audiogenic seizures more potently than it produced motor impairment. NBQX administered i.p. protected against DMCM-induced seizures when given 15 min but not 5 min before testing, whereas after i.v. administration NBQX produced anticonvulsant and motor-impairing effects in the same dose range. NBQX only slightly and non-dose-dependently attenuated the discriminative effects of pentylenetetrazole in rats, showing a limited anxiolytic potential. NBQX produced no PCP-like or morphine-like discriminative effects in rats, suggesting lack of PCP or opiate-like subjective effects. These data demonstrate that NBQX has anticonvulsant effects, has limited anxiolytic effects, and does not produce subjective effects of PCP or opiate type.

  15. Anticonvulsants for tinnitus.

    NARCIS (Netherlands)

    Hoekstra, C.E.; Rynja, S.P.; Zanten, G.A.; Rovers, M.M.

    2011-01-01

    BACKGROUND: Tinnitus is the perception of sound or noise in the absence of an external or internal acoustic stimulation. It is a common and potentially distressing symptom for which no adequate therapy exists. OBJECTIVES: To assess the effectiveness of anticonvulsants in patients with chronic

  16. The efficacy and safety of newer anticonvulsants in patients with dementia.

    Science.gov (United States)

    Dolder, Christian R; Nealy, Kimberly L

    2012-08-01

    Anticonvulsants are a class of medications that have received considerable interest as possible treatments in patients with behavioural disturbances in dementia. The role of these medications for such a use remains controversial. The current paper reviews the published evidence surrounding the safety and efficacy (i.e. as a behavioural and cognitive treatment) of newer anticonvulsants in patients with dementia. A MEDLINE, International Pharmaceutical Abstracts, PsycINFO and clinicaltrials.gov search through to December 2011 was conducted for anticonvulsants that have received regulatory approval since 1996. Studies reporting behavioural or cognitive outcomes in patients with dementia were included. Nine trials involving only four medications met selection criteria and were included: levetiracetam (n = 4), oxcarbazepine (n = 1), topiramate (n = 2) and zonisamide (n = 2). Levetiracetam may have a role in the treatment of behavioural symptoms in dementia but study limitations substantially hinder the strength of such a recommendation. Oxcarbazepine and topiramate, based on limited data, do not appear to be effective treatments of behavioural symptoms in dementia. A lack of trials do not allow for conclusions to be made regarding zonisamide. From a cognitive standpoint, levetiracetam was the anticonvulsant most examined in patients with dementia, it appears to have less deleterious effects than some anticonvulsants. Limited data are available on the safety of these medications in elderly patients; however, studies completed thus far have demonstrated some adverse events that are more common or problematic with the use of these drugs in this patient population (i.e. somnolence, dizziness, hyponatraemia, weight loss).

  17. Anticonvulsant and Neuroprotective Activities of Phragmanthera austroarabica Extract in Pentylenetetrazole-Kindled Mice

    Directory of Open Access Journals (Sweden)

    Hibah M. Aldawsari

    2017-01-01

    Full Text Available Anticonvulsant and neuroprotective activity of Phragmanthera austroarabica extract were tested in pentylenetetrazole-kindled mice. All the chemical constituents of the plant extract were identified. Additionally, the extract was standardized and proved to contain total phenolic contents equal to 379.92±1.32 mg gallic acid equivalents/g dry plant extract. Induction of kindling was achieved by repeated intraperitoneal administration of pentylenetetrazole (35 mg/kg twice weekly. Male albino mice were given P. austroarabica extract (200, 400, or 800 mg/kg. The two higher doses (400 or 800 mg/kg of the extract significantly caused notable reduction in seizure activity and hippocampal malondialdehyde level compared to pentylenetetrazole control group. The highest dose enhanced cortical GSH level and showed intact DNA in the laddering assay. Upon studying the neuroprotective effect, mice treated with the higher dose of the extract demonstrated an improvement in the percent of surviving neurons in the cortex and hippocampus. We concluded that P. austroarabica extract ameliorated seizure activity and protected cortical and hippocampal neurons against pentylenetetrazole-induced kindling in mice.

  18. Anticonvulsant potentials of ethanolic extract of Eleusine indica

    Directory of Open Access Journals (Sweden)

    Ette Okon Ettebong

    2016-11-01

    Full Text Available Objective: To assess the anticonvulsant potentials of ethanolic extract of Eleusine indica. Methods: Albino Wistar mice were separated into five groups with six animals in each group and thereafter pretreated with distilled water, various doses of the extract (200–600 mg/kg and standard drug diazepam (0.5 mg/kg. Thirty minutes later, pentylenetetrazole (70 mg/kg, aminophylline (280 mg/kg and isoniazid (250 mg/kg were used to induce convulsions by intraperitoneal administration. These mice were then placed in plexiglas cages and monitored for the occurrence of seizures over a thirty-minute time period. The latency of convulsions, duration of tonic convulsions and mortality protection were recorded. Data obtained were analyzed using GraphPad InStat 3.10. Results: The results showed that the extract exhibited a dose-dependent increase in the latency of clonic convulsions and decrease in duration of tonic convulsions as compared to the control and these effects were statistically significant (P < 0.001. The extract also provided protection against the mortality which was similar to that produced by the standard drug diazepam. Conclusions: The significant increase in the latency of clonic convulsions and decrease in duration of tonic convulsions caused by the extract show anticonvulsant activity and corroborate with the claims of the traditional use of the plant as an anticonvulsant remedy.

  19. Activation of voltage-gated KCNQ/Kv7 channels by anticonvulsant retigabine attenuates mechanical allodynia of inflammatory temporomandibular joint in rats

    Directory of Open Access Journals (Sweden)

    Xu Wen

    2010-08-01

    Full Text Available Abstract Background Temporomandibular disorders (TMDs are characterized by persistent orofacial pain and have diverse etiologic factors that are not well understood. It is thought that central sensitization leads to neuronal hyperexcitability and contributes to hyperalgesia and spontaneous pain. Nonsteroidal anti-inflammatory drugs (NSAIDs are currently the first choice of drug to relieve TMD pain. NSAIDS were shown to exhibit anticonvulsant properties and suppress cortical neuron activities by enhancing neuronal voltage-gated potassium KCNQ/Kv7 channels (M-current, suggesting that specific activation of M-current might be beneficial for TMD pain. Results In this study, we selected a new anticonvulsant drug retigabine that specifically activates M-current, and investigated the effect of retigabine on inflammation of the temporomandibular joint (TMJ induced by complete Freund's adjuvant (CFA in rats. The results show that the head withdrawal threshold for escape from mechanical stimulation applied to facial skin over the TMJ in inflamed rats was significantly lower than that in control rats. Administration of centrally acting M-channel opener retigabine (2.5 and 7.5 mg/kg can dose-dependently raise the head withdrawal threshold of mechanical allodynia, and this analgesic effect can be reversed by the specific KCNQ channel blocker XE991 (3 mg/kg. Food intake is known to be negatively associated with TMJ inflammation. Food intake was increased significantly by the administration of retigabine (2.5 and 7.5 mg/kg, and this effect was reversed by XE991 (3 mg/kg. Furthermore, intracerebralventricular injection of retigabine further confirmed the analgesic effect of central retigabine on inflammatory TMJ. Conclusions Our findings indicate that central sensitization is involved in inflammatory TMJ pain and pharmacological intervention for controlling central hyperexcitability by activation of neuronal KCNQ/M-channels may have therapeutic potential for

  20. Convulsions induced by centrally administered NMDA in mice: effects of NMDA antagonists, benzodiazepines, minor tranquilizers and anticonvulsants.

    Science.gov (United States)

    Moreau, J. L.; Pieri, L.; Prud'hon, B.

    1989-01-01

    1. Convulsions were induced reproducibly by intracerebroventricular injection of N-methyl-D-aspartic acid (NMDA) to conscious mice. 2. Competitive (carboxypiperazine-propylphosphonic acid, CPP; 2-amino-7-phosphonoheptanoic acid, AP7) and non-competitive (MK801; phencyclidine, PCP; thienylcyclohexylpiperidine, TCP; dextrorphan; dextromethorphan) NMDA antagonists prevented NMDA-induced convulsions. 3. Benzodiazepine receptor agonists and partial agonists (triazolam, diazepam, clonazepam, Ro 16-6028), classical anticonvulsants (diphenylhydantoin, phenobarbitone, sodium valproate) and meprobamate were also found to prevent NMDA-induced convulsions. 4. Flumazenil (a benzodiazepine receptor antagonist) and the GABA agonists THIP and muscimol (up to subtoxic doses) were without effect. 5. Flumazenil reversed the anticonvulsant action of diazepam, but not that of MK801. 6. Results obtained in this model differ somewhat from those described in a seizure model with systemic administration of NMDA. An explanation for this discrepancy is offered. 7. This model is a simple test for assessing the in vivo activity of NMDA antagonists and also expands the battery of chemically-induced seizure models for characterizing anticonvulsants not acting at NMDA receptors. PMID:2574061

  1. Synthesis and nootropic activity of some 2,3-dihydro-1H-isoindol-1-one derivatives structurally related with piracetam.

    Science.gov (United States)

    Reyes, Adelfo; Huerta, Leticia; Alfaro, Marisol; Navarrete, Andrés

    2010-11-01

    Three 2,3-dihydro-1H-isoindol-1-ones structurally related with piracetam (=2-oxopyrrolidine-1-acetamide) have been synthesized and tested for their nootropic effects in the passive avoidance test in mice. Compounds (RS)-2, (R,R)-3, and (R,S)-3 were obtained in good yields in only two steps starting from methyl DL-phthaloylalanine. Compound (RS)-2 exhibited nootropic activity at lower doses than piracetam, used as reference drug, but it showed lower efficacy. Whereas diastereoisomers (R,R)-3 and (R,S)-3 were as potent as piracetam to revert amnesia induced by scopolamine, (R,S)-3 showed lower efficacy than (R,R)-3. Only (R,R)-3 showed myorelaxant effect at doses of 10 and 30 mg/kg; other compounds did not exhibit any anticonvulsant, sedative, myorelaxant, or impaired motor-coordination effect in mice. These synthesized 2,3-dihydro-1H-isoindol-1-one derivatives constitute a new kind of nootropic compounds.

  2. In vivo antinociceptive and anticonvulsant activity of extracts of Heliotropium strigosum.

    Science.gov (United States)

    Khan, Haroon; Khan, Murad Ali; Hussain, Sajid; Gaffar, Rukhsana; Ashraf, Nadeem

    2016-05-01

    Natural healing agents are primarily focused to overcome unwanted side effects with synthetic drugs worldwide. In the proposed study, crude extracts and subsequent solvent fractions of Heliotropium strigosum were evaluated for antinociceptive and anticonvulsant activity in animal paradigms. In post acetic acid-induced writhing test, crude extract and fractions (hexane, ethyl acetate, and aqueous) demonstrated marked attenuation of nociception at test doses (50, 100, and 200 mg/kg i.p.). When challenged against thermally induced pain model, pretreatment of extracts exhibited prominent amelioration at test dose (50, 100, and 200 mg/kg i.p.). In both tests, inhibition of noxious stimulation was in a dose-dependent manner, and ethyl acetate fraction was most dominant. However, extracts did not antagonize the seizures and mortality induced by pentylenetetrazole. In conclusion, the extracts of H. strigosum illustrated significant antinociceptive effect in both centrally and peripherally acting pain models. © The Author(s) 2013.

  3. Anticonvulsants to treat post-traumatic stress disorder.

    Science.gov (United States)

    Wang, Hee Ryung; Woo, Young Sup; Bahk, Won-Myong

    2014-09-01

    We reviewed the existing literature on the efficacy of anticonvulsants in treating post-traumatic stress disorder. We performed a literature search using PubMed, EMBASE and the Cochrane database on 30 September 2013. Randomized,controlled studies that investigated the efficacy of anticonvulsants for post-traumatic stress disorder were included in this review. Studies with retrospective designs, case reports and case series were excluded. A total of seven studies met the inclusion criteria for this review. Three studies used topiramate with negative findings regarding its efficacy. Two studies used divalproex, both of which failed to show superiority over placebo. One study used lamotrigine, with favourable results, and one study used tiagabine, with negative results. Future long-term studies with larger sample sizes are needed to investigate the clinical utility of anticonvulsants for posttraumatic stress disorder treatment.

  4. Anticonvulsant and Anxiolytic Properties of the Roots of Grewia ...

    African Journals Online (AJOL)

    Materials and Methods: The ethanolic extract of the root of G. bicolourat (200, 400 and 800 mg/kg, i.p was studied for its anticonvulsant effect on four in vivo rat models (Maximal Electroshock Seizure (MES), Pentylenetetrazole (PTZ)-, picrotoxin (PIC)- and Strychnine (STR) - induced seizures). Simple activity meter was used ...

  5. SYNTHESIS AND STUDY OF HALOGENATED BENZYLAMIDES OF SOME ISOCYCLIC AND HETEROCYCLIC ACIDS AS POTENTIAL ANTICONVULSANTS.

    Science.gov (United States)

    Strupińska, Marzanna; Rostafińska-Suchar, Grażyna; Pirianowicz-Chaber, Elżbieta; Grabczuk, Mateusz; Józwenko, Magdalena; Kowalczyk, Hubert; Szuba, Joanna; Wójcicka, Monika; Chen, Tracy; Mazurek, Aleksander P

    2015-01-01

    A series of potential anticonvulsants have been synthesized. There are eight fluorobenzylamides and three chlorobenzylamides of isocyclic or heterocyclic acids. Two not halogenated benzylamides were also synthesized to compare the effect of halogenation. The aim of the research performed was to evaluate whether halogenation of the mother structure is able to improve its anticonvulsant activity. The compounds were tested in Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Compound 1 showed MES ED50 = 80.32 mg/kg, PI = 3.16. Compound 7 showed CKM ED50 = 56.72 mg/kg. Compound 8 showed MES ED50 = 34.23 mg/kg and scPTZ ED50 > 300 mg/kg, PI = 8.53.Compound 13 showed 6Hz ED50 = 78.96, PI = 3.37. The results indicate that fluorination does not improve activity, whereas chlorination in our experiment even reduces it.

  6. Structural Exploration of Quinazolin-4(3H)-ones as Anticonvulsants: Rational Design, Synthesis, Pharmacological Evaluation, and Molecular Docking Studies.

    Science.gov (United States)

    Ugale, Vinod G; Bari, Sanjay B

    2016-11-01

    Anticonvulsants effective against multiple seizures are of wide interest as antiepileptic drugs, especially if active against pharmaco-resistant seizures. Herein, we synthesized 16 different, rationally designed 2-((6,7-dimethoxy-4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-N-(substituted phenyl)acetamides and screened for anticonvulsant activities through in vivo experiments. Compound 4d emerged as prototype with excellent anti-seizure action in mice against electroshock, chemically induced and pharmaco-resistant 6-Hz seizure models with no symptoms of neurotoxicity and hepatotoxicity (ED 50  = 23.5 mg/kg, MES, mice, i.p.; ED 50  = 32.6 mg/kg, scPTZ, mice, i.p.; ED 50  = 45.2 mg/kg, 6-Hz, mice, i.p.; TD 50  = 325.9 mg/kg, mice, i.p.). In addition, investigation of compound 4l in mice for its pharmacological profile proved it as safer anticonvulsant, devoid of the side effects such as motor dysfunction and hepatotoxicity of classical antiepileptic drugs (ED 50  = 26.1 mg/kg, MES, mice, i.p.; ED 50  = 79.4 mg/kg, scPTZ, mice, i.p.; TD 50  = 361.2 mg/kg, mice, i.p.). We also predicted physiochemical and pharmacokinetic properties of structurally optimized quinazolin-4(3H)-ones by a computational protocol. A combination of in vivo anticonvulsant profile, ex vivo toxicity, and in silico studies suggested that the synthesized compounds may be useful as broad-spectrum anti-seizure drug candidates with favorable pharmacokinetic parameters. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Melatonin potentiates the anticonvulsant action of phenobarbital in neonatal rats.

    Science.gov (United States)

    Forcelli, Patrick A; Soper, Colin; Duckles, Anne; Gale, Karen; Kondratyev, Alexei

    2013-12-01

    Phenobarbital is the most commonly utilized drug for neonatal seizures. However, questions regarding safety and efficacy of this drug make it particularly compelling to identify adjunct therapies that could boost therapeutic benefit. One potential adjunct therapy is melatonin. Melatonin is used clinically in neonatal and pediatric populations, and moreover, it exerts anticonvulsant actions in adult rats. However, it has not been previously evaluated for anticonvulsant effects in neonatal rats. Here, we tested the hypothesis that melatonin would exert anticonvulsant effects, either alone, or in combination with phenobarbital. Postnatal day (P)7 rats were treated with phenobarbital (0-40mg/kg) and/or melatonin (0-80mg/kg) prior to chemoconvulsant challenge with pentylenetetrazole (100mg/kg). We found that melatonin significantly potentiated the anticonvulsant efficacy of phenobarbital, but did not exert anticonvulsant effects on its own. These data provide additional evidence for the further examination of melatonin as an adjunct therapy in neonatal/pediatric epilepsy. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. The psychopharmacology of aggressive behavior: a translational approach: part 2: clinical studies using atypical antipsychotics, anticonvulsants, and lithium.

    Science.gov (United States)

    Comai, Stefano; Tau, Michael; Pavlovic, Zoran; Gobbi, Gabriella

    2012-04-01

    Patients experiencing mental disorders are at an elevated risk for developing aggressive behavior. In the past 10 years, the psychopharmacological treatment of aggression has changed dramatically owing to the introduction of atypical antipsychotics on the market and the increased use of anticonvulsants and lithium in the treatment of aggressive patients.This review (second of 2 parts) uses a translational medicine approach to examine the neurobiology of aggression, discussing the major neurotransmitter systems implicated in its pathogenesis (serotonin, glutamate, norepinephrine, dopamine, and γ-aminobutyric acid) and the neuropharmacological rationale for using atypical antipsychotics, anticonvulsants, and lithium in the therapeutics of aggressive behavior. A critical review of all clinical trials using atypical antipsychotics (aripiprazole, clozapine, loxapine, olanzapine, quetiapine, risperidone, ziprasidone, and amisulpride), anticonvulsants (topiramate, valproate, lamotrigine, and gabapentin), and lithium are presented. Given the complex, multifaceted nature of aggression, a multifunctional combined therapy, targeting different receptors, seems to be the best strategy for treating aggressive behavior. This therapeutic strategy is supported by translational studies and a few human studies, even if additional randomized, double-blind, clinical trials are needed to confirm the clinical efficacy of this framework.

  9. Evaluation of anticonvulsant effects of methanolic extract of Olax ...

    African Journals Online (AJOL)

    Anticonvulsant activity of MEOS was evaluated in chicks using maximal electroshock test, and in mice using pentylenetetrazole and strychnine-induced seizure models at doses of 100, 200 and 400 mg/kg. The intraperitoneal median lethal dose of MEOS was estimated to be 3800 mg/kg body weight in mice. MEOS at doses ...

  10. Imidazole incorporated semicarbazone derivatives as a new class of anticonvulsants: design, synthesis and in-vivo screening.

    Science.gov (United States)

    Amir, Mohammad; Ali, Israr; Hassan, Mohd Zaheen

    2013-06-01

    A series of novel imidazole incorporated semicarbazones was synthesized using an appropriate synthetic route and characterized by spectral analysis (IR, 1H NMR, 13C NMR and Mass). The anticonvulsant activity of the synthesized compounds was determined using doses of 30, 100, and 300 mg kg-1 against maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) induced seizure and minimal neurotoxicity test. Six compounds exhibited protection in both models and 2-(1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene)-N-p-tolylsemicarbazone emerged as the most active compound of the series without any neurotoxicity and significant CNS depressant effect. Liver enzyme estimations (SGOT, SGPT, Alkaline phosphatase) of the compound also showed no significant change in the enzymes levels. Moreover, it caused 80% elevation of γ-amino butyric acid (GABA) levels in the whole mice brain, thus indicating that it could be a promising candidate in designing of a potent anticonvulsant drug.

  11. Evaluation of Anti-Convulsant Activity of Methanolic Extract of Seeds of Cassia Fistula against Pentylenetetrazole induced convulsions in mice

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    Nilesh P. Sawadadkar

    2014-06-01

    Full Text Available Cassia Fistula is a popular Indian herb which is used as tonic, laxative, anti-pyretic, astringent, febrifuge, strong purgative etc. The aim of present study was to evaluate anticonvulsant activity of methanolic extract of seeds of Cassia Fistula against pentylenetetrazol (PTZ induced convulsions in mice. All the animals were divided into four groups of six mice each and were injected PTZ (60mg/kg intraperitonially Group I was served as toxic control, Group II was pretreated with  Gabapentin (200mg/kg P.O.. Group III was pretreated with  methanolic extract of seeds of Cassia Fistula (100 mg/kg P.O. for 7 days. Group IV was pretreated with  methanolic extract of seeds of Cassia Fistula (200mg/kg P.O. for 7 days.The result shows that methanolic extract of seeds of Cassia Fistula significantly reduced duration of clonic convulsions and also delayed the onset of convulsions induced by pentylenetetrazol. The result was expressed as mean ± SEM and were statistically analyzed by one way ANOVA. It is concluded that methanolic extract of seeds of Cassia Fistula can show anticonvulsant activity against pentylenetetrazol induced convulsions in mice.

  12. Synthesis, and anticonvulsant activity of new amides derived from 3-methyl- or 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids.

    Science.gov (United States)

    Obniska, Jolanta; Rapacz, Anna; Rybka, Sabina; Góra, Małgorzata; Kamiński, Krzysztof; Sałat, Kinga; Żmudzki, Paweł

    2016-04-15

    This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6 Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED50=32.08 mg/kg, MES test) and 9 (ED50=40.34 mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action. Copyright © 2016. Published by Elsevier Ltd.

  13. Non-imidazole-based histamine H3 receptor antagonists with anticonvulsant activity in different seizure models in male adult rats

    Directory of Open Access Journals (Sweden)

    Sadek B

    2016-11-01

    Full Text Available Bassem Sadek,1 Ali Saad,1 Gniewomir Latacz,2 Kamil Kuder,2 Agnieszka Olejarz,2 Tadeusz Karcz,2 Holger Stark,3 Katarzyna Kieć-Kononowicz2 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland; 3Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Düsseldorf, Germany Abstract: A series of twelve novel non-imidazole-based ligands (3–14 was developed and evaluated for its in vitro binding properties at the human histamine H3 receptor (hH3R. The novel ligands were investigated for their in vivo protective effects in different seizure models in male adult rats. Among the H3R ligands (3–14 tested, ligand 14 showed significant and dose-dependent reduction in the duration of tonic hind limb extension in maximal electroshock (MES-induced seizure model subsequent to acute systemic administration (5, 10, and 20 mg/kg, intraperitoneally, whereas ligands 4, 6, and 7 without appreciable protection in MES model were most promising in pentylenetetrazole (PTZ model. Moreover, the protective effect observed for ligand 14 in MES model was lower than that observed for the reference drug phenytoin and was entirely abrogated when rats were co-administered with the brain-penetrant H1R antagonist pyrilamine (PYR but not the brain-penetrant H2R antagonist zolantidine (ZOL, demonstrating that histaminergic neurotransmission by activation of postsynaptically located H1Rs seems to be involved in the protective action. On the contrary, PYR and ZOL failed to abrogate the full protection provided by 4 in PTZ model and the moderate protective effect by 14 in strychnine (STR model. Moreover, the experimental and in silico estimation of properties such as metabolism was

  14. Antinociceptive and anticonvulsant effects of the monoterpene linalool oxide.

    Science.gov (United States)

    Souto-Maior, Flávia Negromonte; Fonsêca, Diogo Vilar da; Salgado, Paula Regina Rodrigues; Monte, Lucas de Oliveira; de Sousa, Damião Pergentino; de Almeida, Reinaldo Nóbrega

    2017-12-01

    Linalool oxide (OXL) (a monoterpene) is found in the essential oils of certain aromatic plants, or it is derived from linalool. The motivation for this work is the lack of psychopharmacological studies on this substance. To evaluate OXL's acute toxicity, along with its anticonvulsant and antinociceptive activities in male Swiss mice. OXL (50, 100 and 150 mg/kg, i.p.) was investigated for acute toxicity and in the Rota-rod test. Antinociceptive activity was evaluated by the acetic acid-induced writhing test, and by formalin testing. Anticonvulsant effects were demonstrated by testing for pentylenetetrazol (PTZ)-induced seizures and by Maximum Electroshock headset (MES) test. OXL was administered to the animals intraperitoneally 30 min before for pharmacological tests. OXL showed an LD 50 of ∼721 (681-765) mg/kg. In the Rota-rod test, it was observed that OXL caused no damage to the animal's motor coordination. OXL significantly reduced (p monoterpene may lead to the development of a new molecule with even higher potency and selectivity.

  15. Prophylactic antibiotics and anticonvulsants in neurosurgery.

    Science.gov (United States)

    Ratilal, B; Sampaio, C

    2011-01-01

    The prophylactic administration of antibiotics to prevent infection and the prophylactic administration of anticonvulsants to prevent first seizure episodes are common practice in neurosurgery. If prophylactic medication therapy is not indicated, the patient not only incurs the discomfort and the inconvenience resulting from drug treatment but is also unnecessarily exposed to adverse drug reactions, and incurs extra costs. The main situations in which prophylactic anticonvulsants and antibiotics are used are described and those situations we found controversial in the literature and lack further investigation are identified: anticonvulsants for preventing seizures in patients with chronic subdural hematomas, antiepileptic drugs for preventing seizures in those suffering from brain tumors, antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures, and antibiotic prophylaxis for the surgical introduction of intracranial ventricular shunts.In the following we present systematic reviews of the literature in accordance with the standard protocol of The Cochrane Collaboration to evaluate the effectiveness of the use of these prophylactic medications in the situations mentioned. Our goal was to efficiently integrate valid information and provide a basis for rational decision-making.

  16. Anticonvulsants Based on the α-Substituted Amide Group Pharmacophore Bind to and Inhibit Function of Neuronal Nicotinic Acetylcholine Receptors.

    Science.gov (United States)

    Krivoshein, Arcadius V

    2016-03-16

    Although the antiepileptic properties of α-substituted lactams, acetamides, and cyclic imides have been known for over 60 years, the mechanism by which they act remains unclear. I report here that these compounds bind to the nicotinic acetylcholine receptor (nAChR) and inhibit its function. Using transient kinetic measurements with functionally active, nondesensitized receptors, I have discovered that (i) α-substituted lactams and cyclic imides are noncompetitive inhibitors of heteromeric subtypes (such as α4β2 and α3β4) of neuronal nAChRs and (ii) the binding affinity of these compounds toward the nAChR correlates with their potency in preventing maximal electroshock (MES)-induced convulsions in mice. Based on the hypothesis that α-substituted amide group is the essential pharmacophore of these drugs, I found and tested a simple compound, 2-phenylbutyramide. This compound indeed inhibits nAChR and shows good anticonvulsant activity in mice. Molecular docking simulations suggest that α-substituted lactams, acetamides, and cyclic imides bind to the same sites on the extracellular domain of the receptor. These new findings indicate that inhibition of brain nAChRs may play an important role in the action of these antiepileptic drugs, a role that has not been previously recognized.

  17. A systematic review on the role of anticonvulsants in the treatment of acute bipolar depression.

    Science.gov (United States)

    Reinares, María; Rosa, Adriane R; Franco, Carolina; Goikolea, José Manuel; Fountoulakis, Kostas; Siamouli, Melina; Gonda, Xenia; Frangou, Sophia; Vieta, Eduard

    2013-03-01

    Despite the high morbidity and mortality associated with bipolar depression, the optimal treatment for this phase is still a matter of debate. The aim of the current review was to provide updated evidence about the efficacy and tolerability of anticonvulsants in the treatment of acute bipolar depression. A comprehensive review of randomized controlled trials (RCTs) evaluating the use of anticonvulsants for the treatment of acute bipolar depression up to June 2011 was conducted by means of the PubMed-Medline database. Eligibility criteria included active comparator-controlled or placebo-controlled randomized studies involving monotherapy or combination therapy. A total of 18 RCTs fulfilled the inclusion criteria. Studies supported the efficacy of divalproex as monotherapy in acute bipolar depression but small sample size was a common methodological limitation. Findings were inconclusive for lamotrigine and carbamazepine although overall lamotrigine may have a beneficial but modest effect. Negative results were found for levetiracetam and gabapentin but the evidence base on these agents is scant. All anticonvulsants were generally well tolerated. No double-blind RCTs were found for the use of other anticonvulsants such as oxcarbazepine, licarbazepine, zonisamide, retigabine, pregabalin, tiagabine, felbamate and vigabatrine in the acute treatment of bipolar depression. To sum up, taking into consideration the efficacy and tolerability profiles of anticonvulsants, current evidence supports the use of divalproex and lamotrigine in the treatment of acute bipolar depression. However, available data for most other anticonvulsants are inconclusive and further RCTs with larger sample sizes are needed before drawing firm conclusions.

  18. Studsvik's R2 reactor - Review of activities

    Energy Technology Data Exchange (ETDEWEB)

    Grounes, Mikael; Tomani, Hans; Graeslund, Christian; Rundquist, Hans; Skoeld, Kurt [Studsvik Nuclear AB, Nykoeping (Sweden)

    1993-07-01

    A general description of the R2 reactor, its associated facilities and its history is given. The facilities and range of work are described for the following types of activities: fuel testing, materials testing, neutron transmutation doping of silicon, activation analysis, radioisotope production and basic research including thermal neutron scattering, nuclear chemistry and neutron capture radiography. (author)

  19. Synthesis, Biological Activity, and Docking Study of Novel Isatin Coupled Thiazolidin-4-one Derivatives as Anticonvulsants.

    Science.gov (United States)

    Nikalje, Anna P; Ansari, Altamash; Bari, Sanjay; Ugale, Vinod

    2015-06-01

    A series of 2-(substituted-phenyl)-3-(2-oxoindolin-3-ylidene)amino)-thiazolidin-4-one derivatives were designed and synthesized under microwave irradiation, using an eco-friendly, efficient, microwave-assisted synthetic protocol that involves cyclocondensation of 3-substituted benzylidine-hydrazono-indolin-2-one 3a-j with thioglycolic acid in dimethyl formamide (DMF) as solvent and anhydrous zinc chloride as a catalyst, keeping in view the structural requirement of the pharmacophore. The intermediate compounds 3a-j were obtained by condensation of the hydrazone of indoline-2,3-dione with aromatic aldehydes. The synthesized derivatives were evaluated for CNS depressant activity and anticonvulsant activity in mice using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (sc-PTZ) induced seizure tests. All the derivatives showed good CNS depressant activity and showed protection in the MES test, indicative of their ability to inhibit the seizure spread. A histopathological study was performed to evaluate liver toxicity caused by the synthesized compounds. The compounds were nontoxic. A computational study was performed, in which log P values were calculated experimentally. Virtual screening was performed by molecular docking of the designed compounds into the ATP binding sites of the NMDA and AMPA receptors, to predict if these compounds have analogous binding modes. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. 2-Methylpyridinium/pyridinium 5-(2,4-dinitrophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olates as potent anticonvulsant agents—synthesis and crystal structure

    Energy Technology Data Exchange (ETDEWEB)

    Mangaiyarkarasi, G.; Kalaivani, D., E-mail: kalaivbalaj@yahoo.co.in [Affiliated to Bharathidasan University, Post Graduate and Research Department of Chemistry, Seethalakshmi Ramaswami College, Tiruchirappalli-620 002 (India)

    2013-12-15

    The molecular salt, 2-methylpyridinium 5-(2,4-dinitrophenyl)-2,6-dioxo-1,2,3,6-tetrahydropy-rimidin-4-olate) (I), is prepared from the ethanolic solution of 1-chloro-2,4-dinitrobenzene, pyrimidine-2,4,6-(1H,3H,5H)-trione (barbituric acid) and 2-methylpyridine at room temperature, and the molecular salt, pyridinium 5-(2,4-dinitrophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate (II), is prepared from the same reactants, by dissolving them in hot DMSO and ethanol mixture at 70°C. The structures of I and II are characterized by visible, IR, {sup 1}H-NMR, {sup 13}C-NMR and elemental analysis and confirmed by single crystal X-ray analysis. Both the salts crystallize in triclinic crystal system with sp. gr. P-bar1. They possess noticeable anticonvulsant activity even at low concentration (25 mg/kg). Acute toxicity studies of these complexes indicate that LD{sub 50} values are greater than 1500 mg/kg and the tested animals do not show any behavioural changes.

  1. 2-Methylpyridinium/pyridinium 5-(2,4-dinitrophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olates as potent anticonvulsant agents—synthesis and crystal structure

    International Nuclear Information System (INIS)

    Mangaiyarkarasi, G.; Kalaivani, D.

    2013-01-01

    The molecular salt, 2-methylpyridinium 5-(2,4-dinitrophenyl)-2,6-dioxo-1,2,3,6-tetrahydropy-rimidin-4-olate) (I), is prepared from the ethanolic solution of 1-chloro-2,4-dinitrobenzene, pyrimidine-2,4,6-(1H,3H,5H)-trione (barbituric acid) and 2-methylpyridine at room temperature, and the molecular salt, pyridinium 5-(2,4-dinitrophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate (II), is prepared from the same reactants, by dissolving them in hot DMSO and ethanol mixture at 70°C. The structures of I and II are characterized by visible, IR, 1 H-NMR, 13 C-NMR and elemental analysis and confirmed by single crystal X-ray analysis. Both the salts crystallize in triclinic crystal system with sp. gr. P-bar1. They possess noticeable anticonvulsant activity even at low concentration (25 mg/kg). Acute toxicity studies of these complexes indicate that LD 50 values are greater than 1500 mg/kg and the tested animals do not show any behavioural changes

  2. Pixe analysis of trace elements in tissues of rats treated with anticonvulsants

    Science.gov (United States)

    Hurd, R. W.; Van Rinsvelt, H. A.; Kinyua, A. M.; O'Neill, M. P.; Wilder, B. J.; Houdayer, A.; Hinrichsen, P. F.

    1987-04-01

    Several lines of evidence implicate metals in epilepsy. Anticonvulsant drugs are noted to alter levels of metals in humans and animals. PIXE analysis was used to investigate effects of three anticonvulsant drugs on tissue and brain cortex trace elements. The content of zinc and copper was increased in liver and spleen of rats treated with anticonvulsants while selenium was decreased in cortex.

  3. PIXE analysis of trace elements in tissues of rats treated with anticonvulsants

    Energy Technology Data Exchange (ETDEWEB)

    Hurd, R.W.; Van Rinsvelt, H.A.; Kinyua, A.M.; O' Neill, M.P.; Wilder, B.J.; Houdayer, A.; Hinrichsen, P.F.

    1987-04-01

    Several lines of evidence implicate metals in epilepsy. Anticonvulsant drugs are noted to alter levels of metals in humans and animals. PIXE analysis was used to investigate effects of three anticonvulsant drugs on tissue and brain cortex trace elements. The content of zinc and copper was increased in liver and spleen of rats treated with anticonvulsants while selenium was decreased in cortex.

  4. PIXE analysis of trace elements in tissues of rats treated with anticonvulsants

    International Nuclear Information System (INIS)

    Hurd, R.W.; Van Rinsvelt, H.A.; Kinyua, A.M.; O'Neill, M.P.; Wilder, B.J.; Florida Univ., Gainesville; Houdayer, A.; Hinrichsen, P.F.

    1987-01-01

    Several lines of evidence implicate metals in epilepsy. Anticonvulsant drugs are noted to alter levels of metals in humans and animals. PIXE analysis was used to investigate effects of three anticonvulsant drugs on tissue and brain cortex trace elements. The content of zinc and copper was increased in liver and spleen of rats treated with anticonvulsants while selenium was decreased in cortex. (orig.)

  5. Design, synthesis and biological evaluation of new hybrid anticonvulsants derived from N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide and 2-(2,5-dioxopyrrolidin-1-yl)butanamide derivatives.

    Science.gov (United States)

    Kamiński, Krzysztof; Rapacz, Anna; Łuszczki, Jarogniew J; Latacz, Gniewomir; Obniska, Jolanta; Kieć-Kononowicz, Katarzyna; Filipek, Barbara

    2015-05-15

    The purpose of this study was to synthesize the library of 33 new N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamides, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanamides, and 2-(2,5-dioxopyrrolidin-1-yl)butanamides as potential new hybrid anticonvulsant agents. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. The coupling reaction of the 2-(2,5-dioxopyrrolidin-1-yl)propanoic acid, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanoic acid, or 2-(2,5-dioxopyrrolidin-1-yl)butanoic acid with the appropriately substituted benzylamines in the presence of the coupling reagent, N,N-carbonyldiimidazole (CDI) generated the final compounds 4-36. Spectral data acquired via (1)H NMR, (13)C NMR, and LC-MS confirmed the chemical structures of the newly prepared compounds. The initial anticonvulsant screening was performed in mice intraperitoneally (ip), using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The rotarod test determined the acute neurological toxicity (NT). The results of preliminary pharmacological screening revealed that 25 compounds showed protection in half or more of the animals tested in the MES and/or scPTZ seizure models at the fixed dose of 100mg/kg. The broad spectra of activity across the preclinical seizure models displayed compounds 4, 7, 8, 13, 15-18, 24, and 26. The quantitative pharmacological studies in mice demonstrated the highest protection for compounds 4 (ED50 MES=67.65 mg/kg, ED50scPTZ=42.83 mg/kg); 8 (ED50 MES=54.90 mg/kg, ED50scPTZ=50.29 mg/kg); and 20 (ED50scPTZ=47.39 mg/kg). These compounds were distinctly more potent and provided better safety profiles in the rotarod test compared to valproic acid or ethosuximide, which were used as model AEDs. Compound 8 underwent only a slight metabolic change by the human liver microsomes (HLMs), and also did not affect the activity of human cytochrome P450 isoform

  6. Anticonvulsant Efficacy in Sturge-Weber Syndrome

    Science.gov (United States)

    Kaplan, Emma H.; Kossoff, Eric H.; Bachur, Catherine D.; Gholston, Milton; Hahn, Jihoon; Widlus, Matthew; Comi, Anne M.

    2016-01-01

    OBJECTIVE We analyzed individuals with epilepsy due to Sturge-Weber syndrome to determine which anticonvulsants provided optimal seizure control and which resulted in the fewest side effects. METHODS One-hundred-eight records from a single center were retrospectively analyzed for Sturge-Weber syndrome brain involvement, epilepsy, Sturge-Weber syndrome neuroscores, and currently used anticonvulsants. RESULTS Of the fourteen anticonvulsants that had been employed, the most often used agents were oxcarbazepine or carbamazepine, and levetiracetam. Individuals whose seizures at the most recent visit were fully controlled (seizure-free) for 6 months or longer were more likely to have ever tried, or currently used, oxcarbazepine or carbamazepine than those with uncontrolled seizures. Thirty-nine of 69 individuals (56.5%) were seizure-free with oxcarbazepine or carbamazepine history versus 11 of 35 individuals (31.4%) who had not taken these agents (P anticonvulsants versus 12 of 42 (28.6%) not taking them (P < 0.01). Patients with seizure control for 6 months or longer were less likely to have ever tried, or to currently be taking, levetiracetam than those without control. Sixteen of 56 individuals (28.6%) were seizure-free with levetiracetam history versus 34 of 48 (70.8%) without it (P < 0.001); 14 of 43 individuals (32.6%) were seizure-free and currently taking levetiracetam versus 36 of 61 (59.0%) not taking it (P < 0.01). When topiramate was added as second-line medication, five of nine patients (55.6%) experienced decreased seizure severity, and worsening of glaucoma was not reported. CONCLUSIONS Carbamazepine and oxcarbazepine were associated with better seizure control than levetiracetam in this Sturge-Weber syndrome cohort and so may be preferred as the initial therapy. When used as adjunctive therapy, topiramate was effective in this limited analysis without a clear increased incidence of glaucoma. PMID:26997037

  7. Concurrent Anticonvulsant/Ketogenic Diet Efficacy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2009-09-01

    Full Text Available Researchers at the Johns Hopkins Hospital, Baltimore, studied retrospectively the comparative efficacy of six most frequently used anticonvulsants when employed in combination with the ketogenic diet (KD for treatment of 115 children with epilepsy.

  8. Volume-selective proton MR spectroscopy for in-vitro quantification of anticonvulsants

    Energy Technology Data Exchange (ETDEWEB)

    Braun, J.; Tolxdorff, T. [Inst. of Medical Informatics, Biometry and Epidemiology, University Hospital Benjamin Franklin, Berlin (Germany); Seyfert, S.; Marx, P. [Freie Univ. Berlin (Germany). Abt. fuer Neurologie; Bernarding, J. [Inst. of Medical Informatics, Biometry and Epidemiology, University Hospital Benjamin Franklin, Berlin (Germany); Freie Univ. Berlin (Germany). Klinik fuer Radiologie, Nuklearmedizin und Physikalische Therapie; Schilling, A. [Freie Univ. Berlin (Germany). Klinik fuer Radiologie, Nuklearmedizin und Physikalische Therapie

    2001-03-01

    Administration of anticonvulsant drugs is clinically monitored by checking seizure frequency and by determining the serum concentration of the drug. In a few reports, drug concentrations in brain parenchyma have been determined using ex vivo techniques. Little is known about the in vivo concentration in the brain parenchyma. Our goals were to characterise the NMR spectra of the anticonvulsants at therapeutic concentrations, to determine the minimum detectable concentrations, and to quantify the drugs noninvasively. Volume-selective 1H-MR spectroscopy (MRS) was performed under standard clinical conditions using a single-voxel STEAM (stimulated-echo acquisition mode) sequence at 1.5 T. Spectra of the anticonvulsants carbamazepine, phenobarbital, phenytoin and valproate were acquired in vitro in hydrous solutions at increasing dilution. Phenytoin, phenobarbital and valproate were detectable below maximum therapeutic serum concentrations. Within therapeutic ranges, there was good agreement between concentrations determined by 1H-MRS and those by standard fluorescence polarisation immunoassay. Due to the absence of signals of brain metabolites, the aromatic protons of phenobarbital, phenytoin and carbamazepine, with resonance lines around 7.4 ppm, allow the drugs to be detected. Valproate, with two resonances around 1.2 ppm, should be differentiable from potential brain metabolites using nonlinear analysis of the brain spectrum. Volume-selective 1H-MRS is therefore expected to be able to monitor anticonvulsant therapy in vivo. (orig.)

  9. Volume-selective proton MR spectroscopy for in-vitro quantification of anticonvulsants

    International Nuclear Information System (INIS)

    Braun, J.; Tolxdorff, T.; Seyfert, S.; Marx, P.; Bernarding, J.; Freie Univ. Berlin; Schilling, A.

    2001-01-01

    Administration of anticonvulsant drugs is clinically monitored by checking seizure frequency and by determining the serum concentration of the drug. In a few reports, drug concentrations in brain parenchyma have been determined using ex vivo techniques. Little is known about the in vivo concentration in the brain parenchyma. Our goals were to characterise the NMR spectra of the anticonvulsants at therapeutic concentrations, to determine the minimum detectable concentrations, and to quantify the drugs noninvasively. Volume-selective 1H-MR spectroscopy (MRS) was performed under standard clinical conditions using a single-voxel STEAM (stimulated-echo acquisition mode) sequence at 1.5 T. Spectra of the anticonvulsants carbamazepine, phenobarbital, phenytoin and valproate were acquired in vitro in hydrous solutions at increasing dilution. Phenytoin, phenobarbital and valproate were detectable below maximum therapeutic serum concentrations. Within therapeutic ranges, there was good agreement between concentrations determined by 1H-MRS and those by standard fluorescence polarisation immunoassay. Due to the absence of signals of brain metabolites, the aromatic protons of phenobarbital, phenytoin and carbamazepine, with resonance lines around 7.4 ppm, allow the drugs to be detected. Valproate, with two resonances around 1.2 ppm, should be differentiable from potential brain metabolites using nonlinear analysis of the brain spectrum. Volume-selective 1H-MRS is therefore expected to be able to monitor anticonvulsant therapy in vivo. (orig.)

  10. Prophylactic Anticonvulsants in patients with brain tumour

    International Nuclear Information System (INIS)

    Forsyth, P.A.; Weaver, S.; Fulton, D.

    2003-01-01

    We conducted a clinical trial to determine if prophylactic anticonvulsants in brain tumour patients (without prior seizures) reduced seizure frequency. We stopped accrual at 100 patients on the basis of the interim analysis. One hundred newly diagnosed brain tumour patients received anticonvulsants (AC Group) or not (No AC Group) in this prospective randomized unblinded study. Sixty patients had metastatic, and 40 had primary brain tumours. Forty-six (46%) patients were randomized to the AC Group and 54 (54%) to the No AC Group. Median follow-up was 5.44 months (range 0.13 -30.1 months). Seizures occurred in 26 (26%) patients, eleven in the AC Group and 15 in the No AC Group. Seizure-free survivals were not different; at three months 87% of the AC Group and 90% of the No AC Group were seizure-free (log rank test, p=0.98). Seventy patients died (unrelated to seizures) and survival rates were equivalent in both groups (median survival = 6.8 months versus 5.6 months, respectively; log rank test, p=0.50). We then terminated accrual at 100 patients because seizure and survival rates were much lower than expected; we would need ≥900 patients to have a suitably powered study. These data should be used by individuals contemplating a clinical trial to determine if prophylactic anticonvulsants are effective in subsets of brain tumour patients (e.g. only anaplastic astrocytomas). When taken together with the results of a similar randomized trial, prophylactic anticonvulsants are unlikely to be effective or useful in brain tumour patients who have not had a seizure. (author)

  11. Prophylactic Anticonvulsants in patients with brain tumour

    Energy Technology Data Exchange (ETDEWEB)

    Forsyth, P.A. [Depts. of Oncology and Clinical Neurosciences, Univ. of Calgary, Calgary, Alberta (Canada); Tom Baker Cancer Centre, Calgary, Alberta (Canada); Weaver, S. [Depts. of Neurology and Medicine, Albany Medical College, Albany, New York (United States); Fulton, D. [Dept. of Radiation Oncology, Cross Cancer Institute and Dept. of Medicine/Neurology, Univ. of Alberta, Edmonton, Alberta (Canada)

    2003-05-01

    We conducted a clinical trial to determine if prophylactic anticonvulsants in brain tumour patients (without prior seizures) reduced seizure frequency. We stopped accrual at 100 patients on the basis of the interim analysis. One hundred newly diagnosed brain tumour patients received anticonvulsants (AC Group) or not (No AC Group) in this prospective randomized unblinded study. Sixty patients had metastatic, and 40 had primary brain tumours. Forty-six (46%) patients were randomized to the AC Group and 54 (54%) to the No AC Group. Median follow-up was 5.44 months (range 0.13 -30.1 months). Seizures occurred in 26 (26%) patients, eleven in the AC Group and 15 in the No AC Group. Seizure-free survivals were not different; at three months 87% of the AC Group and 90% of the No AC Group were seizure-free (log rank test, p=0.98). Seventy patients died (unrelated to seizures) and survival rates were equivalent in both groups (median survival = 6.8 months versus 5.6 months, respectively; log rank test, p=0.50). We then terminated accrual at 100 patients because seizure and survival rates were much lower than expected; we would need {>=}900 patients to have a suitably powered study. These data should be used by individuals contemplating a clinical trial to determine if prophylactic anticonvulsants are effective in subsets of brain tumour patients (e.g. only anaplastic astrocytomas). When taken together with the results of a similar randomized trial, prophylactic anticonvulsants are unlikely to be effective or useful in brain tumour patients who have not had a seizure. (author)

  12. At clinically relevant concentrations the anaesthetic/amnesic thiopental but not the anticonvulsant phenobarbital interferes with hippocampal sharp wave-ripple complexes

    Directory of Open Access Journals (Sweden)

    Sotiriou Evangelos

    2007-07-01

    Full Text Available Abstract Background Many sedative agents, including anesthetics, produce explicit memory impairment by largely unknown mechanisms. Sharp-wave ripple (SPW-R complexes are network activity thought to represent the neuronal substrate for information transfer from the hippocampal to neocortical circuits, contributing to the explicit memory consolidation. In this study we examined and compared the actions of two barbiturates with distinct amnesic actions, the general anesthetic thiopental and the anticonvulsant phenobarbital, on in vitro SPW-R activity. Results Using an in vitro model of SPW-R activity we found that thiopental (50–200 μM significantly and concentration-dependently reduced the incidence of SPW-R events (it increased the inter-event period by 70–430 %. At the concentration of 25 μM, which clinically produces mild sedation and explicit memory impairment, thiopental significantly reduced the quantity of ripple oscillation (it reduced the number of ripples and the duration of ripple episodes by 20 ± 5%, n = 12, P P P Conclusion We hypothesize that thiopental, by interfering with SPW-R activity, through enhancement of the GABAA receptor-mediated transmission, affects memory processes which involve hippocampal circuit activation. The quantity but not the frequency of ripple oscillation was affected by the drug.

  13. Anticonvulsant prescription patterns in patients covered by the Colombian Health System.

    Science.gov (United States)

    Morales-Plaza, C D; Machado-Alba, J E

    Epilepsy is a group of long-term neurological disorders characterised by seizures that may respond to pharmacological treatment. Determine the prescribing patterns of anticonvulsants for patients covered by the healthcare system in Colombia. Cross-sectional study using a database containing 6.5 million people. From among residents in 88 Colombian cities, we selected patients of both sexes and all ages who were treated continuously with anticonvulsants between June and August 2012. We designed a drug consumption database and performed multivariate analysis for combination treatment and co-medication using SPSS 20.0. A total of 13,793 patients with mean age of 48.9±22.0 years were studied; 52.9% of the participants were women. Of the patient total, 74.4% were treated in monotherapy and 25.6% received two or more anticonvulsants. Globally, 72.9% of the patients were initially treated with classic anticonvulsants and 27.1% with new drugs. The most frequently used drugs were valproic acid (33.3%), carbamazepine (30.2%), clonazepam (15.7%), pregabalin (10.3%), phenytoin (10.0%) and levetiracetam (7.9%). Most agents were used in higher doses than recommended. The most common combinations were valproic acid+clonazepam (10.9%), valproic acid+carbamazepine (10.0%), carbamazepine+clonazepam (5.6%), valproic acid+phenytoin (4.4%). The most frequently prescribed co-medications were antihypertensives (61.0%), lipid-lowering drugs (45.8%), antidepressants (36.7%), antipsychotics (20.1%), anxiolytics (7.9%), and lithium (1.8%). Doctors predominantly prescribe drugs with a high therapeutic value and favour anticonvulsant monotherapy. Most agents were used in higher doses than recommended. This underlines the need to design educational strategies addressing these prescribing habits, and to undertake research on the effectiveness of treatment. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  14. Synthesis of some new substituted quinazolin-4-3H-ones as potent anticonvulsant agents

    International Nuclear Information System (INIS)

    Garg, N.; Chandra, T.; Lata, K.K.

    2009-01-01

    A new series of 3-(4-(2-(6,8-dibromo-3 (substituted phenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl)methyl) hydrazinyl)thiazol-2-yl)-2-phenylthiazolidin-4-ones were synthesized and their structures were elucidated on the basis of elemental analyses and spectroscopic studies (IR, 1H-NMR). All the synthesized compounds 1-32 were screened for their anticonvulsant activity at a dose of 30 mg/kg. The compound 31 was found to be the most potent compound of this series showing 90% protection against MES. (author)

  15. Anticonvulsants for preventing seizures in patients with chronic subdural haematoma.

    Science.gov (United States)

    Ratilal, Bernardo O; Pappamikail, Lia; Costa, João; Sampaio, Cristina

    2013-06-06

    Anticonvulsant therapy is sometimes used prophylactically in patients with chronic subdural haematoma, although the benefit is unclear. To assess the effects of prophylactic anticonvulsants in patients with chronic subdural haematoma, in both the pre- and post-operative periods. We searched the Cochrane Injuries Group's Specialised Register, CENTRAL (The Cochrane Library), MEDLINE (OvidSP), EMBASE (OvidSP), PubMed, LILACS, and the databases clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and Current Controlled Trials. The search was through 27th March 2013. Randomised controlled trials comparing any anticonvulsant versus placebo or no intervention. Three authors screened the search results to identify relevant studies. No studies met the inclusion criteria for the review. No randomised controlled trials were identified. No formal recommendations can be made about the use of prophylactic anticonvulsants in patients with chronic subdural haematoma based on the literature currently available. There are no randomised controlled trials on this topic, and non-controlled studies have conflicting results. There is an urgent need for well-designed randomised controlled trials.

  16. Compliance and persistence of antidepressants versus anticonvulsants in patients with neuropathic pain during the first year of therapy.

    Science.gov (United States)

    Gharibian, Derenik; Polzin, Jennifer K; Rho, Jay P

    2013-05-01

    Neuropathic pain (NP) is a chronic condition that has human, social, and economic consequences. A variety of agents can be used for treatment; however, antidepressants and anticonvulsants are the 2 classes most widely studied and represent first-line agents in the management of NP. Little information is known about the adherence patterns of these medications during the first year of therapy in patients with NP. To examine the compliance and persistence of antidepressants versus anticonvulsants in patients with NP during the first year of therapy. Using electronic medical and pharmacy data for the Kaiser Permanente Southern California region, the adherence patterns for patients with a NP diagnosis prescribed an antidepressant or an anticonvulsant were studied. Compliance and persistence were measured using the medication possession ratio and the Refill-Sequence model, respectively. The study included 1817 patients with NP diagnosis taking either an antidepressant or an anticonvulsant. Within the antidepressant group, 42.9% were considered compliant, compared with 43.7% in the anticonvulsant group. Subanalysis of the 2 cohorts revealed that patients on venlafaxine were the most compliant (69.4%) compared with patients taking gabapentin (44.4%) and tricyclic antidepressants (41.8%) (Panticonvulsant group were considered persistent with their medication refills. Compliance and persistence rates were similar for patients with NP diagnosis taking antidepressants and anticonvulsants. Higher compliance was observed among patients taking venlafaxine; however, this population did have a small sample size.

  17. Adaptation of Lorke's method to determine and compare ED50 values: the cases of two anticonvulsants drugs.

    Science.gov (United States)

    Garrido-Acosta, Osvaldo; Meza-Toledo, Sergio Enrique; Anguiano-Robledo, Liliana; Valencia-Hernández, Ignacio; Chamorro-Cevallos, Germán

    2014-01-01

    We determined the median effective dose (ED50) values for the anticonvulsants phenobarbital and sodium valproate using a modification of Lorke's method. This modification allowed appropriate statistical analysis and the use of a smaller number of mice per compound tested. The anticonvulsant activities of phenobarbital and sodium valproate were evaluated in male CD1 mice by maximal electroshock (MES) and intraperitoneal administration of pentylenetetrazole (PTZ). The anticonvulsant ED50 values were obtained through modifications of Lorke's method that involved changes in the selection of the three first doses in the initial test and the fourth dose in the second test. Furthermore, a test was added to evaluate the ED50 calculated by the modified Lorke's method, allowing statistical analysis of the data and determination of the confidence limits for ED50. The ED50 for phenobarbital against MES- and PTZ-induced seizures was 16.3mg/kg and 12.7mg/kg, respectively. The sodium valproate values were 261.2mg/kg and 159.7mg/kg, respectively. These results are similar to those found using the traditional methods of finding ED50, suggesting that the modifications made to Lorke's method generate equal results using fewer mice while increasing confidence in the statistical analysis. This adaptation of Lorke's method can be used to determine median letal dose (LD50) or ED50 for compounds with other pharmacological activities. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Suspected zonisamide-related anticonvulsant hypersensitivity syndrome in a cat.

    Science.gov (United States)

    Collinet, Audrey; Sammut, Veronique

    2017-12-15

    CASE DESCRIPTION A 2-year-old neutered male domestic shorthair cat was evaluated for sudden onset of cluster seizures. CLINICAL FINDINGS At an emergency clinic, the cat had hyperimmunoglobulinemia and thrombocytopenia. On referral, treatment with levetiracetam, zonisamide, and phenobarbital initially provided good control of cluster seizure activity (attributable to epilepsy of unknow origin). Two weeks later, assessments revealed that serum phenobarbital concentration was within the ideal range but serum zonisamide concentration exceeded the recommended therapeutic range. The dosage of zonisamide was therefore decreased. Four days after dosage reduction, the cat developed generalized lymphadenopathy. Cytologic analysis of lymph node aspirate samples revealed a heterogeneous population of well-differentiated lymphocytes, interpreted as marked reactivity. Although neoplasia could not be ruled out, hypersensitivity to phenobarbital was suspected, and this treatment was discontinued. TREATMENT AND OUTCOME Despite cessation of phenobarbital administration, generalized peripheral lymphadenopathy progressed and hyperglobulinemia and cytopenias developed. These abnormalities resolved after discontinuation of zonisamide administration. The cat remained seizure free with no recurrence of the aforementioned concerns after reinstitution of phenobarbital treatment. CLINICAL RELEVANCE To the authors' knowledge, this is the first reported case of zonisamide-related lymphadenopathy, hyperglobulinemia, and cytopenias in a cat. Anticonvulsant hypersensitivity syndrome is well documented in human medicine, but little information has been published in the veterinary medical literature. Although the effects of anticonvulsant hypersensitivity syndrome in this cat were serious, these effects were reversible with treatment discontinuation.

  19. Involvement of ATP-sensitive potassium channels and the opioid system in the anticonvulsive effect of zolpidem in mice.

    Science.gov (United States)

    Sheikhi, Mehdi; Shirzadian, Armin; Dehdashtian, Amir; Amiri, Shayan; Ostadhadi, Sattar; Ghasemi, Mehdi; Dehpour, Ahmad Reza

    2016-09-01

    Zolpidem is a hypnotic medication that mainly exerts its function through activating γ-aminobutyric acid (GABA)A receptors. There is some evidence that zolpidem may have anticonvulsive effects. However, the mechanisms underlying this effect have not been elucidated yet. In the present study, we used the pentylentetrazole (PTZ)-induced generalized seizure model in mice to investigate whether zolpidem can affect seizure threshold. We also further evaluated the roles of ATP-sensitive potassium (KATP) channels as well as μ-opioid receptors in the effects of zolpidem on seizure threshold. Our data showed that zolpidem in a dose-dependent manner increased the PTZ-induced seizure threshold. The noneffective (i.e., did not significantly alter the PTZ-induced seizure threshold by itself) doses of KATP channel blocker (glibenclamide) and nonselective opioid receptor antagonist (naloxone) were able to inhibit the anticonvulsive effect of zolpidem. Additionally, noneffective doses of either KATP channel opener (cromakalim) or nonselective μ-opioid receptor agonist (morphine) in combination with a noneffective dose of zolpidem exerted a significant anticonvulsive effect on PTZ-induced seizures in mice. A combination of noneffective doses of naloxone and glibenclamide, which separately did not affect zolpidem effect on seizure threshold, inhibited the anticonvulsive effects of zolpidem. These results suggest a role for KATP channels and the opioid system, alone or in combination, in the anticonvulsive effects of zolpidem. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. ß-Adrenergic Stimulation Increases RyR2 Activity via Intracellular Ca2+ and Mg2+ Regulation

    Science.gov (United States)

    Li, Jiao; Imtiaz, Mohammad S.; Beard, Nicole A.; Dulhunty, Angela F.; Thorne, Rick; vanHelden, Dirk F.; Laver, Derek R.

    2013-01-01

    Here we investigate how ß-adrenergic stimulation of the heart alters regulation of ryanodine receptors (RyRs) by intracellular Ca2+ and Mg2+ and the role of these changes in SR Ca2+ release. RyRs were isolated from rat hearts, perfused in a Langendorff apparatus for 5 min and subject to 1 min perfusion with 1 µM isoproterenol or without (control) and snap frozen in liquid N2 to capture their phosphorylation state. Western Blots show that RyR2 phosphorylation was increased by isoproterenol, confirming that RyR2 were subject to normal ß-adrenergic signaling. Under basal conditions, S2808 and S2814 had phosphorylation levels of 69% and 15%, respectively. These levels were increased to 83% and 60%, respectively, after 60 s of ß-adrenergic stimulation consistent with other reports that ß-adrenergic stimulation of the heart can phosphorylate RyRs at specific residues including S2808 and S2814 causing an increase in RyR activity. At cytoplasmic [Ca2+] adrenergic stimulation increased luminal Ca2+ activation of single RyR channels, decreased luminal Mg2+ inhibition and decreased inhibition of RyRs by mM cytoplasmic Mg2+. At cytoplasmic [Ca2+] >1 µM, ß-adrenergic stimulation only decreased cytoplasmic Mg2+ and Ca2+ inhibition of RyRs. The Ka and maximum levels of cytoplasmic Ca2+ activation site were not affected by ß-adrenergic stimulation. Our RyR2 gating model was fitted to the single channel data. It predicted that in diastole, ß-adrenergic stimulation is mediated by 1) increasing the activating potency of Ca2+ binding to the luminal Ca2+ site and decreasing its affinity for luminal Mg2+ and 2) decreasing affinity of the low-affinity Ca2+/Mg2+ cytoplasmic inhibition site. However in systole, ß-adrenergic stimulation is mediated mainly by the latter. PMID:23533585

  1. Quantitative Structure-Activity Relationship Analysis of the ...

    African Journals Online (AJOL)

    Erah

    Quantitative Structure-Activity Relationship Analysis of the Anticonvulsant ... Two types of molecular descriptors, including the 2D autocorrelation ..... It is based on the simulation of natural .... clustering anticonvulsant, antidepressant, and.

  2. Use of anticonvulsants as prophylaxis for seizures in patients on clozapine.

    Science.gov (United States)

    Caetano, Dorgival

    2014-02-01

    The aim of this study is to conduct a critical review of the literature regarding the use of anticonvulsants in the prophylaxis of clozapine-induced seizures, to examine the relationship of the latter with clozapine daily dose, serum concentration and other factors than dosage that effect clozapine blood concentration, and to make recommendations for the management of clozapine-induced seizures. A systematic review of English-language MEDLINE articles was undertaken. Clozapine-induced seizures may occur at any dose; the risk increases with dose and goes up to 4% at ≥ 600 mg/day. Some authors have advocated that patients on that dose regimen have anticonvulsant added as a primary prophylactic measure. The author discusses the pitfalls of this recommendation and highlights that seizures are better predicted from serum concentration (1300 ng/ml) rather than dose alone, and that serum concentration is strongly influenced by sex, age, smoking habit, drug-drug interactions and variations in the 1A2, 2D6 and 3A4 genotypes. Anticonvulsants are not recommended as a primary prophylaxis for clozapine-induced seizures. When deemed necessary as secondary prophylaxis, the clinician's choice should consider drug-drug interactions that may increase/decrease clozapine serum concentration and lead to more side effects, including neutropenia/agranulocytosis and seizures, or compromise therapeutic response. Recommendations for primary and secondary prophylaxis of clozapine related-seizures are provided.

  3. Anticonvulsant effect of minocycline on pentylenetetrazole-induced seizure in mice: involvement of nitric oxide and N-methyl-D-aspartate receptor.

    Science.gov (United States)

    Amini-Khoei, Hossein; Kordjazy, Nastaran; Haj-Mirzaian, Arya; Amiri, Shayan; Haj-Mirzaian, Arvin; Shirzadian, Armin; Hasanvand, Amin; Balali-Dehkordi, Shima; Hassanipoor, Mahsa; Dehpour, Ahmad Reza

    2018-03-20

    Anticonvulsant effects of minocycline have been explored recently. This study was designed to examine the anticonvulsant effect of acute administration of minocycline on pentylenetetrazole (PTZ)-induced seizures in mouse considering the possible role of nitric oxide (NO)/NMDA pathway. We induced seizure using intravenous administration of PTZ. Our results showed that acute administration of minocycline increased the seizure threshold. Furthermore, co-administration of sub-effective doses of the non-selective nitric oxide synthase (NOS) inhibitor, L-NAME (10 mg/kg) and the neuronal NOS inhibitor, 7-nitroindazole (40 mg/kg) enhanced the anticonvulsant effect of sub-effective dose of minocycline (40 mg/kg). We found that inducible NOS inhibitor, aminoguanidine (100 mg/kg), had no effect on the anti-seizure effect of minocycline. Moreover, L-arginine (60 mg/kg), as a NOS substrate, reduced the anticonvulsant effect of minocycline. We also demonstrated that pretreatment with NMDA receptor antagonists, ketamine (0.5 mg/kg) and MK-801 (0.05 mg/kg) increased the anticonvulsant effect of sub-effective dose of minocycline. Results showed that minocycline significantly decreased the hippocampal nitrite level. Furthermore, co-administration of nNOS inhibitor like NMDA receptor antagonists augmented the effect of minocycline on the hippocampal nitrite level. In conclusion, we revealed that anticonvulsant effect of minocycline might be, at least in part, due to decline in constitutive hippocampal nitric oxide activity as well as inhibition of NMDA receptors.

  4. Changes in the pharmacodynamics and pharmacokinetics of psycholeptic drugs in radiation-sickness. Effect of X-ray radiation on pharmacodynamic activity of nitrazepam in animals

    International Nuclear Information System (INIS)

    Szczawinska, K.; Chodera, A.; Wojciak, Z.; Kozaryn, I.

    1975-01-01

    The anticonvulsive effect of nitrazepam was determined in animals exposed to a single 600 R radiation and the exploring activity of the animals was studied after nitrazepam administered during radiation sickness caused by this exposure. On the 1st day after exposure the activity, reducing effect was slightly weaker but on days 3rd and 6th this effect was significantly stronger. The anticonvulsant effect of nitrazepam on the 3rd day after exposure was significantly greater as compared with control animals, but on the 6th day no difference in the power of anticonvulsant activity between the two groups of animals was found. (author)

  5. Experimental allergic encephalomyelitis: peculiarities of pain-relieving therapy and place of anticonvulsants as analgetics

    Directory of Open Access Journals (Sweden)

    Nefyodov O.O.

    2015-11-01

    Full Text Available Multiple sclerosis (MS is the most common demyelinating disease affecting mainly young people of the working age (16-45 years and quickly leading to disability. Available data constitute that up to 80% of MS patients suffer from pain at different disease periods. Pain management and the analgesic drug choice in MS patients may be difficult. Anticonvulsant drugs possess an analgesic activity and are widely used in patients presenting painful neuropathic symptoms. Based on that, we aimed to investigate the nociceptive potential changes as well as the research-oriented behavior using the "open field" test in rat. An experimental animal equivalent of multiple sclerosis has been modeled, based on the methylprednisolone (M administration. Animals were also administered anticonvulsants (carbamazepine, topiramate, sodium volproat, pregabalin and gabapentin. The stu­dy showed advantages of gabapentin and pregabalin use in simulated disease treatment. This statement is based on the "open field" test results, where the motor-oriented rats’ behavior was evaluated. Administration of M+gabapentin and M+pregabalin showed positive dynamics of the motor activity: the number of squares crossed increased by 80.86% (p<0.05 and 81.73% (р<0.05 respectively. Maximum recovery of the research activity (peeking in "mink" was re­gis­tered in animals administered M+pregabalin: the increase rate was 300% (r<0.05 comparing with the 12th day of ex­periment. It was shown, that 5-days administration of M+gabapentin and M+pregabalin caused muscle tone impro­ve­ment by 190% (p<0.05 and 200% (p<0.05 respectively, comparing with animals with untreated multiple sclerosis. A sig­ni­fi­cant increase of analgesic activity of M+pregabalin and M+gabapentin combinations used together with me­thyl­pred­nisolone by 4.1 (p<0.05 and 3.6 (p<0.05 times was registered comparing with the initial methylprednisolone background.

  6. Anticonvulsant pharmacotherapy for generalized and localized vulvodynia : a critical review of the literature

    NARCIS (Netherlands)

    Spoelstra, Symen K.; Borg, Charmaine; Schultz, Willibrord C. M. Weijmar

    Anticonvulsant therapy has occasionally been recommended to treat vulvodynia. However, convincing evidence to support this therapeutic option is lacking. The goal of this study was to critically review studies published on the effectiveness of anticonvulsants for the treatment of vulvodynia.

  7. Association between consistent purchase of anticonvulsants or lithium and suicide risk: a longitudinal cohort study from Denmark, 1995-2001.

    Science.gov (United States)

    Smith, Eric G; Søndergård, Lars; Lopez, Ana Garcia; Andersen, Per Kragh; Kessing, Lars Vedel

    2009-10-01

    Prior studies suggest anticonvulsants purchasers may be at greater risk of suicide than lithium purchasers. Longitudinal, retrospective cohort study of all individuals in Denmark purchasing anticonvulsants (valproic acid, carbamazepine, oxcarbazepine or lamotrigine) (n=9952) or lithium (n=6693) from 1995-2001 who also purchased antipsychotics at least once (to select out nonpsychiatric anticonvulsant use). Poisson regression of suicides by medication purchased (anticonvulsants or lithium) was conducted, controlling for age, sex, and calendar year. Confounding by indication was addressed by restricting the comparison to individuals prescribed the same medication: individuals with minimal medication exposure (e.g., who purchased only a single prescription of anticonvulsants) were compared to those individuals with more consistent medication exposure (i.e., purchasing > or = 6 prescriptions of anticonvulsants). Demographics and frequency of anticonvulsant, lithium, or antipsychotic use were similar between lithium and anticonvulsant purchasers. Among patients who also purchased antipsychotic at least once during the study period, purchasing anticonvulsants more consistently (> or = 6 prescriptions) was associated with a substantial reduction in the risk of suicide (RR=0.22, 95% CI=0.11-0.42, panticonvulsant and consistent lithium purchasers were similar. Lack of information about diagnoses and potential confounders, as well as other covariates that may differ between minimal and consistent medication purchasers, are limitations to this study. In this longitudinal study of anticonvulsant purchasers likely to have psychiatric disorders, consistent anticonvulsant treatment was associated with decreased risk of completed suicide.

  8. Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage

    Energy Technology Data Exchange (ETDEWEB)

    Kadriu, Bashkim; Guidotti, Alessandro; Costa, Erminio [Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612 (United States); Auta, James [Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612 (United States)

    2009-02-27

    Organophosphate (OP)-nerve agent poisoning may lead to prolonged epileptiform seizure activity, which can result in irreversible neuronal brain damage. A timely and effective control of seizures with pharmacological agents can minimize the secondary and long-term neuropathology that may result from this damage. Diazepam, the current anticonvulsant of choice in the management of OP poisoning, is associated with unwanted effects such as sedation, amnesia, cardio-respiratory depression, anticonvulsant tolerance, and dependence liabilities. In search for an efficacious and safer anticonvulsant benzodiazepine, we studied imidazenil, a potent anticonvulsant that is devoid of sedative action and has a low intrinsic efficacy at {alpha}1- but is a high efficacy positive allosteric modulator at {alpha}5-containing GABA{sub A} receptors. We compared the potency of a combination of 2 mg/kg, i.p. atropine with: (a) imidazenil 0.05-0.5 mg/kg i.p. or (b) equipotent anti-bicuculline doses of diazepam (0.5-5 mg/kg, i.p.), against diisopropyl fluorophosphate (DFP; 1.5 mg/kg, s.c.)-induced status epilepticus and its associated neuronal damage. The severity and frequency of seizure activities were determined by continuous radio telemetry recordings while the extent of neuronal damage and neuronal degeneration were assessed using the TUNEL-based cleaved DNA end-labeling technique or neuron-specific nuclear protein (NeuN)-immunolabeling and Fluoro-Jade B (FJB) staining, respectively. We report here that the combination of atropine and imidazenil is at least 10-fold more potent and longer lasting than the combination with diazepam at protecting rats from DFP-induced seizures and the associated neuronal damage or ongoing degeneration in the anterior cingulate cortex, CA1 hippocampus, and dentate gyrus. While 0.5 mg/kg imidazenil effectively attenuated DFP-induced neuronal damage and the ongoing neuronal degeneration in the anterior cingulate cortex, dentate gyrus, and CA1 hippocampus, 5

  9. Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage

    International Nuclear Information System (INIS)

    Kadriu, Bashkim; Guidotti, Alessandro; Costa, Erminio; Auta, James

    2009-01-01

    Organophosphate (OP)-nerve agent poisoning may lead to prolonged epileptiform seizure activity, which can result in irreversible neuronal brain damage. A timely and effective control of seizures with pharmacological agents can minimize the secondary and long-term neuropathology that may result from this damage. Diazepam, the current anticonvulsant of choice in the management of OP poisoning, is associated with unwanted effects such as sedation, amnesia, cardio-respiratory depression, anticonvulsant tolerance, and dependence liabilities. In search for an efficacious and safer anticonvulsant benzodiazepine, we studied imidazenil, a potent anticonvulsant that is devoid of sedative action and has a low intrinsic efficacy at α1- but is a high efficacy positive allosteric modulator at α5-containing GABA A receptors. We compared the potency of a combination of 2 mg/kg, i.p. atropine with: (a) imidazenil 0.05-0.5 mg/kg i.p. or (b) equipotent anti-bicuculline doses of diazepam (0.5-5 mg/kg, i.p.), against diisopropyl fluorophosphate (DFP; 1.5 mg/kg, s.c.)-induced status epilepticus and its associated neuronal damage. The severity and frequency of seizure activities were determined by continuous radio telemetry recordings while the extent of neuronal damage and neuronal degeneration were assessed using the TUNEL-based cleaved DNA end-labeling technique or neuron-specific nuclear protein (NeuN)-immunolabeling and Fluoro-Jade B (FJB) staining, respectively. We report here that the combination of atropine and imidazenil is at least 10-fold more potent and longer lasting than the combination with diazepam at protecting rats from DFP-induced seizures and the associated neuronal damage or ongoing degeneration in the anterior cingulate cortex, CA1 hippocampus, and dentate gyrus. While 0.5 mg/kg imidazenil effectively attenuated DFP-induced neuronal damage and the ongoing neuronal degeneration in the anterior cingulate cortex, dentate gyrus, and CA1 hippocampus, 5 mg/kg or a

  10. H{sub 2} R and D activities in the Nordic Countries

    Energy Technology Data Exchange (ETDEWEB)

    Holst Joergensen, B.

    2003-10-01

    The report describes hydrogen related R and D activities in the five Nordic countries from 1998 and onwards. It is not a comprehensive account of all hydrogen related R and D as much relevant research is not described under the heading of hydrogen energy but integrated in other programmes or part of more generic basic research. Also much industry conducted H2 R and D activities are not published. It gives some background information on R and D in the five Nordic countries and gives account of the R and D efforts. At Nordic level through the Nordic Energy Research a number of R and D projects are also conducted and shortly described. At EU level, Nordic stakeholders are represented in a number of hydrogen and fuel cell R and D projects and short descriptions are provided. In the appendix, more detaield informaiton is given on the R and D projects at national, EU and Nordic levels. (au)

  11. Characteristics of fetal anticonvulsant syndrome associated autistic disorder.

    Science.gov (United States)

    Rasalam, A D; Hailey, H; Williams, J H G; Moore, S J; Turnpenny, P D; Lloyd, D J; Dean, J C S

    2005-08-01

    The aim of this study was to evaluate the clinical features and frequency of autistic disorder or Asperger syndrome (AS; according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV] criteria) in children exposed to anticonvulsant medication in utero. During a 20-year study period, 626 children were born in Aberdeen to mothers taking antiepileptic drugs (AEDs). The study examined long-term effects of prenatal exposure to AEDs in 260 children (122 males, 138 females). Of these, 26 (16 males) were reported by parents to have social or behavioural difficulties. Eleven children (6 males, 5 females) fulfilled the DSM-IV criteria for autistic disorder and one (female) fulfilled the DSM-IV criteria for AS. These children comprised 4.6% of the exposed children studied, and 1.9% of all exposed children born during the study period. Mean age of these children at diagnosis was 5 years 4 months (SD 2y 11mo) and 9 years 10 months (SD 3y 10mo) at the time of this study. Other children from the group of 26 had difficulties in areas of speech and language development and social communication but did not meet the criteria for an autism spectrum disorder (ASD). Sodium valproate was the drug most commonly associated with autistic disorder, five of 56 (8.9%) of the study children exposed to sodium valproate alone had either autistic disorder or AS. It was concluded that prenatal exposure to anticonvulsant medication is a risk factor for the development of an ASD. Fetal anticonvulsant syndrome associated autistic disorder is characterized by an even sex ratio, absence of regression or skill loss, and language delay in the absence of global delay.

  12. Effect of anticonvulsants on plasma testosterone and sex hormone binding globulin levels.

    Science.gov (United States)

    Barragry, J M; Makin, H L; Trafford, D J; Scott, D F

    1978-01-01

    Plasma sex hormone binding globulin (SHBG) and testosterone levels were measured in 29 patients with epilepsy (16 men and 13 women), most of them on chronic therapy with anticonvulsant drugs. Sex hormone binding globulin concentrations were increased in both sexes and testosterone levels in male patients. It is postulated that anticonvulsants may induce hepatic synthesis of SHBG. PMID:569688

  13. Anticonvulsant evaluation of Rauvolfia ligustrina Willd. ex Roem. & Schult., Apocynaceae, in rodents

    Directory of Open Access Journals (Sweden)

    Lucindo J. Quintans-Júnior

    Full Text Available The Aim of this study was to evaluated the effects of the ethanol extract of Rauvolfia ligustrina Willd. ex Roem. & Schult., Apocynaceae, roots (EER in animal models of epilepsy. The EER increased the latency for convulsions significantly different from control (p<0,05 and in the PTZ induced convulsions test on 62,5 mg/kg (i.p. decreased mortality. This effect was blocked by flumazenil administration, suggesting an involvement of GABAergic system in the anticonvulsant activity of EER. The EER had a moderate effect only against PIC- or STR-induced convulsions at doses 125 and 250 mg/kg. But in the MES test it did not demonstrate effect on this animal model. Therefore, the EER reduced the development of PTZ-induced kindling in both experimental groups. It also significantly (p<0.05 decreased the latency for convulsions and reduced its percentage. Our results suggest that EER owns anticonvulsant property.

  14. ß-Adrenergic stimulation increases RyR2 activity via intracellular Ca2+ and Mg2+ regulation.

    Directory of Open Access Journals (Sweden)

    Jiao Li

    Full Text Available Here we investigate how ß-adrenergic stimulation of the heart alters regulation of ryanodine receptors (RyRs by intracellular Ca(2+ and Mg(2+ and the role of these changes in SR Ca(2+ release. RyRs were isolated from rat hearts, perfused in a Langendorff apparatus for 5 min and subject to 1 min perfusion with 1 µM isoproterenol or without (control and snap frozen in liquid N2 to capture their phosphorylation state. Western Blots show that RyR2 phosphorylation was increased by isoproterenol, confirming that RyR2 were subject to normal ß-adrenergic signaling. Under basal conditions, S2808 and S2814 had phosphorylation levels of 69% and 15%, respectively. These levels were increased to 83% and 60%, respectively, after 60 s of ß-adrenergic stimulation consistent with other reports that ß-adrenergic stimulation of the heart can phosphorylate RyRs at specific residues including S2808 and S2814 causing an increase in RyR activity. At cytoplasmic [Ca(2+] 1 µM, ß-adrenergic stimulation only decreased cytoplasmic Mg(2+ and Ca(2+ inhibition of RyRs. The Ka and maximum levels of cytoplasmic Ca(2+ activation site were not affected by ß-adrenergic stimulation. Our RyR2 gating model was fitted to the single channel data. It predicted that in diastole, ß-adrenergic stimulation is mediated by 1 increasing the activating potency of Ca(2+ binding to the luminal Ca(2+ site and decreasing its affinity for luminal Mg(2+ and 2 decreasing affinity of the low-affinity Ca(2+/Mg(2+ cytoplasmic inhibition site. However in systole, ß-adrenergic stimulation is mediated mainly by the latter.

  15. Potential role of anticonvulsants in the treatment of obsessive-compulsive and related disorders.

    Science.gov (United States)

    Wang, Hee Ryung; Woo, Young Sup; Bahk, Won-Myong

    2014-10-01

    We reviewed the extant literature to evaluate the current evidence regarding the efficacy and safety of anticonvulsants in the treatment of obsessive-compulsive and related disorders. Relevant literature was accessed using the Cochrane database, embase and PubMed on 29 October 2013. Prospective studies examining the efficacy of anticonvulsants in obsessive-compulsive and related disorders were included. Case reports, case series, and retrospective studies were excluded. A total of 10 studies were included in this review. The studies of obsessive-compulsive disorder, except for two negative studies, showed favorable efficacy results of anticonvulsants. In one study on body dysmorphic disorder, levetiracetam showed favorable efficacy. In two lamotrigine studies for pathologic skin-picking, the efficacy findings were inconsistent. In one trichotillomania study, topiramate had reduced hair-pulling symptoms. Despite limited evidence, our review suggests that anticonvulsants have a potential role in the treatment of obsessive-compulsive and related disorders. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.

  16. The signaling pathway of dopamine D2 receptor (D2R) activation using normal mode analysis (NMA) and the construction of pharmacophore models for D2R ligands.

    Science.gov (United States)

    Salmas, Ramin Ekhteiari; Stein, Matthias; Yurtsever, Mine; Seeman, Philip; Erol, Ismail; Mestanoglu, Mert; Durdagi, Serdar

    2017-07-01

    G-protein-coupled receptors (GPCRs) are targets of more than 30% of marketed drugs. Investigation on the GPCRs may shed light on upcoming drug design studies. In the present study, we performed a combination of receptor- and ligand-based analysis targeting the dopamine D2 receptor (D2R). The signaling pathway of D2R activation and the construction of universal pharmacophore models for D2R ligands were also studied. The key amino acids, which contributed to the regular activation of the D2R, were in detail investigated by means of normal mode analysis (NMA). A derived cross-correlation matrix provided us an understanding of the degree of pair residue correlations. Although negative correlations were not observed in the case of the inactive D2R state, a high degree of correlation appeared between the residues in the active state. NMA results showed that the cytoplasmic side of the TM5 plays a significant role in promoting of residue-residue correlations in the active state of D2R. Tracing motions of the amino acids Arg219, Arg220, Val223, Asn224, Lys226, and Ser228 in the position of the TM5 are found to be critical in signal transduction. Complementing the receptor-based modeling, ligand-based modeling was also performed using known D2R ligands. The top-scored pharmacophore models were found as 5-sited (AADPR.671, AADRR.1398, AAPRR.3900, and ADHRR.2864) hypotheses from PHASE modeling from a pool consisting of more than 100 initial candidates. The constructed models using 38 D2R ligands (in the training set) were validated with 15 additional test set compounds. The resulting model correctly predicted the pIC 50 values of an additional test set compounds as true unknowns.

  17. A STUDY OF ANTICONVULSANT EFFECT OF FLUNARIZINE AND NIFEDIPINE IN COMPARISON WITH SODIUM VALPROATE ON MES AND PTZ MODELS OF EPILEPSY IN ALBINO RATS

    Directory of Open Access Journals (Sweden)

    Umesh G.

    2015-03-01

    Full Text Available BACKGROUND : CA +2 ions are involved in initiation as well as spread of seizures. Hence current study was undertaken to evaluate the anticonvulsant effect of calcium channel blockers flunarizine, nifedipine and compare their efficacy with that of sodium valproate, the broad spectrum anticonvulsant in MES and PTZ induced seizures in albino rats. MATERIALS AND METHODS : Albino rats were treated with nife dipine 2.5mg/kg, 5mg/kg, flunarizine 7.5mg/kg,15mg/kg and sodium valproate 250mg/kg bodyweight intraperitoneally and the effects were observed in MES and PTZ models of epilepsy. The parameters observed in MES model was , duration of HLTE phase . Convulsive p hase, and post ictal depressive phase. In PTZ model duration of seizure latency, duration of convulsion , and duration post ictal depression were observed. RESULTS : our study demonstrated that both calcium channel blockers afford protection against convulsi ons induced in both models, and flunarizine affords higher degree of protection than nifedipine, with its efficacy almost approaching that of sodium valproate. CONCLUSION : Flunarizine has significant, while nifedipine has moderate degree of anticonvulsant activity as compared to sodium valproate

  18. The effect of various opiate receptor agonists on the seizure threshold in the rat. Is dynorphin an endogenous anticonvulsant?

    Science.gov (United States)

    Przewłocka, B; Stala, L; Lasoń, W; Przewłocki, R

    1983-01-01

    The effects of various opiate receptor agonists on the seizure threshold after an intravenous infusion of pentylenetetrazol were investigated in rats. The mu- and epsilon-receptor agonists, morphine (20-40 micrograms) and beta-endorphin (5-10 micrograms) show proconvulsant properties towards clonic and tonic seizures. The delta-receptor agonist (D-Ala2,D-Leu5-enkephalin, DADL 5-40 micrograms) and alpha-neoendorphin (20-40 micrograms) show pro- and anticonvulsant properties towards clonic and tonic seizures, respectively. Anticonvulsant properties of DADL are possibly due to its action on the spinal cord, since after the intrathecal injection this effect is still observed. Similarities between DADL and alpha-neoendorphin suggest that they may act through the same receptor. The kappa-receptor agonist dynorphin A (5-20 micrograms) and its degradation-resistant analogue D-Arg-dynorphin1-13 (10 micrograms) show significant anticonvulsant properties. Our present results suggest that the kappa-receptor agonist dynorphin may act physiologically as an endogenous anticonvulsant, in contrast to other opioid peptides.

  19. Mood-Stabilizing Anticonvulsants, Spina Bifida, and Folate Supplementation: Commentary.

    Science.gov (United States)

    Patel, Neil; Viguera, Adele C; Baldessarini, Ross J

    2018-02-01

    High risks of neural tube defects and other teratogenic effects are associated with exposure in early pregnancy to some anticonvulsants, including in women with bipolar disorder. Based on a semistructured review of recent literature, we summarized findings pertaining to this topic. Valproate and carbamazepine are commonly used empirically (off-label) for putative long-term mood-stabilizing effects. Both anticonvulsants have high risks of teratogenic effects during pregnancy. Risks of neural tube defects (especially spina bifida) and other major malformations are especially great with valproate and can arise even before pregnancy is diagnosed. Standard supplementation of folic acid during pregnancy can reduce risk of spontaneous spina bifida, but not that associated with valproate or carbamazepine. In contrast, lamotrigine has regulatory approval for long-term use in bipolar disorder and appears not to have teratogenic effects in humans. Lack of protective effects against anticonvulsant-associated neural tube defects by folic acid supplements in anticipation of and during pregnancy is not widely recognized. This limitation and high risks of neural tube and other major teratogenic effects, especially of valproate, indicate the need for great caution in the use of valproate and carbamazepine to treat bipolar disorder in women of child-bearing age.

  20. Use of Lithium and Anticonvulsants and the Rate of Chronic Kidney Disease

    DEFF Research Database (Denmark)

    Kessing, Lars Vedel; Gerds, Thomas Alexander; Feldt-Rasmussen, Bo

    2015-01-01

    -stage CKD among individuals exposed to successive prescriptions of lithium, anticonvulsants, or other drugs used for bipolar disorder. DESIGN, SETTING, AND PARTICIPANTS: This is a Danish nationwide population-based study of 2 cohorts. Cohort 1 comprised a randomly selected sample of 1.5 million individuals......IMPORTANCE: Lithium is the main mood stabilizing drug for bipolar disorder. However, it is controversial whether long-term maintenance treatment with lithium or other drugs for bipolar disorder causes chronic kidney disease (CKD). OBJECTIVE: To compare rates of CKD and in particular rates of end...... among all persons who were registered in Denmark on January 1, 1995, all patients with a diagnosis of a single manic episode or bipolar disorder between January 1, 1994, and December 31, 2012 (n =10 591), and all patients exposed to either lithium (n = 26 731) or anticonvulsants (n=420 959). Cohort 2...

  1. Effects of anticonvulsants and inactivity on bone disease in epileptics

    Science.gov (United States)

    Murchison, Lilian E.; Bewsher, P. D.; Chesters, Marion; Gilbert, J.; Catto, G.; Law, Elizabeth; McKay, E.; Ross, H. S.

    1975-01-01

    No significant biochemical or radiological features of vitamin D deficiency were found in groups of juvenile and adult epileptics and control groups of non-epileptic patients in hospitals for the mentally retarded. There was evidence of hepatic enzyme induction in patients on anticonvulsants, in that urinary D-glucaric acid concentration and excretion were raised. No effect was found of prolonged anticonvulsant therapy on bone densitometry, but in children immobility was closely associated with decreased bone density. The evidence suggests that disuse osteoporosis is the major bone disease in these mentally retarded children. PMID:1161672

  2. Novel, broad-spectrum anticonvulsants containing a sulfamide group: advancement of N-((benzo[b]thien-3-yl)methyl)sulfamide (JNJ-26990990) into human clinical studies.

    Science.gov (United States)

    Parker, Michael H; Smith-Swintosky, Virginia L; McComsey, David F; Huang, Yifang; Brenneman, Douglas; Klein, Brian; Malatynska, Ewa; White, H Steve; Milewski, Michael E; Herb, Mark; Finley, Michael F A; Liu, Yi; Lubin, Mary Lou; Qin, Ning; Iannucci, Robert; Leclercq, Laurent; Cuyckens, Filip; Reitz, Allen B; Maryanoff, Bruce E

    2009-12-10

    In seeking broad-spectrum anticonvulsants to treat epilepsy and other neurological disorders, we synthesized and tested a group of sulfamide derivatives (4a-k, 5), which led to the clinical development of 4a (JNJ-26990990). This compound exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures, with very weak inhibition of human carbonic anhydrase-II (IC(50) = 110 microM). The pharmacological profile for 4a supports its potential in the treatment of multiple forms of epilepsy, including pharmacoresistant variants. Mechanistically, 4a inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels but was not effective as a K(+) channel opener. The pharmacokinetics and metabolic properties of 4a are discussed.

  3. Studies on long-lasting consequences of prenatal exposure to anticonvulsant drugs

    NARCIS (Netherlands)

    Dessens, A. B.; Boer, K.; Koppe, J. G.; van de Poll, N. E.; Cohen-Kettenis, P. T.

    1994-01-01

    Based on neonatal examination at birth, it has been estimated that epileptic women have a 2-3 times greater risk of giving birth to an infant with congenital anomalies. But anticonvulsant drugs may also have more subtle influences on the developing foetus which are not visible at birth but only

  4. Anticonvulsant and Antioxidant Effects of Tilia americana var. mexicana and Flavonoids Constituents in the Pentylenetetrazole-Induced Seizures

    Science.gov (United States)

    Cárdenas-Rodríguez, Noemí; González-Trujano, María Eva; Aguirre-Hernández, Eva; Ruíz-García, Matilde; Sampieri, Aristides; Coballase-Urrutia, Elvia; Carmona-Aparicio, Liliana

    2014-01-01

    Tilia genus is commonly used around the world for its central nervous system properties; it is prepared as tea and used as tranquilizing, anticonvulsant, and analgesic. In this study, anticonvulsant activity of the Tilia americana var. mexicana inflorescences and leaves was investigated by evaluating organic and aqueous extracts (100, 300, and 600 mg/kg, i.p.) and some flavonoids in the pentylenetetrazole-induced seizures in mice. Moreover, antioxidant effect of these extracts and flavonoids was examined in an in vitro study by using spectrophotometric technique. Significant activity was observed in the methanol extract from inflorescences. An HPLC analysis of the methanol extract from inflorescences and leaves of Tilia allowed demonstrating the respective presence of some partial responsible flavonoid constituents: quercetin (20.09 ± 1.20 μg/mg and 3.39 ± 0.10 μg/mg), rutin (3.52 ± 0.21 μg/mg and 8.94 ± 0.45 μg/mg), and isoquercitrin (1.74 ± 0.01 μg/mg and 1.24 ± 0.13 μg/mg). In addition, significant but different antioxidant properties were obtained among the flavonoids and the extracts investigated. Our results provide evidence of the anticonvulsant activity of Tilia reinforcing its utility for central nervous system diseases whose mechanism of action might involve partial antioxidant effects due to the presence of flavonoids. PMID:25197430

  5. Use of Lithium and Anticonvulsants and the Rate of Chronic Kidney Disease: A Nationwide Population-Based Study.

    Science.gov (United States)

    Kessing, Lars Vedel; Gerds, Thomas Alexander; Feldt-Rasmussen, Bo; Andersen, Per Kragh; Licht, Rasmus W

    2015-12-01

    Lithium is the main mood stabilizing drug for bipolar disorder. However, it is controversial whether long-term maintenance treatment with lithium or other drugs for bipolar disorder causes chronic kidney disease (CKD). To compare rates of CKD and in particular rates of end-stage CKD among individuals exposed to successive prescriptions of lithium, anticonvulsants, or other drugs used for bipolar disorder. This is a Danish nationwide population-based study of 2 cohorts. Cohort 1 comprised a randomly selected sample of 1.5 million individuals among all persons who were registered in Denmark on January 1, 1995, all patients with a diagnosis of a single manic episode or bipolar disorder between January 1, 1994, and December 31, 2012 (n =10,591), and all patients exposed to either lithium (n = 26,731) or anticonvulsants (n=420,959). Cohort 2 included the subgroup of 10,591 patients diagnosed as having bipolar disorder. Possible CKD, definite CKD, and end-stage CKD (defined as long-term dialysis or renal transplantation). A total of 14,727 (0.8%), 18,762 (1.0%), and 3407 (0.2%) in cohort 1 and 278 (2.6%), 319 (3.0%), and 62 (0.6%) in cohort 2 were diagnosed as having possible, definite, or end-stage CKD, respectively. Based on the total sample and not considering diagnoses, use of lithium was associated with an increased rate of definite CKD (0 prescriptions: hazard ratio [HR] = 1.09, 95% CI, 0.81-1.45; ≥60 prescriptions: HR = 3.65, 95% CI, 2.64-5.05; P for trend anticonvulsants, antipsychotics, or antidepressants was not. Neither use of lithium nor use of any other drug class was associated with increasing rates of end-stage CKD. In patients with bipolar disorder, use of lithium was associated with an increased rate of definite CKD (1-2 prescriptions: HR = 0.89, 95% CI, 0.39-2.06; ≥60 prescriptions: HR = 2.54, 95% CI, 1.81-3.57; P for trend anticonvulsants (definite CKD, 1-2 prescriptions: HR = 1.23, 95% CI, 0.76-1.99; ≥60

  6. Anticonvulsant Effect of the Aqueous Extract and Essential Oil of Carum Carvi L. Seeds in a Pentylenetetrazol Model of Seizure in Mice

    Science.gov (United States)

    Showraki, Alireza; Emamghoreishi, Masoumeh; Oftadegan, Somayeh

    2016-01-01

    Background: Carum carvi L. (caraway), known as black zeera in Iran, has been indicated for the treatment of epilepsy in Iranian folk medicine. This study evaluated whether the aqueous extract and essential oil of caraway seeds have anticonvulsant effects in mice. Methods: The anticonvulsant effects of the aqueous extract (200, 400, 800, 1600, and 3200 mg/kg, i.p.) and essential oil (25, 50, 100, 200, and 400 mg/kg, i.p.) of caraway were assessed using pentylenetetrazol (PTZ; 95 mg/kg i.p.) induced convulsions. Diazepam (3 mg/kg) was used as positive control. The latency time before the onset of myoclonic, clonic, and tonic convulsions and the percentage of mortality were recorded. In addition, the effect of caraway on neuromuscular coordination was evaluated using the rotarod performance test. Results: The extract and essential oil dose-dependently increased the latency time to the onset of myoclonic (ED50, 1257 and 62.2 mg/kg, respectively) and clonic (ED50, 929 and 42.3 mg/kg, respectively) seizures. The extract and essential oil of caraway prevented the animals from tonic seizure with ED50s of 2142.4 and 97.6 mg/kg, respectively. The extract and essential oil of caraway protected 28.6 and 71.4% of the animals from PTZ-induced death, respectively, and had no significant effect on neuromuscular coordination. Conclusion: This study showed that the aqueous extract and essential oil of caraway had anticonvulsant properties. However, the essential oil was more potent and effective than was the aqueous extract as an anticonvulsant. Additionally, the anticonvulsant effect of caraway was not due to a muscle relaxant activity. These findings support the acclaimed antiepileptic effect of caraway in folk medicine and propose its potential use in petit mal seizure in humans. PMID:27217604

  7. Canine Pancreas-Specific Lipase and C-reactive Protein in Dogs Treated With Anticonvulsants (Phenobarbital and Potassium Bromide).

    Science.gov (United States)

    Albarracín, Viviana; Teles, Mariana; Meléndez-Lazo, Antonio; Rodón, Jaume; Pastor, Josep

    2015-06-01

    Animals treated with anticonvulsant drugs may have increased canine pancreas-specific lipase (cPLI) values. Inflammatory conditions and specifically acute pancreatitis are of major concern in these animals. Elevation in C-reactive protein is being associated with inflammatory status in dogs and it has been correlated with the clinical severity of pancreatitis. In the present study, we investigated if there is a correlation between the cPLI increase, changes in C-reactive protein and hepatic enzymes, as well as the incidence of severe acute pancreatitis (AP) in dogs with anticonvulsant treatment (phenobarbital, or potassium bromide or both). Increased values of pancreas-specific lipase were found in 6.8% of the animals in treatment with anticonvulsants, and this increase is correlated with the increase in triglycerides, alkaline phosphatase, and alanine aminotransferase but not with C-reactive protein levels, which suggests a possible induction or release phenomenon rather than a clear severe AP. C-reactive protein levels did not affect cPLI values on the population studied. Only 2 animals had clinical and analytical data suggestive of AP, indicating a low prevalence (0.6%). In conclusion, cPLI may be increased in a low percentage of animals with anticonvulsants treatment and its increase may not be associated with severe AP. It may be induced by the anticonvulsants drugs; however, further studies are advised to rule out other possible causes that increased cPLI. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. At clinically relevant concentrations the anaesthetic/amnesic thiopental but not the anticonvulsant phenobarbital interferes with hippocampal sharp wave-ripple complexes

    Science.gov (United States)

    Papatheodoropoulos, Costas; Sotiriou, Evangelos; Kotzadimitriou, Dimitrios; Drimala, Panagiota

    2007-01-01

    Background Many sedative agents, including anesthetics, produce explicit memory impairment by largely unknown mechanisms. Sharp-wave ripple (SPW-R) complexes are network activity thought to represent the neuronal substrate for information transfer from the hippocampal to neocortical circuits, contributing to the explicit memory consolidation. In this study we examined and compared the actions of two barbiturates with distinct amnesic actions, the general anesthetic thiopental and the anticonvulsant phenobarbital, on in vitro SPW-R activity. Results Using an in vitro model of SPW-R activity we found that thiopental (50–200 μM) significantly and concentration-dependently reduced the incidence of SPW-R events (it increased the inter-event period by 70–430 %). At the concentration of 25 μM, which clinically produces mild sedation and explicit memory impairment, thiopental significantly reduced the quantity of ripple oscillation (it reduced the number of ripples and the duration of ripple episodes by 20 ± 5%, n = 12, P Phenobarbital significantly accelerated SPWs at 50 and 100 μM whereas it reduced their rate at 200 and 400 μM. Furthermore, it significantly prolonged SPWs, reduced their synchrony and reduced the quantity of ripples only at the clinically very high concentration of 400 μM, reported to affect memory. Conclusion We hypothesize that thiopental, by interfering with SPW-R activity, through enhancement of the GABAA receptor-mediated transmission, affects memory processes which involve hippocampal circuit activation. The quantity but not the frequency of ripple oscillation was affected by the drug. PMID:17672909

  9. Association between anticonvulsant drugs and teeth-grinding in children and adolescents with cerebral palsy.

    Science.gov (United States)

    Ortega, A O L; Dos Santos, M T B R; Mendes, F M; Ciamponi, A L

    2014-09-01

    The relation between teeth-grinding and the use of drugs acting on the central nervous system of cerebral palsy (CP) patients has not yet been described. The aim of this research was to evaluate the presence or absence of teeth-grinding (sleep and/or awake periods) in normal and in CP children and adolescents, as well as the association of teeth-grinding and use of anticonvulsant drugs. The sample consisted of 207 children and adolescents, divided into three groups: G1, individuals with CP who did not take anticonvulsant drugs; G2, individuals with CP administered medications on a regular basis; and CG, normal individuals. Logistic regression analyses were performed to evaluate the association of teeth-grinding with some variables. No significant statistical differences were observed regarding the presence or absence of teeth-grinding when G1 and G2 were compared. However, compared with the CG, a statistically significant difference was determined, with the CG showing fewer children presenting teeth-grinding (P grinding. CP children and adolescents show a greater and significant presence of grinding of the teeth compared with normal individuals. Subjects taking barbiturate drugs showed greater presence of teeth-grinding, than those who were taking medications from the other groups of anticonvulsant drugs. © 2014 John Wiley & Sons Ltd.

  10. Effects of WIN 55,212-2 mesylate on the anticonvulsant action of lamotrigine, oxcarbazepine, pregabalin and topiramate against maximal electroshock-induced seizures in mice.

    Science.gov (United States)

    Luszczki, Jarogniew J; Wlaz, Aleksandra; Karwan, Slawomir; Florek-Luszczki, Magdalena; Czuczwar, Stanislaw J

    2013-11-15

    The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN - a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four second-generation antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), the step-through passive avoidance task (assessing long-term memory) and the grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by high-pressure liquid chromatography to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5mg/kg, i.p.) significantly enhanced the anticonvulsant action of lamotrigine (Poxcarbazepine in the maximal electroshock-induced tonic seizure test in mice. Furthermore, none of the investigated combinations of WIN with antiepileptic drugs were associated with any concurrent adverse effects with regards to motor performance, long-term memory or muscular strength. Pharmacokinetic characterization revealed that WIN had no impact on total brain concentrations of lamotrigine, oxcarbazepine, pregabalin and topiramate in mice. These preclinical data would suggest that WIN in combination with lamotrigine, pregabalin and topiramate is associated with beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced tonic seizure test. © 2013 Published by Elsevier B.V.

  11. Anticonvulsants for Nerve Agent-Induced Seizures: The Influence of the Therapeutic Dose of Atropine

    National Research Council Canada - National Science Library

    Shih, Tsung-Ming; Rowland, Tami C; McDonough, John H

    2007-01-01

    Two guinea pig models were used to study the anticonvulsant potency of diazepam, midazolam, and scopolamine against seizures induced by the nerve agents tabun, sarin, soman, cyclosarin, O-ethyl S-(2-(diisopropylamino)ethyl...

  12. Quantitative determination of bone mineral concentrations using quotient densitometry in patients under long-term anticonvulsant therapy

    International Nuclear Information System (INIS)

    Schulz, H.

    1980-01-01

    The effect on bone mineral concentration of anticonvulsive long-term therapy was investigated in order to find out if there is a relation between the occurence and extent of osteomalacial lesions on the one hand and the type and time of application of anticonvulsants. The hydroxyl apatite content was determined by X-ray densitometry. The method is considered to be suitable for yearly skeletal monitoring of epilepticians treated with anticonvulsants. (orig./HP) [de

  13. Comparative studies on the effects of clinically used anticonvulsants on the oxidative stress biomarkers in pentylenetetrazole-induced kindling model of epileptogenesis in mice.

    Science.gov (United States)

    Mazhar, Faizan; Malhi, Saima M; Simjee, Shabana U

    2017-01-01

    Oxidative stress plays a key role in the pathogenesis of epilepsy and contributes in underlying epileptogenesis process. Anticonvulsant drugs targeting the oxidative stress domain of epileptogenesis may provide better control of seizure. The present study was carried out to investigate the effect of clinically used anti-epileptic drugs (AEDs) on the course of pentylenetetrazole (PTZ)-induced kindling and oxidative stress markers in mice. Six mechanistically heterogeneous anticonvulsants: phenobarbital, phenytoin, levetiracetam, pregabalin, topiramate, and felbamate were selected and their redox profiles were determined. Diazepam was used as a drug control for comparison. Kindling was induced by repeated injections of a sub-convulsive dose of PTZ (50 mg/kg, s.c.) on alternate days until seizure score 5 was evoked in the control kindled group. Anticonvulsants were administered daily. Following PTZ kindling, oxidative stress biomarkers were assessed in homogenized whole brain samples and estimated for the levels of nitric oxide, peroxide, malondialdehyde, protein carbonyl, reduced glutathione, and activities of nitric oxide synthase and superoxide dismutase. Biochemical analysis revealed a significant increase in the levels of reactive oxygen species with a parallel decrease in endogenous anti-oxidants in PTZ-kindled control animals. Daily treatment with levetiracetam and felbamate significantly decreased the PTZ-induced seizure score as well as the levels of nitric oxide (panticonvulsant effect by the diversified mechanism of action such as levetiracetam, felbamate, and topiramate exhibited superior anti-oxidative stress activity in addition to their anticonvulsant activity.

  14. Increasing use of atypical antipsychotics and anticonvulsants during pregnancy

    Science.gov (United States)

    Epstein, Richard A.; Bobo, William V.; Shelton, Richard C.; Arbogast, Patrick G.; Morrow, James A.; Wang, Wei; Chandrasekhar, Rameela; Cooper, William O.

    2013-01-01

    Purpose To quantify maternal use of atypical antipsychotics, typical antipsychotics, anticonvulsants and lithium during pregnancy. Methods Tennessee birth and death records were linked to Tennessee Medicaid data to conduct a retrospective cohort study of 296,817 women enrolled in Tennessee Medicaid throughout pregnancy who had a live birth or fetal death from 1985 to 2005. Results During the study time period, the adjusted rate of use of any study medication during pregnancy increased from nearly 14 to 31 per 1,000 pregnancies (β = 0.08, 95% CI = 0.07, 0.09). Significant increases were reported in use of anticonvulsants alone among mothers with pain and other psychiatric disorders, atypical antipsychotics alone among mothers with bipolar disorders, schizophrenia, unipolar depressive disorders, and other psychiatric disorders, and more than one studied medication for mothers with epilepsy, pain disorders, bipolar disorders, unipolar depressive disorders, and other psychiatric disorders. Significant decreases were reported in use of lithium alone and typical antipsychotics alone for all clinically meaningful diagnosis groups. Conclusions There was a substantial increase in use of atypical antipsychotics alone, anticonvulsants alone, and medications from multiple studied categories among Tennessee Medicaid-insured pregnant women during the study period. Further examination of the maternal and fetal consequences of exposure to these medications during pregnancy is warranted. PMID:23124892

  15. Do carbamazepine, gabapentin, or other anticonvulsants exert sufficient radioprotective effects to alter responses from trigeminal neuralgia radiosurgery?

    Science.gov (United States)

    Flickinger, John C; Kim, Hyun; Kano, Hideyuki; Greenberger, Joel S; Arai, Yoshio; Niranjan, Ajay; Lunsford, L Dade; Kondziolka, Douglas; Flickinger, John C

    2012-07-15

    trigeminal neuralgia pain compared with 25% (7 of 28), 20% (23 of 114), and 33% (4 of 12) of patients taking no anticonvulsants, age >70 years, and partly atypical Type 2 trigeminal neuralgia, respectively. The use of carbamazepine or gabapentin at the time of radiosurgery does not decrease the rates of obtaining partial or complete pain relief after radiosurgery, but gabapentin may reduce the risks of developing post-radiosurgery trigeminal neuropathy. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Do Carbamazepine, Gabapentin, or Other Anticonvulsants Exert Sufficient Radioprotective Effects to Alter Responses From Trigeminal Neuralgia Radiosurgery?

    Energy Technology Data Exchange (ETDEWEB)

    Flickinger, John C. [Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States); College of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA (United States); Kim, Hyun [Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Kano, Hideyuki [Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Greenberger, Joel S.; Arai, Yoshio [Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Pittsburgh Cancer Institute, Pittsburgh, PA (United States); Niranjan, Ajay [Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Lunsford, L. Dade; Kondziolka, Douglas [Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Pittsburgh Cancer Institute, Pittsburgh, PA (United States); Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Flickinger, John C., E-mail: flickingerjc@upmc.edu [Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Pittsburgh Cancer Institute, Pittsburgh, PA (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States)

    2012-07-15

    {<=}70 years, and Type 1 typical trigeminal neuralgia pain compared with 25% (7 of 28), 20% (23 of 114), and 33% (4 of 12) of patients taking no anticonvulsants, age >70 years, and partly atypical Type 2 trigeminal neuralgia, respectively. Conclusions: The use of carbamazepine or gabapentin at the time of radiosurgery does not decrease the rates of obtaining partial or complete pain relief after radiosurgery, but gabapentin may reduce the risks of developing post-radiosurgery trigeminal neuropathy.

  17. Do Carbamazepine, Gabapentin, or Other Anticonvulsants Exert Sufficient Radioprotective Effects to Alter Responses From Trigeminal Neuralgia Radiosurgery?

    International Nuclear Information System (INIS)

    Flickinger, John C.; Kim, Hyun; Kano, Hideyuki; Greenberger, Joel S.; Arai, Yoshio; Niranjan, Ajay; Lunsford, L. Dade; Kondziolka, Douglas; Flickinger, John C.

    2012-01-01

    age ≤70 years, and Type 1 typical trigeminal neuralgia pain compared with 25% (7 of 28), 20% (23 of 114), and 33% (4 of 12) of patients taking no anticonvulsants, age >70 years, and partly atypical Type 2 trigeminal neuralgia, respectively. Conclusions: The use of carbamazepine or gabapentin at the time of radiosurgery does not decrease the rates of obtaining partial or complete pain relief after radiosurgery, but gabapentin may reduce the risks of developing post-radiosurgery trigeminal neuropathy.

  18. Alteration of bioelectrically-controlled processes in the embryo: a teratogenic mechanism for anticonvulsants.

    Science.gov (United States)

    Hernández-Díaz, Sonia; Levin, Michael

    2014-08-01

    Maternal use of anticonvulsants during the first trimester of pregnancy has been associated with an elevated risk of major congenital malformations in the offspring. Whether the increased risk is caused by the specific pharmacological mechanisms of certain anticonvulsants, the underlying epilepsy, or common genetic or environmental risk factors shared by epilepsy and malformations has been controversial. We hypothesize that anticonvulsant therapies during pregnancy that attain more successful inhibition of neurotransmission might lead to both better seizure control in the mother and stronger alteration of bioelectrically-controlled processes in the embryo that result in structural malformations. We propose that development of pharmaceuticals that do not alter cell resting transmembrane voltage levels could result in safer drugs. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Excavating Anticonvulsant Compounds from Prescriptions of Traditional Chinese Medicine in the Treatment of Epilepsy.

    Science.gov (United States)

    Zhao, Zefeng; He, Xirui; Ma, Cuixia; Wu, Shaoping; Cuan, Ye; Sun, Ying; Bai, Yajun; Huang, Linhong; Chen, Xufei; Gao, Tian; Zheng, Xiaohui

    2018-05-08

    Traditional Chinese medicine (TCM) has a long history and been widely used in prevention and treatment of epilepsy in China. This paper is intended to review the advances in the active anticonvulsant compounds isolated from herbs in the prescription of TCM in the treatment of epilepsy. These compounds were introduced with the details including classification, CAS number specific structure and druggability data. Meanwhile, much of the research in these compounds in the last two decades has shown that they exhibited favorable pharmacological properties in treatment of epilepsy both in in vivo and in vitro models. In addition, in this present review, the evaluation of the effects of the anticonvulsant classical TCM prescriptions is discussed. According to these rewarding pharmacological effects and chemical substances, the prescription of TCM herbs could be an effective therapeutic strategy for epilepsy patients, and also could be a promising source for the development of new drugs.

  20. Anti-convulsant therapy in eclampsia.

    Directory of Open Access Journals (Sweden)

    Maheshwari J

    1989-04-01

    Full Text Available Seventy four patients presented with eclampsia at N.W.M. Hospital. Bombay. Among the patients with eclampsia, 64.9% were primis, 29.7% were gravida II-IV and 5.4% were grand multis. As many as 40.5% patients were less than 20 years of age, while 2.7% were over 30 years of age. 48.7% had antepartum convulsions, 40.5% had intrapartum convulsions, while 8 patients convulsed in the postpartum period. Besides standard management of eclamptic patients, 3 protocols of anticonvulsant therapy were utilised. 27% were managed with diphenyl hydantoin sodium, 43% with magnesium sulphate, and 30% by combination of diazepam and pentazocine. The maternal and perinatal outcome was evaluated. Control of convulsions was superior with magnesium sulphate while perinatal outcome was best with diphenyl hydantoin.

  1. Design and synthesis of novel diphenyl oxalamide and diphenyl acetamide derivatives as anticonvulsants.

    Science.gov (United States)

    Nikalje, Anna Pratima G; Ghodke, Mangesh; Girbane, Amol

    2012-01-01

    A series of novel N(1) -substituted-N(2) ,N(2) -diphenyl oxalamides 3a-l were synthesized in good yield by stirring diphenylcarbamoyl formyl chloride (2) and various substituted aliphatic, alicyclic, aromatic, heterocyclic amines in DMF and K(2) CO(3) . Also 2-substituted amino-N,N-diphenylacetamides 5a-m were designed by pharmacophore generation and synthesized by stirring 2-chloro-N,N-diphenylacetamide (4) and various substituted amines in acetone using triethyl amine as a catalyst. All the synthesized compounds were screened for anticonvulsant activity in Swiss albino mice by MES and ScPTZ induced seizure tests. Neurotoxicity screening and behavioral testing was also carried out. Some of the synthesized test compounds were found to be more potent than the standard drug. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling.

    Science.gov (United States)

    Su, Rui; Dong, Lei; Li, Chenying; Nachtergaele, Sigrid; Wunderlich, Mark; Qing, Ying; Deng, Xiaolan; Wang, Yungui; Weng, Xiaocheng; Hu, Chao; Yu, Mengxia; Skibbe, Jennifer; Dai, Qing; Zou, Dongling; Wu, Tong; Yu, Kangkang; Weng, Hengyou; Huang, Huilin; Ferchen, Kyle; Qin, Xi; Zhang, Bin; Qi, Jun; Sasaki, Atsuo T; Plas, David R; Bradner, James E; Wei, Minjie; Marcucci, Guido; Jiang, Xi; Mulloy, James C; Jin, Jie; He, Chuan; Chen, Jianjun

    2018-01-11

    R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N 6 -methyladenosine (m 6 A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m 6 A/MYC/CEBPA signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Concomitant Anticonvulsants With Bitemporal Electroconvulsive Therapy: A Randomized Controlled Trial With Clinical and Neurobiological Application.

    Science.gov (United States)

    Rakesh, Gopalkumar; Thirthalli, Jagadisha; Kumar, Channaveerachari Naveen; Muralidharan, Kesavan; Phutane, Vivek H; Gangadhar, Bangalore N

    2017-03-01

    Electroconvulsive therapy (ECT) is an effective treatment for major affective disorders. The combined use of ECT and anticonvulsant mood stabilizers is a common clinical scenario. There is dearth of systematic studies on the use of this combination with regard to clinical or cognitive outcomes. We aimed to compare clinical improvement and cognitive adverse effects between patients who received only ECT versus those who received ECT and anticonvulsants. We hypothesized that improvement would be fastest in patients who received only ECT. We conducted a randomized controlled trial in which patients prescribed ECT while being treated with anticonvulsants were randomized into 3 groups: full-dose (FD), half-dose (HD), and stop anticonvulsant. A blind rater assessed clinical improvement in patients using rating scales [Young's Mania Rating Scale (YMRS) and Clinical Global Impression] for clinical improvement and cognitive adverse effects (Postgraduate Institute memory scale). Analysis was done using mixed-effects modeling to delineate differences in clinical and cognitive outcomes across the 3 arms of the study over the course of ECT. Of the 54 patients recruited, 36 patients went into treatment allocation arms per the initial randomization plan. The main anticonvulsants prescribed were sodium valproate and carbamazepine. Patients in the 3 groups were comparable on clinical features. The most common diagnosis was bipolar affective disorder-with current episode of mania. Overall, there was no difference across the 3 groups in final clinical outcome scores (YMRS and Clinical Global Impression) when analyzed as intention to treat (ITT) or "as treated." In both analyses, group × time interaction was significant when comparing trend of YMRS scores between the FD anticonvulsant group and the HD group from baseline to last ECT (P = 0.0435 in ITT and P = 0.0055 in as treated). Patients in the FD group improved faster than those in the HD group. There were no differences across

  4. Anticonvulsants Teratogenic Mechanism Involves Alteration of Bioelectrically-controlled Processes in the Embryo. A hypothesis

    Science.gov (United States)

    Hernández-Díaz, Sonia; Levin, Michael

    2014-01-01

    Maternal use of anticonvulsants during the first trimester of pregnancy has been associated with an elevated risk of major congenital malformations in the offspring. Whether the increased risk is caused by the specific pharmacological mechanisms of certain anticonvulsants, the underlying epilepsy, or common genetic or environmental risk factors shared by epilepsy and malformations is controversial. We hypothesize that anticonvulsant therapies during pregnancy that attain more successful inhibition of neurotransmission might lead to both better seizure control in the mother and stronger alteration of bioelectrically-controlled processes in the embryo that result in structural malformations. If our theory were correct, development of pharmaceuticals that do not alter cell resting transmembrane voltage levels could result in safer drugs. PMID:24815983

  5. Retrospective Analysis of Nonepileptic Patients With Isolated Epileptiform Discharges Treated With Anticonvulsants.

    Science.gov (United States)

    Swatzyna, Ronald J; Tarnow, Jay D; Proler, Meyer L; Roark, Alexandra J; MacInerney, Erin K; Kozlowski, Gerald P

    2017-09-01

    Many antiepileptic drugs (AEDs) have been tested on nonepileptic patients with a variety of diagnoses. The Food and Drug Administration has only approved certain AEDs for a small number of psychiatric conditions. There are few studies of nonepileptic patients that recommend an empirical trial of AEDs when isolated epileptiform discharges (IEDs) are identified in the electroencephalogram (EEG). However, no trials have been published. The purpose of this study is to evaluate the outcome of treating nonepileptic patients with AEDs when IEDs are present. Refractory cases were reviewed from a multidisciplinary practice whose EEG readings contained IEDs and were subsequently medicated with anticonvulsants by the clinic's psychiatrist. The psychiatrist's progress notes were assessed to determine the impact of adding anticonvulsants based on parent reports, teacher reports, and clinical observation. The final sample was composed of 76 refractory cases. Of the 76 patients treated with anticonvulsants, the majority were found to be improved in follow-up progress notes: 65 improved (85.53%), 6 unchanged (7.89%), and 5 more severe (6.58%). These observational findings suggest that further studies will be needed to show that IEDs may predict positive treatment outcome to anticonvulsant medication and act as a step toward an evidence-based treatment. Also, EEG screening may prove to be useful for refractory cases regardless of age, gender, or diagnosis.

  6. Anticonvulsant and antipunishment effects of toluene.

    Science.gov (United States)

    Wood, R W; Coleman, J B; Schuler, R; Cox, C

    1984-08-01

    Toluene can have striking acute behavioral effects and is subject to abuse by inhalation. To determine if its actions resemble those of drugs used in the treatment of anxiety ("anxiolytics"), two sets of experiments were undertaken. Inasmuch as prevention of pentylenetetrazol-induced convulsions is an identifying property of this class of agents, we first demonstrated that pretreatment with injections of toluene delayed the onset of convulsive signs and prevented the tonic extension phase of the convulsant activity in a dose-related manner. Injections of another alkyl benzene, m-xylene, were of comparable potency to toluene. Inhalation of toluene delayed the time to death after pentylenetetrazol injection in a manner related to the duration and concentration of exposure; at lower convulsant doses, inhalation of moderate concentrations (EC50, 1311 ppm) prevented death. Treatment with a benzodiazepine receptor antagonist (Ro 15-1788) failed to reduce the anticonvulsant activity of inhaled toluene. Anxiolytics also attenuate the reduction in response rate produced by punishment with electric shock. Toluene increased rates of responding suppressed by punishment when responding was maintained under a multiple fixed-interval fixed-interval punishment schedule of reinforcement. Distinct antipunishment effects were observed after 2 hr of exposure to 1780 and 3000 ppm of toluene; the rate-increasing effects of toluene were related to concentration and to time after the termination of exposure. Thus, toluene and m-xylene resemble in several respects clinically useful drugs such as the benzodiazepines.

  7. Anticonvulsant Effects of Fractions Isolated from Dinoponera quadriceps (Kempt Ant Venom (Formicidae: Ponerinae

    Directory of Open Access Journals (Sweden)

    Diana Aline Morais Ferreira Nôga

    2016-12-01

    Full Text Available Natural products, sources of new pharmacological substances, have large chemical diversity and architectural complexity. In this context, some toxins obtained from invertebrate venoms have anticonvulsant effects. Epilepsy is a neurological disorder that affects about 65 million people worldwide, and approximately 30% of cases are resistant to pharmacological treatment. Previous studies from our group show that the denatured venom of the ant Dinoponera quadriceps (Kempt protects mice against bicuculline (BIC-induced seizures and death. The aim of this study was to investigate the anticonvulsant activity of compounds isolated from D. quadriceps venom against seizures induced by BIC in mice. Crude venom was fractionated by high-performance liquid chromatography (HPLC resulting in six fractions referred to as DqTx1–DqTx6. A liquid chromatography-mass spectrometry (LC/MS analysis revealed a major 431 Da compound in fractions DqTx1 and DqTx2. Fractions DqTx3 and DqTx4 showed a compound of 2451 Da and DqTx5 revealed a 2436 Da compound. Furthermore, the DqTx6 fraction exhibited a major component with a molecular weight of 13,196 Da. Each fraction (1 mg/mL was microinjected into the lateral ventricle of mice, and the animals were observed in an open field. We did not observe behavioral alterations when the fractions were given alone. Conversely, when the fractions were microinjected 20 min prior to the administration of BIC (21.6 nM, DqTx1, DqTx4, and DqTx6 fractions increased the latency for onset of tonic-clonic seizures. Moreover, all fractions, except DqTx5, increased latency to death. The more relevant result was obtained with the DqTx6 fraction, which protected 62.5% of the animals against tonic-clonic seizures. Furthermore, this fraction protected 100% of the animals from seizure episodes followed by death. Taken together, these findings indicate that compounds from ant venom might be a potential source of new anticonvulsants molecules.

  8. Increasing use of atypical antipsychotics and anticonvulsants during pregnancy.

    Science.gov (United States)

    Epstein, Richard A; Bobo, William V; Shelton, Richard C; Arbogast, Patrick G; Morrow, James A; Wang, Wei; Chandrasekhar, Rameela; Cooper, William O

    2013-07-01

    To quantify maternal use of atypical antipsychotics, typical antipsychotics, anticonvulsants, and lithium during pregnancy. Tennessee birth and death records were linked to Tennessee Medicaid data to conduct a retrospective cohort study of 296,817 women enrolled in Tennessee Medicaid throughout pregnancy who had a live birth or fetal death from 1985 to 2005. During the study time period, the adjusted rate of use of any study medication during pregnancy increased from nearly 14 to 31 per 1000 pregnancies (β = 0.08, 95% CI = 0.07, 0.09). Significant increases were reported in use of anticonvulsants alone among mothers with pain and other psychiatric disorders, atypical antipsychotics alone among mothers with bipolar disorders, schizophrenia, unipolar depressive disorders, and other psychiatric disorders, and more than one studied medication for mothers with epilepsy, pain disorders, bipolar disorders, unipolar depressive disorders, and other psychiatric disorders. Significant decreases were reported in use of lithium alone and typical antipsychotics alone for all clinically meaningful diagnosis groups. There was a substantial increase in use of atypical antipsychotics alone, anticonvulsants alone, and medications from multiple studied categories among Tennessee Medicaid-insured pregnant women during the study period. Further examination of the maternal and fetal consequences of exposure to these medications during pregnancy is warranted. Copyright © 2012 John Wiley & Sons, Ltd.

  9. Synergistic anticonvulsant effects of pregabalin and amlodipine on acute seizure model of epilepsy in mice.

    Science.gov (United States)

    Qureshi, Itefaq Hussain; Riaz, Azra; Khan, Rafeeq Alam; Siddiqui, Afaq Ahmed

    2017-08-01

    Status epilepticus is a life threatening neurological medical emergency. It may cause serious damage to the brain and even death in many cases if not treated properly. There is limited choice of drugs for the short term and long term management of status epilepticus and the dugs recommended for status epilepticus possess various side effects. The present study was designed to investigate synergistic anticonvulsant effects of pregabalin with amlodipine on acute seizure model of epilepsy in mice. Pentylenetetrazole was used to induce acute seizures which mimic status epilepticus. Pregabalin and amlodipine were used in combination to evaluate synergistic anti-seizure effects on acute seizure model of epilepsy in mice. Diazepam and valproate were used as reference dugs. The acute anti-convulsive activity of pregabalin with amlodipine was evaluated in vivo by the chemical induced seizures and their anti-seizure effects were compared with pentylenetetrazole, reference drugs and to their individual effects. The anti-seizure effects of tested drugs were recorded in seconds on seizure characteristics such as latency of onset of threshold seizures, rearing and fallings and Hind limbs tonic extensions. The seizure protection and mortality to the animals exhibited by the drugs were recorded in percentage. Combination regimen of pregabalin with amlodipine exhibited dose dependent significant synergistic anticonvulsant effects on acute seizures which were superior to their individual effects and equivalent to reference drugs.

  10. Mechanisms underlying the benefits of anticonvulsants over lithium in the treatment of bipolar disorder.

    Science.gov (United States)

    Corrado, Alisa C; Walsh, John P

    2016-02-10

    Close to 3% of the world's population suffers from bipolar disease (I and II). Of this 3%, bipolar disease affects largely women (∼ 3 : 2 compared with men). The median age of diagnosis is 25 in women and even lower in men. A diagnosis of bipolar disease is an expensive psychiatric diagnosis, costing patients more than twice as much money as a diagnosis of unipolar depression. Bipolar I is characterized by one or more manic or mixed episodes, with both mania and depression occurring each day for at least 1 week, whereas bipolar II is characterized by one or more major depressive episode and at least one episode of hypomania. Bipolar I is the more severe diagnosis. A wide range of medications are available to help patients maintain a healthy lifestyle, including lithium, antidepressants, and anticonvulsants. Improved methods for identifying bipolar disease, including a more structured approach and a more complete use of medical records, have increased the rate of diagnosis, especially in children, which underscores the need for innovation in development and in practice of new treatment options for treating bipolar disease. Although lithium has been the 'gold standard' for treating bipolar disorder for decades, new research into other forms of treatment has shown anticonvulsants to be a particularly useful therapy for treating bipolar disease. Anticonvulsants have remarkable mood-stabilization abilities and they do not lead to serious side effects, which increases the tolerability, and consequently, patient adherence to this form of treatment. Recent studies have shown that anticonvulsants improve behavior in bipolar disease by modulating the balance of excitatory and inhibitory synapses through a number of complementary molecular cascades that affect gene expression and cell survival.

  11. Comparative neurocognitive effects of lithium and anticonvulsants in long-term stable bipolar patients.

    Science.gov (United States)

    Sabater, Ana; García-Blanco, Ana C; Verdet, Hélade M; Sierra, Pilar; Ribes, Josep; Villar, Irene; Lara, Mª José; Arnal, Pilar; Rojo, Luis; Livianos, Lorenzo

    2016-01-15

    The aim of choosing a mood-stabilizing drug (lithium or anticonvulsants) or a combination of them with minimal neurocognitive effects is to stimulate the development of criteria for a therapeutic adequacy, particularly in Bipolar Disorder (BD) patients who are clinically stabilized. Three groups of BD patients were established according to their treatment: (i) lithium monotherapy (n=29); (ii) lithium together with one or more anticonvulsants (n=28); and (iii) one or more anticonvulsants (n=16). A group of healthy controls served as the control (n=25). The following tests were applied: Wechsler Adult Intelligence Scale, Trail Making Test, Wechsler Memory Scale, Rey Complex Figure Test, Stroop color-word test, Wisconsin Card Sorting Test, Tower of Hanoi, Frontal Assessment Battery, and Reading the Mind in the Eyes Test. Relative to healthy controls, BD patients showed the following: (i) those on lithium monotherapy, but not other BD groups, had preserved short-term auditory memory, long-term memory, and attention; (ii) those who took only anticonvulsants showed worse findings in short-term visual memory, working memory, and several executive functions; and (iii) all BD patients showed worse performance in processing speed, resistance to interference, and emotion recognition. Medication alone cannot explain why all BD patients showed common cognitive deficits despite different pharmacological treatment. The impairment on some executive functions and emotion recognition is an inherent trait in BD patients, regardless of their pharmacological treatment. However, while memory, attention, and most of the executive functions are preserved in long-term stable BD patients, these cognitive functions are impaired in those who take anticonvulsants. Copyright © 2015. Published by Elsevier B.V.

  12. Interleukin-2 (rIL-2)-induced lymphokine-activated killer (LAK) cells and their precursors express the VGO1 antigen

    International Nuclear Information System (INIS)

    Denegri, J.F.; Peterson, J.; Tilley, P.

    1989-01-01

    Precursor and effector cells of recombinant interleukin-2 (r-IL-2)-induced lymphokine-activated killer (LAK) activity were investigated for their expression of VGO1. Peripheral blood lymphocytes (PBL) from normal donors were purified and separated in a FACS 420 into VGO1+- and VGO1- cell fractions before and after culture for 96 hr with 100 U/ml of r-IL-2. Their lytic activity against K 562 and Daudi cells was measured in a 51Cr release assay. The majority, if not all, of the LAK effector and precursor cells was VGO1+ lymphocytes. The expression of VGO1 by LAK precursor cells remained stable under the culture conditions used in our experiments. VGO1- lymphocytes cultured with r-IL-2 demonstrated neither LAK-induced activity nor expression of VGO1 antigen

  13. Nitric oxide mediates the anticonvulsant effects of thalidomide on pentylenetetrazole-induced clonic seizures in mice.

    Science.gov (United States)

    Payandemehr, Borna; Rahimian, Reza; Gooshe, Maziar; Bahremand, Arash; Gholizadeh, Ramtin; Berijani, Sina; Ahmadi-Dastgerdi, Mohammad; Aminizade, Mehdi; Sarreshte-Dari, Ali; Dianati, Vahid; Amanlou, Massoud; Dehpour, Ahmad Reza

    2014-05-01

    Thalidomide is an old glutamic acid derivative which was initially used as a sedative medication but withdrawn from the market due to the high incidence of teratogenicity. Recently, it has reemerged because of its potential for counteracting number of diseases, including neurodegenerative disorders. Other than the antiemetic and hypnotic aspects, thalidomide exerts some anticonvulsant properties in experimental settings. However, the underlying mechanisms of thalidomide actions are not fully realized yet. Some investigations revealed that thalidomide could elicit immunomodulatory or neuromodulatory properties by affecting different targets, including cytokines (such as TNF α), neurotransmitters, and nitric oxide (NO). In this regard, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of thalidomide is affected through modulation of the l-arginine-nitric oxide pathway or not. Injection of a single effective dose of thalidomide (10 mg/kg, i.p. or higher) significantly increased the seizure threshold (P<0.05). On the one hand, pretreatment with low and per se noneffective dose of l-arginine [NO precursor] (10, 30 and 60 mg/kg) prevented the anticonvulsant effect of thalidomide. On the other hand, NOS inhibitors [l-NAME and 7-NI] augmented the anticonvulsant effect of a subeffective dose of thalidomide (1 and 5 mg/kg, i.p.) at relatively low doses. Meanwhile, several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of thalidomide significantly. In summary, our findings demonstrated that the l-arginine-nitric oxide pathway can be involved in the anticonvulsant properties of thalidomide, and the role of constitutive nNOS is prominent in the reported neuroprotective feature. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Analgesic and anticonvulsant effects of extracts from the leaves of Kalanchoe crenata (Andrews) Haworth (Crassulaceae).

    Science.gov (United States)

    Nguelefack, T B; Nana, P; Atsamo, A D; Dimo, T; Watcho, P; Dongmo, A B; Tapondjou, L A; Njamen, D; Wansi, S L; Kamanyi, A

    2006-06-15

    Kalanchoe crenata Andr. (Crassulaceae) is a fleshy herbaceous plant used in the African traditional medicine as remedies against otitis, headache, inflammations, convulsions and general debility. In the present work, the analgesic effects of methylene chloride/methanol (1:1) (CH(2)Cl(2)/CH(3)OH) extract and its hexane, methylene chloride (CH(2)Cl(2)), ethyl acetate, n-butanol fractions and aqueous residue have been evaluated using acetic acid, formalin and pressure test. The anticonvulsant effects of the CH(2)Cl(2)/CH(3)OH extract were also investigated on seizures induced by pentylenetetrazol (PTZ 70 mg/kg), strychnine sulphate (STN 2.5 mg/kg) and thiosemicarbazide (TSC 50 mg/kg). CH(2)Cl(2)/CH(3)OH extract and its fractions, administered orally at the doses of 150 and 300 mg/kg, exhibited protective effect of at least 30% on the pain induced by acetic acid. The CH(2)Cl(2) fraction at 300 mg/kg showed a maximal effect of 78.49%. The CH(2)Cl(2)/CH(3)OH extract and its CH(2)Cl(2) fraction at the doses of 150 and 300 mg/kg significantly reduced the first phase of pain induced by formalin while the second phase was completely inhibited. The CH(2)Cl(2) fraction produced more than 45% reduction in the sensitivity to pain induced by pressure. The CH(2)Cl(2)/CH(3)OH extract of Kalanchoe crenata significantly increased the latency period in seizures induced by PTZ and significantly reduced the duration of seizures induced by the three convulsant agents. The extract protected 20% of animals against death in seizures induced by TSC and STN. These results suggest a peripheral and central analgesic activities as well as an anticonvulsant effect of the leaves of Kalanchoe crenata.

  15. Isothermal (vapour + liquid) equilibrium for the binary {l_brace}1,1,2,2-tetrafluoroethane (R134) + propane (R290){r_brace} and {l_brace}1,1,2,2-tetrafluoroethane (R134) + isobutane (R600a){r_brace} systems

    Energy Technology Data Exchange (ETDEWEB)

    Dong Xueqiang [Key Laboratory of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, P.O. Box 2711, Beijing 100190 (China); Graduate University of Chinese Academy of Sciences, Beijing 100039 (China); Gong Maoqiong, E-mail: gongmq@mail.ipc.ac.c [Key Laboratory of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, P.O. Box 2711, Beijing 100190 (China); Liu Junsheng [Key Laboratory of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, P.O. Box 2711, Beijing 100190 (China); Graduate University of Chinese Academy of Sciences, Beijing 100039 (China); Wu Jianfeng, E-mail: jfwu@mail.ipc.ac.c [Key Laboratory of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, P.O. Box 2711, Beijing 100190 (China)

    2010-09-15

    (Vapour + liquid) equilibrium (VLE) data for the binary systems of {l_brace}1,1,2,2-tetrafluoroethane (R134) + propane (R290){r_brace} and {l_brace}1,1,2,2-tetrafluoroethane (R134) + isobutane (R600a){r_brace} were measured with a recirculation method at the temperatures ranging from (263.15 to 278.15) K and (268.15 to 288.15) K, respectively. All of the data were correlated by the Peng-Robinson (PR) equation of state (EoS) with the Huron-Vidal (HV) mixing rules utilizing the non-random two-liquid (NRTL) activity coefficient model. Good agreement can be found between the experimental data and the correlated results. Azeotropic behaviour can be found at the measured temperature ranges for these two mixtures.

  16. Activation of type 2 cannabinoid receptors (CB2R) promotes fatty acid oxidation through the SIRT1/PGC-1α pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Xuqin [Department of Endocrinology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province 210029 (China); Sun, Tao [Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province 210002 (China); Wang, Xiaodong, E-mail: xdwang666@hotmail.com [Department of Endocrinology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province 210029 (China)

    2013-07-05

    Highlights: •TC, a CB2R specific agonist, stimulates SIRT1 activity by PKA/CREB pathway. •TC promotes PGC-1α transcriptional activity by increasing its deacetylation. •TC increases the expression of genes linked to FAO and promotes the rate of FAO. •The effects of TC in FAO are dependent on CB2R. •Suggesting CB2R as a target to treat diseases with lipid dysregulation. -- Abstract: Abnormal fatty acid oxidation has been associated with obesity and type 2 diabetes. At the transcriptional level, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) has been reported to strongly increase the ability of hormone nuclear receptors PPARα and ERRα to drive transcription of fatty acid oxidation enzymes. In this study, we report that a specific agonist of the type 2 cannabinoid receptor (CB2R) can lead to fatty acid oxidation through the PGC-1α pathway. We have found that CB2R is expressed in differentiated C2C12 myotubes, and that use of the specific agonist trans-caryophyllene (TC) stimulates sirtuin 1 (SIRT1) deacetylase activity by increasing the phosphorylation of cAMP response element-binding protein (CREB), thus leading to increased levels of PGC-1α deacetylation. This use of TC treatment increases the expression of genes linked to the fatty acid oxidation pathway in a SIRT1/PGC-1α-dependent mechanism and also drastically accelerates the rate of complete fatty acid oxidation in C2C12 myotubes, neither of which occur when CB2R mRNA is knocked down using siRNA. These results reveal that activation of CB2R by a selective agonist promotes lipid oxidation through a signaling/transcriptional pathway. Our findings imply that pharmacological manipulation of CB2R may provide therapeutic possibilities to treat metabolic diseases associated with lipid dysregulation.

  17. A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists.

    Science.gov (United States)

    Miller, Steven L; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H; Prager, Eric M; Almeida-Suhett, Camila P; Apland, James P; Braga, Maria F M

    2015-04-15

    Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD50 of 62μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS) at 2mg/kg, administered 20 min after soman exposure (1.2×LD50), terminated seizures. ATS at 0.5mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1h post-exposure, prevents brain pathology and behavioral deficits. Published by Elsevier Inc.

  18. The Odorant ( R)-Citronellal Attenuates Caffeine Bitterness by Inhibiting the Bitter Receptors TAS2R43 and TAS2R46.

    Science.gov (United States)

    Suess, Barbara; Brockhoff, Anne; Meyerhof, Wolfgang; Hofmann, Thomas

    2018-03-14

    Sensory studies showed the volatile fraction of lemon grass and its main constituent, the odor-active citronellal, to significantly decrease the perceived bitterness of a black tea infusion as well as caffeine solutions. Seven citronellal-related derivatives were synthesized and shown to inhibit the perceived bitterness of caffeine in a structure-dependent manner. The aldehyde function at carbon 1, the ( R)-configuration of the methyl-branched carbon 3, and a hydrophobic carbon chain were found to favor the bitter inhibitory activity of citronellal; for example, even low concentrations of 25 ppm were observed to reduce bitterness perception of caffeine solution (6 mmol/L) by 32%, whereas ( R)-citronellic acid (100 pm) showed a reduction of only 21% and ( R)-citronellol (100 pm) was completely inactive. Cell-based functional experiments, conducted with the human bitter taste receptors TAS2R7, TAS2R10, TAS2R14, TAS2R43, and TAS2R46 reported to be sensitive to caffeine, revealed ( R)-citronellal to completely block caffeine-induced calcium signals in TAS2R43-expressing cells, and, to a lesser extent, in TAS2R46-expressing cells. Stimulation of TAS2R43-expressing cells with structurally different bitter agonists identified ( R)-citronellal as a general allosteric inhibitor of TAS2R43. Further structure/activity studies indicated 3-methyl-branched aliphatic aldehydes with a carbon chain of ≥4 C atoms as best TAS2R43 antagonists. Whereas odor-taste interactions have been mainly interpreted in the literature to be caused by a central neuronal integration of odors and tastes, rather than by peripheral events at the level of reception, the findings of this study open up a new dimension regarding the interaction of the two chemical senses.

  19. Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity.

    Directory of Open Access Journals (Sweden)

    Yang Shu

    Full Text Available Recent studies have linked certain single nucleotide polymorphisms in the leucine-rich repeat kinase 2 (LRRK2 gene with Parkinson's disease (PD. Among the mutations, LRRK2 c.4883G>C (R1628P variant was identified to have a significant association with the risk of PD in ethnic Han-Chinese populations. But the molecular pathological mechanisms of R1628P mutation in PD is still unknown.Unlike other LRRK2 mutants in the Roc-COR-Kinase domain, the R1628P mutation didn't alter the LRRK2 kinase activity and promote neuronal death directly. LRRK2 R1628P mutation increased the binding affinity of LRRK2 with Cyclin-dependent kinase 5 (Cdk5. Interestingly, R1628P mutation turned its adjacent amino acid residue S1627 on LRRK2 protein to a novel phosphorylation site of Cdk5, which could be defined as a typical type II (+ phosphorylation-related single nucleotide polymorphism. Importantly, we showed that the phosphorylation of S1627 by Cdk5 could activate the LRRK2 kinase, and neurons ectopically expressing R1628P displayed a higher sensitivity to 1-methyl-4-phenylpyridinium, a bioactive metabolite of environmental toxin MPTP, in a Cdk5-dependent manner.Our data indicate that Parkinson-related LRRK2 mutation R1628P leads to Cdk5 phosphorylation of LRRK2 at S1627, which would upregulate the kinase activity of LRRK2 and consequently cause neuronal death.

  20. Anticonvulsant effect of time-restricted feeding in a pilocarpine-induced seizure model: Metabolic and epigenetic implications.

    Directory of Open Access Journals (Sweden)

    Jorge eLandgrave-Gómez

    2016-01-01

    Full Text Available A new generation of antiepileptic drugs has emerged; however, one-third of epilepsy patients do not properly respond to pharmacological treatments. The purpose of the present study was to investigate whether time-restricted feeding has an anticonvulsant effect and whether this restrictive diet promotes changes in energy metabolism and epigenetic modifications in a pilocarpine-induced seizure model. To resolve our hypothesis, one group of rats had free access to food and water ad libitum (AL and a second group underwent a time-restricted feeding (TRF schedule. We used the lithium-pilocarpine model to induce status epilepticus (SE, and behavioral seizure monitoring was analyzed. Additionally, an electroencephalography (EEG recording was performed to verify the effect of TRF on cortical electrical activity after a pilocarpine injection. For biochemical analysis, animals were sacrificed 24 hours after SE and hippocampal homogenates were used to evaluate the proteins related to metabolism and chromatin structure. Our results showed that TRF had an anticonvulsant effect as measured by the prolonged latency of forelimb clonus seizure, a decrease in the seizure severity score and fewer animals reaching SE. Additionally, the power of the late phase EEG recordings in the AL group was significantly higher than the TRF group. Moreover, we found that TRF is capable of inducing alterations in signaling pathways that regulate energy metabolism, including an increase in the phosphorylation of AMP dependent kinase (AMPK and a decrease in the phosphorylation of Akt kinase. Furthermore, we found that TRF was able to significantly increase the beta hydroxybutyrate (β-HB concentration, an endogenous inhibitor of histone deacetylases (HDACs. Finally, we found a significant decrease in HDAC activity as well as an increase in acetylation on histone 3 (H3 in hippocampal homogenates from the TRF group. These findings suggest that alterations in energy metabolism and the

  1. Synthesis and research of benzylamides of some isocyclic and heterocyclic acids as potential anticonvulsants.

    Science.gov (United States)

    Strupińska, Marzanna; Rostafińska-Suchar, Grazyna; Pirianowicz-Chaber, Elzbieta; Stables, James P; Jiang, Jeff; Paruszewski, Ryszard

    2013-01-01

    A series of benzylamides of isocyclic and heterocyclic acids was synthesized and tested in Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Near all synthesized derivatives of heterocyclic acids showed activity. All obtained derivatives of mono- and bicyclic isocyclic acids were inactive. The power of action of heterocyclic acids derivatives seems does not depend upon kind of heteroatom (N, O or S). One of the compounds (2-furoic acid benzylamide (4)) appeared most promising. It showed in minimal clonic seizure (6Hz) test (ASP) in rats after i. p. administration: MES ED50 = 36.5 mg/kg, TOX TD50 = 269.75 mg/kg, and PI = 7.39.

  2. Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients

    Science.gov (United States)

    Tartara, A.; Galimberti, C.A.; Manni, R.; Parietti, L.; Zucca, C.; Baasch, H.; Caresia, L.; Mück, W.; Barzaghi, N.; Gatti, G.; Perucca, E.

    1991-01-01

    1 The single dose pharmacokinetics of orally administered nimodipine (60 mg) were investigated in normal subjects and in two groups of epileptic patients receiving chronic treatment with hepatic microsomal enzyme-inducing anticonvulsants (carbamazepine, phenobarbitone or phenytoin) and sodium valproate, respectively. 2 Compared with the values found in the control group, mean areas under the plasma nimodipine concentration curve were lowered by about seven-fold (P anticonvulsants and increased by about 50% (P < 0.05) in patients taking sodium valproate. 3 Nimodipine half-lives were shorter in enzyme-induced patients than in controls (3.9 ± 2.0 h vs 9.1 ± 3.4 h, means ± s.d., P < 0.01), but this difference could be artifactual since in the patients drug concentrations declined rapidly below the limit of assay, thus preventing identification of a possible slower terminal phase. In valproate-treated patients, half-lives (8.2 ± 1.8 h) were similar to those found in controls. PMID:1777370

  3. Analysis of the DNA-Binding Activities of the Arabidopsis R2R3-MYB Transcription Factor Family by One-Hybrid Experiments in Yeast.

    Directory of Open Access Journals (Sweden)

    Zsolt Kelemen

    Full Text Available The control of growth and development of all living organisms is a complex and dynamic process that requires the harmonious expression of numerous genes. Gene expression is mainly controlled by the activity of sequence-specific DNA binding proteins called transcription factors (TFs. Amongst the various classes of eukaryotic TFs, the MYB superfamily is one of the largest and most diverse, and it has considerably expanded in the plant kingdom. R2R3-MYBs have been extensively studied over the last 15 years. However, DNA-binding specificity has been characterized for only a small subset of these proteins. Therefore, one of the remaining challenges is the exhaustive characterization of the DNA-binding specificity of all R2R3-MYB proteins. In this study, we have developed a library of Arabidopsis thaliana R2R3-MYB open reading frames, whose DNA-binding activities were assayed in vivo (yeast one-hybrid experiments with a pool of selected cis-regulatory elements. Altogether 1904 interactions were assayed leading to the discovery of specific patterns of interactions between the various R2R3-MYB subgroups and their DNA target sequences and to the identification of key features that govern these interactions. The present work provides a comprehensive in vivo analysis of R2R3-MYB binding activities that should help in predicting new DNA motifs and identifying new putative target genes for each member of this very large family of TFs. In a broader perspective, the generated data will help to better understand how TF interact with their target DNA sequences.

  4. Optically active antifungal azoles. XII. Synthesis and antifungal activity of the water-soluble prodrugs of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone.

    Science.gov (United States)

    Ichikawa, T; Kitazaki, T; Matsushita, Y; Yamada, M; Hayashi, R; Yamaguchi, M; Kiyota, Y; Okonogi, K; Itoh, K

    2001-09-01

    1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1: TAK-456) was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, the quaternary triazolium salts 2 were designed as water-soluble prodrugs. Among the prodrugs prepared, 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1-terazolyl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium chloride (2a: TAK-457) was selected as an injectable candidate for clinical trials based on the results of evaluations on solubility, stability, hemolytic effect and in vivo antifungal activities.

  5. Modulation of seizure activity in mice by metabotropic glutamate receptor ligands

    DEFF Research Database (Denmark)

    Dalby, Nils Ole; Thomsen, C

    1996-01-01

    The anticonvulsant properties of ligands at metabotropic glutamate receptors (mGluRs) were examined in different seizure models by use of intracerebroventricular infusion. The mGluR1a antagonist/mGluR2 agonist, (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3HPG] dose-dependently antagonized...... pentylenetetrazol- and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-2-carboxylate (DMCM)-induced clonic convulsions in mice with ED50 values of 400 and 180 nmol/mice, respectively. A modest increase in electrical seizure threshold was observed in mice injected with (S)-4C3HPG. No effect on seizures induced...... by systemic administration of N-methyl-D-aspartate was observed by prior intracerebroventricular infusion of (S)-4C3HPG. The more selective (but less potent) mGluR1a antagonist, (S)-4-carboxyphenylglycine, was a weak anticonvulsant in similar seizure models with the exception of convulsions induced...

  6. The anticonvulsant gabapentin (neurontin) does not act through gamma-aminobutyric acid-B receptors

    DEFF Research Database (Denmark)

    Jensen, Anders A.; Mosbacher, Johannes; Elg, Susanne

    2002-01-01

    The actions of the anticonvulsant gabapentin [1-(aminomethyl)cyclohexaneacetic acid, Neurontin] have been somewhat enigmatic until recently, when it was claimed to be a gamma-aminobutyric acid-B (GABA(B)) receptor agonist acting exclusively at a heterodimeric complex containing the GABA(B(1a...... in vitro assays. In light of these results, we find it highly questionable that gabapentin is a GABA(B) receptor agonist. Hence, the anticonvulsive effects of the compound have to arise from GABA(B) receptor-independent mechanisms. This also implies that the first GABA(B) receptor splice variant...

  7. Effect of reduction of anticonvulsants on wellbeing.

    Science.gov (United States)

    Fischbacher, E

    1982-01-01

    An attempt was made over a period of a year to reduce the number of anticonvulsants used to treat epilepsy in a hospital for the mentally handicapped. At least one drug was withdrawn for each of 20 patients, without loss of seizure control. Effect on wellbeing was assessed by a behavioural scale completed before and after withdrawal, and in the 20 cases of successful withdrawal wellbeing was significantly improved. PMID:6809110

  8. Teratogenic risk and contraceptive counselling in psychiatric practice: analysis of anticonvulsant therapy

    Science.gov (United States)

    2013-01-01

    Background Anticonvulsants have been used to manage psychiatric conditions for over 50 years. It is recognised that some, particularly valproate, carbamazepine and lamotrigine, are human teratogens, while others including topiramate require further investigation. We aimed to appraise the documentation of this risk by psychiatrists and review discussion around contraceptive issues. Methods A retrospective review of prescribing patterns of four anticonvulsants (valproate, carbamazepine, lamotrigine and topiramate) in women of child bearing age was undertaken. Documented evidence of discussion surrounding teratogenicity and contraceptive issues was sought. Results Valproate was most commonly prescribed (n=67). Evidence of teratogenic risk counselling at medication initiation was sub-optimal – 40% of individuals prescribed carbamazepine and 22% of valproate. Documentation surrounding contraceptive issues was also low- 17% of individuals prescribed carbamazepine and 13% of valproate. Conclusion We found both low rates of teratogenic risk counselling and low rates of contraception advice in our cohort. Given the high rates of unplanned pregnancies combined with the relatively high risk of major congenital malformations, it is essential that a detailed appraisal of the risks and benefits associated with anticonvulsant medication occurs and is documented within patients’ psychiatric notes. PMID:24066860

  9. Enhancement of inhibitory neurotransmission and inhibition of excitatory mechanisms underlie the anticonvulsant effects of Mallotus oppositifolius

    Directory of Open Access Journals (Sweden)

    Kennedy Kwami Edem Kukuia

    2016-01-01

    Full Text Available Context: Mallotus oppositifolius is a shrub that is used traditionally to treat epilepsy, but its potential has not been scientifically validated. Aims: This study investigated the anticonvulsant properties and possible mechanism of action of the 70% v/v hydroalcoholic extract of the leaves of M. oppositifolius.Materials and Methods: Inprinting control region (ICR mice (25–30 g were pretreated with the M. oppositifolius leaf extract (10–100 mg/kg before administering the respective convulsants (pentylenetetrazole [PTZ], picrotoxin [PTX], strychnine [STR], 4-aminopyridine [4-AP], and pilocarpine. The effect of the extract in maximal electroshock seizure (MES model was investigated also. Statistical Analysis: Data were presented as mean ± standard error of the mean and were analyzed with one-way analysis of variance (ANOVA or two-way ANOVA where appropriate with Newman–Keuls or Bonferroni post hoc test respectively. P< 0.05 was considered significant. Results: In both PTX and PTZ test, extract delayed the onset of seizures and reduced the frequency and duration of seizures. In the STR-induced seizure test, the extract significantly delayed the onset of seizures and reduced the duration of seizures. The extract also delayed the onset of clonic and tonic seizures as well as increasing the survival of mice in the 4-AP-induced seizure test. It further reduced the duration of tonic limb extensions in the MES test. In the pilocarpine-induced status epilepticus, the extract significantly delayed the onset of clonic convulsions and reduced the frequency and duration of seizures. Moreover, the anticonvulsant effect of the extract was attenuated by flumazenil, a benzodiazepine/gamma-aminobutyric acid (GABA receptor antagonist. Conclusion: These findings show that the extract has anticonvulsant effect possible mediated by GABAergic, glycinergic neurotransmission, and potassium channel conductions. It may also be acting by antagonizing muscarinic

  10. Progressive anticonvulsant hypersensitivity syndrome associated with change of drug product

    DEFF Research Database (Denmark)

    Sabroe, T.P.; Sabers, A.

    2008-01-01

    This report describes the laboratory and physical manifestations of lamotrigine-like toxicity in a young man with refractory epilepsy receiving lamotrigine presenting as anticonvulsant hypersensitivity syndrome (AHS) associated with an abrupt change of drug product Udgivelsesdato: 2008/6...

  11. Synthesis of carbon-14 and tritium labeled cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzamidehydrochloride, an anticonvulsant agent

    International Nuclear Information System (INIS)

    Hsi, R.S.P.; Stolle, W.T.; Ayer, D.E.

    1992-01-01

    The title compound, U-54494A, is an anticonvulsant agent with clinical potential for treating epilepsy and a broad spectrum of seizure disorders. Structurally it is related to kappa opiod agonists and shares their anticonvulsant properties, but appears to be devoid of analgesic, sedative, and diuretic side effects. It also has been shown to inhibit neuronal damage and seizures induced by excitatory amino acids. This report describes the synthesis of the racemic U-54494A labeled with carbon-14 at the carboxamide carbon and with tritium in the pyrrolidine ring at C-3 and C-4. These radioisotope labeled versions of U-54494A were prepared for conducting drug disposition studies of this compound in test animals and human subjects

  12. Association between consistent purchase of anticonvulsants or lithium and suicide risk: a longitudinal cohort study from Denmark, 1995-2001

    DEFF Research Database (Denmark)

    Smith, Eric G; Søndergård, Lars; Lopez, Ana Garcia

    2009-01-01

    BACKGROUND: Prior studies suggest anticonvulsants purchasers may be at greater risk of suicide than lithium purchasers. METHODS: Longitudinal, retrospective cohort study of all individuals in Denmark purchasing anticonvulsants (valproic acid, carbamazepine, oxcarbazepine or lamotrigine) (n=9952...

  13. The efficacy of anticonvulsants on orofacial pain: a systematic review

    NARCIS (Netherlands)

    Martin, W.J.J.M.; Forouzanfar, T.

    2011-01-01

    Objective. Controversy exists about the effectiveness of anticonvulsants for the management of orofacial pain disorders. To ascertain appropriate therapies, a systematic review was conducted of existing randomized controlled trials. Study design. Trials were identified from PubMed, Cochrane, and

  14. Derivatives of valproic acid are active against pentetrazol-induced seizures in immature rats

    Czech Academy of Sciences Publication Activity Database

    Mareš, Pavel; Kubová, Hana; Hen, N.; Yagen, B.; Bialer, M.

    2013-01-01

    Roč. 106, 1-2 (2013), s. 64-73 ISSN 0920-1211 R&D Projects: GA ČR(CZ) GAP304/10/1274; GA ČR(CZ) GBP304/12/G069 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : experimental seizures * anticonvulsant action * derivatives of valproic acid * immature rats Subject RIV: FH - Neurology Impact factor: 2.190, year: 2013

  15. Synthesis and biological characterization of (3R,4R)-4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol and its stereoisomers for activity toward monoamine transporters.

    Science.gov (United States)

    Kharkar, Prashant S; Batman, Angela M; Zhen, Juan; Beardsley, Patrick M; Reith, Maarten E A; Dutta, Aloke K

    2009-07-01

    A novel series of optically active molecules based on a 4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol template were developed. Depending on stereochemistry, the compounds exhibit various degrees of affinity for three dopamine, serotonin, and norepinephrine transporters. These molecules have the potential for treating several neurological disorders such as drug abuse, depression, and attention deficit hyperactivity disorder.Herein we describe the synthesis and biological evaluation of a series of asymmetric 4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol-based dihydroxy compounds in which the hydroxy groups are located on both the piperidine ring and the N-phenylethyl side chain. In vitro uptake inhibition data of these molecules indicate high affinity for the dopamine transporter (DAT) in addition to moderate to high affinity for the norepinephrine transporter (NET). Interestingly, compounds 9 b and 9 d exhibit affinities for all three monoamine transporters, with highest potency at DAT and NET, and moderate potency at the serotonin transporter (SERT) (K(i): 2.29, 78.4, and 155 nM for 9 b and 1.55, 14.1, and 259 nM for 9 d, respectively). Selected compounds 9 a, 9 d, and 9 d' were tested for their locomotor activity effects in mice and for their ability to occasion the cocaine-discriminative stimulus in rats. These test compounds generally exhibit a much longer duration of action than cocaine for elevating locomotor activity, and completely generalize the cocaine-discriminative stimulus in a dose-dependent manner.

  16. Mitochondrial Profiles and the Anticonvulsant Effect of the Ketogenic Diet

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-09-01

    Full Text Available A study of the anticonvulsant effect of the ketogenic diet (KD in adolescent rats, at Emory University and other centers, found that the hippocampus responds by inducing mitochondrial biogenesis, enhancing metabolic gene expression, and increasing energy reserves.

  17. Anticonvulsant and proconvulsant roles of nitric oxide in experimental epilepsy models

    Directory of Open Access Journals (Sweden)

    Del-Bel E.A.

    1997-01-01

    Full Text Available The effect of acute (120 mg/kg and chronic (25 mg/kg, twice a day, for 4 days intraperitonial injection of the nitric oxide (NO synthase (NOS inhibitor NG-nitro-L-arginine (L-NOARG was evaluated on seizure induction by drugs such as pilocarpine and pentylenetetrazole (PTZ and by sound stimulation of audiogenic seizure-resistant (R and audiogenic seizure-susceptible (S rats. Seizures were elicited by a subconvulsant dose of pilocarpine (100 mg/kg only after NOS inhibition. NOS inhibition also simultaneously potentiated the severity of PTZ-induced limbic seizures (60 mg/kg and protected against PTZ-induced tonic seizures (80 mg/kg. The audiogenic seizure susceptibility of S or R rats did not change after similar treatments. In conclusion, proconvulsant effects of NOS inhibition are suggested to occur in the pilocarpine model and in the limbic components of PTZ-induced seizures, while an anticonvulsant role is suggested for the tonic seizures induced by higher doses of PTZ, revealing inhibitor-specific interactions with convulsant dose and also confirming the hypothesis that the effects of NOS inhibitors vary with the model of seizure

  18. Anticonvulsant actions of LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid).

    Science.gov (United States)

    Chapman, A G; Yip, P K; Yap, J S; Quinn, L P; Tang, E; Harris, J R; Meldrum, B S

    1999-02-26

    We have studied the effects in three rodent models of generalised convulsive or absence epilepsy of two antagonists of group I metabotropic glutamate receptors that are selective for the mGlu1 receptor. LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid) have been administered intracerebroventricularly (i.c.v.) to DBA/2 mice and lethargic mice (lh/lh), and focally into the inferior colliculus of genetically epilepsy prone rats (GEPR). In DBA/2 mice both compounds produce a rapid, transient suppression of sound-induced clonic seizures (LY 367385: ED50 = 12 nmol, i.c.v., 5 min; AIDA: ED50 = 79 nmol, i.c.v., 15 min). In lethargic mice both compounds significantly reduce the incidence of spontaneous spike and wave discharges on the electroencephalogram, from 150 min after the administration of AIDA, 500 nmol, i.c.v., and from 30 to >150 min after the administration of LY 367385, 250 nmol, i.c.v. LY 367385, 50 nmol, suppresses spontaneous spike and wave discharges from 30 to 60 min. In genetically epilepsy prone rats both compounds reduce sound-induced clonic seizures. LY 367385, 160 nmol bilaterally, fully suppresses clonic seizures after 2-4 h. AIDA is fully effective 30 min after 100 nmol bilaterally. It is concluded that antagonists of mGlu1 receptors are potential anticonvulsant agents and that activation of mGlu1 receptors probably contributes to a variety of epileptic syndromes.

  19. Anticonvulsant and sedative effect of Fufang Changniu pills and ...

    African Journals Online (AJOL)

    Results: Gallic acid, liquiritin, cinnamyl alcohol, cinnamic acid and glycyrrhizic acid were detected in. FCP decoction. FCP (50, 100 and 200 mg/kg) showed significant anticonvulsant and sedative effects on epileptic mice induced by MES (p < 0.05) and PTZ (p < 0.05). Moreover, pentobarbital sodium-induced sleeping time ...

  20. Evidence for use of mood stabilizers and anticonvulsants in the treatment of nonaffective disorders in children and adolescents.

    Science.gov (United States)

    Amaladoss, Alfred; Roberts, Nasreen; Amaladoss, Franklin

    2010-01-01

    Mood stabilizers and anticonvulsants have been frequently used to control behaviors in children and adolescent with nonaffective disorders. The purpose of this study was to review the literature to evaluate the evidence of these agents as treatment options in this subset of patients. We reviewed all the literature between 1949 and 2009 on the use of anticonvulsants and mood stabilizers in controlling severe behavior dysregulation and aggression in child and adolescent who do not meet the criteria for any mood disorder. The review revealed a total of 19 studies. Of the different mood stabilizers/anticonvulsants, both lithium and divalproex showed some promise in treating children and adolescents with nonmood disorders. Larger studies are nevertheless needed to support the ongoing use of these current anticonvulsants and mood stabilizers in children and adolescents with nonmood disorders. Also, further investigation to the potential use in the long term would need to be established, bearing in mind the balance of side effects and treatment benefit.

  1. Anticonvulsants or Antidepressants in Combination Pharmacotherapy for Treatment of Neuropathic Pain in Cancer Patients: A Systematic Review and Meta-analysis.

    Science.gov (United States)

    Guan, Jia; Tanaka, Shiro; Kawakami, Koji

    2016-08-01

    To investigate the efficacy of anticonvulsants or antidepressants in combination pharmacotherapy for treatment of neuropathic pain in cancer patients. We systematically searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and the metaRegister of Controlled Trials for randomized controlled trials that compared anticonvulsants or antidepressants in combination pharmacotherapy (experimental group) with treatments without anticonvulsants or antidepressants (control group) for neuropathic pain in cancer patients. Risk of bias was evaluated in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was a mean difference (MD) in change in global pain analyzed by a random-effects model. Eight trials met the inclusion criteria with a total of 1359 participants of whom 698 received an experimental intervention. The MD in change in global pain suggested a favorable association with anticonvulsants or antidepressants in combination pharmacotherapy compared with control groups (MD, -0.41; 95% confidence interval, -0.70 to -0.12) with no heterogeneity across trials (I=0%). The MD in change estimated in all sensitivity analyses ranged from -0.36 to -0.47, suggesting that these effects were consistent across different study designs and statistical assumptions. Anticonvulsants or antidepressants in combination pharmacotherapy reduce neuropathic pain in cancer patients compared with treatments without anticonvulsants or antidepressants. Limited evidence precludes a recommendation on specific adjuvants in combination pharmacotherapy.

  2. Synthesis, physical-chemical properties, antimicrobial and antifungal activity of some 2-(2-((5-(adamantane-1-yl-4-R-1,2,4-triazole-3-ylthioacetyl-N-R1–hydrazine-carbothioamides

    Directory of Open Access Journals (Sweden)

    V. M. Odyntsova

    2017-12-01

    Full Text Available Special attention of pharmaceutical scientists is attracted to the creation of new potential substances. They select natural heterocyclic molecules that exhibit various types of pharmacological activity as basic structures. Adamantane derivatives, as well as a number of other framework compounds, in the vast majority are biologically active substances. This fact causes interest to the given classes of organic compounds as potential sources for the development of new drugs. Due to the high pharmacological action of 1,2,4-triazole derivatives, the combination of adamantane and 1,2,4-triazole in one molecule can lead to the formation of high-level pharmacological substances. The aim of this work is the synthesis of some 2- (2 - ((5- (adamantane-1-yl -4-R-1,2,4-triasole-3-yl thio acetyl -N-R1-hydrazine-carbothioamides, study of their physical and chemical properties, antimicrobial and antifungal activity. Materials and methods. The chemical names of the compounds are given in accordance with the requirements of the IUPAC nomenclature (1979 and the recommendations of the IUPAC (1993. Study of the physical and chemical properties of 2-(2-((5-(adamantane-1-yl-4-R-1,2,4-triazole-3-ylthioacetyl-N-R1-hydrazine-carbothioamides have been carried out on the certified and licensed equipment in the ZSMU physical-chemical laboratories. The melting temperature was determined by an open capillary method on the Opti Melt MPA 100. The elemental composition of the synthesized compounds was determined on the universal analyzer Elementar Vario L cube (CHNS (standard – sulfanilamide. 1H NMR spectra were recorded on a spectrometer Varian Mercury VX-200 (1H, 200 MHz in dimethylsulfoxide-d6solvent (tetramethylsilane - internal standard and are decoded using ADVASP(tmAnalyzer program (Umatek International Inc.. Chromatographic mass spectral studies were performed on a gas-liquid chromatograph Agilent 1260 Infinity HPLC equipped with an Agilent 6120 mass spectrometer

  3. GABAA Receptors, Anesthetics and Anticonvulsants in Brain Development

    Science.gov (United States)

    Henschel, Oliver; Gipson, Keith E.; Bordey, Angelique

    2008-01-01

    GABA, acting via GABAA receptors, is well-accepted as the main inhibitory neurotransmitter of the mature brain, where it dampens neuronal excitability. The receptor's properties have been studied extensively, yielding important information about its structure, pharmacology, and regulation that are summarized in this review. Several GABAergic drugs have been commonly used as anesthetics, sedatives, and anticonvulsants for decades. However, findings that GABA has critical functions in brain development, in particular during the late embryonic and neonatal period, raise worthwhile questions regarding the side effects of GABAergic drugs that may lead to long-term cognitive deficits. Here, we will review some of these drugs in parallel with the control of CNS development that GABA exerts via activation of GABAA receptors. This review aims to provide a basic science and clinical perspective on the function of GABA and related pharmaceuticals acting at GABAA receptors. PMID:18537647

  4. Structure-activity relationship of daptomycin analogues with substitution at (2S, 3R) 3-methyl glutamic acid position.

    Science.gov (United States)

    Lin, Du'an; Lam, Hiu Yung; Han, Wenbo; Cotroneo, Nicole; Pandya, Bhaumik A; Li, Xuechen

    2017-02-01

    Daptomycin is a highly effective lipopeptide antibiotic against Gram-positive pathogens. The presence of (2S, 3R) 3-methyl glutamic acid (mGlu) in daptomycin has been found to be important to the antibacterial activity. However the role of (2S, 3R) mGlu is yet to be revealed. Herein, we reported the syntheses of three daptomycin analogues with (2S, 3R) mGlu substituted by (2S, 3R) methyl glutamine (mGln), dimethyl glutamic acid and (2S, 3R) ethyl glutamic acid (eGlu), respectively, and their antibacterial activities. The detailed synthesis of dimethyl glutamic acid was also reported. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. R2E strategy and activities during LS1

    International Nuclear Information System (INIS)

    Perrot, A.L.

    2012-01-01

    The level of the flux of hadrons with energy in the multi MeV range expected from the collimation system at Point 7 and from the collisions at the interaction Points 1, 5 and 8 will induce Single Event Errors (SEEs) of the standard electronics present in the equipment located around these Points. Such events would perturb LHC operation. As a consequence, within the framework of the R2E (Radiation to Electronics) Mitigation Project, the sensitive equipment will be shielded or relocated to safer areas. These mitigation activities will be performed mainly during Long Shutdown 1 (LS1). About 15 groups (including equipment owners) will be involved in these activities with work periods from a few days to several months. Some of them will have to work in parallel in several LHC points. This document presents these mitigation activities with their associated planning, organization process, and main concerns as identified today. (author)

  6. Overexpression of DOC-1R inhibits cell cycle G1/S transition by repressing CDK2 expression and activation.

    Science.gov (United States)

    Liu, Qi; Liu, Xing; Gao, Jinlan; Shi, Xiuyan; Hu, Xihua; Wang, Shusen; Luo, Yang

    2013-01-01

    DOC-1R (deleted in oral cancer-1 related) is a novel putative tumor suppressor. This study investigated DOC-1R antitumor activity and the underlying molecular mechanisms. Cell phenotypes were assessed using flow cytometry, BrdU incorporation and CDK2 kinase assays in DOC-1R overexpressing HeLa cells. In addition, RT-PCR and Western blot assays were used to detect underlying molecular changes in these cells. The interaction between DOC-1R and CDK2 proteins was assayed by GST pull-down and immunoprecipitation-Western blot assays. The data showed that DOC-1R overexpression inhibited G1/S phase transition, DNA replication and suppressed CDK2 activity. Molecularly, DOC-1R inhibited CDK2 expression at the mRNA and protein levels, and there were decreased levels of G1-phase cyclins (cyclin D1 and E) and elevated levels of p21, p27, and p53 proteins. Meanwhile, DOC-1R associated with CDK2 and inhibited CDK2 activation by obstructing its association with cyclin E and A. In conclusion, the antitumor effects of DOC-1R may be mediated by negatively regulating G1 phase progression and G1/S transition through inhibiting CDK2 expression and activation.

  7. Prenatal exposure to anticonvulsant drugs and spatial ability in adulthood

    NARCIS (Netherlands)

    Dessens, A.; Cohen-Kettenis, P.; Mellenbergh, G.; van de Poll, N.; Koppe, J.; Boer, K.

    1998-01-01

    By disturbing steroid hormone balances in the fetus, the anticonvulsant drugs phenobarbital and phenytoin may affect certain aspects of cognitive functioning. In order to test this hypothesis, we studied hormone related cognitive functioning in 72 men and 75 women who had been prenatally exposed to

  8. Association of anticonvulsant hypersensitivity syndrome with Herpesvirus 6, 7.

    Science.gov (United States)

    Oskay, Tuğba; Karademir, Asli; Ertürk, Ozcan I

    2006-07-01

    Anticonvulsant hypersensitivity syndrome (AHS) is one of the most severe forms of drug eruption with potentially lethal, and multiorgan involvement. Recently, it has been suggested that Human Herpesvirus (HHV) infection has been involved in this syndrome, although the pathogenesis of this syndrome remains still unclear. The objective of this study was to determine the clinical characteristics of AHS and the possible role of viral infection as a co-factor. We prospectively analyzed clinical, laboratory and virological findings for 23 cases of AHS. A viral study including viral serology and a polymerase chain reaction (PCR) was performed. The most common anticonvulsant was carbamazepine (12) followed by phenytoin (6), phenobarbital (4) and gabapentin (1). All patients met fulfill the clinical criteria of AHS. Even though internal organ involvement such as liver (52%), kidney (34%), and lung (13%) has been observed, involvement of heart, lung, thyroid, muscle, pancreas, spleen, and brain was less frequent. We also noted two patients who died due to multiorgan failure. No association with viral infection including HSV, VZV, HHV-8, CMV, EBV, measles, rubella and parvovirus B19 was detected in the current series. Increased serum anti-HHV-6 IgG and HHV-7 titers and presence of HHV-6 and -7 DNA in serum, revealed by PCR analysis, suggested reactivation of HHV-6. In contrast to the control groups, DNA for HHV-6 was detected in serum in 5 out of the 23 patients while HHV-7 was seen in two patients. We found an evidence to link reactivation of HHV-6 or HHV-7 in the development of only carbamazepine-induced AHS. We propose that some cases of AHS are accompanied by reactivation of not only HHV-6 but also HHV-7. HHV infection may contribute to the severity, prolongation, or relapse of AHS and may possibly have fatal consequences in some susceptible individuals receiving the anticonvulsants.

  9. Design and synthesis of novel stiripentol analogues as potential anticonvulsants.

    Science.gov (United States)

    Aboul-Enein, Mohamed N; El-Azzouny, Aida A; Attia, Mohamed I; Maklad, Yousreya A; Amin, Kamilia M; Abdel-Rehim, Mohamed; El-Behairy, Mohammed F

    2012-01-01

    A series of stiripentol (STP) analogues namely, 2-[(1E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-ylidene]-N-(aryl/H)hydrazinecarboxamides 7a-h, (±)-(5RS)-N-(aryl/H)-(1,3-benzodioxol-5-yl)-3-tert-butyl-4,5-dihydro-1H-pyrazole-1-carboxamides (±)-8a-h, and (±)-[(5RS)-(1,3-benzodioxol-5-yl)-3-tert-butyl-4,5-dihydro-1H-pyrazol-1-yl](aryl)methanones (±)-13a-f was synthesized by adopting appropriate synthetic routes and was pharmacologically evaluated in the preliminary anticonvulsant screens. The selected bioactive new chemical entities were subjected to ED(50) determination and neurotoxicity evaluation. The most active congeners are 7h in MES screen and (±)-13b in scPTZ screen which displayed ED(50) values of 87 and 110 mg/kg, respectively, as compared to that of STP (ED(50) = 277.7 and 115 mg/kg in MES and scPTZ, respectively). Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  10. A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Miller, Steven L., E-mail: stevenmiller17@gmail.com [Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (United States); Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (United States); Aroniadou-Anderjaska, Vassiliki, E-mail: vanderjaska@usuhs.edu [Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (United States); Department of Psychiatry, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (United States); Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (United States); Figueiredo, Taiza H., E-mail: taiza.figueiredo.ctr@usuhs.edu [Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (United States); Prager, Eric M., E-mail: eric.prager683@gmail.com [Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (United States); Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (United States); Almeida-Suhett, Camila P., E-mail: camilapalmeida@gmail.com [Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (United States); Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (United States); Apland, James P., E-mail: james.p.apland.civ@mail.mil [Neurotoxicology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010 (United States); and others

    2015-04-15

    Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD{sub 50} of 62 μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS) at 2 mg/kg, administered 20 min after soman exposure (1.2 × LD{sub 50}), terminated seizures. ATS at 0.5 mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1 h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90 days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1 h post-exposure, prevents brain pathology and behavioral deficits. - Highlights: • The LD{sub 50} of soman was determined in postnatal-day-21 rats. • Rats with no seizures after 1.2XLD{sub 50} soman had less reduction of AChE in the amygdala. • Atropine sulfate (ATS) at 2 mg/kg, given at 20 min after

  11. A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists

    International Nuclear Information System (INIS)

    Miller, Steven L.; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H.; Prager, Eric M.; Almeida-Suhett, Camila P.; Apland, James P.

    2015-01-01

    Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD 50 of 62 μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS) at 2 mg/kg, administered 20 min after soman exposure (1.2 × LD 50 ), terminated seizures. ATS at 0.5 mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1 h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90 days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1 h post-exposure, prevents brain pathology and behavioral deficits. - Highlights: • The LD 50 of soman was determined in postnatal-day-21 rats. • Rats with no seizures after 1.2XLD 50 soman had less reduction of AChE in the amygdala. • Atropine sulfate (ATS) at 2 mg/kg, given at 20 min after soman, blocked

  12. The anticonvulsant action of nafimidone on kindled amygdaloid seizures in rats.

    Science.gov (United States)

    Albertson, T E; Walby, W F

    1988-01-01

    The anticonvulsant effectiveness of nafimidone (1-[2-naphthoylmethyl]imidazole hydrochloride) was evaluated in the kindled amygdaloid seizure model in rats. Nafimidone (3.1-120 mg/kg i.p.) was evaluated at 30 min in previously kindled rats using both threshold (20 microA increments) and supranthreshold (400 microA) paradigms. Nafimidone (25-50 mg/kg) significantly reduced supranthreshold elicited afterdischarge length and seizure severity only at doses with some prestimulation toxicity. The maximum anticonvulsant effectiveness for the 25 mg/kg i.p. dose of nafimidone was seen between 15 and 30 min utilizing a suprathreshold kindling paradigm. Nafimidone did not significantly elevate seizure thresholds at the doses tested; however, nafimidone (3.1-50 mg/kg) reduced the severity and afterdischarge duration of threshold elicited seizures in a non-dose response manner. Drug-induced electroencephalographic spikes were seen in both cortex and amygdala in most kindled rats receiving 100-120 mg/kg i.p. within 30 min of dosing before electrical stimulation. The frequency of spike and wave complexes increased in most of these animals leading to drug-induced spontaneous seizures and death in approximately 25% before electrical stimulation. This study has demonstrated that although nafimidone can modify both threshold and suprathreshold elicited kindled amygdaloid seizures, it lacks significant specificity in this model of epilepsy.

  13. Ca 2+ signaling by plant Arabidopsis thaliana Pep peptides depends on AtPepR1, a receptor with guanylyl cyclase activity, and cGMP-activated Ca 2+ channels

    KAUST Repository

    Qia, Zhi

    2010-11-18

    A family of peptide signaling molecules (AtPeps) and their plasma membrane receptor AtPepR1 are known to act in pathogendefense signaling cascades in plants. Little is currently known about the molecular mechanisms that link these signaling peptides and their receptor, a leucine-rich repeat receptor-like kinase, to downstream pathogen-defense responses. We identify some cellular activities of these molecules that provide the context for a model for their action in signaling cascades. AtPeps activate plasma membrane inwardly conducting Ca 2+ permeable channels in mesophyll cells, resulting in cytosolic Ca 2+ elevation. This activity is dependent on their receptor as well as a cyclic nucleotide-gated channel (CNGC2). We also show that the leucine-rich repeat receptor- like kinase receptor AtPepR1 has guanylyl cyclase activity, generating cGMP from GTP, and that cGMP can activate CNGC2- dependent cytosolic Ca 2+ elevation. AtPep-dependent expression of pathogen-defense genes (PDF1.2, MPK3, and WRKY33) is mediated by the Ca 2+ signaling pathway associated with AtPep peptides and their receptor. The work presented here indicates that extracellular AtPeps, which can act as danger-associated molecular patterns, signal by interaction with their receptor, AtPepR1, a plasma membrane protein that can generate cGMP. Downstream from AtPep and AtPepR1 in a signaling cascade, the cGMP-activated channel CNGC2 is involved in AtPep- and AtPepR1-dependent inward Ca 2+ conductance and resulting cytosolic Ca 2+ elevation. The signaling cascade initiated by AtPeps leads to expression of pathogen- defense genes in a Ca 2+-dependent manner.

  14. Quantitative determination of anticonvulsant-induced bone demineralization by an improved x-ray densitometry technique

    Energy Technology Data Exchange (ETDEWEB)

    Wolschendorf, K.; Vanselow, K.; Schulz, H.; Moeller, W.D.

    1983-10-01

    Quantitative studies of the influence of anticonvulsant drugs on bone mineral content of 88 epileptics were performed by a microcomputer-aided densitometer system. The results showed that the mineral content decreases significantly with the duration of the therapy. This decrease was found to be approximately 1.2% per year for a Diphenylhydantoin (DPH) monotherapy and 1.8% per year and 2.0% per year for a DPH plus Phenobarbital and DPH plus Carbamazepin combination therapy.

  15. Synthesis of 1-(4-methylsulfone-phenyl)-5-(4-fluoro-phenyl)-5-[14C]-1,2,3- triazole and 1-(4-sulfonamide-phenyl)-5-(4-fluoro-phenyl)-5-[14C]-1,2,3- triazole as novel carbon-14 anticonvulsant

    International Nuclear Information System (INIS)

    Saemian, N.; Shirvani, G.; Matloubi, H.

    2006-01-01

    Two 1,2,3-triazole anticonvulsants, 1-(4-methylsulfone-phenyl)-5-(4-fluoro-phenyl)-5-[ 14 C]-1,2,3-triazole and 1-(4-sulfonamide-phenyl)-5-(4- fluoro-phenyl)-5-[ 14 C]-1,2,3-triazole, both labeled with carbon-14 in the 5-position were prepared from para-fluoro-benzonitrile-[cyano- 14 C]. (author)

  16. (Biphenyl-4-yl)methylammonium chlorides: potent anticonvulsants that modulate Na+ currents.

    Science.gov (United States)

    Lee, Hyosung; Park, Ki Duk; Yang, Xiao-Fang; Dustrude, Erik T; Wilson, Sarah M; Khanna, Rajesh; Kohn, Harold

    2013-07-25

    We have reported that compounds containing a biaryl linked unit (Ar-X-Ar') modulated Na(+) currents by promoting slow inactivation and fast inactivation processes and by inducing frequency (use)-dependent inhibition of Na(+) currents. These electrophysiological properties have been associated with the mode of action of several antiepileptic drugs. In this study, we demonstrate that the readily accessible (biphenyl-4-yl)methylammonium chlorides (compound class B) exhibited a broad range of anticonvulsant activities in animal models, and in the maximal electroshock seizure test the activity of (3'-trifluoromethoxybiphenyl-4-yl)methylammonium chloride (8) exceeded that of phenobarbital and phenytoin upon oral administration to rats. Electrophysiological studies of 8 using mouse catecholamine A-differentiated cells and rat embryonic cortical neurons confirmed that 8 promoted slow and fast inactivation in both cell types but did not affect the frequency (use)-dependent block of Na(+) currents.

  17. The novel anticonvulsant neuropeptide and galanin analogue, NAX-5055, does not alter energy and amino acid metabolism in cultured brain cells

    DEFF Research Database (Denmark)

    Aldana, Blanca I; Waagepetersen, Helle S; Schousboe, Arne

    2017-01-01

    A large body of evidence suggests that the neuropeptide galanin plays an important role in seizure control. In line with this, it was demonstrated that the galanin analogue, NAX-5055, exerts a potent anticonvulsant activity in animal seizure models. We recently found that the NAX-5055-mediated an...

  18. NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

    Science.gov (United States)

    Alagarsamy, Sudar; Saugstad, Julie; Warren, Lee; Mansuy, Isabelle M.; Gereau, Robert W.; Conn, P. Jeffrey

    2010-01-01

    Previous reports have shown that activation of N-methyl-D-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor. 2005 Elsevier Ltd. All rights reserved. PMID:16005030

  19. CNS activity of leaves extract of Calotropis gigantea

    Directory of Open Access Journals (Sweden)

    Santosh Dattatraya Ghule

    2014-09-01

    Full Text Available Objective: To study central nervous system activity of ethanolic extract of leaves of Calotropis gigantea (C. gigantea (Asclepiadaceae, such as anticonvulsant, sedative and muscle relaxation activity. Methods: The ethanolic extract of C. gigantea administered orally in experimental animals at different doses 100, 200 and 500 mg/kg body weight. The anticonvulsant properties were studied on maximal electroshock test and strychnine-induced convulsions model. Sedative property studied using actophotometer and skeletal muscle relaxant property studied using rota rod. Results: This extract protected rats against maximal electroshock induced seizures, but had no or a moderate effect only against strychnine-induced seizures. Locomotor activity in mice found to be decreased and motor coordination was also decreased. The acute toxicity study revealed safely of the extract up to a dose of 2 000 mg/kg. Conclusions: With these effects, the leaves of C. gigantea possess anticonvulsant sedative and muscle relaxant effect that might explain its use as a traditional medicine.

  20. An audit of therapeutic drug monitoring of anticonvulsants.

    Science.gov (United States)

    Sharpe, P. C.; Morrow, J.; Trimble, E. R.

    1995-01-01

    An audit of therapeutic drug monitoring (TDM) of anticonvulsants was performed to assess both its use and misuse in the management of patients with epilepsy. Over a four week period all samples received for phenytoin, carbamazepine, sodium valproate and phenobarbitone assays were included in the audit. The aims were to establish the source of the specimens, the reasons for the requests and to ascertain what action, if any, would be taken when the result of the assay was provided. A total of 163 separate assays were performed over the four week period (43 phenytoin, 74 carbamazepine, 41 valproate, 5 phenobarbitone). Only 18.7% of all requests originated from the adult neurology department. The vast majority of tests had been ordered by junior medical staff (only 10% by consultants) and approximately 50% were 'routine' with no satisfactory clinical reason for the request offered. There was a tendency to manipulate prescribed doses on the basis of drug levels alone without taking the clinical picture into consideration. These results demonstrate a general ignorance, especially amongst junior medical staff, of the value of TDM of anticonvulsants, and reinforce the need for both an educative and interpretive service to be provided by the Chemical Pathology Department. PMID:8533181

  1. Towards cheminformatics-based estimation of drug therapeutic index: Predicting the protective index of anticonvulsants using a new quantitative structure-index relationship approach.

    Science.gov (United States)

    Chen, Shangying; Zhang, Peng; Liu, Xin; Qin, Chu; Tao, Lin; Zhang, Cheng; Yang, Sheng Yong; Chen, Yu Zong; Chui, Wai Keung

    2016-06-01

    The overall efficacy and safety profile of a new drug is partially evaluated by the therapeutic index in clinical studies and by the protective index (PI) in preclinical studies. In-silico predictive methods may facilitate the assessment of these indicators. Although QSAR and QSTR models can be used for predicting PI, their predictive capability has not been evaluated. To test this capability, we developed QSAR and QSTR models for predicting the activity and toxicity of anticonvulsants at accuracy levels above the literature-reported threshold (LT) of good QSAR models as tested by both the internal 5-fold cross validation and external validation method. These models showed significantly compromised PI predictive capability due to the cumulative errors of the QSAR and QSTR models. Therefore, in this investigation a new quantitative structure-index relationship (QSIR) model was devised and it showed improved PI predictive capability that superseded the LT of good QSAR models. The QSAR, QSTR and QSIR models were developed using support vector regression (SVR) method with the parameters optimized by using the greedy search method. The molecular descriptors relevant to the prediction of anticonvulsant activities, toxicities and PIs were analyzed by a recursive feature elimination method. The selected molecular descriptors are primarily associated with the drug-like, pharmacological and toxicological features and those used in the published anticonvulsant QSAR and QSTR models. This study suggested that QSIR is useful for estimating the therapeutic index of drug candidates. Copyright © 2016. Published by Elsevier Inc.

  2. Clinical significance of the changes of serum levels of the rheumatoid activity markers IL-2, sIL-2R, HA and VEGF

    International Nuclear Information System (INIS)

    Bao Yong; Long Wubin; Yu Ke; Zeng Ying; Liu Deying

    2004-01-01

    Objective: To explore the relationship between rheumatoid activity and serum levels of the cytokines interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R), hyaluronic acid (HA), vascular endothelial growth factor (VEGF) in patients with rheumatoid arthritis. Methods: Serum IL-2, HA(with RIA) and sIL-2R, VEGF (with ELISA) levels were determined in 30 controls, 30 patients with active rheumatoid arthritis and 30 patients with rheumatoid arthritis in remission. Sensitivity and specificity for each marker were analyzed. Results: In patients with active rheumatoid arthritis, the serum levels of sIL-2R, HA, VEGF were significantly higher and serum levels of IL-2 significantly lower than those in patients in remission and controls (p<0.01). Determination of VEGF levels possessed the highest specificity (93.3%) and also a high sensitivity (93.3% as well). Conclusion: Determination of the serum levels of any of these markers was valuable for monitoring the activity of the rheumatoid process. It is more desirable to take measurements of VEGF levels due to its highest specificity

  3. Insilico study of the A(2A)R-D (2)R kinetics and interfacial contact surface for heteromerization.

    Science.gov (United States)

    Prakash, Amresh; Luthra, Pratibha Mehta

    2012-10-01

    G-protein-coupled receptors (GPCRs) are cell surface receptors. The dynamic property of receptor-receptor interactions in GPCRs modulates the kinetics of G-protein signaling and stability. In the present work, the structural and dynamic study of A(2A)R-D(2)R interactions was carried to acquire the understanding of the A(2A)R-D(2)R receptor activation and deactivation process, facilitating the design of novel drugs and therapeutic target for Parkinson's disease. The structure-based features (Alpha, Beta, SurfAlpha, and SurfBeta; GapIndex, Leakiness and Gap Volume) and slow mode model (ENM) facilitated the prediction of kinetics (K (off), K (on), and K (d)) of A(2A)R-D(2)R interactions. The results demonstrated the correlation coefficient 0.294 for K (d) and K (on) and the correlation coefficient 0.635 for K (d) and K (off), and indicated stable interfacial contacts in the formation of heterodimer. The coulombic interaction involving the C-terminal tails of the A(2A)R and intracellular loops (ICLs) of D(2)R led to the formation of interfacial contacts between A(2A)R-D(2)R. The properties of structural dynamics, ENM and KFC server-based hot-spot analysis illustrated the stoichiometry of A(2A)R-D(2)R contact interfaces as dimer. The propensity of amino acid residues involved in A(2A)R-D(2)R interaction revealed the presence of positively (R, H and K) and negatively (E and D) charged structural motif of TMs and ICL3 of A(2A)R and D(2)R at interface of dimer contact. Essentially, in silico structural and dynamic study of A(2A)R-D(2)R interactions will provide the basic understanding of the A(2A)R-D(2)R interfacial contact surface for activation and deactivation processes, and could be used as constructive model to recognize the protein-protein interactions in receptor assimilations.

  4. Evidence for involvement of the astrocytic benzodiazepine receptor in the mechanism of action of convulsant and anticonvulsant drugs

    International Nuclear Information System (INIS)

    Bender, A.S.; Hertz, L.

    1988-01-01

    The anticonvulsant drugs carbamazepine, phenobarbital, trimethadione, valproic acid and ethosuximide at pharmacologically relevant concentrations inhibit [ 3 H]diazepam binding to astrocytes in primary cultures but have much less effect on a corresponding preparation of neurons. Phenytoin as well as pentobarbital (which is not used chronically as an anticonvulsant) are equipotent in the two cell types. The convulsants picrotoxinin and pentylenetetrazol, the convulsant benzodiazepine RO 5-3663 and the two convulsant barbiturates DMBB and CHEB similarly inhibit diazepam binding to astrocytes but have little effect on neurons. On the basis of these findings it is suggested that these convulsants and anticonvulsants owe at least part of their effect to an interaction with the astrocytic benzodiazepine receptor, perhaps by interference with a calcium channel

  5. Site of anticonvulsant action on sodium channels: autoradiographic and electrophysiological studies in rat brain

    International Nuclear Information System (INIS)

    Worley, P.F.; Baraban, J.M.

    1987-01-01

    The anticonvulsants phenytoin and carbamazepine interact allosterically with the batrachotoxin binding site of sodium channels. In the present study, we demonstrate an autoradiographic technique to localize the batrachotoxin binding site on sodium channels in rat brain using [ 3 H]batrachotoxinin-A 20-alpha-benzoate (BTX-B). Binding of [ 3 H]BTX-B to brain sections is dependent on potentiating allosteric interactions with scorpion venom and is displaced by BTX-B (Kd approximately 200 nM), aconitine, veratridine, and phenytoin with the same rank order of potencies as described in brain synaptosomes. The maximum number of [ 3 H]BTX-B binding sites in forebrain sections also agrees with biochemical determinations. Autoradiographic localizations indicate that [ 3 H]BTX-B binding sites are not restricted to cell bodies and axons but are present in synaptic zones throughout the brain. For example, a particularly dense concentration of these sites in the substantia nigra is associated with afferent terminals of the striatonigral projection. By contrast, myelinated structures possess much lower densities of binding sites. In addition, we present electrophysiological evidence that synaptic transmission, as opposed to axonal conduction, is preferentially sensitive to the action of aconitine and veratridine. Finally, the synaptic block produced by these sodium channel activators is inhibited by phenytoin and carbamazepine at therapeutic anticonvulsant concentrations

  6. The effects of lithium and anticonvulsants on brain structure in bipolar disorder.

    Science.gov (United States)

    Germaná, C; Kempton, M J; Sarnicola, A; Christodoulou, T; Haldane, M; Hadjulis, M; Girardi, P; Tatarelli, R; Frangou, S

    2010-12-01

    To investigate the effect of lithium, anticonvulsants and antipsychotics on brain structure in bipolar disorder (BD). A cross-sectional structural brain magnetic resonance imaging study of 74 remitted patients with BD, aged 18-65, who were receiving long-term prophylactic treatment with lithium or anticonvulsants or antipsychotics. Global and regional grey matter, white matter, and cerebrospinal fluid volumes were compared between treatment groups. Grey matter in the subgenual anterior cingulate gyrus on the right (extending into the hypothalamus) and in the postcentral gyrus, the hippocampus/amygdale complex and the insula on the left was greater in BD patients on lithium treatment compared to all other treatment groups. Lithium treatment in BD has a significant effect on brain structure particularly in limbic/paralimbic regions associated with emotional processing. © 2010 John Wiley & Sons A/S.

  7. Effect of amino acid substitution on biological activity of cyanophlyctin-β and brevinin-2R

    Science.gov (United States)

    Ghorani-Azam, Adel; Balali-Mood, Mahdi; Aryan, Ehsan; Karimi, Gholamreza; Riahi-Zanjani, Bamdad

    2018-04-01

    Antimicrobial peptides (AMPs), as ancient immune components, are found in almost all types of living organisms. They are bioactive components with strong antibacterial, antiviral, and anti-tumor properties. In this study, we designed three sequences of antimicrobial peptides to study the effects of structural changes in biological activity compared with original peptides, cyanophlyctin β, and brevinin-2R. For antibacterial activity, two Gram-positive (Staphylococcus aureus and S. epidermidis) and two Gram-negative bacteria (Escherichia coli and Pseudomonas aeroginosa) were assayed. Unlike cyanophlyctin β and brevinin-2R, the synthesized peptide (brevinin-M1, brevinin-M2 and brevinin-M3) showed no considerable antibacterial properties. Hemolytic activity of these peptides was also ignorable even at very high concentrations of 2 mg/ml. However, after proteolytic digestion by trypsin, the peptides showed antibacterial activity comparable to their original template sequences. Structural prediction suggested that the motif sequence responsible for antibacterial activity may be re-exposed to bacterial cell membrane after proteolytic digestion. Also, findings showed that only a small change in primary sequence and therefore structure of peptides may result in a significant alteration in biological activity.

  8. Evaluation of anticonvulsant and nootropic effect of ondansetron in mice.

    Science.gov (United States)

    Jain, S; Agarwal, N B; Mediratta, P K; Sharma, K K

    2012-09-01

    The role of serotonin receptors have been implicated in various types of experimentally induced seizures. Ondansetron is a highly selective 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonist used as antiemetic agent for chemotherapy-, and radiotherapy-induced nausea and vomiting. The present study was carried out to examine the effect of ondansetron on electroshock, pentylenetetrazole (PTZ)-induced seizures and cognitive functions in mice. Ondansetron was administered intraperitoneally (i.p.) at doses of 0.5, 1.0 and 2.0 mg/kg (single dose) to observe its effect on the increasing current electroshock seizure (ICES) test and PTZ-induced seizure test. In addition, a chronic study (21 days) was also performed to assess the effects of ondansetron on electroshock-induced convulsions and cognitive functions. The effect on cognition was assessed by elevated plus maze and passive avoidance paradigms. Phenytoin (25 mg/kg, i.p.) was used as a standard anticonvulsant drug and piracetam (200 mg/kg) was administered as a standard nootropic drug. The results were compared with an acute study, wherein it was found that the administration of ondansetron (1.0 and 2.0 mg/kg) significantly raised the seizure-threshold current as compared to control group in the ICES test. Similar results were observed after chronic administration of ondansetron. In PTZ test, ondansetron in all the three tested doses failed to show protective effect against PTZ-induced seizure test. Administration of ondansetron for 21 days significantly decreased the transfer latency (TL) and prolonged the step-down latency (SDL). The results of present study suggest the anticonvulsant and memory-enhancing effect of ondansetron in mice.

  9. Fabrication of TiO2 nanorod assembly grafted rGO (rGO@TiO2-NR) hybridized flake-like photocatalyst

    Science.gov (United States)

    Lv, Kangle; Fang, Shun; Si, Lingling; Xia, Yang; Ho, Wingkei; Li, Mei

    2017-01-01

    To efficiently separate the photo-generated electron-hole pairs of TiO2 hybrid, anatase TiO2 nanorod assembly grafted reduced graphene oxides (rGO@TiO2-NR) hybrid was successfully fabricated using potassium titanium oxalate (PTO) and graphene oxides (GO) as starting materials and diethylene glycol (DEG) as reductant. The effect of GO content on the structure and photocatalytic activity of rGO@TiO2-NR composite was systematically studied. Results show that, in the absence of GO, only TiO2 microsphere assembly is obtained from TiO2 nanorods. The presence of GO results in the formation of a flake-like TiO2-nanorod-assembled grafted rGO hybrid. The photocatalytic activity of rGO@TiO2-NR composite increases first and then decreases with increase in the amount of GO from 0 wt.% to 10 wt.%. The hybridized S4 sample prepared with 4 wt.% GO possesses the highest photocatalytic activity with a constant rate of 0.039 min-1 in the photocataytic degradation of Brilliant X-3B dye (X3B); this sample was enhanced more than three times when compared with pure TiO2 sample (0.012 min-1). The enhanced photocatalytic activity of the rGO@TiO2-NR hybrid was attributed to the strong interaction between TiO2 nanorods and rGO. The unique hierarchical structure of 1D nanorod assembly TiO2-rGO flakes facilitates the injection and transfer of photo-generated electrons from TiO2 to graphene, thus retarding the recombination of electron-hole pairs and enhancing the photocatalytic activity. The enlarged BET surface areas, not only increasing the number of active sites, but also facilitating the adsorption of the dye, and improved light-harvesting ability also contribute to the enhanced photoreactivity of rGO@TiO2-NR hybrid.

  10. Anticonvulsant mechanism of saponins fraction from adventitious roots of Ficus religiosa: possible modulation of GABAergic, calcium and sodium channel functions

    Directory of Open Access Journals (Sweden)

    Damanpreet Singh

    Full Text Available ABSTRACT In our previous studies, quantified saponins-rich fraction from adventitious root extract of Ficus religiosa L., Moraceae, showed anticonvulsant effect in acute, as well as chronic mice models of epilepsy. The present study was designed to reveal putative anticonvulsant mechanism of quantified saponins-rich fraction using target specific animal models. The anticonvulsant effect of quantified saponins-rich fraction was initially studied in maximal electroshock and pentylenetetrazol test at 1, 2 and 4 mg/kg; i.p. doses. Based on the results of initial anticonvulsant testing, different groups of mice were injected with vehicle or quantified saponins-rich fraction (4 mg/kg; i.p., 30 min prior to an injection of N-methyl-D-aspartic acid (100 mg/kg; s.c., bicuculline (5 mg/kg; i.p., strychnine hydrochloride (2 mg/kg; i.p., BAY k-8644 (37.5 µg; i.c.v., veratridine (500 µg/kg; i.p. and the convulsive episodes were studied. Treatment with the extract (1, 2 and 4 mg/kg showed significant protection in maximal electroshock and pentylenetetrazol-induced convulsion tests, in a dose-dependent manner. Moreover, quantified saponins-rich fraction at 4 mg/kg dose showed significant increase in latency to clonic convulsions, decrease in seizure severity and increase in average wave amplitude in bicuculline, BAY k-8644 and veratridine tests, respectively, as compared to vehicle control. However, SRF treatment failed to abolish N-methyl-D-aspartic acid and strychnine-induced convulsions, indicated by insignificant change in the appearance of turning behavior and onset of tonic extension, respectively, as compared to vehicle control. From the results of present study, it is concluded that quantified saponins-rich fraction suppress maximal electroshock, pentylenetetrazol, bicuculline, BAY k-8644 and veratridine-induced convulsions, indicating its GABAergic, Na+ and Ca2+ channel modulatory effects. Further it can be correlated that quantified saponins

  11. Mitochondrial targeted curcumin exhibits anticancer effects through disruption of mitochondrial redox and modulation of TrxR2 activity.

    Science.gov (United States)

    Jayakumar, Sundarraj; Patwardhan, Raghavendra S; Pal, Debojyoti; Singh, Babita; Sharma, Deepak; Kutala, Vijay Kumar; Sandur, Santosh Kumar

    2017-12-01

    Mitocurcumin is a derivative of curcumin, which has been shown to selectively enter mitochondria. Here we describe the anti-tumor efficacy of mitocurcumin in lung cancer cells and its mechanism of action. Mitocurcumin, showed 25-50 fold higher efficacy in killing lung cancer cells as compared to curcumin as demonstrated by clonogenic assay, flow cytometry and high throughput screening assay. Treatment of lung cancer cells with mitocurcumin significantly decreased the frequency of cancer stem cells. Mitocurcumin increased the mitochondrial reactive oxygen species (ROS), decreased the mitochondrial glutathione levels and induced strand breaks in the mitochondrial DNA. As a result, we observed increased BAX to BCL-2 ratio, cytochrome C release into the cytosol, loss of mitochondrial membrane potential and increased caspase-3 activity suggesting that mitocurcumin activates the intrinsic apoptotic pathway. Docking studies using mitocurcumin revealed that it binds to the active site of the mitochondrial thioredoxin reductase (TrxR2) with high affinity. In corroboration with the above finding, mitocurcumin decreased TrxR activity in cell free as well as the cellular system. The anti-cancer activity of mitocurcumin measured in terms of apoptotic cell death and the decrease in cancer stem cell frequency was accentuated by TrxR2 overexpression. This was due to modulation of TrxR2 activity to NADPH oxidase like activity by mitocurcumin, resulting in higher ROS accumulation and cell death. Thus, our findings reveal mitocurcumin as a potent anticancer agent with better efficacy than curcumin. This study also demonstrates the role of TrxR2 and mitochondrial DNA damage in mitocurcumin mediated killing of cancer cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Regulation of Rac1 GTPase activity by quinine through G-protein and bitter taste receptor T2R4.

    Science.gov (United States)

    Sidhu, Crystal; Jaggupilli, Appalaraju; Chelikani, Prashen; Bhullar, Rajinder P

    2017-02-01

    Rac1 belongs to the Rho family of small GTPases and regulates actin cytoskeleton reorganization. T2R4 is a bitter taste receptor belonging to the G protein-coupled receptor family of proteins. In addition to mediating bitter taste perception from the tongue, T2R4s are found in extra-oral tissues, e.g., nasal epithelium, airways, brain, testis suggesting a much broader physiological function for these receptors. Anti-malarial drug and a bitter tasting compound, quinine, is a known agonist for T2R4, whereas BCML (Nα,Nα-Bis(carboxymethyl)-L-lysine) acts as an inverse agonist. Using western blot and Ca ++ mobilization assays, the effects of quinine on Rac1 activity in HEK293T cells stably expressing T2R4/Gα 16/44 , T2R4, or Gα 16/44 and transiently transfected with HA-Rac1 were investigated. Quinine treatment caused a significant reduction in the amount of active Rac1, whereas in the presence of BCML, quinine failed to cause any significant change in active Rac1. No significant change in Rac1 activity was observed in BAPTA-AM plus quinine-treated Gα 16/44 cells, suggesting possibility of a pathway in addition to the canonical Ca ++ -dependent pathway. A noticeable role for Gα 16/44 independent of T2R4 is observed in quinine-mediated Rac1 inactivation. Further, a significant difference in quinine-induced Ca ++ response in T2R4/Gα 16/44 or T2R4 cells was observed validating the partial role of calcium and importance of Gα 16/44 . This study is the first to show an inhibitory downstream action of a T2R4 agonist on Rac1 function. Further investigation will help in better understanding the downstream signal transduction network of T2R4 and its extra-oral physiological roles.

  13. Fabrication of TiO_2 nanorod assembly grafted rGO (rGO@TiO_2-NR) hybridized flake-like photocatalyst

    International Nuclear Information System (INIS)

    Lv, Kangle; Fang, Shun; Si, Lingling; Xia, Yang; Ho, Wingkei; Li, Mei

    2017-01-01

    Highlights: • TiO_2 nanorod assembly grafted with GO hybrid was successfully fabricated. • TiO_2 nanorods can reduce the aggregation of TiO_2 nanoparticles on graphene. • This unique structure facilitates the injection of electron from TiO_2 to graphene. - Abstract: To efficiently separate the photo-generated electron–hole pairs of TiO_2 hybrid, anatase TiO_2 nanorod assembly grafted reduced graphene oxides (rGO@TiO_2-NR) hybrid was successfully fabricated using potassium titanium oxalate (PTO) and graphene oxides (GO) as starting materials and diethylene glycol (DEG) as reductant. The effect of GO content on the structure and photocatalytic activity of rGO@TiO_2-NR composite was systematically studied. Results show that, in the absence of GO, only TiO_2 microsphere assembly is obtained from TiO_2 nanorods. The presence of GO results in the formation of a flake-like TiO_2-nanorod-assembled grafted rGO hybrid. The photocatalytic activity of rGO@TiO_2-NR composite increases first and then decreases with increase in the amount of GO from 0 wt.% to 10 wt.%. The hybridized S4 sample prepared with 4 wt.% GO possesses the highest photocatalytic activity with a constant rate of 0.039 min"−"1 in the photocataytic degradation of Brilliant X-3B dye (X3B); this sample was enhanced more than three times when compared with pure TiO_2 sample (0.012 min"−"1). The enhanced photocatalytic activity of the rGO@TiO_2-NR hybrid was attributed to the strong interaction between TiO_2 nanorods and rGO. The unique hierarchical structure of 1D nanorod assembly TiO_2rGO flakes facilitates the injection and transfer of photo-generated electrons from TiO_2 to graphene, thus retarding the recombination of electron–hole pairs and enhancing the photocatalytic activity. The enlarged BET surface areas, not only increasing the number of active sites, but also facilitating the adsorption of the dye, and improved light-harvesting ability also contribute to the enhanced photoreactivity

  14. Agmatine reduces extracellular glutamate during pentylenetetrazole-induced seizures in rat brain: A potential mechanism for the anticonvulsive effects

    Science.gov (United States)

    Feng, Yangzheng; LeBlanc, Michael H.; Regunathan, Soundar

    2010-01-01

    Glutamate has been implicated in the initiation and spread of seizure activity. Agmatine, an endogenous neuromodulator, is an antagonist of NMDA receptors and has anticonvulsive effects. Whether agmatine regulate glutamate release, as measured by in vivo microdialysis, is not known. In this study, we used pentylenetetrazole (PTZ)-induced seizure model to determine the effect of agmatine on extracellular glutamate in rat brain. We also determined the time course and the amount of agmatine that reached brain after peripheral injection. After i.p. injection of agmatine (50 mg/kg), increase of agmatine in rat cortex and hippocampus was observed in 15 min with levels returning to baseline in one hour. Rats, naïve and implanted with microdialysis cannula into the cortex, were administered PTZ (60 mg/kg, i.p.) with prior injection of agmatine (100 mg/kg, i.p.) or saline. Seizure grades were recorded and microdialysis samples were collected every 15 min for 75 min. Agmatine pre-treatment significantly reduced the seizure grade and increased the onset time. The levels of extracellular glutamate in frontal cortex rose two- to three-fold after PTZ injection and agmatine significantly inhibited this increase. In conclusion, the present data suggest that the anticonvulsant activity of agmatine, in part, could be related to the inhibition glutamate release. PMID:16125317

  15. A quantitative determination of anticonvulsant-induced bone demineralization by an improved x-ray densitometry technique

    International Nuclear Information System (INIS)

    Wolschendorf, K.; Vanselow, K.; Schulz, H.; Moeller, W.D.

    1983-01-01

    Quantitative studies of the influence of anticonvulsant drugs on bone mineral content of 88 epileptics were performed by a microcomputer-aided densitometer system. The results showed that the mineral content decreases significantly with the duration of the therapy. This decrease was found to be approximately 1.2% per year for a Diphenylhydantoin (DPH) monotherapy and 1.8% per year and 2.0% per year for a DPH plus Phenobarbital and DPH plus Carbamazepin combination therapy. (orig.)

  16. Heparin modulates the endopeptidase activity of Leishmania mexicana cysteine protease cathepsin L-Like rCPB2.8.

    Directory of Open Access Journals (Sweden)

    Wagner A S Judice

    Full Text Available Cysteine protease B is considered crucial for the survival and infectivity of the Leishmania in its human host. Several microorganism pathogens bind to the heparin-like glycosaminoglycans chains of proteoglycans at host-cell surface to promote their attachment and internalization. Here, we have investigated the influence of heparin upon Leishmania mexicana cysteine protease rCPB2.8 activity.THE DATA ANALYSIS REVEALED THAT THE PRESENCE OF HEPARIN AFFECTS ALL STEPS OF THE ENZYME REACTION: (i it decreases 3.5-fold the k 1 and 4.0-fold the k -1, (ii it affects the acyl-enzyme accumulation with pronounced decrease in k 2 (2.7-fold, and also decrease in k 3 (3.5-fold. The large values of ΔG  =  12 kJ/mol for the association and dissociation steps indicate substantial structural strains linked to the formation/dissociation of the ES complex in the presence of heparin, which underscore a conformational change that prevents the diffusion of substrate in the rCPB2.8 active site. Binding to heparin also significantly decreases the α-helix content of the rCPB2.8 and perturbs the intrinsic fluorescence emission of the enzyme. The data strongly suggest that heparin is altering the ionization of catalytic (Cys(25-S(-/(His(163-Im(+ H ion pair of the rCPB2.8. Moreover, the interaction of heparin with the N-terminal pro-region of rCPB2.8 significantly decreased its inhibitory activity against the mature enzyme.Taken together, depending on their concentration, heparin-like glycosaminoglycans can either stimulate or antagonize the activity of cysteine protease B enzymes during parasite infection, suggesting that this glycoconjugate can anchor parasite cysteine protease at host cell surface.

  17. Agmatine reduces extracellular glutamate during pentylenetetrazole-induced seizures in rat brain: A potential mechanism for the anticonvulsive effects

    OpenAIRE

    Feng, Yangzheng; LeBlanc, Michael H.; Regunathan, Soundar

    2005-01-01

    Glutamate has been implicated in the initiation and spread of seizure activity. Agmatine, an endogenous neuromodulator, is an antagonist of NMDA receptors and has anticonvulsive effects. Whether agmatine regulate glutamate release, as measured by in vivo microdialysis, is not known. In this study, we used pentylenetetrazole (PTZ)-induced seizure model to determine the effect of agmatine on extracellular glutamate in rat brain. We also determined the time course and the amount of agmatine that...

  18. Pro- and anticonvulsant actions of morphine and the endogenous opioids: involvement and interactions of multiple opiate and non-opiate systems.

    Science.gov (United States)

    Frenk, H

    1983-10-01

    The proconvulsant actions of high doses of systemic morphine are probably mediated by 3 different systems. One of them produces non-convulsant electrographic seizures and can be activated separately from the others both by intracerebroventricular injections as well as microinjections into discrete subcortical areas. The enkephalins and beta-endorphin, when administered to the same loci, produce similar effects. Pharmacological evidence suggests that specific opiate receptors of the delta-subtype mediate the epileptiform effects produced by this system. The second system mediating proconvulsant effects of systemic morphine is not mediated by stereo-specific opiate receptors. It produces behavioral convulsions, and the GABA-ergic system has been implicated in its action. A third proconvulsant action of systemic morphine can be activated separately from the other two systems by administering this compound with other convulsive agents or manipulations. Specific mu-type opiate receptors are implicated in this effect. In addition to potent proconvulsant effects, systemic morphine also has anticonvulsant properties which are mediated by specific opiate mu-receptors. The conditions under which morphine acts as a proconvulsant rather than an anticonvulsant agent are, as yet, not understood.

  19. Binding interactions of convulsant and anticonvulsant gamma-butyrolactones and gamma-thiobutyrolactones with the picrotoxin receptor

    International Nuclear Information System (INIS)

    Holland, K.D.; McKeon, A.C.; Covey, D.F.; Ferrendelli, J.A.

    1990-01-01

    Alkyl-substituted gamma-butyrolactones (GBLs) and gamma-thiobutyrolactones (TBLs) are neuroactive chemicals. beta-Substituted compounds are convulsant, whereas alpha-alkyl substituted GBLs and TBLs are anticonvulsant. The structural similarities between beta-alkyl GBLs and the convulsant picrotoxinin suggested that alkyl substituted GBLs and TBLs act at the picrotoxin receptor. To test this hypothesis we examined the interactions of convulsant and anticonvulsant GBLs and TBLs with the picrotoxin, benzodiazepine and gamma-aminobutyric acid (GABA) binding sites of the GABA receptor complex. All of these convulsants and anticonvulsants studied competitively displaced 35S-t-butylbicyclophosphorothionate (35S-TBPS), a ligand that binds to the picrotoxin receptor. This inhibition of 35S-TBPS binding was not blocked by the GABA antagonist bicuculline methobromide. The convulsant GBLs and TBLs also partially inhibited [3H]muscimol binding to the GABA site and [3H]flunitrazepam binding to the benzodiazepine site, but they did so at concentrations substantially greater than those that inhibited 35S-TBPS binding. The anticonvulsant GBLs and TBLs had no effect on either [3H]muscimol or [3H]flunitrazepam binding. In contrast to the GBLs and TBLs, pentobarbital inhibited TBPS binding in a manner that was blocked by bicuculline methobromide, and it enhanced both [3H]flunitrazepam and [3H]muscimol binding. Both ethosuximide and tetramethylsuccinimide, neuroactive compounds structurally similar to GBLs, competitively displaced 35S-TBPS from the picrotoxin receptor and both compounds were weak inhibitors of [3H] muscimol binding. In addition, ethosuximide also partially diminished [3H]flunitrazepam binding. These data demonstrate that the site of action of alkyl-substituted GBLs and TBLs is different from that of GABA, barbiturates and benzodiazepines

  20. R2R-printed inverted OPV modules - towards arbitrary patterned designs

    Science.gov (United States)

    Välimäki, M.; Apilo, P.; Po, R.; Jansson, E.; Bernardi, A.; Ylikunnari, M.; Vilkman, M.; Corso, G.; Puustinen, J.; Tuominen, J.; Hast, J.

    2015-05-01

    We describe the fabrication of roll-to-roll (R2R) printed organic photovoltaic (OPV) modules using gravure printing and rotary screen-printing processes. These two-dimensional printing techniques are differentiating factors from coated OPVs enabling the direct patterning of arbitrarily shaped and sized features into visual shapes and, increasing the freedom to connect the cells in modules. The inverted OPV structures comprise five layers that are either printed or patterned in an R2R printing process. We examined the rheological properties of the inks used and their relationship with the printability, the compatibility between the processed inks, and the morphology of the R2R-printed layers. We also evaluate the dimensional accuracy of the printed pattern, which is an important consideration in designing arbitrarily-shaped OPV structures. The photoactive layer and top electrode exhibited excellent cross-dimensional accuracy corresponding to the designed width. The transparent electron transport layer extended 300 µm beyond the designed values, whereas the hole transport layer shrank 100 µm. We also examined the repeatability of the R2R fabrication process when the active area of the module varied from 32.2 cm2 to 96.5 cm2. A thorough layer-by-layer optimization of the R2R printing processes resulted in realization of R2R-printed 96.5 cm2 sized modules with a maximum power conversion efficiency of 2.1% (mean 1.8%) processed with high functionality.

  1. Structural requirements for bioactivation of anticonvulsants to cytotoxic metabolites in vitro.

    Science.gov (United States)

    Riley, R J; Kitteringham, N R; Park, B K

    1989-01-01

    The formation of cytotoxic metabolites from the anticonvulsants phenytoin and carbamazepine was investigated in vitro using a hepatic microsomal enzyme system and human mononuclear leucocytes as target cells. Both drugs were metabolised to cytotoxic products. In order to assess the structural requirements for this bioactivation, a series of structurally related compounds was investigated. It was found that molecules which contain either an amide function or an aryl ring may undergo activation in vitro, but only the metabolism-dependent toxicity of the latter is potentiated by pre-treatment of the target cells with an epoxide hydrolase inhibitor. Taken collectively, these data are consistent with the concept that reactive epoxide metabolites of both phenytoin and carbamazepine may produce toxicity in individuals with an inherited deficiency in epoxide hydrolase. PMID:2590607

  2. Chronic administration of anticonvulsants but not antidepressants impairs bone strength: clinical implications.

    Science.gov (United States)

    Gold, P W; Pavlatou, M G; Michelson, D; Mouro, C M; Kling, M A; Wong, M-L; Licinio, J; Goldstein, S A

    2015-06-02

    Major depression and bipolar disorder are associated with decreased bone mineral density (BMD). Antidepressants such as imipramine (IMIP) and specific serotonin reuptake inhibitors (SSRIs) have been implicated in reduced BMD and/or fracture in older depressed patients. Moreover, anticonvulsants such as valproate (VAL) and carbamazepine (CBZ) are also known to increase fracture rates. Although BMD is a predictor of susceptibility to fracture, bone strength is a more sensitive predictor. We measured mechanical and geometrical properties of bone in 68 male Sprague Dawley rats on IMIP, fluoxetine (FLX), VAL, CBZ, CBZ vehicle and saline (SAL), given intraperitoneally daily for 8 weeks. Distinct regions were tested to failure by four-point bending, whereas load displacement was used to determine stiffness. The left femurs were scanned in a MicroCT system to calculate mid-diaphyseal moments of inertia. None of these parameters were affected by antidepressants. However, VAL resulted in a significant decrease in stiffness and a reduction in yield, and CBZ induced a decrease in stiffness. Only CBZ induced alterations in mechanical properties that were accompanied by significant geometrical changes. These data reveal that chronic antidepressant treatment does not reduce bone strength, in contrast to chronic anticonvulsant treatment. Thus, decreased BMD and increased fracture rates in older patients on antidepressants are more likely to represent factors intrinsic to depression that weaken bone rather than antidepressants per se. Patients with affective illness on anticonvulsants may be at particularly high risk for fracture, especially as they grow older, as bone strength falls progressively with age.

  3. Anticonvulsant activity of Aloe vera leaf extract in acute and chronic models of epilepsy in mice.

    Science.gov (United States)

    Rathor, Naveen; Arora, Tarun; Manocha, Sachin; Patil, Amol N; Mediratta, Pramod K; Sharma, Krishna K

    2014-03-01

    The effect of Aloe vera in epilepsy has not yet been explored. This study was done to explore the effect of aqueous extract of Aloe vera leaf powder on three acute and one chronic model of epilepsy. In acute study, aqueous extract of Aloe vera leaf (extract) powder was administered in doses 100, 200 and 400 mg/kg p.o. Dose of 400 mg/kg of Aloe vera leaf extract was chosen for chronic administration. Oxidative stress parameters viz. malondialdehyde (MDA) and reduced glutathione (GSH) were also estimated in brain of kindled animals. In acute study, Aloe vera leaf (extract) powder in a dose-dependent manner significantly decreased duration of tonic hind limb extension in maximal electroshock seizure model, increased seizure threshold current in increasing current electroshock seizure model, and increased latency to onset and decreased duration of clonic convulsion in pentylenetetrazole (PTZ) model as compared with control group. In chronic study, Aloe vera leaf (extract) powder prevented progression of kindling in PTZ-kindled mice. Aloe vera leaf (extract) powder 400 mg/kg p.o. also reduced brain levels of MDA and increased GSH levels as compared to the PTZ-kindled non-treated group. The results of study showed that Aloe vera leaf (extract) powder possessed significant anticonvulsant and anti-oxidant activity. © 2013 Royal Pharmaceutical Society.

  4. Participation of mitochondrial diazepam binding inhibitor receptors in the anticonflict, antineophobic and anticonvulsant action of 2-aryl-3-indoleacetamide and imidazopyridine derivatives.

    Science.gov (United States)

    Auta, J; Romeo, E; Kozikowski, A; Ma, D; Costa, E; Guidotti, A

    1993-05-01

    The 2-hexyl-indoleacetamide derivative, FGIN-1-27 [N,N-di-n-hexyl-2- (4-fluorophenyl)indole-3-acetamide], and the imidazopyridine derivative, alpidem, both bind with high affinity to glial mitochondrial diazepam binding inhibitor receptors (MDR) and increase mitochondrial steroidogenesis. Although FGIN-1-27 is selective for the MDR, alpidem also binds to the allosteric modulatory site of the gamma-aminobutyric acidA receptor where the benzodiazepines bind. FGIN-1-27 and alpidem, like the neurosteroid 3 alpha,21-dehydroxy-5 alpha-pregnane-20-one (THDOC), clonazepam and zolpidem (the direct allosteric modulators of gamma-aminobutyric acidA receptors) delay the onset of isoniazid and metrazol-induced convulsions. The anti-isoniazid convulsant action of FGIN-1-27 and alpidem, but not that of THDOC, is blocked by PK 11195. In contrast, flumazenil blocked completely the anticonvulsant action of clonazepam and zolpidem and partially blocked that of alpidem, but it did not affect the anticonvulsant action of THDOC and FGIN-1-27. Alpidem, like clonazepam, zolpidem and diazepam, but not THDOC or FGIN-1-27, delay the onset of bicuculline-induced convulsions. In two animal models of anxiety, the neophobic behavior in the elevated plus maze test and the conflict-punishment behavior in the Vogel conflict test, THDOC and FGIN-1-27 elicited anxiolytic-like effects in a manner that is flumazenil insensitive, whereas alpidem elicited a similar anxiolytic effect, but is partially blocked by flumazenil. Whereas PK 11195 blocked the effect of FGIN-1-27 and partially blocked alpidem, it did not affect THDOC in both animal models of anxiety.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Comparative MD Simulations Indicate a Dual Role for Arg1323.50 in Dopamine-Dependent D2R Activation.

    Directory of Open Access Journals (Sweden)

    Ralf C Kling

    Full Text Available Residue Arg3.50 belongs to the highly conserved DRY-motif of class A GPCRs, which is located at the bottom of TM3. On the one hand, Arg3.50 has been reported to help stabilize the inactive state of GPCRs, but on the other hand has also been shown to be crucial for stabilizing active receptor conformations and mediating receptor-G protein coupling. The combined results of these studies suggest that the exact function of Arg3.50 is likely to be receptor-dependent and must be characterized independently for every GPCR. Consequently, we now present comparative molecular-dynamics simulations that use our recently described inactive-state and Gα-bound active-state homology models of the dopamine D2 receptor (D2R, which are either bound to dopamine or ligand-free, performed to identify the function of Arg1323.50 in D2R. Our results are consistent with a dynamic model of D2R activation in which Arg1323.50 adopts a dual role, both by stabilizing the inactive-state receptor conformation and enhancing dopamine-dependent D2R-G protein coupling.

  6. The preparation of TiO2@rGO nanocomposite efficiently activated with UVA/LED and H2O2 for high rate oxidation of acetaminophen: Catalyst characterization and acetaminophen degradation and mineralization

    Science.gov (United States)

    Cheshme Khavar, Amir Hossein; Moussavi, Gholamreza; Mahjoub, Ali Reza

    2018-05-01

    The present work was focused on the preparation of TiO2@rGO nanocomposite using an innovative facile synthesis method and the investigation of its photocatalytic activity in a UVA/LED photoreactor. The XRD patterns indicated anatase structure for all samples. Presence of rGO in nanocomposites was confirmed by FT-IR and Raman spectra. Also, mono-dispersed TiO2 nanoparticles on rGO sheet were shown in the SEM and HRTEM images. The prepared TiO2@rGO nanocomposite was used as the photocatalyst for degradation of acetaminophen (ACT) in the photoreactor illuminated with UVA/LEDs having the intensity of 95 μW/cm2. The complete degradation of 50 mg/L ACT was attained within 50 min in the LED/TiO2@rGO process while P25/LED process only showed 17% ACT degradation under similar experimental conditions. The photocatalytic activity was strongly affected by the rGO to TiO2 ratio in the nanocomposites and the highest photocatalytic activity was observed at 3.0 wt.% of rGO. Reaction with free radOH was the main mechanism involved in the ACT photodegradation in the TiO2@rGO/LED process under the selected conditions. The performance of LED/TiO2@rGO process improved by four and three times in ACT degradation and mineralization, respectively, at the presence of H2O2. As made TiO2@rGO nanocompsite could preserve its catalytic activity during five consecutive recycles in the process. Accordingly, TiO2@rGO nanocomposite is an active and stable catalyst in the UVA/LED photoreactor for high rate degradation of pharmaceuticals in the contaminated water.

  7. Ca 2+ signaling by plant Arabidopsis thaliana Pep peptides depends on AtPepR1, a receptor with guanylyl cyclase activity, and cGMP-activated Ca 2+ channels

    KAUST Repository

    Qia, Zhi; Verma, Rajeev K.; Gehring, Christoph A; Yamaguchi, Yube; Zhao, Yichen; Ryan, Clarence A.; Berkowitz, Gerald A.

    2010-01-01

    receptor- like kinase receptor AtPepR1 has guanylyl cyclase activity, generating cGMP from GTP, and that cGMP can activate CNGC2- dependent cytosolic Ca 2+ elevation. AtPep-dependent expression of pathogen-defense genes (PDF1.2, MPK3, and WRKY33

  8. A cold active (2R,3R)-(-)-di-O-benzoyl-tartrate hydrolyzing esterase from Rhodotorula mucilaginosa.

    Science.gov (United States)

    Zimmer, Christian; Platz, Tanja; Cadez, Neza; Giffhorn, Friedrich; Kohring, Gert-Wieland

    2006-11-01

    In a screening procedure a pink-colored yeast was isolated from enrichment cultures with (2R,3R)-(-)-di-O-benzoyl-tartrate (benzoyl-tartrate) as the sole carbon source. The organism saar1 was identified by morphological, physiological, and 18S ribosomal DNA/internal transcribed spacer analysis as Rhodotorula mucilaginosa, a basidiomycetous yeast. During growth the yeast hydrolyzed the dibenzoyl ester stoichiometrically to the monoester using the separated benzoate as the growth substrate, before the monoester was further cleaved into benzoate and tartrate, which were both metabolized. The corresponding benzoyl esterase was purified from the culture supernatant and characterized as a monomeric glycosylated 86-kDa protein with an optimum pH of 7.5 and an optimum temperature of 45 degrees C. At 0 degrees C the esterase still exhibited 20% of the corresponding activity at 30 degrees C, which correlates it to psychrophilic enzymes. The esterase could hydrolyze short chain p-nitrophenyl-alkyl esters and several benzoyl esters like benzoyl-methyl ester, ethylene-glycol-dibenzoyl ester, phenyl-benzoyl ester, cocaine, and 1,5-anhydro-D: -fructose-tribenzoyl ester. However feruloyl-ethyl ester was not hydrolyzed. The activity characteristics let the enzyme appear as a promising tool for synthesis of benzoylated compounds for pharmaceutical, cosmetic, or fine chemical applications, even at low temperatures.

  9. Spina bifida and cleft lip among newborns of Norwegian women with epilepsy: changes related to the use of anticonvulsants.

    Science.gov (United States)

    King, P B; Lie, R T; Irgens, L M

    1996-01-01

    OBJECTIVES: This study examined the connection between the use of anticonvulsants for epilepsy during or before pregnancy and the risk of spina bifida and cleft lip in newborns. METHODS: Among mothers registered from 1967 to 1992 by the Medical Birth Registry of Norway, 7588 who had epilepsy were identified and their newborns' prevalence of spina bifida and cleft lip examined. RESULTS: The odds ratio of spina bifida in children of mothers with epilepsy compared with other children increased from 1.5 in 1967 through 1980 (95% confidence interval [CI] = 0.3, 4.5) to 4.4 in 1981 through 1992 (95% CI = 2.0, 8.5). The odds ratio of cleft lip, however, decreased from 3.0 before 1981 (95% CI = 1.6, 5.1) to 1.1 after 1981 (95% CI = 0.4, 2.3). CONCLUSIONS: This shift toward more serious birth defects is consistent with the different teratogenic effects of newer and older anticonvulsants. PMID:8876519

  10. elPBN neurons regulate rVLM activity through elPBN-rVLM projections during activation of cardiac sympathetic afferent nerves

    Science.gov (United States)

    Longhurst, John C.; Tjen-A-Looi, Stephanie C.; Fu, Liang-Wu

    2016-01-01

    The external lateral parabrachial nucleus (elPBN) within the pons and rostral ventrolateral medulla (rVLM) contributes to central processing of excitatory cardiovascular reflexes during stimulation of cardiac sympathetic afferent nerves (CSAN). However, the importance of elPBN cardiovascular neurons in regulation of rVLM activity during CSAN activation remains unclear. We hypothesized that CSAN stimulation excites the elPBN cardiovascular neurons and, in turn, increases rVLM activity through elPBN-rVLM projections. Compared with controls, in rats subjected to microinjection of retrograde tracer into the rVLM, the numbers of elPBN neurons double-labeled with c-Fos (an immediate early gene) and the tracer were increased after CSAN stimulation (P < 0.05). The majority of these elPBN neurons contain vesicular glutamate transporter 3. In cats, epicardial bradykinin and electrical stimulation of CSAN increased the activity of elPBN cardiovascular neurons, which was attenuated (n = 6, P < 0.05) after blockade of glutamate receptors with iontophoresis of kynurenic acid (Kyn, 25 mM). In separate cats, microinjection of Kyn (1.25 nmol/50 nl) into the elPBN reduced rVLM activity evoked by both bradykinin and electrical stimulation (n = 5, P < 0.05). Excitation of the elPBN with microinjection of dl-homocysteic acid (2 nmol/50 nl) significantly increased basal and CSAN-evoked rVLM activity. However, the enhanced rVLM activity induced by dl-homocysteic acid injected into the elPBN was reversed following iontophoresis of Kyn into the rVLM (n = 7, P < 0.05). These data suggest that cardiac sympathetic afferent stimulation activates cardiovascular neurons in the elPBN and rVLM sequentially through a monosynaptic (glutamatergic) excitatory elPBN-rVLM pathway. PMID:27225950

  11. Synthesis, physical and chemical properties, antihypoxic activity of some 5-[((5-(adamantane-1-yl-4-R-4H-1,2,4-triazole-3-ylthiomethyl]-N-R1-1,3,4-thiadiazole-2-amines and 5-[((5-(adamantane-1-yl-4-R-4H-1,2,4-triazole-3-ylthiomethyl]-4-R1-4H-1,2,4-t

    Directory of Open Access Journals (Sweden)

    V. M. Odyntsova

    2018-03-01

    Full Text Available Today, an increase of natural and technogenic situations leads to the disorders of the central nervous system, functional-metabolic processes, vascular diseases, in particular, acute cerebral blood flow disorders. In addition, the changes occurring on the molecular and cellular levels are in the basis of the functional violations of individual systems and the organism as a whole. Hypoxia not only complicates the disease course, but in most cases, determines its outcome. The important role in the fight against hypoxia belongs to antioxidants, which improve the circulating oxygen utilization by the body, reduce its need for the organs and tissues, which is not only expedient but necessary for the treatment of many acute and chronic pathological processes. So, the frequency of the hypoxic states and a wide range of factors causing them determine the relevance of new ways and methods finding to overcome the oxygen deficiency. The aim of this work is the purposeful search of some 5-[((5-(adamantane-1-yl-4-R-4H-1,2,4-triazole-3-ylthiomethyl]-N-R1-1,3,4-thiadiazole-2-amines and 5-[((5-(adamantane-1-yl-4-R-4H-1,2,4-triazole-3-ylthiomethyl]-4-R1-4H-1,2,4-triazole-3-thiols, the study of their physical and chemical properties and pharmacological screening of the antihypoxic activity of the obtained compounds. Materials and methods. The study of physical and chemical properties was conducted on certified and licensed modern equipment. Antihypoxic activity was studied during the modeling process of hypoxia with hypercapnia. Mexidol was used as a comparison drug in studies at a dose of 100 mg/kg. Results. As the result of the study, it was found that the synthesized compounds and the comparison drug influenced on rats’ life span differently. Compounds, the antihypoxic activity of which exceeded control have been discovered, and others’ were at the level of Mexidol. A number of compounds showed a somewhat less activity in comparison with control, and two

  12. Anticonvulsant Effects of Memantine and MK-801 in Guinea Pig Hippocampal Neurons.

    Science.gov (United States)

    investigation we compared the anticonvulsant properties of Mem to those of MK-801 in guinea pig hippocampal slices. Extracellular recordings were...obtained from area CA1 of guinea pig hippocampal slices in a total submersion chamber at 32 deg C in normal oxygenated artificial cerebrospinal fluid (ACSF

  13. Anticonvulsant effects of Searsia dentata (Anacardiaceae) leaf extract in rats

    DEFF Research Database (Denmark)

    Pedersen, Mikael Egebjerg; Baldwin, Roger A; Niquet, Jerome

    2010-01-01

    Searsia species are used in South Africa to treat epilepsy. Previous studies have demonstrated an in vitro N-methyl-D-aspartic acid (NMDA) receptor antagonistic effect of the ethanolic leaf extract. The aim of this study was to evaluate the potential anticonvulsant properties of the ethanolic ext...

  14. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia.

    Science.gov (United States)

    Duley, Lelia; Gülmezoglu, A Metin; Henderson-Smart, David J; Chou, Doris

    2010-11-10

    Eclampsia, the occurrence of a seizure (fit) in association with pre-eclampsia, is rare but potentially life-threatening. Magnesium sulphate is the drug of choice for treating eclampsia. This review assesses its use for preventing eclampsia. To assess the effects of magnesium sulphate, and other anticonvulsants, for prevention of eclampsia. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (4 June 2010), and the Cochrane Central Register of Controlled Trials Register (The Cochrane Library 2010, Issue 3). Randomised trials comparing anticonvulsants with placebo or no anticonvulsant, or comparisons of different drugs, for pre-eclampsia. Two authors assessed trial quality and extracted data independently. We included 15 trials. Six (11,444 women) compared magnesium sulphate with placebo or no anticonvulsant: magnesium sulphate more than a halved the risk of eclampsia (risk ratio (RR) 0.41, 95% confidence interval (CI) 0.29 to 0.58; number needed to treat for an additional beneficial outcome (NNTB) 100, 95% CI 50 to 100), with a non-significant reduction in maternal death (RR 0.54, 95% CI 0.26 to 1.10) but no clear difference in serious maternal morbidity (RR 1.08, 95% CI 0.89 to 1.32). It reduced the risk of placental abruption (RR 0.64, 95% CI 0.50 to 0.83; NNTB 100, 95% CI 50 to 1000), and increased caesarean section (RR 1.05, 95% CI 1.01 to 1.10). There was no clear difference in stillbirth or neonatal death (RR 1.04, 95% CI 0.93 to 1.15). Side effects, primarily flushing, were more common with magnesium sulphate (24% versus 5%; RR 5.26, 95% CI 4.59 to 6.03; number need to treat for an additional harmful outcome (NNTH) 6, 95% CI 5 to 6).Follow-up was reported by one trial comparing magnesium sulphate with placebo: for 3375 women there was no clear difference in death (RR 1.79, 95% CI 0.71 to 4.53) or morbidity potentially related to pre-eclampsia (RR 0.84, 95% CI 0.55 to 1.26) (median follow-up 26 months); for 3283 children exposed in utero

  15. Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine : efficacy, safety and dosing

    NARCIS (Netherlands)

    van den Broek, Marcel P. H.; Rademaker, Carin M. A.; van Straaten, Henrica L. M.; Huitema, Alwin D. R.; Toet, Mona C.; de Vries, Linda S.; Egberts, Antoine C. G.; Groenendaal, Floris

    BACKGROUND: Lidocaine is an antiarrythmicum used as an anticonvulsant for neonatal seizures, also during therapeutic hypothermia following (perinatal) asphyxia. Hypothermia may affect the efficacy, safety and dosing of lidocaine in these patients. OBJECTIVE: To study the efficacy and safety of

  16. Glutamate metabotropic receptors as targets for drug therapy in epilepsy.

    Science.gov (United States)

    Moldrich, Randal X; Chapman, Astrid G; De Sarro, Giovambattista; Meldrum, Brian S

    2003-08-22

    Metabotropic glutamate (mGlu) receptors have multiple actions on neuronal excitability through G-protein-linked modifications of enzymes and ion channels. They act presynaptically to modify glutamatergic and gamma-aminobutyric acid (GABA)-ergic transmission and can contribute to long-term changes in synaptic function. The recent identification of subtype-selective agonists and antagonists has permitted evaluation of mGlu receptors as potential targets in the treatment of epilepsy. Agonists acting on group I mGlu receptors (mGlu1 and mGlu5) are convulsant. Antagonists acting on mGlu1 or mGlu5 receptors are anticonvulsant against 3,5-dihydroxyphenylglycine (DHPG)-induced seizures and in mouse models of generalized motor seizures and absence seizures. The competitive, phenylglycine mGlu1/5 receptor antagonists generally require intracerebroventricular administration for potent anticonvulsant efficacy but noncompetitive antagonists, e.g., (3aS,6aS)-6a-naphthalen-2-ylmethyl-5-methyliden-hexahydrocyclopenta[c]furan-1-on (BAY36-7620), 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), and 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893) block generalized seizures with systemic administration. Agonists acting on group II mGlu receptors (mGlu2, mGlu3) to reduce glutamate release are anticonvulsant, e.g., 2R,4R-aminopyrrolidine-2,4-dicarboxylate [(2R,4R)-APDC], (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268). The classical agonists acting on group III mGlu receptors such as L-(+)-2-amino-4-phosphonobutyric acid, and L-serine-O-phosphate are acutely proconvulsant with some anticonvulsant activity. The more recently identified agonists (R,S)-4-phosphonophenylglycine [(R,S)-PPG] and (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG] and (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid [ACPT-1] are all anticonvulsant without proconvulsant effects. Studies in animal models of kindling

  17. The Monoceros R2 Molecular Cloud

    Science.gov (United States)

    Carpenter, J. M.; Hodapp, K. W.

    2008-12-01

    The Monoceros R2 region was first recognized as a chain of reflection nebulae illuminated by A- and B-type stars. These nebulae are associated with a giant molecular cloud that is one of the closest massive star forming regions to the Sun. This chapter reviews the properties of the Mon R2 region, including the namesake reflection nebulae, the large scale molecula= r cloud, global star formation activity, and properties of prominent star forming regions in the cloud.

  18. Computer-Aided Identification of Anticonvulsant Effect of Natural Nonnutritive Sweeteners Stevioside and Rebaudioside A

    Science.gov (United States)

    Di Ianni, Mauricio E.; del Valle, Mara E.; Enrique, Andrea V.; Rosella, Mara A.; Bruno, Fiorella; Bruno-Blanch, Luis E.

    2015-01-01

    Abstract Steviol glycosides are natural constituents of Stevia rebaudiana (Bert.) Bert. (Asteraceae) that have recently gained worldwide approval as nonnutritive sweeteners by the Joint Food and Agriculture Organization/World Organization Expert Committee on Food Additives. Cheminformatic tools suggested that the aglycone steviol and several of its phase I metabolites were predicted as potential anticonvulsant agents effective in the seizure animal model maximal electroshock seizure (MES) test. Thus, aqueous infusion from S. rebaudiana was tested in the MES test (mice, intraperitoneal administration), confirming dose-dependent anticonvulsant effect. Afterward, isolated stevioside and rebaudioside A were tested in the MES test, with positive results. Though drug repositioning most often focuses on known therapeutics, this article illustrates the possibilities of this strategy to find new functionalities and therapeutic indications for food constituents and natural products. PMID:26258457

  19. The bitter pill: clinical drugs that activate the human bitter taste receptor TAS2R14.

    Science.gov (United States)

    Levit, Anat; Nowak, Stefanie; Peters, Maximilian; Wiener, Ayana; Meyerhof, Wolfgang; Behrens, Maik; Niv, Masha Y

    2014-03-01

    Bitter taste receptors (TAS2Rs) mediate aversive response to toxic food, which is often bitter. These G-protein-coupled receptors are also expressed in extraoral tissues, and emerge as novel targets for therapeutic indications such as asthma and infection. Our goal was to identify ligands of the broadly tuned TAS2R14 among clinical drugs. Molecular properties of known human bitter taste receptor TAS2R14 agonists were incorporated into pharmacophore- and shape-based models and used to computationally predict additional ligands. Predictions were tested by calcium imaging of TAS2R14-transfected HEK293 cells. In vitro testing of the virtual screening predictions resulted in 30-80% success rates, and 15 clinical drugs were found to activate the TAS2R14. hERG potassium channel, which is predominantly expressed in the heart, emerged as a common off-target of bitter drugs. Despite immense chemical diversity of known TAS2R14 ligands, novel ligands and previously unknown polypharmacology of drugs were unraveled by in vitro screening of computational predictions. This enables rational repurposing of traditional and standard drugs for bitter taste signaling modulation for therapeutic indications.

  20. Novel Triazole linked 2-phenyl benzoxazole derivatives induce apoptosis by inhibiting miR-2, miR-13 and miR-14 function in Drosophila melanogaster.

    Science.gov (United States)

    Mondal, Tanmoy; Lavanya, A V S; Mallick, Akash; Dadmala, Tulshiram L; Kumbhare, Ravindra M; Bhadra, Utpal; Bhadra, Manika Pal

    2017-06-01

    Apoptosis is an important phenomenon in multi cellular organisms for maintaining tissue homeostasis and embryonic development. Defect in apoptosis leads to a number of disorders like- autoimmune disorder, immunodeficiency and cancer. 21-22 nucleotides containing micro RNAs (miRNAs/miRs) function as a crucial regulator of apoptosis alike other cellular pathways. Recently, small molecules have been identified as a potent inducer of apoptosis. In this study, we have identified novel Triazole linked 2-phenyl benzoxazole derivatives (13j and 13h) as a negative regulator of apoptosis inhibiting micro RNAs (miR-2, miR-13 and miR-14) in a well established in vivo model Drosophila melanogaster where the process of apoptosis is very similar to human apoptosis. These compounds inhibit miR-2, miR-13 and miR-14 activity at their target sites, which induce an increased caspase activity, and in turn influence the caspase dependent apoptotic pathway. These two compounds also increase the mitochondrial reactive oxygen species (ROS) level to trigger apoptotic cell death.

  1. A combination of luxR1 and luxR2 genes activates Pr-promoters of psychrophilic Aliivibrio logei lux-operon independently of chaperonin GroEL/ES and protease Lon at high concentrations of autoinducer.

    Science.gov (United States)

    Konopleva, Maria N; Khrulnova, Svetlana A; Baranova, Ancha; Ekimov, Leonid V; Bazhenov, Sergey V; Goryanin, Ignatiy I; Manukhov, Ilya V

    2016-05-13

    Lux-operon of psychrophilic bacteria Aliivibrio logei contains two copies of luxR and is regulated by Type I quorum sensing (QS). Activation of lux-operon of psychrophilic bacteria A. logei by LuxR1 requires about 100 times higher concentrations of autoinducer (AI) than the activation by LuxR2. On the other hand, LuxR1 does not require GroEL/ES chaperonin for its folding and cannot be degraded by protease Lon, while LuxR2 sensitive to Lon and requires GroEL/ES. Here we show that at 10(-5) - 10(-4)М concentrations of AI a combination of luxR1 and luxR2 products is capable of activating the Pr-promoters of A. logei lux-operon in Escherichia coli independently of GroEL/ES and protease Lon. The presence of LuxR1 assists LuxR2 in gro(-) cells when AI was added at high concentration, while at low concentration of AI in a cell LuxR1 decreases the LuxR2 activity. These observations may be explained by the formation of LuxR1/LuxR2 heterodimers that act in complex with AI independently from GroEL/ES and protease Lon. This study expands current understanding of QS regulation in A. logei as it implies cooperative regulation of lux-operon by LuxR1 and LuxR2 proteins. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Effects of the benzodiazepine antagonists RO 15-1788, CGS-8216 and PK-11195 on amygdaloid kindled seizures and the anticonvulsant efficacy of diazepam.

    Science.gov (United States)

    Albertson, T E; Walby, W F

    1986-11-01

    The anticonvulsant effectiveness of the benzodiazepine antagonists RO 15-1788, CGS-8216 and PK-11195 were evaluated against threshold and suprathreshold (400 microA) stimulation in fully amygdaloid-kindled rats. Pretreatment with either RO 15-1788 (3, 10 and 30 mg/kg), CGS-8216 (3, 10 and 30 mg/kg) or PK-11195 (10 and 60 mg/kg) failed in this study to modify consistently either the afterdischarge thresholds or elicited suprathreshold seizures or duration of afterdischarge. Using a double injection paradigm, the effectiveness of these three benzodiazepine antagonists to reverse the anti-convulsant and behavioral effects of diazepam were studied. When diazepam (3 mg/kg) was injected 15 min before or after a second injection of the vehicle control DMSO (0.25 ml/kg), a significant reduction in the duration of afterdischarge and seizure rank, elicited by a suprathreshold stimulation in amygdaloid-kindled rats, occurred. When either CGS 8216 (10 mg/kg) or RO 15-1788 (10 mg/kg) were given 15 min before diazepam (3 mg/kg) prior to stimulation, the anticonvulsant properties of diazepam were blocked. When RO 15-1788 (10 mg/kg) was given 15 min after diazepam, antagonism of the anticonvulsant effects on diazepam was shown. However, when either CGS-8216 (10 mg/kg) or PK-11195 (10 and 60 mg/kg) were given 15 min after diazepam (3 mg/kg), the anticonvulsant properties of diazepam were not blocked. The anticonvulsant effects of diazepam were reversed when CGS-8216 (10 mg/kg) was given 5 min after diazepam (3 mg/kg) or when a larger dose (30 mg/kg) was given at the same 15 min interval.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Enzyme-inducing anticonvulsants increase plasma clearance of dexmedetomidine: a pharmacokinetic and pharmacodynamic study.

    Science.gov (United States)

    Flexman, Alana M; Wong, Harvey; Riggs, K Wayne; Shih, Tina; Garcia, Paul A; Vacas, Susana; Talke, Pekka O

    2014-05-01

    Dexmedetomidine is useful during mapping of epileptic foci as it facilitates electrocorticography unlike most other anesthetic agents. Patients with seizure disorders taking enzyme-inducing anticonvulsants appear to be resistant to its sedative effects. The objective of the study was to compare the pharmacokinetic and pharmacodynamic profile of dexmedetomidine in healthy volunteers with volunteers with seizure disorders receiving enzyme-inducing anticonvulsant medications. Dexmedetomidine was administered using a step-wise, computer-controlled infusion to healthy volunteers (n = 8) and volunteers with seizure disorders (n = 8) taking phenytoin or carbamazapine. Sedation and dexmedetomidine plasma levels were assessed at baseline, during the infusion steps, and after discontinuation of the infusion. Sedation was assessed by using the Observer's Assessment of Alertness/Sedation Scale, Ramsay Sedation Scale, and Visual Analog Scale and processed electroencephalography (entropy) monitoring. Pharmacokinetic analysis was performed on both groups, and differences between groups were determined using the standard two-stage approach. A two-compartment model was fit to dexmedetomidine concentration-time data. Dexmedetomidine plasma clearance was 43% higher in the seizure group compared with the control group (42.7 vs. 29.9 l/h; P = 0.007). In contrast, distributional clearance and the volume of distribution of the central and peripheral compartments were similar between the groups. No difference in sedation was detected between the two groups during a controlled range of target plasma concentrations. This study demonstrates that subjects with seizure disorders taking enzyme-inducing anticonvulsant medications have an increased plasma clearance of dexmedetomidine as compared with healthy control subjects.

  4. Concomitant alpha7 and beta2 nicotinic AChR subunit deficiency leads to impaired energy homeostasis and increased physical activity in mice.

    Science.gov (United States)

    Somm, Emmanuel; Guérardel, Audrey; Maouche, Kamel; Toulotte, Audrey; Veyrat-Durebex, Christelle; Rohner-Jeanrenaud, Françoise; Maskos, Uwe; Hüppi, Petra S; Schwitzgebel, Valérie M

    2014-05-01

    Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated cation channels well characterized in neuronal signal transmission. Moreover, recent studies have revealed nAChR expression in nonneuronal cell types throughout the body, including tissues involved in metabolism. In the present study, we screen gene expression of nAChR subunits in pancreatic islets and adipose tissues. Mice pancreatic islets present predominant expression of α7 and β2 nAChR subunits but at a lower level than in central structures. Characterization of glucose and energy homeostasis in α7β2nAChR(-/-) mice revealed no major defect in insulin secretion and sensitivity but decreased glycemia apparently unrelated to gluconeogenesis or glycogenolysis. α7β2nAChR(-/-) mice presented an increase in lean and bone body mass and a decrease in fat storage with normal body weight. These observations were associated with elevated spontaneous physical activity in α7β2nAChR(-/-) mice, mainly due to elevation in fine vertical (rearing) activity while their horizontal (ambulatory) activity remained unchanged. In contrast to α7nAChR(-/-) mice presenting glucose intolerance and insulin resistance associated to excessive inflammation of adipose tissue, the present metabolic phenotyping of α7β2nAChR(-/-) mice revealed a metabolic improvement possibly linked to the increase in spontaneous physical activity related to central β2nAChR deficiency. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Nitric oxide (NO) is an endogenous anticonvulsant but not a mediator of the increase in cerebral blood flow accompanying bicuculline-induced seizures in rats

    DEFF Research Database (Denmark)

    Wang, Qian; Theard, M A; Pelligrino, D A

    1994-01-01

    Neurons synthesize NO, which may act as a retrograde messenger, involved in either potentiating or depressing neuronal excitability. NO may also play a role in the cerebral vasodilatory response to increased neuronal activity (i.e., seizures). In this study, two questions were asked: (1) is NO an......Neurons synthesize NO, which may act as a retrograde messenger, involved in either potentiating or depressing neuronal excitability. NO may also play a role in the cerebral vasodilatory response to increased neuronal activity (i.e., seizures). In this study, two questions were asked: (1......) is NO an endogenous anticonvulsant or proconvulsant substance? and (2) is the cerebral blood flow (CBF) increase accompanying bicuculline (BC)-induced seizures mediated by NO? The experiments were performed in 300-400-g Wistar rats anesthetized with 0.6% halothane and 70% N2O/30% O2. CBF was measured using...

  6. [Lithium and anticonvulsants in the treatment of mania and in the prophylaxis of recurrences].

    Science.gov (United States)

    Salvi, Virginio; Cat Berro, Alberto; Bechon, Elisa; Bogetto, Filippo; Maina, Giuseppe

    2011-01-01

    A mood stabilizer is an agent effective in treating both poles of the illness and at the same time being able to prevent both manic and depressive episodes in bipolar disorder. According to a broader definition, a mood stabilizer should be effective in decreasing the frequency or severity of any type of episode in bipolar disorder, without worsening the frequency or severity of episodes of opposite polarity. According to this, anticonvulsants and atypical antipsychotics can be considered as mood stabilizers. In this paper we review the use of lithium and other anticonvulsants that have proved effective in randomized controlled trials of the treatment of manic episodes and prevention of recurrences of bipolar disorder. Lithium and valproate are considered as first-line treatment options for acute mania while evidence regarding carbamazepine is insufficient to consider it as a first-line agent. Patients who fail to respond to first-line treatments may benefit from the adjunct of an atypical antipsychotic such as olanzapine, quetiapine, risperidone or aripiprazole. Lithium retains the strongest evidence of efficacy in the prophylaxis of manic episodes, lamotrigine in the prevention of depressive episodes. Valproate and carbamazepine have no indication for long-term treatment of bipolar disorder. Lithium can still be considered a gold standard in the treatment of manic episodes as well as in the prophylaxis of recurrences. Other anticonvulsants should be employed in particular situations, such as valproic acid in the treatment of mania and lamotrigine in the prevention of depressive recurrences.

  7. Fabrication of TiO{sub 2} nanorod assembly grafted rGO (rGO@TiO{sub 2}-NR) hybridized flake-like photocatalyst

    Energy Technology Data Exchange (ETDEWEB)

    Lv, Kangle, E-mail: lvkangle@mail.scuec.edu.cn [Department of Science and Environmental Studies, The Hong Kong Institute of Education, Taipo, N.T., Hong Kong (China); Key Laboratory of Catalysis and Materials Science of the State Ethnic Affairs Commission and Ministry of Education, College of Resources and Environmental Science, South-Central University for Nationalities, Wuhan 430074 (China); Fang, Shun; Si, Lingling; Xia, Yang [Key Laboratory of Catalysis and Materials Science of the State Ethnic Affairs Commission and Ministry of Education, College of Resources and Environmental Science, South-Central University for Nationalities, Wuhan 430074 (China); Ho, Wingkei, E-mail: keithho@ied.edu.hk [Department of Science and Environmental Studies, The Hong Kong Institute of Education, Taipo, N.T., Hong Kong (China); Li, Mei [Key Laboratory of Catalysis and Materials Science of the State Ethnic Affairs Commission and Ministry of Education, College of Resources and Environmental Science, South-Central University for Nationalities, Wuhan 430074 (China)

    2017-01-01

    Highlights: • TiO{sub 2} nanorod assembly grafted with GO hybrid was successfully fabricated. • TiO{sub 2} nanorods can reduce the aggregation of TiO{sub 2} nanoparticles on graphene. • This unique structure facilitates the injection of electron from TiO{sub 2} to graphene. - Abstract: To efficiently separate the photo-generated electron–hole pairs of TiO{sub 2} hybrid, anatase TiO{sub 2} nanorod assembly grafted reduced graphene oxides (rGO@TiO{sub 2}-NR) hybrid was successfully fabricated using potassium titanium oxalate (PTO) and graphene oxides (GO) as starting materials and diethylene glycol (DEG) as reductant. The effect of GO content on the structure and photocatalytic activity of rGO@TiO{sub 2}-NR composite was systematically studied. Results show that, in the absence of GO, only TiO{sub 2} microsphere assembly is obtained from TiO{sub 2} nanorods. The presence of GO results in the formation of a flake-like TiO{sub 2}-nanorod-assembled grafted rGO hybrid. The photocatalytic activity of rGO@TiO{sub 2}-NR composite increases first and then decreases with increase in the amount of GO from 0 wt.% to 10 wt.%. The hybridized S4 sample prepared with 4 wt.% GO possesses the highest photocatalytic activity with a constant rate of 0.039 min{sup −1} in the photocataytic degradation of Brilliant X-3B dye (X3B); this sample was enhanced more than three times when compared with pure TiO{sub 2} sample (0.012 min{sup −1}). The enhanced photocatalytic activity of the rGO@TiO{sub 2}-NR hybrid was attributed to the strong interaction between TiO{sub 2} nanorods and rGO. The unique hierarchical structure of 1D nanorod assembly TiO{sub 2}–rGO flakes facilitates the injection and transfer of photo-generated electrons from TiO{sub 2} to graphene, thus retarding the recombination of electron–hole pairs and enhancing the photocatalytic activity. The enlarged BET surface areas, not only increasing the number of active sites, but also facilitating the adsorption of

  8. Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2+P253R mice

    Directory of Open Access Journals (Sweden)

    Hill Cheryl A

    2010-02-01

    Full Text Available Abstract Background Apert syndrome is characterized by craniosynostosis and limb abnormalities and is primarily caused by FGFR2 +/P253R and +/S252W mutations. The former mutation is present in approximately one third whereas the latter mutation is present in two-thirds of the patients with this condition. We previously reported an inbred transgenic mouse model with the Fgfr2 +/S252W mutation on the C57BL/6J background for Apert syndrome. Here we present a mouse model for the Fgfr2+/P253R mutation. Results We generated inbred Fgfr2+/P253R mice on the same C56BL/6J genetic background and analyzed their skeletal abnormalities. 3D micro-CT scans of the skulls of the Fgfr2+/P253R mice revealed that the skull length was shortened with the length of the anterior cranial base significantly shorter than that of the Fgfr2+/S252W mice at P0. The Fgfr2+/P253R mice presented with synostosis of the coronal suture and proximate fronts with disorganized cellularity in sagittal and lambdoid sutures. Abnormal osteogenesis and proliferation were observed at the developing coronal suture and long bones of the Fgfr2+/P253R mice as in the Fgfr2+/S252W mice. Activation of mitogen-activated protein kinases (MAPK was observed in the Fgfr2+/P253R neurocranium with an increase in phosphorylated p38 as well as ERK1/2, whereas phosphorylated AKT and PKCα were not obviously changed as compared to those of wild-type controls. There were localized phenotypic and molecular variations among individual embryos with different mutations and among those with the same mutation. Conclusions Our in vivo studies demonstrated that the Fgfr2 +/P253R mutation resulted in mice with cranial features that resemble those of the Fgfr2+/S252W mice and human Apert syndrome. Activated p38 in addition to the ERK1/2 signaling pathways may mediate the mutant neurocranial phenotype. Though Apert syndrome is traditionally thought to be a consistent phenotype, our results suggest localized and regional

  9. Neuroprotective effects of anticonvulsants in rat hippocampal slice cultures exposed to oxygen/glucose deprivation

    DEFF Research Database (Denmark)

    Rekling, Jens C

    2003-01-01

    cell death induced by OGD. The newer anticonvulsants carbamazepine, felbamate, lamotrigine, tiagabine, and oxcarbazepine also had significant neuroprotective effects, but gabapentin, valproic acid (10 mM), levetiracetam and retigabine were not neuroprotective at a concentration up to 300 micro...

  10. Ambulatory care of children treated with anticonvulsants - pitfalls after discharge from hospital.

    Science.gov (United States)

    Bertsche, A; Dahse, A-J; Neininger, M P; Bernhard, M K; Syrbe, S; Frontini, R; Kiess, W; Merkenschlager, A; Bertsche, T

    2013-09-01

    Anticonvulsants require special consideration particularly at the interface from hospital to ambulatory care. Observational study for 6 months with prospectively enrolled consecutive patients in a neuropediatric ward of a university hospital (age 0-anticonvulsant. Assessment of outpatient prescriptions after discharge. Parent interviews for emergency treatment for acute seizures and safety precautions. We identified changes of the brand in 19/82 (23%) patients caused by hospital's discharge letters (4/82; 5%) or in ambulatory care (15/82; 18%). In 37/76 (49%) of patients who were deemed to require rescue medication, no recommendation for such a medication was included in the discharge letters. 17/76 (22%) of the respective parents stated that they had no immediate access to rescue medication. Safety precautions were applicable in 44 epilepsy patients. We identified knowledge deficits in 27/44 (61%) of parents. Switching of brands after discharge was frequent. In the discharge letters, rescue medications were insufficiently recommended. Additionally, parents frequently displayed knowledge deficits in risk management. © Georg Thieme Verlag KG Stuttgart · New York.

  11. Anticonvulsant effects of a triheptanoin diet in two mouse chronic seizure models

    Science.gov (United States)

    Willis, Sarah; Stoll, James; Sweetman, Lawrence; Borges, Karin

    2010-01-01

    We hypothesized that in epileptic brains citric acid cycle intermediate levels may be deficient leading to hyperexcitability. Anaplerosis is the metabolic refilling of deficient metabolites. Our goal was to determine the anticonvulsant effects of feeding triheptanoin, the triglyceride of anaplerotic heptanoate. CF1 mice were fed 0-35% calories from triheptanoin. Body weights and dietary intake were similar in mice fed triheptanoin vs. standard diet. Triheptanoin feeding increased blood propionyl-carnitine levels, signifying its metabolism. 35%, but not 20%, triheptanoin delayed development of corneal kindled seizures. After pilocarpine-induced status epilepticus (SE), triheptanoin feeding increased the pentylenetetrazole tonic seizure threshold during the chronically epileptic stage. Mice in the chronically epileptic stage showed various changes in brain metabolite levels, including a reduction in malate. Triheptanoin feeding largely restored a reduction in propionyl-CoA levels and increased methylmalonyl-CoA levels in SE mice. In summary, triheptanoin was anticonvulsant in two chronic mouse models and increased levels of anaplerotic precursor metabolites in epileptic mouse brains. The mechanisms of triheptanoin's effects and its efficacy in humans suffering from epilepsy remain to be determined. PMID:20691264

  12. Phytochemicals from Ruta graveolens Activate TAS2R Bitter Taste Receptors and TRP Channels Involved in Gustation and Nociception.

    Science.gov (United States)

    Mancuso, Giuseppe; Borgonovo, Gigliola; Scaglioni, Leonardo; Bassoli, Angela

    2015-10-16

    Ruta graveolens (rue) is a spontaneous plant in the Mediterranean area with a strong aroma and a very intense bitter taste, used in gastronomy and in folk medicine. From the leaves, stems and fruits of rue, we isolated rutin, rutamarin, three furanocoumarins, two quinolinic alkaloids, a dicoumarin and two long chain ketones. Bitter taste and chemesthetic properties have been evaluated by in vitro assays with twenty receptors of the TAS2R family and four TRP ion channels involved in gustation and nociception. Among the alkaloids, skimmianine was active as a specific agonist of T2R14, whereas kokusaginin did not activate any of the tested receptors. The furanocoumarins activates TAS2R10, 14, and 49 with different degrees of selectivity, as well as the TRPA1 somatosensory ion channel. Rutamarin is an agonist of TRPM5 and TRPV1 and a strong antagonist of TRPM8 ion channels.

  13. Distribution of rSlo Ca2+-activated K+ channels in rat astrocyte perivascular endfeet.

    Science.gov (United States)

    Price, Diana L; Ludwig, Jeffrey W; Mi, Huaiyu; Schwarz, Thomas L; Ellisman, Mark H

    2002-11-29

    Evidence that Ca(2+)-activated K(+) (K(Ca)) channels play a role in cell volume changes and K(+) homeostasis led to a prediction that astrocytes would have K(Ca) channels near blood vessels in order to maintain K(+) homeostasis. Consistent with this thinking the present study demonstrates that rSlo K(Ca) channels are in glial cells of the adult rat central nervous system (CNS) and highly localized to specializations of astrocytes associated with the brain vasculature. Using confocal and thin-section electron microscopic immunolabeling methods the distribution of rSlo was examined in adult rat brain. Strong rSlo immunolabeling was present around the vasculature of most brain regions. Examination of dye-filled hippocampal astrocytes revealed rSlo immunolabeling polarized in astrocytic endfeet. Ultrastructural analysis confirmed that the rSlo staining was concentrated in astrocytic endfeet ensheathing capillaries as well as abutting the pia mater. Immunostaining within the endfeet was predominantly distributed at the plasma membrane directly adjacent to either the vascular basal lamina or the pial surface. The distribution of the aquaporin-4 (AQP-4) water channel was also examined using dye-filled hippocampal astrocytes. In confirmation of earlier reports, intense AQP-4 immunolabeling was generally observed at the perimeter of blood vessels, and coincided with perivascular endfeet and rSlo labeling. We propose that rSlo K(Ca) channels, with their sensitivity to membrane depolarization and intracellular calcium, play a role in the K(+) modulation of cerebral blood flow. Additional knowledge of the molecular and cellular machinery present at perivascular endfeet may provide insight into the structural and functional molecular elements responsible for the neuronal activity-dependent regulation of cerebral blood flow. Copyright 2002 Elsevier Science B.V.

  14. Anti-cancer stemness and anti-invasive activity of bitter taste receptors, TAS2R8 and TAS2R10, in human neuroblastoma cells.

    Directory of Open Access Journals (Sweden)

    Yoona Seo

    Full Text Available Neuroblastoma (NB originates from immature neuronal cells and currently has a poor clinical outcome. NB cells possess cancer stem cells (CSCs characteristics that facilitate the initiation of a tumor, as well as its metastasis. Human bitter taste receptors, referred to as TAS2Rs, are one of five types of basic taste receptors and they belong to a family of G-protein coupled receptors. The recent finding that taste receptors are expressed in non-gustatory tissues suggest that they mediate additional functions distinct from taste perception. While it is generally admitted that the recognition of bitter tastes may be associated with a self-defense system to prevent the ingestion of poisonous food compounds, this recognition may also serve as a disease-related function in the human body. In particular, the anti-cancer stemness and invasion effects of TAS2Rs on NB cells remain poorly understood. In the present study, endogenous expression of TAS2R8 and TAS2R10 in SK-N-BE(2C and SH-SY5Y cells was examined. In addition, higher levels of TAS2R8 and TAS2R10 expression were investigated in more differentiated SY5Y cells. Both TAS2Rs were up-regulated following the induction of neuronal cell differentiation by retinoic acid. In addition, ectopic transfection of the two TAS2Rs induced neurite elongation in the BE(2C cells, and down-regulated CSCs markers (including DLK1, CD133, Notch1, and Sox2, and suppressed self-renewal characteristics. In particular, TAS2RS inhibited tumorigenicity. Furthermore, when TAS2Rs was over-expressed, cell migration, cell invasion, and matrix metalloproteinases activity were inhibited. Expression levels of hypoxia-inducible factor-1α, a well-known regulator of tumor metastasis, as well as its downstream targets, vascular endothelial growth factor and glucose transporter-1, were also suppressed by TAS2Rs. Taken together, these novel findings suggest that TAS2Rs targets CSCs by suppressing cancer stemness characteristics and NB

  15. Effect of caffeine on the anticonvulsant effects of oxcarbazepine, lamotrigine and tiagabine in a mouse model of generalized tonic-clonic seizures.

    Science.gov (United States)

    Chrościńska-Krawczyk, Magdalena; Ratnaraj, Neville; Patsalos, Philip N; Czuczwar, Stanisław J

    2009-01-01

    Caffeine has been reported to be proconvulsant and to reduce the anticonvulsant efficacy of a variety of antiepileptic drugs (carbamazepine, phenobarbital, phenytoin, valproate and topiramate) in animal models of epilepsy and to increase seizure frequency in patients with epilepsy. Using the mouse maximal electroshock model, the present study was undertaken so as to ascertain whether caffeine affects the anticonvulsant efficacy of the new antiepileptic drugs lamotrigine, oxcarbazepine and tiagabine. The results indicate that neither acute nor chronic caffeine administration (up to 46.2 mg/kg) affected the ED(50) values of oxcarbazepine or lamotrigine against maximal electroshock. Similarly, caffeine did not modify the tiagabine electroconvulsive threshold. Furthermore, caffeine had no effect on oxcarbazepine, lamotrigine and tiagabine associated adverse effects such as impairment of motor coordination (measured by the chimney test) or long-term memory (measured by the passive avoidance task). Concurrent plasma concentration measurements revealed no significant effect on lamotrigine and oxcarbazepine concentrations. For tiagabine, however, chronic caffeine (4 mg/kg) administration was associated with an increase in tiagabine concentrations. In conclusion, caffeine did not impair the anticonvulsant effects of lamotrigine, oxcarbazepine, or tiagabine as assessed by electroconvulsions in mice. Also, caffeine was without effect upon the adverse potential of the studied antiepileptic drugs. Thus caffeine may not necessarily adversely affect the efficacy of all antiepileptic drugs and this is an important observation.

  16. Phytochemicals from Ruta graveolens Activate TAS2R Bitter Taste Receptors and TRP Channels Involved in Gustation and Nociception

    Directory of Open Access Journals (Sweden)

    Giuseppe Mancuso

    2015-10-01

    Full Text Available Ruta graveolens (rue is a spontaneous plant in the Mediterranean area with a strong aroma and a very intense bitter taste, used in gastronomy and in folk medicine. From the leaves, stems and fruits of rue, we isolated rutin, rutamarin, three furanocoumarins, two quinolinic alkaloids, a dicoumarin and two long chain ketones. Bitter taste and chemesthetic properties have been evaluated by in vitro assays with twenty receptors of the TAS2R family and four TRP ion channels involved in gustation and nociception. Among the alkaloids, skimmianine was active as a specific agonist of T2R14, whereas kokusaginin did not activate any of the tested receptors. The furanocoumarins activates TAS2R10, 14, and 49 with different degrees of selectivity, as well as the TRPA1 somatosensory ion channel. Rutamarin is an agonist of TRPM5 and TRPV1 and a strong antagonist of TRPM8 ion channels.

  17. Synthesis and structure of new 4-amino-5-(2-R1-phenyl-1,2,4-triazole-3-thiol alkilderivatives

    Directory of Open Access Journals (Sweden)

    Ye. S. Pruglo

    2017-08-01

    Full Text Available Chemistry of heterocyclic systems is a separate branch of organic chemistry with a long history and future prospects. The ring system of 1,2,4-triazole continuously attracts the interest of chemists, pharmacologists and pharmacists in finding medicinal compounds through its universal potential interactions with biological systems. Today it is known that 1,2,4-triazole derivatives have antibacterial, antifungal, antiinflammatory, anticonvulsant, antiviral, antituberculosis, antioxidant, anticancer and antitumor activities. They also have analgesic, local anesthetic, antimalarial, antiproliferative effects, antihypertensive, antidepressant, sedative, antihistamine, hepatoprotective, hypoglycemic, diuretic, antipyretic and countless number of action types. Therefore, the search of biologically active remedies and creating of new drugs on its base is highly efficient topical issue of medical and pharmaceutical work. The purpose of these studies is the synthesis, establishment of physical-chemical parameters of new 4-amino-5-(2-R1-phenyl-1,2,4-triazole-3-thiol alkylderivatives. Materials and methods. The studying of physical and chemical properties of compounds was made in accordance with the methods described in the State Pharmacopoeia of Ukraine 2.0. The melting point was determined on an automatic gear MPA100. The elemental composition of the compounds was set on the analyzer Elementar Vario EL cube. 1H NMR spectra were recorded using the spectrometer Varian Mercury VX-200 (1H, 200 MHz and decrypted by a computer program SpinWorks 3.1.8. Chromatography-mass spectral studies were carried out in the gas-liquid chromatograph Agilent 1260 Infinity HPLC equipped with a mass spectrometer Agilent 6120 (in electrospray ionization (ESI. Results. 4-amino-5-phenyl-4H-1,2,4-triazole-3-thiol and 4-amino-5-(2-bromophenyl-4H-1,2,4-triazol-3-thiol were used as the initial materials. These compounds were obtained by reaction of benzoic acid hydrazide and 2

  18. Stevens-Johnson syndrome and toxic epidermal necrolysis due to anticonvulsants share certain clinical and laboratory features with drug-induced hypersensitivity syndrome, despite differences in cutaneous presentations.

    Science.gov (United States)

    Teraki, Y; Shibuya, M; Izaki, S

    2010-10-01

    Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is characterized by late disease onset, fever, rash, hepatic dysfunction, haematological abnormalities, lymphadenopathy and often, human herpesvirus (HHV) reactivation. The diagnosis of DIHS is based on the combined presence of these findings. Anticonvulsants are a major cause of DIHS and may also cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We examined whether SJS/TEN due to anticonvulsants display similar clinical and laboratory features seen in DIHS. Patients diagnosed with SJS or TEN due to anticonvulsants (n = 8) were examined and their clinical features and laboratory findings were compared with patients with anticonvulsant-related DIHS (n = 6). Seven of the eight patients with SJS/TEN developed symptoms > 3 weeks after starting anticonvulsants. Hepatic dysfunction was present in six patients with SJS/TEN and five patients with DIHS. Leucocytosis and/or eosinophilia was noted in seven patients with SJS/TEN and four patients with DIHS. Only one patient in the SJS/TEN group had atypical lymphocytosis; this was present in four patients with DIHS. Reactivation of HHV-6 was detected in one of the four patients tested in the SJS/TEN group, although it was seen in five of the six patients with DIHS. TSJS/TEN due to anticonvulsants may exhibit some clinical and laboratory features of DIHS. The nature of the cutaneous involvement should be emphasized in the diagnosis of DIHS. © 2009 The Author(s). Journal compilation © 2009 British Association of Dermatologists.

  19. Nitric oxide (NO) is an endogenous anticonvulsant but not a mediator of the increase in cerebral blood flow accompanying bicuculline-induced seizures in rats

    DEFF Research Database (Denmark)

    Wang, Qian; Theard, M A; Pelligrino, D A

    1994-01-01

    ) is NO an endogenous anticonvulsant or proconvulsant substance? and (2) is the cerebral blood flow (CBF) increase accompanying bicuculline (BC)-induced seizures mediated by NO? The experiments were performed in 300-400-g Wistar rats anesthetized with 0.6% halothane and 70% N2O/30% O2. CBF was measured using...

  20. Clinical-grade quality platelet-rich plasma releasate (PRP-R/SRGF) from CaCl2 -activated platelet concentrates promoted expansion of mesenchymal stromal cells.

    Science.gov (United States)

    Borghese, C; Agostini, F; Durante, C; Colombatti, A; Mazzucato, M; Aldinucci, D

    2016-08-01

    The aim of our study was to test a platelet-rich plasma releasate (PRP-R/SRGF) from CaCl2 -activated platelets as a source of growth factors for the expansion of mesenchymal stromal cells (MSCs). PRP-R/SRGF, obtained with a low-cost procedure, is characterized by a reduced variability of growth factor release. PRP-R/SRGF is a clinical-grade quality solution obtained from CaCl2 -activated platelets. Its activity was evaluated by measuring the proliferation, the phenotype, the differentiation potential and the immunosuppressive properties of MSCs derived from bone marrow (BM) and adipose tissue (AT). PRP-R/SRGF was more active than FBS to expand BM- and AT-derived MSCs. PRP-R/SRGF treatment did not affect the expression of typical MSCs surface markers, neither MSCs differentiation potential nor their capability to inhibit activated T-cell proliferation. The clinical-grade PRP-R/SRGF may be used in the clinical setting for the expansion of MSCs. © 2016 International Society of Blood Transfusion.

  1. The study of antimicrobial activity of 2-((4-R-3-(morpholinomethylene-4H-1,2,4-triazole-5-ylthioacetic acid salts

    Directory of Open Access Journals (Sweden)

    R. О. Shcherbyna

    2016-08-01

    Full Text Available The purpose of the work was to study the antimicrobial activity of 2-((4-R-3-(morfolinomethylene-4H-1,2,4-triazole-5-ylthio acetic acid salts by "hanging drop" and “serial dilution” methods in broth (limiting concentration option and establish some patterns of "structure – action" depending. Materials and methods. The objects of research were 9 new compounds of 2-((4-R-3-(morfolinomethylene-4H-1,2,4-triazole-5-ylthio acetic acid salts. These compounds are the crystal substances which are odorless, soluble in water and organic solvents. To achieve a more objective picture of the research we applied two methods: "hanging drop" and “serial dilution” in broth (limiting concentration option. To study the effectiveness of substances we used the test cultures of E. coli, Salmonella typhymurium, Staphylococcus epidermidis, P. aeruginosa. Results and discussion. In the study we have found that 2-((4-R-3-(morfolinomethylene-4H-1,2,4-triazole-5-ylthio acetic acid salts can differently inhibit the growth of test cultures. The results show that the data obtained by two methods correlated with each other. Thus, the 2-((4-R-3-(morfolinomethylene-4H-1,2,4-triazole-5-ylthio acetic acid salts are active against most strains of E. Coli. and Salmonella typhymurium. Analyzing the impact of 2-((4-R-3-(morfolinomethylene-4H-1,2,4-triazole-5-ylthio acetic acid salts we have noted that the replacement of the phenyl radical (PKR-135, 139 on the free amino group at N4 nitrogen of 1,2,4- triazole cycle (PKR-173, 177 leads to the disappearance of antimicrobial activity against the studied strains. It was established that the transition from morfolin cation (PKR-133 to the piperydyn cation (PKR-134 in the molecules of 2-((4-phenyl-3-(morfolinometylen-4H-1,2,4-triazole-5-yl thio acetic acid is accompanied by a significant increase in antimicrobial effect. It was interesting that among all the cations in the molecules of 2-((4-amino-3-(morfolinometylen-4H-1,2

  2. Effect of anticonvulsant drugs on (/sup 35/S)t-butylbicyclophosphorothionate binding in vitro and ex vivo

    Energy Technology Data Exchange (ETDEWEB)

    Pitkaenen, A.; Riekkinen, P.J.; Saano, V.; Tuomisto, L.

    1987-01-01

    Using several concentrations of eight anticonvulsant drugs in clinical use (carbamazepine, clonazepam, phenytoin, phenobarbital, ethosuximide, primidone, sodium valproate, and D,L-..gamma..-vinyl GABA), we studied their abilities in vitro to displace (/sup 35/S)t-butylbicyclophosphorothionate (/sup 35/S-TBPS) from its binding site in a homogenate of rat brain. Thereafter ethosuximide (150 mg/kg), phenobarbital (30 mg/kg), clonazepam (0.3 mg/kg), or phenytoin (100 mg/kg) was injected intraperitoneally into rats for 16-20 days; and the effect of drug administration on /sup 35/S-TBPS binding was studied in the cortex and hippocampus ex vivo. Phenobarbital (100 ..mu..M, P<0.001), ethosuximide (500 ..mu..M, P<0.001), and phenytoin (40 ..mu..M, P<0.001) decreased the specific /sup 35/S-TBPS binding in vitro by 10-16%. After drug administration of phenobarbital (concentration in plasma 168 ..mu..M), the number of binding sites decreased and the binding affinity (p<0.05) in the cortex increased. Other anticonvulsants did not modulate /sup 35/S-TBPS binding in vitro at the concentration analogous to therapeutic plasma levels or ex vivo at the dose used. These results suggest that the use of phenobarbital may modulate the TBPS binding site, but the role of the present findings in the anticonvulsant action of phenobarbital needs to be further studied.

  3. The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation.

    Science.gov (United States)

    Pack, Thomas F; Orlen, Margo I; Ray, Caroline; Peterson, Sean M; Caron, Marc G

    2018-04-20

    The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) that is critical for many central nervous system functions. The D2R carries out these functions by signaling through two transducers: G proteins and β-arrestins (βarrs). Selectively engaging either the G protein or βarr pathway may be a way to improve drugs targeting GPCRs. The current model of GPCR signal transduction posits a chain of events where G protein activation ultimately leads to βarr recruitment. GPCR kinases (GRKs), which are regulated by G proteins and whose kinase action facilitates βarr recruitment, bridge these pathways. Therefore, βarr recruitment appears to be intimately tied to G protein activation via GRKs. Here we sought to understand how GRK2 action at the D2R would be disrupted when G protein activation is eliminated and the effect of this on βarr recruitment. We used two recently developed biased D2R mutants that can preferentially interact either with G proteins or βarrs as well as a βarr-biased D2R ligand, UNC9994. With these functionally selective tools, we investigated the mechanism whereby the βarr-preferring D2R achieves βarr pathway activation in the complete absence of G protein activation. We describe how direct, G protein-independent recruitment of GRK2 drives interactions at the βarr-preferring D2R and also contributes to βarr recruitment at the WT D2R. Additionally, we found an additive interaction between the βarr-preferring D2R mutant and UNC9994. These results reveal that the D2R can directly recruit GRK2 without G protein activation and that this mechanism may have relevance to achieving βarr-biased signaling. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. The effects of anticonvulsants on 4-aminopyridine-induced bursting: in vitro studies on rat peripheral nerve and dorsal roots.

    Science.gov (United States)

    Lees, G.

    1996-01-01

    1. Aminopyridines have been used as beneficial symptomatic treatments in a variety of neurological conditions including multiple sclerosis but have been associated with considerable toxicity in the form of abdominal pain, paraesthesias and (rarely) convulsions. 2. Extracellular and intracellular recording was used to characterize action potentials in rat sciatic nerves and dorsal roots and the effects of 4-aminopyridine (4-AP). 3. In sciatic nerve trunks, 1 mM 4-AP produced pronounced after potentials at room temperature secondary to regenerative firing in affected axons (5-10 spikes per stimulus). At physiological temperatures, after potentials (2-3 spikes) were greatly attenuated in peripheral axons. 4. 4-AP evoked more pronounced and prolonged after discharges in isolated dorsal roots at 37 degrees C (3-5.5 mV and 80-100 ms succeeded by a smaller inhibitory/depolarizing voltage shift) which were used to assess the effects of anticonvulsants. 5. Phenytoin, carbamazepine and lamotrigine dose-dependently reduced the area of 4-AP-induced after potentials at 100 and 320 microM but the amplitude of compound action potentials (evoked at 0.5 Hz) was depressed in parallel. 6. The tonic block of sensory action potentials by all three drugs (at 320 microM) was enhanced by high frequency stimulation (5-500 Hz). 7. The lack of selectivity of these frequency-dependent Na+ channel blockers for burst firing compared to low-frequency spikes, is discussed in contrast to their effects on 4-AP-induced seizures and paroxysmal activity in CNS tissue (which is associated with large and sustained depolarizing plateau potentials). 8. In conclusion, these in vitro results confirm the marked sensitivity of sensory axons to 4-AP (the presumptive basis for paraesthesias). Burst firing was not preferentially impaired at relatively high concentrations suggesting that anticonvulsants will not overcome the toxic peripheral actions of 4-AP in neurological patients. PMID:8821551

  5. Apoptosis Induction by Targeting Interferon Gamma Receptor 2 (IFNgammaR2) in Prostate Cancer: Ligand (IFNgamma) Independent Novel Function of IFNgammaR2 as a Bax Inhibitor

    Science.gov (United States)

    2016-10-01

    Cisplatin (2uM, 30 hrs) PN (5uM, 55hrs) + Cisplatin (2uM, 30 hrs) •  Thorough studies are needed to examine the unknown mechanism of IFNgR2 and Bax as well as...mouse xenograft model. Task3: To determine the mechanism of increased IFNγR2 expression in PCa. We found that NFkB inhibitor suppressed IFNγR2 expression...suggesting that hyper-activation of NFkB may be one of the mechanisms of IFNγR2 overexpression in PCa. These results support our hypothesis that

  6. Safe dismantling of the SVAFO research reactors R2 and R2-0 in Sweden

    International Nuclear Information System (INIS)

    ARNOLD, Hans-Uwe; BROY, Yvonne; Dirk Schneider

    2017-01-01

    The R2 and R2-0 reactors were part of the Swedish government's research program on nuclear power from the early 1960's. Both reactors were shut down in 2005 following a decision by former operator Studsvik Nuclear AB. The decommissioning of the R2 and R2-0 reactors is divided into three phases. The first phase - awarded to AREVA - involved dismantling of the reactors and associated systems in the reactor pool, treatment of the disassembled components as well as draining, cleaning and emptying the pool. In the second phase, the pool structure itself will be dismantled, while removal of remaining reactor systems, treatment and disposal of materials and clean-up will be carried out in the third stage. The entire work is planned to be completed before the end of this decade. The paper describes the several steps of phase 1 - starting with the team building, followed by the dismantling operations and covers challenges encountered and lessons learned as well. The reactors consist of 5.400 kg aluminum, 6.000 kg stainless steel restraint structures as well as, connection elements of the mostly flanged components (1.000 kg). The most demanding - from a radiological point of view - was the R2-0 reactor that was limited to ∼ 1 m"3 construction volumes but with an extremely heterogeneous activation profile. Based on the calculated radiological entrance data and later sampling, nuclide vectors for both reactors depending on the real placement of the single component and on the material (aluminum and stainless steel) were created. Finally, for the highest activated component from R2 reactor, 85 Sv/h were measured. The dismantling principles - adopted on a safety point of view - were the following: The always protected base area of the ponds served as a flexible buffer area for waste components and packaging. Specific protections were also installed on the walls to protect them from mechanical stress which may occur during dismantling work. A specific work platform was

  7. The transcriptional repressor protein NsrR senses nitric oxide directly via a [2Fe-2S] cluster.

    Directory of Open Access Journals (Sweden)

    Nicholas P Tucker

    Full Text Available The regulatory protein NsrR, a member of the Rrf2 family of transcription repressors, is specifically dedicated to sensing nitric oxide (NO in a variety of pathogenic and non-pathogenic bacteria. It has been proposed that NO directly modulates NsrR activity by interacting with a predicted [Fe-S] cluster in the NsrR protein, but no experimental evidence has been published to support this hypothesis. Here we report the purification of NsrR from the obligate aerobe Streptomyces coelicolor. We demonstrate using UV-visible, near UV CD and EPR spectroscopy that the protein contains an NO-sensitive [2Fe-2S] cluster when purified from E. coli. Upon exposure of NsrR to NO, the cluster is nitrosylated, which results in the loss of DNA binding activity as detected by bandshift assays. Removal of the [2Fe-2S] cluster to generate apo-NsrR also resulted in loss of DNA binding activity. This is the first demonstration that NsrR contains an NO-sensitive [2Fe-2S] cluster that is required for DNA binding activity.

  8. R2/R0-WTR decommissioning cost. Comparison and benchmarking analysis

    International Nuclear Information System (INIS)

    Varley, Geoff; Rusch, Chris

    2001-10-01

    SKI charged NAC International with the task of determining whether or not the decommissioning cost estimates of R2/R0 (hereafter simply referred to as R2) and Aagesta research reactors are reasonable. The associated work was performed in two phases. The objective in Phase I was to make global comparisons of the R2 and Aagesta decommissioning estimates with the estimates/actual costs for the decommissioning of similar research reactors in other countries. This report presents the results of the Phase II investigations. Phase II focused on selected discrete work packages within the decommissioning program of the WTR reactor. To the extent possible a comparison of those tasks with estimates for the R2 reactor has been made, as a basis for providing an opinion on the reasonableness of the R2 estimate. The specific WTR packages include: reactor vessel and internals dismantling; biological shield dismantling; primary coolant piping dismantling; electrical equipment removal; waste packaging; transportation and disposal of radioactive concrete and reactor components; project management, licensing and engineering; and removal of ancillary facilities. The specific tasks were characterised and analysed in terms of fundamental parameters including: task definition; labour hours expended; labour cost; labour productivity; length of work week; working efficiency; working environment and impact on job execution; external costs (contract labour, materials and equipment); total cost; waste volumes; and waste packaging and transport costs. Based on such detailed raw data, normalised unit resources have been derived for selected parts of the decommissioning program, as a first step towards developing benchmarking data for D and D activities at research reactors. Several general conclusions emerged from the WTR decommissioning project. Site characterisation can confirm or negate major assumptions, quantify waste volumes, delineate obstacles to completing work, provide an understanding

  9. What is the role of sedating antidepressants, antipsychotics, and anticonvulsants in the management of insomnia?

    Science.gov (United States)

    McCall, Catherine; McCall, W Vaughn

    2012-10-01

    Psychiatric medications such as antidepressants, antipsychotics, and anticonvulsants are commonly prescribed by physicians for the off-label use of improving sleep. Reasons for preferential prescription of these medications over FDA-approved insomnia drugs may include a desire to treat concurrent sleep problems and psychiatric illness with a single medication, and/or an attempt to avoid hypnotic drugs due to their publicized side effects. However, there have been few large studies demonstrating the efficacy and safety of most off-label medications prescribed to treat insomnia. In addition, many of these medications have significant known side effect profiles themselves. Here we review the pertinent research studies published in recent years on antidepressant, antipsychotic, and anticonvulsant medications frequently prescribed for sleep difficulties. Although there have been few large-scale studies for most of these medications, some may be appropriate in the treatment of sleep issues in specific well-defined populations.

  10. Solvothermal fabrication of activated semi-coke supported TiO{sub 2}-rGO nanocomposite photocatalysts and application for NO removal under visible light

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Weiwei; Li, Chunhu, E-mail: lichunhu@ouc.edu.cn; Wang, Liang; Sun, ShengNan; Yan, Xin

    2015-10-30

    Highlights: • Activated semi-coke supported TiO{sub 2}-rGO photocatalysts were fabricated by one-step solvothermal method. • The photocatalytic performance for NO removal was studied under visible light irradiation. • The introduction of rGO is responsible for superior photocatalytic activity. • Optimum operational parameters at 70 °C, with 8% O{sub 2} and 8% relative humidity were obtained. • Thermal vapor regeneration is the most suitable generation method. - Abstract: The photocatalysts of activated semi-coke supported TiO{sub 2}-rGO nanocomposite (TiO{sub 2}-rGO/ASC) with different contents of reduced graphene oxide were fabricated by one-step solvothermal method for NO removal under visible light irradiation. It was confirmed that 8% content of reduced graphene oxide presented the best NO photooxidation performance under visible light irradiation at 70 °C with 350–400 mg/m{sup 3} NO,5% O{sub 2} and 5% relative humidity. The reasons for improved activity were discussed, alloyed with the mechanism of producing CO. Detailed structural information of TiO{sub 2}-rGO/ASC photocatalysts was characterized by scanning electron microscope (SEM), energy dispersive X-ray Spectroscopy (EDX), X-ray diffraction analysis (XRD), UV–Vis diffuse reflectance spectra (UV–Vis DRS) and photoluminescence (PL), which indicated that the introduction of rGO was responsible for well dispersion, smaller crystalline size, red shift of absorption band and suppressing quick photo-induced charges recombination of TiO{sub 2}-rGO/ASC photocatalysts. Optimization of operational parameters with 70 °C, 8% O{sub 2} and 8% relative humidity were also obtained. Deactivation of TiO{sub 2}-rGO/ASC photocatalysts for NO removal was investigated by Fourier-transform infrared (FTIR) analysis. Regeneration experiments showed that thermal vapor regeneration would be optimal method owing to excellent regenerative capacity and inexpensive procedure.

  11. Tolerance and withdrawal to anticonvulsant action of clonazepam: role of nitric oxide.

    Science.gov (United States)

    Gupta, N; Bhargava, V K; Pandhi, P

    2000-05-01

    The use of clonazepam in the long-term treatment of epilepsy is greatly inhibited by its capacity to induce tolerance and dependence. A means of preventing or minimizing the tolerance and dependence inducing properties is required. Here the role of nitric oxide in preventing the development of tolerance and withdrawal hyperexcitability was studied. In Wistar rats, clonazepam at a dose of 0.25 mg/kg i.p. twice daily produced tolerance to its anticonvulsant action in 28 days. After sudden cessation of therapy it produced hyperexcitability. Tolerance was shown by a decrease in seizure threshold to near control value while withdrawal hyperexcitability was evidenced by a significant decrease in seizure threshold below the control value. L-Arginine (a donor of nitric oxide) and N omega-nitro-L-arginine (an inhibitor of nitric oxide synthase) were given in doses of 150 mg/kg and 8 mg/kg, respectively on day 1, 3, 7, 14, 21 and 28 with clonazepam. Withdrawal hyperexcitability was seen on day 1, 2 and 4 after cessation of drug therapy. Electroshock was used as a model of epilepsy and seizure thresholds were determined by an up and down method of Kimball et al. L-Arginine was found to inhibit the development tolerance as well as withdrawal hyperexcitability when administered with clonazepam while N omega-L-arginine did not prevent either the development of tolerance or withdrawal hyperexcitability in the electroshock model. In the PTZ model, however, L-arginine had no effect on the anticonvulsant action and withdrawal hyperexcitability while inhibition of nitric oxide synthesis prevented withdrawal hyperexcitability in PTZ-induced seizures.

  12. Structure activity relationships of quinoxalin-2-one derivatives as platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors, derived from molecular modeling.

    Science.gov (United States)

    Mori, Yoshikazu; Hirokawa, Takatsugu; Aoki, Katsuyuki; Satomi, Hisanori; Takeda, Shuichi; Aburada, Masaki; Miyamoto, Ken-ichi

    2008-05-01

    We previously reported a quinoxalin-2-one compound (Compound 1) that had inhibitory activity equivalent to existing platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors. Lead optimization of Compound 1 to increase its activity and selectivity, using structural information regarding PDGFbeta R-ligand interactions, is urgently needed. Here we present models of the PDGFbeta R kinase domain complexed with quinoxalin-2-one derivatives. The models were constructed using comparative modeling, molecular dynamics (MD) and ligand docking. In particular, conformations derived from MD, and ligand binding site information presented by alpha-spheres in the pre-docking processing, allowed us to identify optimal protein structures for docking of target ligands. By carrying out molecular modeling and MD of PDGFbeta R in its inactive state, we obtained two structural models having good Compound 1 binding potentials. In order to distinguish the optimal candidate, we evaluated the structural activity relationships (SAR) between the ligand-binding free energies and inhibitory activity values (IC50 values) for available quinoxalin-2-one derivatives. Consequently, a final model with a high SAR was identified. This model included a molecular interaction between the hydrophobic pocket behind the ATP binding site and the substitution region of the quinoxalin-2-one derivatives. These findings should prove useful in lead optimization of quinoxalin-2-one derivatives as PDGFb R inhibitors.

  13. The Implementation of C-ID, R2D2 Model on Learning Reading Comprehension

    Science.gov (United States)

    Rayanto, Yudi Hari; Rusmawan, Putu Ngurah

    2016-01-01

    The purposes of this research are to find out, (1) whether C-ID, R2D2 model is effective to be implemented on learning Reading comprehension, (2) college students' activity during the implementation of C-ID, R2D2 model on learning Reading comprehension, and 3) college students' learning achievement during the implementation of C-ID, R2D2 model on…

  14. Evaluation of Anticonvulsive ٍEffect of Magnesium Oxide Nanoparticles in Comparison with Conventional MgO in Diabetic and Non-diabetic Male Mice

    Directory of Open Access Journals (Sweden)

    Leila Jahangiri

    2014-05-01

    Full Text Available Introduction: Some studies show magnesium has anticonvulsive effect in some animal models. Despite of the availability of well-studied anticonvulsant drugs, this evaluation was not carried on new kind of magnesium supplement, magnesium oxide nanoparticles (nMgO. According to the interaction between magnesium and convulsion, this study was designed to evaluate the effect of nMgO on strychnine-induced convulsive model in compared to its conventional in diabetic and normal mice. Methods: Healthy male albino mice were divided to 10 groups. Diabete mellitus was induced by streptozocin in 5 groups. Conventional and nanoparticle MgO (5&10mg/kg in presence and absence diabetes injected to mice, then strychnine injected and onset of convulsions and time of death were measured after strychnine administration. Results: Convulsive parameters did not change in normal and diabetic mice. cMgO pretreatment did not have anticonvulsant effect in strychnine-induced convulsion in normal and diabetic mice. But nMgO significantly changed convulsion onset and death time after strychnine administration in normal and diabetic status. Discussion: According to our results It seems that nMgO may be important in prevention or treatment of epilepsy and has more efficacy than its conventional form to showing anticonvulsive effect that probably is related to the physicochemical properties of nMgO, specially in diabetic subjects, a point that need to further investigation.

  15. Resolution of 1-n-butyl-3-methyl-3-phospholene 1-oxide with TADDOL derivatives and calcium salts of O,O'-Dibenzoyl-(2R,3R)- or O,O'-di-p-toluoyl-(2R,3R)-tartaric acid.

    Science.gov (United States)

    Bagi, Péter; Fekete, András; Kállay, Mihály; Hessz, Dóra; Kubinyi, Miklós; Holczbauer, Tamás; Czugler, Mátyás; Fogassy, Elemér; Keglevich, György

    2014-03-01

    The resolution methods applying (-)-(4R,5R)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane ("TADDOL"), (-)-(2R,3R)-α,α,α',α'-tetraphenyl-1,4-dioxaspiro[4.5]decan-2,3-dimethanol ("spiro-TADDOL"), as well as the acidic and neutral Ca(2+) salts of (-)-O,O'-dibenzoyl- and (-)-O,O'-di-p-toluoyl-(2R,3R)-tartaric acid were extended for the preparation of 1-n-butyl-3-methyl-3-phospholene 1-oxide in optically active form. In one case, the intermediate diastereomeric complex could be identified by single-crystal X-ray analysis. The absolute P-configuration of the enantiomers of the phospholene oxide was also determined by comparing the experimentally obtained and calculated CD spectra. © 2014 Wiley Periodicals, Inc.

  16. Crystal structures of 2-methoxyisoindoline-1,3-dione, 1,3-dioxoisoindolin-2-yl methyl carbonate and 1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-2-yl methyl carbonate: three anticonvulsant compounds

    Directory of Open Access Journals (Sweden)

    Fortune Ezemobi

    2014-12-01

    Full Text Available The title compounds, C9H7NO3, (1, C10H7NO5, (2, and C14H9NO5, (3, are three potentially anticonvulsant compounds. Compounds (1 and (2 are isoindoline derivatives and (3 is an isoquinoline derivative. Compounds (2 and (3 crystallize with two independent molecules (A and B in their asymmetric units. In all three cases, the isoindoline and benzoisoquinoline moieties are planar [r.m.s. deviations are 0.021 Å for (1, 0.04 and 0.018 Å for (2, and 0.033 and 0.041 Å for (3]. The substituents attached to the N atom are almost perpendicular to the mean planes of the heterocycles, with dihedral angles of 89.7 (3° for the N—O—Cmethyl group in (1, 71.01 (4 and 80.00 (4° for the N—O—C(=OO—Cmethyl groups in (2, and 75.62 (14 and 74.13 (4° for the same groups in (3. In the crystal of (1, there are unusual intermolecular C=O...C contacts of 2.794 (1 and 2.873 (1 Å present in molecules A and B, respectively. There are also C—H...O hydrogen bonds and π–π interactions [inter-centroid distance = 3.407 (3 Å] present, forming slabs lying parallel to (001. In the crystal of (2, the A and B molecules are linked by C—H...O hydrogen bonds, forming slabs parallel to (10-1, which are in turn linked via a number of π–π interactions [the most significant centroid–centroid distances are 3.4202 (7 and 3.5445 (7 Å], forming a three-dimensional structure. In the crystal of (3, the A and B molecules are linked via C—H...O hydrogen bonds, forming a three-dimensional structure, which is consolidated by π–π interactions [the most significant inter-centroid distances are 3.575 (3 and 3.578 (3 Å].

  17. Evaluation of anticonvulsant and neuroprotective effects of camel milk in strychnine-induced seizure model

    Directory of Open Access Journals (Sweden)

    Humera Khatoon

    2015-10-01

    Full Text Available Objective: To discover the use of camel milk as an alternate medicine for the treatment and prevention of convulsions using strychnine-induced seizure model. Methods: Thirty animals were divided into three equal groups. Group I was on distilled water, Group II was on camel milk for 15 days prior to experiment and Group III was on reference drug diazepam. On the day of experiment, strychnine was administered in all treatment groups after distilled water, camel milk and diazepam treatments respectively. Animals were observed for 30 min for latency of seizure onset, frequency of convulsions and duration of jerks. The mortality rate was also evaluated for each group. Results: Camel milk treatment showed significant seizure protection as observed by delayed seizure onset (P ≤ 0.001, decreased total duration of convulsions (P ≤ 0.001 and mortality rate (P ≤ 0.001 when compared with Group I. Conclusions: Anticonvulsant activity of camel milk could be due to potentiation of glycinergic and GABAergic activities both. Antioxidant activity can also amplify its antiepileptic activity. Further studies are required to confirm the exact mechanism of action.

  18. (1R,2R,3R,4R,5S-2,3-Bis[(2S′-2-acetoxy-2-phenylacetoxy]-4-azido-1-[(2,4-dinitrophenylhydrazonomethyl]bicyclo[3.1.0]hexane

    Directory of Open Access Journals (Sweden)

    Robert McDonald

    2008-02-01

    Full Text Available In the title compound, C38H29N7O12, the five-membered ring adopts an envelope conformation in which the `flap' is cis to the cyclopropane group. This conformation is similar to those of other bicyclo[3.1.0]hexane analogues for which crystal structures have been reported. The absolute configuration of the stereogenic centers on the cyclopentane ring, as determined by comparison with the known configurations of the stereogenic centers in the (2S-2-acetoxy-2-phenylacetoxy groups, is 1(R, 2(R, 3(R, 4(R and 5(S. An intramolecular N—H...O hydrogen bond is present.

  19. Radiological changes in the skeleton due to anticonvulsant therapy in childhood

    Energy Technology Data Exchange (ETDEWEB)

    Fritsch, R.; Heyer, R.; Freyschmidt, J.

    1981-01-01

    Anticonvulsant therapy can lead to severe rachitic changes in the skeleton which closely resemble renal osteopathy. In addition to apparent widening of the epiphyseal plate, there are changes in the cortex of the long bones. Within four to six weeks of the commencement of vitamin D therapy, recalcification of the poorly mineralised osteoid can be recognised. Since the changes are best seen in the hand, further examinations of the skeleton are only indicated if there are positive findings in the hand.

  20. Radiological changes in the skeleton due to anticonvulsant therapy in childhood

    International Nuclear Information System (INIS)

    Fritsch, R.; Heyer, R.; Freyschmidt, J.

    1981-01-01

    Anticonvulsant therapy can lead to severe rachitic changes in the skeleton which closely resemble renal osteopathy. In addition to apparent widening of the epiphyseal plate, there are changes in the cortex of the long bones. Within four to six weeks of the commencement of vitamin D therapy, recalcification of the poorly mineralised osteoid can be recognised. Since the changes are best seen in the hand, further examinations of the skeleton are only indicated if there are positive findings in the hand. (orig.) [de

  1. Montelukast potentiates the anticonvulsant effect of phenobarbital in mice: an isobolographic analysis.

    Science.gov (United States)

    Fleck, Juliana; Marafiga, Joseane Righes; Jesse, Ana Cláudia; Ribeiro, Leandro Rodrigo; Rambo, Leonardo Magno; Mello, Carlos Fernando

    2015-04-01

    Although leukotrienes have been implicated in seizures, no study has systematically investigated whether the blockade of CysLT1 receptors synergistically increases the anticonvulsant action of classic antiepileptics. In this study, behavioral and electroencephalographic methods, as well as isobolographic analysis, are used to show that the CysLT1 inverse agonist montelukast synergistically increases the anticonvulsant action of phenobarbital against pentylenetetrazole-induced seizures. Moreover, it is shown that LTD4 reverses the effect of montelukast. The experimentally derived ED50mix value for a fixed-ratio combination (1:1 proportion) of montelukast plus phenobarbital was 0.06±0.02 μmol, whereas the additively calculated ED50add value was 0.49±0.03 μmol. The calculated interaction index was 0.12, indicating a synergistic interaction. The association of montelukast significantly decreased the antiseizure ED50 for phenobarbital (0.74 and 0.04 μmol in the absence and presence of montelukast, respectively) and, consequently, phenobarbital-induced sedation at equieffective doses. The demonstration of a strong synergism between montelukast and phenobarbital is particularly relevant because both drugs are already used in the clinics, foreseeing an immediate translational application for epileptic patients who have drug-resistant seizures. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Influence of organic surface coatings on the sorption of anticonvulsants on mineral surfaces.

    Science.gov (United States)

    Qu, Shen; Cwiertny, David M

    2013-10-01

    Here, we explore the role that sorption to mineral surfaces plays in the fate of two commonly encountered effluent-derived pharmaceuticals, the anticonvulsants phenytoin and carbamazepine. Adsorption isotherms and pH-edge experiments are consistent with electrostatics governing anticonvulsant uptake on metal oxides typically found in soil and aquifer material (e.g., Si, Al, Fe, Mn, and Ti). Appreciable, albeit limited, adsorption was observed only for phenytoin, which is anionic above pH 8.3, on the iron oxides hematite and ferrihydrite. Adsorption increased substantially in the presence of cationic and anionic surfactants, species also commonly encountered in wastewater effluent. For carbamazepine, we propose the enhanced uptake results entirely from hydrophobic interactions with apolar tails of surfactant surface coatings. For phenytoin, adsorption also arises from the ability of surfactants to alter the net charge of the mineral surface and thereby further enhance favorable electrostatic interactions with its anionic form. Collectively, our results demonstrate that although pristine mineral surfaces are likely not major sinks for phenytoin and carbamazepine in the environment, their alteration with organic matter, particularly surfactants, can considerably increase their ability to retain these emerging pollutants in subsurface systems.

  3. Multiple R2R3-MYB transcription factors involved in the regulation of anthocyanin accumulation in peach flower

    Directory of Open Access Journals (Sweden)

    Hui Zhou

    2016-10-01

    Full Text Available Anthocyanin accumulation is responsible for flower coloration in peach. Here, we report the identification and functional characterization of eight flavonoid-related R2R3-MYB transcription factors, designated PpMYB10.2, PpMYB9, PpMYBPA1, Peace, PpMYB17, PpMYB18, PpMYB19 and PpMYB20, respectively, in peach flower transcriptome. PpMYB10.2 and PpMYB9 are able to activate transcription of anthocyanin biosynthetic genes, whilst PpMYBPA1 and Peace have a strong activation on the promoters of proanthocyanin (PA biosynthetic genes. PpMYB17-20 show a strong repressive effect on transcription of flavonoid pathway genes such as DFR. These results indicate that anthocyanin accumulation in peach flower is coordinately regulated by a set of R2R3-MYB genes. In addition, PpMYB9 and PpMYB10.2 are closely related but separated into two groups, designated MYB9 and MYB10, respectively. PpMYB9 shows a strong activation on the PpUGT78A2 promoter, but with no effect on the promoter of PpUGT78B (commonly called PpUFGT in previous studies. In contrast, PpMYB10.2 is able to activate the PpUFGT promoter, but not for the PpUGT78A2 promoter. Unlike the MYB10 gene that is universally present in plants, the MYB9 gene is lost in most dicot species. Therefore, the PpMYB9 gene represents a novel group of anthocyanin-related MYB activators, which may have diverged in function from the MYB10 genes. Our study will aid in understanding the complex mechanism regulating floral pigmentation in peach and functional divergence of the R2R3-MYB gene family in plants.

  4. IGF-1R Regulates the Extracellular Level of Active MMP-2, Pathological Neovascularization, and Functionality in Retinas of OIR Mouse Model.

    Science.gov (United States)

    Lorenc, Valeria E; Subirada Caldarone, Paula V; Paz, María C; Ferrer, Darío G; Luna, José D; Chiabrando, Gustavo A; Sánchez, María C

    2018-02-01

    In ischemic proliferative diseases such as retinopathies, persistent hypoxia leads to the release of numerous neovascular factors that participate in the formation of abnormal vessels and eventually cause blindness. The upregulation and activation of metalloproteinases (MMP-2 and MMP-9) represent a final common pathway in this process. Although many regulators of the neovascular process have been identified, the complete role of the insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) appears to be significantly more complex. In this study, we used an oxygen-induced retinopathy (OIR) mouse model as well as an in vitro model of hypoxia to study the role of MMP-2 derived from Müller glial cells (MGCs) and its relation with the IGF-1/IGF-1R system. We demonstrated that MMP-2 protein expression increased in P17 OIR mice, which coincided with the active phase of the neovascular process. Also, glutamine synthetase (GS)-positive cells were also positive for MMP-2, whereas IGF-1R was expressed by GFAP-positive cells, indicating that both proteins were expressed in MGCs. In addition, in the OIR model a single intravitreal injection of the IGF-1R blocking antibody (αIR3) administered at P12 effectively prevented pathologic neovascularization, accelerated physiological revascularization, and improved retinal functionality at P17. Finally, in MGC supernatants, the blocking antibody abolished the IGF-1 effect on active MMP-2 under normoxic and hypoxic conditions without affecting the extracellular levels of pro-MMP-2. These results demonstrate, for the first time, that the IGF-1/IGF-1R system regulates active MMP-2 levels in MGCs, thus contributing to MEC remodeling during the retinal neovascular process.

  5. High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Firas Alhasson

    2018-07-01

    Full Text Available High circulatory insulin and leptin followed by underlying inflammation are often ascribed to the ectopic manifestations in non-alcoholic fatty liver disease (NAFLD but the exact molecular pathways remain unclear. We have shown previously that CYP2E1-mediated oxidative stress and circulating leptin in NAFLD is associated with renal disease severity. Extending the studies, we hypothesized that high circulatory leptin in NAFLD causes renal mesangial cell activation and tubular inflammation via a NOX2 dependent pathway that upregulates proinflammatory miR21. High-fat diet (60% kcal was used to induce fatty liver phenotype with parallel insulin and leptin resistance. The kidneys were probed for mesangial cell activation and tubular inflammation that showed accelerated NASH phenotype and oxidative stress in the liver. Results showed that NAFLD kidneys had significant increases in α-SMA, a marker of mesangial cell activation, miR21 levels, tyrosine nitration and renal inflammation while they were significantly decreased in leptin and p47 phox knockout mice. Micro RNA21 knockout mice showed decreased tubular immunotoxicity and proinflammatory mediator release. Mechanistically, use of NOX2 siRNA or apocynin,phenyl boronic acid (FBA, DMPO or miR21 antagomir inhibited leptin primed-miR21-mediated mesangial cell activation in vitro suggesting a direct role of leptin-mediated NOX-2 in miR21-mediated mesangial cell activation. Finally, JAK-STAT inhibitor completely abrogated the mesangial cell activation in leptin-primed cells suggesting that leptin signaling in the mesangial cells depended on the JAK-STAT pathway. Taken together the study reports a novel mechanistic pathway of leptin-mediated renal inflammation that is dependent on NOX-2-miR21 axis in ectopic manifestations underlying NAFLD-induced co-morbidities. Keywords: Leptin, NOX-2, NADPH, Mesangial cells, miR21, Oxidative stress, NAFLD, JAK/STAT, siRNA

  6. Bone mineral density in subjects using central nervous system-active medications.

    Science.gov (United States)

    Kinjo, Mitsuyo; Setoguchi, Soko; Schneeweiss, Sebastian; Solomon, Daniel H

    2005-12-01

    Decreased bone mineral density defines osteoporosis according to the World Health Organization and is an important predictor of future fractures. The use of several types of central nervous system-active drugs, including benzodiazepines, anticonvulsants, antidepressants, and opioids, have all been associated with increased risk of fracture. However, it is unclear whether such an increase in risk is related to an effect of bone mineral density or to other factors, such as increased risk of falls. We sought to examine the relationship between bone mineral density and the use of benzodiazepines, anticonvulsants, antidepressants, and opioids in a representative US population-based sample. We analyzed data on adults aged 17 years and older from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). Total femoral bone mineral density of 7114 male and 7532 female participants was measured by dual-energy x-ray absorptiometry. Multivariable linear regression models were used to quantify the relation between central nervous system medication exposure and total femoral bone mineral density. Models controlled for relevant covariates, including age, sex, and body mass index. In linear regression models, significantly reduced bone mineral density was found in subjects taking anticonvulsants (0.92 g/cm2; 95% confidence interval [CI]: 0.89 to 0.94) and opioids (0.92 g/cm2; 95% CI: 0.88 to 0.95) compared with nonusers (0.95 g/cm2; 95% CI: 0.95 to 0.95) after adjusting for several potential confounders. The other central nervous system-active drugs--benzodiazepines or antidepressants--were not associated with significantly reduced bone mineral density. In cross-sectional analysis of NHANES III, anticonvulsants and opioids (but not benzodiazepines or antidepressants) were associated with significantly reduced bone mineral density. These findings have implications for fracture-prevention strategies.

  7. Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics

    NARCIS (Netherlands)

    Selle, V.; Schalkwijk, S.J.; Vazquez, G.H.; Baldessarini, R.J.

    2014-01-01

    BACKGROUND: Optimal treatments for bipolar depression, and the relative value of specific drugs for that purpose, remain uncertain, including agents other than antidepressants. METHODS: We searched for reports of placebo-controlled, monotherapy trials of mood-stabilizing anticonvulsants,

  8. Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

    DEFF Research Database (Denmark)

    Krogsgaard-Larsen, Niels; Storgaard, Morten; Møller, Charlotte

    2015-01-01

    Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal...... carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD...... and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate...

  9. Solvothermal fabrication of activated semi-coke supported TiO2-rGO nanocomposite photocatalysts and application for NO removal under visible light

    Science.gov (United States)

    Yang, Weiwei; Li, Chunhu; Wang, Liang; Sun, ShengNan; Yan, Xin

    2015-10-01

    The photocatalysts of activated semi-coke supported TiO2-rGO nanocomposite (TiO2-rGO/ASC) with different contents of reduced graphene oxide were fabricated by one-step solvothermal method for NO removal under visible light irradiation. It was confirmed that 8% content of reduced graphene oxide presented the best NO photooxidation performance under visible light irradiation at 70 °C with 350-400 mg/m3 NO,5% O2 and 5% relative humidity. The reasons for improved activity were discussed, alloyed with the mechanism of producing CO. Detailed structural information of TiO2-rGO/ASC photocatalysts was characterized by scanning electron microscope (SEM), energy dispersive X-ray Spectroscopy (EDX), X-ray diffraction analysis (XRD), UV-Vis diffuse reflectance spectra (UV-Vis DRS) and photoluminescence (PL), which indicated that the introduction of rGO was responsible for well dispersion, smaller crystalline size, red shift of absorption band and suppressing quick photo-induced charges recombination of TiO2-rGO/ASC photocatalysts. Optimization of operational parameters with 70 °C, 8% O2 and 8% relative humidity were also obtained. Deactivation of TiO2-rGO/ASC photocatalysts for NO removal was investigated by Fourier-transform infrared (FTIR) analysis. Regeneration experiments showed that thermal vapor regeneration would be optimal method owing to excellent regenerative capacity and inexpensive procedure.

  10. Risk factors of vitamin D deficiency in children with epilepsy taking anticonvulsants at initial and during follow-up

    Directory of Open Access Journals (Sweden)

    Seung Ho Lee

    2015-12-01

    Full Text Available PurposeVitamin D status was evaluated in children with epilepsy taking anticonvulsants to determine the prevalence and risk factors of vitamin D deficiency.MethodsThis study was designed as both a cross-sectional and a retrospective cohort study. A sum of 198 children who were diagnosed with epilepsy at the Department of Pediatrics in Dankook University Hospital was included. Their serum vitamin D levels were reviewed based on clinical information, and analyzed using IBM SPSS ver. 20.0.ResultsOne hundred twenty-four children (62.6% had vitamin D deficiency. Two risk factors were associated: winter to spring season (odds ratio [OR], 3.71; 95% confidence interval [CI], 1.835-7.492 and age more than 12 years (OR, 3.22; 95% CI, 1.377-7.542. Out of the 57 patients who were not vitamin D deficient at the time of initial assay, 47 patients (82.5% became vitamin D deficient during followup. The change of serum 25-hydroxy vitamin D3 (25(OHD levels during follow up showed a weak negative correlation with the duration of medication (r=-0.283, P=0.033. Medication duration was longer and brain magnetic resonance imaging (MRI abnormality, abnormal underlying conditions, and nonambulatory status were more frequently present in twenty-five patients (44% who showed a decline of more than 15 ng/mL during follow-up (P<0.05.ConclusionVitamin D deficiency is common in children with epilepsy taking anticonvulsants, especially in adolescents more than 12 years of age. This study emphasizes the regular monitoring of vitamin D level, especially in the presence of longer duration of medication, brain MRI abnormality, abnormal underlying conditions, and nonambulatory status.

  11. Involvement of AMPA receptor GluR2 and GluR3 trafficking in trigeminal spinal subnucleus caudalis and C1/C2 neurons in acute-facial inflammatory pain.

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    Makiko Miyamoto

    Full Text Available To evaluate the involvement of trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR GluR2 and GluR3 subunits in an acute inflammatory orofacial pain, we analyzed nocifensive behavior, phosphorylated extracellular signal-regulated kinase (pERK and Fos expression in Vi/Vc, Vc and C1/C2 in GluR2 delta7 knock-in (KI, GluR3 delta7 KI mice and wild-type mice. We also studied Vc neuronal activity to address the hypothesis that trafficking of GluR2 and GluR3 subunits plays an important role in Vi/Vc, Vc and C1/C2 neuronal activity associated with orofacial inflammation in these mice. Late nocifensive behavior was significantly depressed in GluR2 delta7 KI and GluR3 delta7 KI mice. In addition, the number of pERK-immunoreactive (IR cells was significantly decreased bilaterally in the Vi/Vc, Vc and C1/C2 in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice at 40 min after formalin injection, and was also significantly smaller in GluR3 delta7 KI compared to GluR2 delta7 KI mice. The number of Fos protein-IR cells in the ipsilateral Vi/Vc, Vc and C1/C2 was also significantly smaller in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice 40 min after formalin injection. Nociceptive neurons functionally identified as wide dynamic range neurons in the Vc, where pERK- and Fos protein-IR cell expression was prominent, showed significantly lower spontaneous activity in GluR2 delta7 KI and GluR3 delta7 KI mice than wild-type mice following formalin injection. These findings suggest that GluR2 and GluR3 trafficking is involved in the enhancement of Vi/Vc, Vc and C1/C2 nociceptive neuronal excitabilities at 16-60 min following formalin injection, resulting in orofacial inflammatory pain.

  12. The anticonvulsant action of AHR-11748 on kindled amygdaloid seizures in rats.

    Science.gov (United States)

    Albertson, T E; Walby, W F

    1987-03-01

    The anticonvulsant effectiveness of AHR-11748 (3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide) was evaluated in the kindled amygdaloid seizure model in rats. Doses of AHR-11748 that did not cause prestimulation toxicity significantly attenuated elicited afterdischarge durations and the severity of the accompanying behavioral convulsive response in previously kindled rats. AHR-11748 (25-100 mg/kg i.p.) was evaluated at 30 min in previously kindled rats using both threshold (20 microA increments) and suprathreshold (400 microA) paradigms. AHR-11748 (50-100.mg/kg) reduced suprathreshold elicited after discharges and seizure severity. Utilizing a suprathreshold kindling paradigm, the maximum anticonvulsant effectiveness for the 100 mg/kg i.p. dose of AHR-11748 was seen at 180 min. AHR-11748 significantly elevated seizure thresholds only at the 100 mg/kg dose. AHR-11748 (25-100 mg/kg) significantly reduced the severity of threshold elicited seizures. When AHR-11748 (50 and 100 mg/kg i.p.) was administered daily during kindling acquisition, the number of daily trials necessary to complete kindling significantly increased. A reduction in both the duration and the severity of the responses induced by the daily stimulations during the acquisition period was seen with AHR-11748 treatment. This study has demonstrated that AHR-11748 significantly modifies both the acquisition of kindling and the fully kindled amygdaloid seizures at doses that do not cause behavioral toxicity.

  13. When lithium does not help: the use of anticonvulsants and calcium channel blockers in the treatment of bipolar disorder in the older person.

    Science.gov (United States)

    Masters, J C

    1996-01-01

    Although anticonvulsant agents and calcium channel blockers do not have any clear advantages over lithium, they do offer patients who cannot (or will not) take lithium another treatment option. It is not yet clear from the literature who will respond best to which drug or combination of drugs. The nurse should be supportive to the patients and family, in what may be a drawn out process, to find the best treatment. Optimism is justified because a lack of response to one drug is not indicative of nonresponse to other drugs. It is important to actively treat bipolar disorder because each episode of mania increases the risk of progression of the illness, with increasingly severe episodes occurring closer together. Bipolar disorder has high social costs (legal, financial, and relationship problems) that make improvements in treatment important for the patient and society. Anticonvulsant agents and calcium channel blockers may also be useful in treating depression. The number of people whose depressive symptoms respond is far less (25% to 30%) than the number who respond to the anti-manic effects, but this is an option when antidepressants and electroconvulsive therapy are not effective.

  14. Anticonvulsive and free radical scavenging actions of two herbs, Uncaria rhynchophylla (MIQ) Jack and Gastrodia elata Bl., in kainic acid-treated rats.

    Science.gov (United States)

    Hsieh, C L; Tang, N Y; Chiang, S Y; Hsieh, C T; Lin, J G

    1999-01-01

    Uncaria rhynchophylla (Miq.) Jack (UR) and Gastrodia elata BI. (GE) are traditional Chinese herbs that are usually used in combination to treat convulsive disorders, such as epilepsy, in China. The aim of this study was to compare the anticonvulsive and free radical scavenging activities of UR alone and UR in combination with GE in rats. For the in vitro studies, brain tissues from 6 male Sprague-Dawley (SD) rats were treated with 120 microg/ml kainic acid (KA), with or without varied concentrations of UR or UR plus GE. For the in vivo studies, male SD rats (6 per group) received intraperitoneal (i.p.) injection of KA 12 mg/kg to induce epileptic seizures and generation of free radicals, with or without oral administration of UR 1 g/kg alone or UR 1 g/kg plus GE 1 g/kg. Epileptic seizures were verified by behavioral observations, and electroencephalography (EEG) and electromyography (EMG) recordings. These results showed that UR alone decreased KA-induced lipid peroxide levels in vitro, whereas UR plus GE did not produce a greater effect than UR alone. UR significantly reduced counts of wet dog shakes (WDS), paw tremor (PT) and facial myoclonia (FM) in KA-treated rats and significantly delayed the onset time of WDS, from 27 min in the control group to 40 min in the UR group. UR plus GE did not inhibit seizures more effectively than UR alone, but did further prolong the onset time of WDS to 63 min (P < 0.05 vs. UR alone). UR alone reduced the levels of free radicals in vivo, as measured by lipid peroxidation in the brain and luminol-chemiluminescence (CL) counts and lucigenin-CL counts in the peripheral whole blood, but the combination of GE and UR did not reduce free radical levels more markedly than UR alone. In conclusion, our results indicate that UR has anticonvulsive and free radical scavenging activities, and UR combined with GE exhibit greater inhibition on the onset time of WDS than UR alone. These findings suggest that the anticonvulsive effects of UR and

  15. Ectopic Overexpression of a Novel R2R3-MYB, NtMYB2 from Chinese Narcissus Represses Anthocyanin Biosynthesis in Tobacco

    Directory of Open Access Journals (Sweden)

    Muhammad Anwar

    2018-03-01

    Full Text Available R2R3 MYB transcription factors play key functions in the regulation of secondary metabolites. In the present study, a R2R3 MYB transcriptional factor NtMYB2 was identified from Chinese narcissus (Narcissus tazetta L. var. Chinensis Roem and functionally characterized. NtMYB2 belongs to subgroup 4 of the R2R3 MYB transcription factor family that are related to repressor MYBs involved in the regulation of anthocyanin and flavonoids. Transient expression confirmed that NtMYB2 strongly reduced the red pigmentation induced by MYB- anthocyanin activators in agro-infiltrated tobacco leaves. Ectopic expression of NtMYB2 in tobacco significantly reduced the pigmentation and altered the floral phenotypes in transgenic tobacco flowers. Gene expression analysis suggested that NtMYB2 repressed the transcript levels of structural genes involved in anthocyanin biosynthesis pathway, especially the UFGT gene. NtMYB2 gene is expressed in all examined narcissus tissues; the levels of transcription in petals and corona is higher than other tissues and the transcription level at the bud stage was highest. These results show that NtMYB2 is involved in the regulation of anthocyanin biosynthesis pathway and may act as a repressor by down regulating the transcripts of key enzyme genes in Chinese narcissus.

  16. Ectopic Overexpression of a Novel R2R3-MYB, NtMYB2 from Chinese Narcissus Represses Anthocyanin Biosynthesis in Tobacco.

    Science.gov (United States)

    Anwar, Muhammad; Wang, Guiqing; Wu, Jiacheng; Waheed, Saquib; Allan, Andrew C; Zeng, Lihui

    2018-03-28

    R2R3 MYB transcription factors play key functions in the regulation of secondary metabolites. In the present study, a R2R3 MYB transcriptional factor NtMYB2 was identified from Chinese narcissus ( Narcissus tazetta L. var. Chinensis Roem) and functionally characterized. NtMYB2 belongs to subgroup 4 of the R2R3 MYB transcription factor family that are related to repressor MYBs involved in the regulation of anthocyanin and flavonoids. Transient expression confirmed that NtMYB2 strongly reduced the red pigmentation induced by MYB- anthocyanin activators in agro-infiltrated tobacco leaves. Ectopic expression of NtMYB2 in tobacco significantly reduced the pigmentation and altered the floral phenotypes in transgenic tobacco flowers. Gene expression analysis suggested that NtMYB2 repressed the transcript levels of structural genes involved in anthocyanin biosynthesis pathway, especially the UFGT gene. NtMYB2 gene is expressed in all examined narcissus tissues; the levels of transcription in petals and corona is higher than other tissues and the transcription level at the bud stage was highest. These results show that NtMYB2 is involved in the regulation of anthocyanin biosynthesis pathway and may act as a repressor by down regulating the transcripts of key enzyme genes in Chinese narcissus.

  17. elPBN neurons regulate rVLM activity through elPBN-rVLM projections during activation of cardiac sympathetic afferent nerves.

    Science.gov (United States)

    Guo, Zhi-Ling; Longhurst, John C; Tjen-A-Looi, Stephanie C; Fu, Liang-Wu

    2016-08-01

    The external lateral parabrachial nucleus (elPBN) within the pons and rostral ventrolateral medulla (rVLM) contributes to central processing of excitatory cardiovascular reflexes during stimulation of cardiac sympathetic afferent nerves (CSAN). However, the importance of elPBN cardiovascular neurons in regulation of rVLM activity during CSAN activation remains unclear. We hypothesized that CSAN stimulation excites the elPBN cardiovascular neurons and, in turn, increases rVLM activity through elPBN-rVLM projections. Compared with controls, in rats subjected to microinjection of retrograde tracer into the rVLM, the numbers of elPBN neurons double-labeled with c-Fos (an immediate early gene) and the tracer were increased after CSAN stimulation (P neurons contain vesicular glutamate transporter 3. In cats, epicardial bradykinin and electrical stimulation of CSAN increased the activity of elPBN cardiovascular neurons, which was attenuated (n = 6, P neurons in the elPBN and rVLM sequentially through a monosynaptic (glutamatergic) excitatory elPBN-rVLM pathway. Copyright © 2016 the American Physiological Society.

  18. Antioxidant activity of salts of 2-(5-R-4-amino-1,2,4-triazole-3-ylthioacetic acid

    Directory of Open Access Journals (Sweden)

    Ye. S. Pruglo

    2017-12-01

    Full Text Available Antioxidants are chemical structures that prevent the oxidation of other chemicals. They protect key cell components by neutralizing the harmful effect of free radicals which are natural products of cell metabolism. Oxidative stress leads to serious cell damage which results in various human diseases such as Alzheimer's disease, Parkinson's disease, atherosclerosis, cancer, arthritis, neurodegenerative disorders etc. The deficiency of antioxidants in food also leads to oxidative stress, which indicates a lack of antioxidant substances consumed by humans. Therefore, the search of substances that could not only prevent but also increase the resistance of the human body to active forms of oxygen or nitrogen and interfere with the processes of oxidative stress is an important task of medicine and pharmacy. The purpose of this work was to study the antioxidant activity (AOA of salts of 2-(5-R-4-R-4H-1,2,4-triazole-3-ylthioacetic acids with non-enzymatic initiation of free radical oxidation and to establish laws concerning chemical structure and biological effects of the studied substances. Materials and methods. Original derivatives of 1,2,4-triazole were used in the series of screening studies. The antioxidant activity of the compounds in vitro was determined according to the methodical recommendations of the State Pharmacological Center MoH Ukraine using the method of non-enzymatic initiation of lipid peroxide oxidation. Results. Dimethylammonium salt of 2-(4-amino-5-(2-bromophenyl-1,2,4-triazole-3-ylthioacetic acid (3c possessed with a high AOA which reduced the content of TBK-AP by 54,95% ( р˂0,001. Derivatives of 4-amino-1,2,4-triazole had the most distinct AOA containing С5 carbon atoms 2-bromophenyl substituent. Thus, methylammonium salt 3b reduced the TBK-AP content by 80,31 (p˂0,001 which exceeds the reference ascorbic acid by 45,05% and the prototype thiotriazoline by 36,64%. Considering the data of experimental studies it was found

  19. Anticonvulsant properties of methanol leaf extract of Laggera Aurita Linn. F. (Asteraceae) in laboratory animals.

    Science.gov (United States)

    Malami, S; Kyari, H; Danjuma, N M; Ya'u, J; Hussaini, I M

    2016-09-15

    Preparation of Laggera aurita Linn. (Asteraceae) is widely used in traditional medicine to treat various kinds of diseases such as epilepsy, malaria, fever, pain and asthma. Its efficacy is widely acclaimed among communities in Northern Nigeria. The present study is aimed at establishing the possible anticonvulsant effects of the methanol leaf extract of Laggera aurita using acute and chronic anticonvulsant models. Median lethal dose (LD50) was determined in mice and rats via oral and intraperitoneal routes. Anticonvulsant screening of the extract was performed using maximal electroshock-induced seizure test in day-old chicks; pentylenetetrazole-, strychnine- and picrotoxin- induced seizure models in mice. Similarly; its effects on pentylenetetrazole-induce kindling in rats as well as when co-administered with fluphenamic and cyproheptadine in mice, were evaluated. Median lethal dose (LD50) values were found to be >5000mg/kg, p.o. and 2154mg/kg, i.p., each for both rats and mice. The extract showed dose dependent protection against tonic hind limb extension (THLE) and significantly (p<0.05) decreased the mean recovery from seizure in the maximal electroshock-induced seizure. In the pentylenetetrazole-induced seizure model, the extract offered 50% protection at 600mg/kg and also increased the mean onset of seizure at all doses with significant (p<0.05) increase at the highest dose (600mg/kg). Similarly the extract produced significant (p<0.05) increase in the onset of seizures in both strychnine- and picrotoxin- induced seizure models, at all the doses except at 150mg/kg for the picrotoxin model. Co-administration of fluphenamic acid (FFA) (5mg/kg) and the extract (600mg/kg) showed an enhanced effect with percentage protection of 70% while co-administration of FFA (5mg/kg) and phenytoin (5mg/kg) as well phenytoin (5mg/kg) and the extract (600mg/kg) produced an additive effect. Administration of the extract (600mg/kg), phenytoin (20mg/kg) and cyproheptadine (4mg

  20. Programmation réactive en OCaml

    OpenAIRE

    Deleuze , Christophe

    2009-01-01

    15 pages; International audience; La programmation réactive permet d'écrire des programmes sous forme d'un ensemble de processus qui s'exécutent de manière synchronisée et communiquent par diffusion de signaux. Ce paradigme peut être fourni par des langages spécialisés (parfois basés sur des langages “classiques”) ou par des bibliothèques. Le langage ReactiveML est un tel langage réactif basé sur OCaml. Nous décrivons ici une bibliothèque OCaml fournissant les construc- tions réactives de Rea...

  1. Antioxidant mechanisms of iso-6-cassine in suppressing seizures induced by pilocarpine

    Directory of Open Access Journals (Sweden)

    Rivelilson Mendes de Freitas

    2011-06-01

    Full Text Available The aim of this study was to evaluate the in vitro antioxidant effects of 12-[(2R,5R,6R-5-hydroxy-6-methylpiperidin-2-yl]dodecan-2-one (iso-6-cassine; ISO and the anticonvulsant effects of ISO on pilocarpine-induced seizures in rats. Wistar rats were treated with 0.9% saline (i.p., control group, pilocarpine (400 mg/kg, i.p., pilocarpine group, and the association of ISO (1.0 mg/kg, i.p. plus pilocarpine (400 mg/kg, i.p., 30 min after administration of ISO (ISO plus pilocarpine group. After the treatments all groups were observed for 1h. The antioxidant effect of ISO on the pilocarpine model was assessed by determining the activity of glutathione peroxidase (GPx, glutathione-S-transferase (GST and catalase (CAT as well as the levels of reactive species (RS and lipid peroxidation (LP. In vitro, ISO (5 μM reduced RS and LP. ISO (1.0 mg/kg and abolished seizures and death induced by pilocarpine in rats. ISO protected against the increase in the RS and LP levels, GST activity as well as the inhibition of GPx activity caused by pilocarpine. In addition, ISO increased the catalase activity in hippocampus of seized rats. In conclusion, the dta suggest that ISO can present anticonvulsant and antioxidant properties in the pilocarpine model of seizures in rats.

  2. Involvement of nitrergic system in anticonvulsant effect of zolpidem in lithium-pilocarpine induced status epilepticus: Evaluation of iNOS and COX-2 genes expression.

    Science.gov (United States)

    Eslami, Seyyed Majid; Ghasemi, Maryam; Bahremand, Taraneh; Momeny, Majid; Gholami, Mahdi; Sharifzadeh, Mohammad; Dehpour, Ahmad Reza

    2017-11-15

    This study aims to investigate the role of zolpidem in lithium-pilocarpine induced status epilepticus (SE) and probable mechanisms involved in seizure threshold alteration. In the present study, lithium chloride (127mg/kg) was administered 20h prior to pilocarpine (60mg/kg) to induce SE in adult male Wistar rats. Different doses of zolpidem (0.1, 1, 2, 5, 10mg/kg) were injected 30min before pilocarpine administration. Furthermore, to find out whether nitric oxide (NO) plays a role in the observed effect, L-arginine and L-NAME were injected 15min before zolpidem. Afterward, we identified the particular NO isoform mediating the effect of zolpidem by injecting aminoguanidine (AG) and 7-Nitroindazole (7-NI) 15min prior to zolpidem. Moreover, in both 6 and 24h after pilocarpine injection, experimental groups underwent hippocampectomy to evaluate cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes expression by quantitative reverse transcription-PCR (qRT-PCR). Pre-treatment with zolpidem significantly prevented the onset of SE in a dose-dependent manner. AG and L-NAME significantly potentiated the anticonvulsant effect of zolpidem while L-arginine inverted this effect. Our qRT-PCR exerted that there was a continuous elevation of iNOS and COX-2 genes expression over 6 and 24h after pilocarpine administration in SE and L-arginine+Zolpidem groups while in AG/L-NAME+Zolpidem and zolpidem groups this upregulation was prevented. Our study indicates that zolpidem prevents the onset of SE through inhibition of iNOS/COX-2 genes upregulation following lithium-pilocarpine administration. Consistent with our results, we suggest that iNOS activation could be probably upstream of COX-2 gene expression. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Improved performance of Yarrowia lipolytica lipase-catalyzed kinetic resolution of (R,S)-2-octanol by an integrated strategy of interfacial activation, bioimprinting and immobilization.

    Science.gov (United States)

    Liu, Ying; Guo, Chen; Sun, Xi-Tong; Liu, Chun-Zhao

    2013-08-01

    Yarrowia lipolytica lipase (YLL) demonstrated an (R)-enantiopreference for efficient resolution of (R,S)-2-octanol. The activity, enantioselectivity, the ratio of substrate to enzyme, acetaldehyde tolerance, and operational stability of YLL were improved by an integrated strategy of interfacial activation, bioimprinting, and immobilization. In comparison with the control, both the enzymatic activity and enantioselectivity increased by a factor of 8.85 and 2.75 by the integrated strategy, respectively. Fifty-one percentage of conversion with 220 of enantioselectivity was obtained using the immobilized YLL prepared by the integrated strategy at a ratio of 104 of substrate to enzyme loaded. The immobilized YLL retained 97% of its initial activity without a decrease in enantioselectivity after 10 successive reuse cycles. Together these results will result in a promising strategy with the YYL for efficient resolution of (R,S)-2-octanol in practice. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Clinical significance of the changes of serum IL-2, SIL-2R and VEGF levels in pediatric patients with pulmonary tuberculosis

    International Nuclear Information System (INIS)

    Zeng Dongliang; Wu Chunfeng; Jiang Huanhao

    2005-01-01

    Objective: To explore the clinical significance of the changes of serum IL-2, soluble IL-2 receptor (SIL-2R) and vascular endothelial growth factor (VEGF) levels in pediatric patients with tuberculosis. Methods: Serum IL-2 (with RIA) and SIL-2R, VEGF (with ELISA) levels were determined in 68 pediatric patients with tuberculosis (30 active and 38 non- active) and 30 controls. Results: In the patients with active tuberculosis, the serum IL-2 levels were significantly lower and SIL-2R, VEGF levels were significantly higher than those in the controls (P<0.01). Conclusion: Determination of serum IL-2, SIL-2R and VEGF levels was useful for monitoring the activity of tuberculosis in pediatric patients. (authors)

  5. Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b.

    Science.gov (United States)

    Rajaram, Murugesan V S; Ni, Bin; Morris, Jessica D; Brooks, Michelle N; Carlson, Tracy K; Bakthavachalu, Baskar; Schoenberg, Daniel R; Torrelles, Jordi B; Schlesinger, Larry S

    2011-10-18

    Contact of Mycobacterium tuberculosis (M.tb) with the immune system requires interactions between microbial surface molecules and host pattern recognition receptors. Major M.tb-exposed cell envelope molecules, such as lipomannan (LM), contain subtle structural variations that affect the nature of the immune response. Here we show that LM from virulent M.tb (TB-LM), but not from avirulent Myocobacterium smegmatis (SmegLM), is a potent inhibitor of TNF biosynthesis in human macrophages. This difference in response is not because of variation in Toll-like receptor 2-dependent activation of the signaling kinase MAPK p38. Rather, TB-LM stimulation leads to destabilization of TNF mRNA transcripts and subsequent failure to produce TNF protein. In contrast, SmegLM enhances MAPK-activated protein kinase 2 phosphorylation, which is critical for maintaining TNF mRNA stability in part by contributing microRNAs (miRNAs). In this context, human miRNA miR-125b binds to the 3' UTR region of TNF mRNA and destabilizes the transcript, whereas miR-155 enhances TNF production by increasing TNF mRNA half-life and limiting expression of SHIP1, a negative regulator of the PI3K/Akt pathway. We show that macrophages incubated with TB-LM and live M.tb induce high miR-125b expression and low miR-155 expression with correspondingly low TNF production. In contrast, SmegLM and live M. smegmatis induce high miR-155 expression and low miR-125b expression with high TNF production. Thus, we identify a unique cellular mechanism underlying the ability of a major M.tb cell wall component, TB-LM, to block TNF biosynthesis in human macrophages, thereby allowing M.tb to subvert host immunity and potentially increase its virulence.

  6. Syntheses of 4-aminobutanoic acid-2,2-/sup 2/H/sub 2/ and -4,4-/sup 2/H/sub 2/ and progabide-2,2-/sup 2/H/sub 2/ and -4,4-/sup 2/H/sub 2/

    Energy Technology Data Exchange (ETDEWEB)

    Davis, B.

    1987-10-01

    4-Aminobutanoic acid-2,2-/sup 2/H/sub 2/ and -4,4-/sup 2/H/sub 2/ were synthesized in high yield with high deuterium incorporation, and then converted into the corresponding deuterium-labelled anti-convulsant drug, progabide, by means of a transimination reaction.

  7. The octopamine receptor Octβ2R regulates ovulation in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Junghwa Lim

    Full Text Available Oviposition is induced upon mating in most insects. Ovulation is a primary step in oviposition, representing an important target to control insect pests and vectors, but limited information is available on the underlying mechanism. Here we report that the beta adrenergic-like octopamine receptor Octβ2R serves as a key signaling molecule for ovulation and recruits protein kinase A and Ca(2+/calmodulin-sensitive kinase II as downstream effectors for this activity. We found that the octβ2r homozygous mutant females are sterile. They displayed normal courtship, copulation, sperm storage and post-mating rejection behavior but were unable to lay eggs. We have previously shown that octopamine neurons in the abdominal ganglion innervate the oviduct epithelium. Consistently, restored expression of Octβ2R in oviduct epithelial cells was sufficient to reinstate ovulation and full fecundity in the octβ2r mutant females, demonstrating that the oviduct epithelium is a major site of Octβ2R's function in oviposition. We also found that overexpression of the protein kinase A catalytic subunit or Ca(2+/calmodulin-sensitive protein kinase II led to partial rescue of octβ2r's sterility. This suggests that Octβ2R activates cAMP as well as additional effectors including Ca(2+/calmodulin-sensitive protein kinase II for oviposition. All three known beta adrenergic-like octopamine receptors stimulate cAMP production in vitro. Octβ1R, when ectopically expressed in the octβ2r's oviduct epithelium, fully reinstated ovulation and fecundity. Ectopically expressed Octβ3R, on the other hand, partly restored ovulation and fecundity while OAMB-K3 and OAMB-AS that increase Ca(2+ levels yielded partial rescue of ovulation but not fecundity deficit. These observations suggest that Octβ2R have distinct signaling capacities in vivo and activate multiple signaling pathways to induce egg laying. The findings reported here narrow the knowledge gap and offer insight into novel

  8. The delta-opioid receptor agonist SNC80 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] synergistically enhances the locomotor-activating effects of some psychomotor stimulants, but not direct dopamine agonists, in rats.

    Science.gov (United States)

    Jutkiewicz, Emily M; Baladi, Michelle G; Folk, John E; Rice, Kenner C; Woods, James H

    2008-02-01

    The nonpeptidic delta-opioid agonist SNC80 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] produces many stimulant-like behavioral effects in rodents and monkeys, such as locomotor stimulation, generalization to cocaine in discrimination procedures, and antiparkinsonian effects. Tolerance to the locomotor-stimulating effects of SNC80 develops after a single administration of SNC80 in rats; it is not known whether cross-tolerance develops to the effects of other stimulant compounds. In the initial studies to determine whether SNC80 produced cross-tolerance to other stimulant compounds, it was discovered that amphetamine-stimulated locomotor activity was greatly enhanced in SNC80-pretreated rats. This study evaluated acute cross-tolerance between delta-opioid agonists and other locomotor-stimulating drugs. Locomotor activity was measured in male Sprague-Dawley rats implanted with radiotransmitters, and activity levels were recorded in the home cage environment. Three-hour SNC80 pretreatment produced tolerance to further delta-opioid receptor stimulation but also augmented greatly amphetamine-stimulated locomotor activity in a dose-dependent manner. Pretreatments with other delta-opioid agonists, (+)BW373U86 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,N-diethylbenzamide] and oxymorphindole (17-methyl-6,7-dehydro-4,5-epoxy-3,14-dihydroxy-6,7,2',3'-indolomorphinan), also modified amphetamine-induced activity levels. SNC80 pretreatment enhanced the stimulatory effects of the dopamine/norepinephrine transporter ligands cocaine and nomifensine (1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-isoquinolinanmine maleate salt), but not the direct dopamine receptor agonists SKF81297 [R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide] and quinpirole [trans-(-)-(4alphaR)-4,4a, 5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g] quinoline

  9. Effect of anticonvulsant drugs on (35S)t-butylbicyclophosphorothionate binding in vitro and ex vivo

    International Nuclear Information System (INIS)

    Pitkaenen, A.; Riekkinen, P.J.; Saano, V.; Tuomisto, L.

    1987-01-01

    Using several concentrations of eight anticonvulsant drugs in clinical use (carbamazepine, clonazepam, phenytoin, phenobarbital, ethosuximide, primidone, sodium valproate, and D,L-γ-vinyl GABA), we studied their abilities in vitro to displace ( 35 S)t-butylbicyclophosphorothionate ( 35 S-TBPS) from its binding site in a homogenate of rat brain. Thereafter ethosuximide (150 mg/kg), phenobarbital (30 mg/kg), clonazepam (0.3 mg/kg), or phenytoin (100 mg/kg) was injected intraperitoneally into rats for 16-20 days; and the effect of drug administration on 35 S-TBPS binding was studied in the cortex and hippocampus ex vivo. Phenobarbital (100 μM, P 35 S-TBPS binding in vitro by 10-16%. After drug administration of phenobarbital (concentration in plasma 168 μM), the number of binding sites decreased and the binding affinity (p 35 S-TBPS binding in vitro at the concentration analogous to therapeutic plasma levels or ex vivo at the dose used. These results suggest that the use of phenobarbital may modulate the TBPS binding site, but the role of the present findings in the anticonvulsant action of phenobarbital needs to be further studied. (author)

  10. Malformaciones congénitas en hijos de madres epilépticas con y sin tratamiento con anticonvulsivantes Congenital malformations in the offspring of epileptic mothers with and without anticonvulsant treatment

    Directory of Open Access Journals (Sweden)

    Jazmín Arteaga-Vázquez

    2012-12-01

    Full Text Available OBJETIVO: Determinar la frecuencia y tipo de malformaciones congénitas (MC en hijos de madres epilépticas (HME tratadas y no tratadas con anticonvulsivantes, la posible correlación anticonvulsivante/MC y la asociación con otras alteraciones del desarrollo. MATERIAL Y MÉTODOS: Estudio multicéntrico de casos y controles en 166 recién nacidos vivos HME identificados en 21 501 recién nacidos con MC y respectivos controles del Registro y Vigilancia Epidemiológica de Malformaciones Congénitas (RYVEMCE. RESULTADOS: La frecuencia de MC en HME tratadas fue mayor, (48.3% que en HME no tratadas (28.3%; (RM= 2.37 IC95% 1.08-5.40, p=0.03. Las MC más frecuentes fueron espina bífida, anomalías en reducción de miembros, labio/paladar hendido, microcefalia, anotia/microtia, hipospadias, paladar hendido, polidactilia, anoftalmia/microftalmia y onfalocele. No hubo diferencias entre uso de mono o politerapia. La difenilhidantoína, carbamazepina y ácido valproico fueron los anticonvulsivantes más utilizados. CONCLUSIONES: Los resultados confirman la teratogenicidad propia de la epilepsia y el efecto sinérgico de ciertos anticonvulsivantes, lo que evidencia la necesidad de un apropiado control periconcepcional de esta enfermedad y su tratamiento.OBJECTIVE: To determine the prevalence at birth and type of congenital malformations (CM in newborns of epileptic mothers (NEM treated and not treated with anticonvulsants, the correlation anticonvulsant/CM and other developmental disorders. MATERIALS AND METHODS: Multicenter case-control study, in 166 live births NEM diagnosed in 21 501 newborns with CM and respective controls from the Registro y Vigilancia Epidemiológica de Malformaciones Congénitas (RYVEMCE. RESULTS: The frequency of CM in NEM treated with anticonvulsants was higher (48.3% than in NEM of untreated mothers (28.3%, (OR= 2.37 IC95% 1.08-5.40, p=0.03. CMs most frequently found were: spina bifida, limb reduction defects, cleft lip palate

  11. Highly Active 2D Layered MoS 2 -rGO Hybrids for Energy Conversion and Storage Applications.

    Science.gov (United States)

    Kamila, Swagatika; Mohanty, Bishnupad; Samantara, Aneeya K; Guha, Puspendu; Ghosh, Arnab; Jena, Bijayalaxmi; Satyam, Parlapalli V; Mishra, B K; Jena, Bikash Kumar

    2017-08-21

    The development of efficient materials for the generation and storage of renewable energy is now an urgent task for future energy demand. In this report, molybdenum disulphide hollow sphere (MoS 2 -HS) and its reduced graphene oxide hybrid (rGO/MoS 2 -S) have been synthesized and explored for energy generation and storage applications. The surface morphology, crystallinity and elemental composition of the as-synthesized materials have been thoroughly analysed. Inspired by the fascinating morphology of the MoS 2 -HS and rGO/MoS 2 -S materials, the electrochemical performance towards hydrogen evolution and supercapacitor has been demonstrated. The rGO/MoS 2 -S shows enhanced gravimetric capacitance values (318 ± 14 Fg -1 ) with higher specific energy/power outputs (44.1 ± 2.1 Whkg -1 and 159.16 ± 7.0 Wkg -1 ) and better cyclic performances (82 ± 0.95% even after 5000 cycles). Further, a prototype of the supercapacitor in a coin cell configuration has been fabricated and demonstrated towards powering a LED. The unique balance of exposed edge site and electrical conductivity of rGO/MoS 2 -S shows remarkably superior HER performances with lower onset over potential (0.16 ± 0.05 V), lower Tafel slope (75 ± 4 mVdec -1 ), higher exchange current density (0.072 ± 0.023 mAcm -2 ) and higher TOF (1.47 ± 0.085 s -1 ) values. The dual performance of the rGO/MoS 2 -S substantiates the promising application for hydrogen generation and supercapacitor application of interest.

  12. Voltage-dependent modulation of cardiac ryanodine receptors (RyR2 by protamine.

    Directory of Open Access Journals (Sweden)

    Paula L Diaz-Sylvester

    Full Text Available It has been reported that protamine (>10 microg/ml blocks single skeletal RyR1 channels and inhibits RyR1-mediated Ca2+ release from sarcoplasmic reticulum microsomes. We extended these studies to cardiac RyR2 reconstituted into planar lipid bilayers. We found that protamine (0.02-20 microg/ml added to the cytosolic surface of fully activated RyR2 affected channel activity in a voltage-dependent manner. At membrane voltage (V(m; SR lumen-cytosol = 0 mV, protamine induced conductance transitions to several intermediate states (substates as well as full block of RyR2. At V(m>10 mV, the substate with the highest level of conductance was predominant. Increasing V(m from 0 to +80 mV, decreased the number of transitions and residence of the channel in this substate. The drop in current amplitude (full opening to substate had the same magnitude at 0 and +80 mV despite the approximately 3-fold increase in amplitude of the full opening. This is more similar to rectification of channel conductance induced by other polycations than to the action of selective conductance modifiers (ryanoids, imperatoxin. A distinctive effect of protamine (which might be shared with polylysines and histones but not with non-peptidic polycations is the activation of RyR2 in the presence of nanomolar cytosolic Ca2+ and millimolar Mg2+ levels. Our results suggest that RyRs would be subject to dual modulation (activation and block by polycationic domains of neighboring proteins via electrostatic interactions. Understanding these interactions could be important as such anomalies may be associated with the increased RyR2-mediated Ca2+ leak observed in cardiac diseases.

  13. Theoretical studies of the tautomerism in 3-(2-R-Phenylhydrazono)-naphthalene- 1,2,4-triones: synthesis of copper(II) complexes and studies of antibacterial and antitumor activities

    International Nuclear Information System (INIS)

    Francisco, Acacio I.; Vargas, Maria D.; Fragoso, Thais P.; Carneiro, J. Walkimar de M.; Silva, Fernando de C. da; Ferreira, Vitor F.; Pessoa, Claudia; Costa-Lotufo, Leticia V.; Marinho Filho, Jose D.B.; Moraes, Manoel O. de; Mangrich, Antonio S.

    2010-01-01

    DFT calculations using the B3LYP and PBE1PBE functionals with the standard 6-31G(d) and 6-311+G(2d,p) basis sets were carried out for the 3-(2-phenylhydrazone)-naphthalene-1,2,4-trione system in solution (dmso) and in the gas phase, and showed the keto-hydrazone forms (rotamers Ia and Ib) to be more stable than the enol-azo forms (rotamers IIa and IIb, by about 14 kcal mol-1) and III (by approximately 6 kcal mol-1), independently of the nature of the substituent in the phenylene ring. These results were confirmed by spectroscopic data on the derivatives HL1-HL13, obtained from 2-hydroxy-1,4-naphthoquinone and arylamines (R = 4-OMe, 4-N 2 -C 6 H 5 , 4-Cl, 4-I, 3-I, 2-I, 4-COOH, 3-COOH, 4-CN, 3-CN, 4-NO 2 , 3-NO 2 , 2-NO 2 ). The in vitro antitumor (against SF-295, HCT-8, MDAMB-435 and HL-60 cancer cell lines) and antibacterial activities (Bacillus cereus, Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia and Pseudomonas aeruginosa) of compounds HL1-HL13 and of their respective copper(II) complexes, [Cu(L1-13) 2 ], were tested. In general, these compounds exhibited low antibacterial activity, except for HL5 (R 3-I), more active than the control; however, the corresponding complex was inactive. In contrast, increased cytotoxicity was observed upon complexation. Complex [Cu(L13) 2 ] (R = 3-NO 2 ) presented moderate cytotoxicity against human leukemia (HL-60). (author)

  14. R2d2 Drives Selfish Sweeps in the House Mouse.

    Science.gov (United States)

    Didion, John P; Morgan, Andrew P; Yadgary, Liran; Bell, Timothy A; McMullan, Rachel C; Ortiz de Solorzano, Lydia; Britton-Davidian, Janice; Bult, Carol J; Campbell, Karl J; Castiglia, Riccardo; Ching, Yung-Hao; Chunco, Amanda J; Crowley, James J; Chesler, Elissa J; Förster, Daniel W; French, John E; Gabriel, Sofia I; Gatti, Daniel M; Garland, Theodore; Giagia-Athanasopoulou, Eva B; Giménez, Mabel D; Grize, Sofia A; Gündüz, İslam; Holmes, Andrew; Hauffe, Heidi C; Herman, Jeremy S; Holt, James M; Hua, Kunjie; Jolley, Wesley J; Lindholm, Anna K; López-Fuster, María J; Mitsainas, George; da Luz Mathias, Maria; McMillan, Leonard; Ramalhinho, Maria da Graça Morgado; Rehermann, Barbara; Rosshart, Stephan P; Searle, Jeremy B; Shiao, Meng-Shin; Solano, Emanuela; Svenson, Karen L; Thomas-Laemont, Patricia; Threadgill, David W; Ventura, Jacint; Weinstock, George M; Pomp, Daniel; Churchill, Gary A; Pardo-Manuel de Villena, Fernando

    2016-06-01

    A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether "selfish" genes are capable of fixation-thereby leaving signatures identical to classical selective sweeps-despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2(HC)) in natural populations. We replicate this finding in multiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2(HC) rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2(HC) is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  15. Human retinal pigment epithelial cells inhibit proliferation and IL2R expression of activated T cells

    DEFF Research Database (Denmark)

    Kaestel, Charlotte G; Jørgensen, Annette; Nielsen, Mette

    2002-01-01

    -Thymidine incorporation assay, respectively. T cells and RPE cells were cultured directly together or in a transwell system for determination of the effect of cell contact. The importance of cell surface molecules was examined by application of a panel of blocking antibodies (CD2, CD18, CD40, CD40L, CD54, CD58......) in addition to use of TCR negative T cell lines. The expression of IL2R-alpha -beta and -gamma chains of activated T cells was analysed by flow cytometry after incubation of T cells alone or with RPE cells. Human RPE cells were found to inhibit the proliferation of activated T cells by a cell contact......-beta and -gamma chain expression within 24 hr after removal from the coculture. It is concluded that the cultured human adult and foetal RPE cells inhibit the proliferation of activated T cells by a process that does not involve apoptosis. It depends on cell contact but the involved surface molecules were...

  16. Activation of anthocyanin biosynthesis by expression of the radish R2R3-MYB transcription factor gene RsMYB1.

    Science.gov (United States)

    Lim, Sun-Hyung; Song, Ji-Hye; Kim, Da-Hye; Kim, Jae Kwang; Lee, Jong-Yeol; Kim, Young-Mi; Ha, Sun-Hwa

    2016-03-01

    RsMYB1, a MYB TF of red radish origin, was characterized as a positive regulator to transcriptionally activate the anthocyanin biosynthetic machinery by itself in Arabidopsis and tobacco plants. Anthocyanins, providing the bright red-orange to blue-violet colors, are flavonoid-derived pigments with strong antioxidant activity that have benefits for human health. We isolated RsMYB1, which encodes an R2R3-MYB transcription factor (TF), from red radish plants (Raphanus sativus L.) that accumulate high levels of anthocyanins. RsMYB1 shows higher expression in red radish than in common white radish, in both leaves and roots, at different growth stages. Consistent with RsMYB1 function as an anthocyanin-promoting TF, red radishes showed higher expression of all six anthocyanin biosynthetic and two anthocyanin regulatory genes. Transient expression of RsMYB1 in tobacco showed that RsMYB1 is a positive regulator of anthocyanin production with better efficiency than the basic helix-loop-helix (bHLH) TF gene B-Peru. Also, the synergistic effect of RsMYB1 with B-Peru was larger than the effect of the MYB TF gene mPAP1D with B-peru. Arabidopsis plants stably expressing RsMYB1 produced red pigmentation throughout the plant, accompanied by up-regulation of the six structural and two regulatory genes for anthocyanin production. This broad transcriptional activation of anthocyanin biosynthetic machinery in Arabidopsis included up-regulation of TRANSPARENT TESTA8, which encodes a bHLH TF. These results suggest that overexpression of RsMYB1 promotes anthocyanin production by triggering the expression of endogenous bHLH genes as potential binding partners for RsMYB1. In addition, RsMYB1-overexpressing Arabidopsis plants had a higher antioxidant capacity than did non-transgenic control plants. Taken together, RsMYB1 is an actively positive regulator for anthocyanins biosynthesis in radish plants and it might be one of the best targets for anthocyanin production by single gene

  17. Antimicrobial and antifungal activity of some (5-(adamantane-1-yl-4R-1,2,4-triazole-3-ylthiols substitutes

    Directory of Open Access Journals (Sweden)

    V. M. Odyntsova

    2016-12-01

    Full Text Available Lately adamantine containing substances have found wide use among the skeleton derivatives. The combination of adamantane and 1,2,4-triazole in one molecule creates significant preconditions to design new potential drugs with low toxicity and pronounced pharmacological activity. The aim of the research is the study of antimicrobial and antifungal activity of (5-(adamantane-1-yl-4-R-1,2,4-triazole-3-ylthiols substitutes. Materials and methods. Determination of antimicrobial and antifungal activity has been carried out by 2-fold serial dilutions method in liquid nutrient media. The substance of the antibacterial drug Trimethoprim has been applied as a control in determining antimicrobial activity of the compounds against the investigated strains of microorganisms. Results. According to the data of experiments the 5-(((5-(adamantane-1-yl-4-ethyl-4H-1,2,4-triazole-3-ylthiomethyl-4-ethyl-4H-1,2,4-triazole-3-thiol shows the same activity as Trimethoprim against P. aeruginosa (MIC is 62.5 µg/ml, MBC – 125 μg/ml, marked activity towards S. aureus (MIC is 15.6 μg/ml, MBC – 31.25 μg/ml while trimethoprim – 31.25 μg/ml, MBC – 62.5 µg/ml, greater fungistatic and fungicidal activity towards C. albicans, which amounted to 31.25 µg/ml, MFC – 62.5 µg/ml (while trimethoprim 62.5 µg/ml, MFC – 125 µg/ml. Reconstration of benzyldenhydrazide group to hydrazide one leads to the slight increase of bacteriostatic activity. Replacing the radical R from -Н to -C2H5 does not influence on the change of fungistatic activity. However, this resulted to the decrease in bacteriostatic activity against E. coli. The same is observed in relation to P. aeruginosa: from 62.5 μg/ml, MFC – 125 mcg/ml to 125 μg/ml, MFC – 125 µg/m respectively. Conclusion. The conducted study has showed that among the synthesized compounds there are some substances which strength of the antimicrobial and antifungal action in some cases exceeds the standard of comparison

  18. R ampersand D activities at DOE applicable to mixed waste

    International Nuclear Information System (INIS)

    Erickson, M.D.; Devgun, J.S.; Brown, J.J.; Beskid, N.J.

    1991-01-01

    The Department of Energy (DOE) has established the Office of Environmental Restoration and Waste Management. Within the new organization, the Office of Technology Development (OTD) is responsible for research, development, demonstration, testing and evaluation (RDDT ampersand E) activities aimed at meeting DOE cleanup goals, while minimizing cost and risk. Because of US governmental activities dating back to the Manhattan project, mixed radioactive and hazardous waste is an area of particular concern to DOE. The OTD is responsible for a number of R ampersand D activities aimed at improving capabilities to characterize, control, and properly dispose of mixed waste. These activities and their progress to date will be reviewed. In addition, needs for additional R ampersand D on managing mixed waste will be presented. 5 refs., 2 tabs

  19. Evaluation of automated enzyme immunoassays for five anticonvulsants and theophylline adapted to a centrifugal analyzer.

    Science.gov (United States)

    Urquhart, N; Godolphin, W; Campbell, D J

    1979-05-01

    We report a clinical evaluation of the enzyme immunoassay (EMIT) performed with the GEMSAEC centrifugal analyzer as compared to gas-liquid and liquid chromatography for anticonvulsant drugs and theophylline, respectively. A good correlation was obtained for all drugs, although some difficulties were experienced with one lot of reagent for ethosuximide. The analyzer has an economic advantage if many samples are being analyzed for few drugs in each sample.

  20. Quantitation of anticonvulsant drugs in serum by gas-chromatography on the stationary phase SP-2510.

    Science.gov (United States)

    Godolphin, W; Thoma, J

    1978-03-01

    A new column packing, SP-2510 DA (Supelco, Inc., Bellefonte, Pa. 16823), is an excellent stationary phase for the determination of a wide variety of anticonvulsant drugs by gas--liquid chromatography without derivatization. However, when uncomplicated extraction procedures are used, serum cholesterol interferes with the determination of primidone. By the simple expedient of adding a short "pre-column" containing another phase (SP-2250 DA) the problem is overcome.

  1. Anticonvulsant treatment of sarin-induced seizures with nasal midazolam: An electrographic, behavioral, and histological study in freely moving rats

    International Nuclear Information System (INIS)

    Gilat, E.; Kadar, T.; Levy, A.; Rabinovitz, I.; Cohen, G.; Kapon, Y.; Sahar, R.; Brandeis, R.

    2005-01-01

    Centrally mediated seizures and convulsions are common consequences of exposure to organophosphates (OPs). These seizures rapidly progress to status epilepticus (SE) and contribute to profound brain injury. Effective management of these seizures is critical for minimization of brain damage. Nasal application of midazolam (1.5 mg/kg) after 5 min of sarin-induced electrographic seizure activity (EGSA) ameliorated EGSA and convulsive behavior (238 ± 90 s). Identical treatment after 30 min was not sufficient to ameliorate ECoG paradoxical activity and convulsive behavior. Nasal midazolam (1.5 mg/kg), together with scopolamine (1 mg/kg, im) after 5 min of EGSA, exerted a powerful and rapid anticonvulsant effect (53 ± 10 s). Delaying the same treatment to 30 min of EGSA leads to attenuation of paroxysmal ECoG activity in all cases but total cessation of paroxysmal activity was not observed in most animals tested. Cognitive tests utilizing the Morris Water Maze demonstrated that nasal midazolam alone or together with scopolamine (im), administered after 5 min of convulsions, abolished the effect of sarin on learning. Both these treatments, when given after 30 min of convulsions, only decreased the sarin-induced learning impairments. Whereas rats which were not subject to the anticonvulsant agents did not show any memory for the platform location, both treatments (at 5 min as well as at 30 min) completely abolished the memory deficits. Both treatments equally blocked the impairment of reversal learning when given at 5 min. However, when administered after 30 min, midazolam alone reversed the impairments in reversal learning, while midazolam with scopolamine did not. Rats exposed to sarin and treated with the therapeutic regimen with the exclusion of midazolam exhibited severe brain lesions that encountered the hippocampus, pyriform cortex, and thalamus. Nasal midazolam at 5 min prevented brain damage, while delaying the midazolam treatment to 30 min of EGSA resulted in

  2. Anticonvulsant treatment of sarin-induced seizures with nasal midazolam: An electrographic, behavioral, and histological study in freely moving rats

    Energy Technology Data Exchange (ETDEWEB)

    Gilat, E [Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100 (Israel); Kadar, T [Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100 (Israel); Levy, A [Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100 (Israel); Rabinovitz, I [Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100 (Israel); Cohen, G [Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100 (Israel); Kapon, Y [Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100 (Israel); Sahar, R [Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100 (Israel); Brandeis, R [Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100 (Israel)

    2005-11-15

    Centrally mediated seizures and convulsions are common consequences of exposure to organophosphates (OPs). These seizures rapidly progress to status epilepticus (SE) and contribute to profound brain injury. Effective management of these seizures is critical for minimization of brain damage. Nasal application of midazolam (1.5 mg/kg) after 5 min of sarin-induced electrographic seizure activity (EGSA) ameliorated EGSA and convulsive behavior (238 {+-} 90 s). Identical treatment after 30 min was not sufficient to ameliorate ECoG paradoxical activity and convulsive behavior. Nasal midazolam (1.5 mg/kg), together with scopolamine (1 mg/kg, im) after 5 min of EGSA, exerted a powerful and rapid anticonvulsant effect (53 {+-} 10 s). Delaying the same treatment to 30 min of EGSA leads to attenuation of paroxysmal ECoG activity in all cases but total cessation of paroxysmal activity was not observed in most animals tested. Cognitive tests utilizing the Morris Water Maze demonstrated that nasal midazolam alone or together with scopolamine (im), administered after 5 min of convulsions, abolished the effect of sarin on learning. Both these treatments, when given after 30 min of convulsions, only decreased the sarin-induced learning impairments. Whereas rats which were not subject to the anticonvulsant agents did not show any memory for the platform location, both treatments (at 5 min as well as at 30 min) completely abolished the memory deficits. Both treatments equally blocked the impairment of reversal learning when given at 5 min. However, when administered after 30 min, midazolam alone reversed the impairments in reversal learning, while midazolam with scopolamine did not. Rats exposed to sarin and treated with the therapeutic regimen with the exclusion of midazolam exhibited severe brain lesions that encountered the hippocampus, pyriform cortex, and thalamus. Nasal midazolam at 5 min prevented brain damage, while delaying the midazolam treatment to 30 min of EGSA resulted

  3. Theoretical studies of the tautomerism in 3-(2-R-Phenylhydrazono)-naphthalene- 1,2,4-triones: synthesis of copper(II) complexes and studies of antibacterial and antitumor activities

    Energy Technology Data Exchange (ETDEWEB)

    Francisco, Acacio I.; Vargas, Maria D.; Fragoso, Thais P.; Carneiro, J. Walkimar de M.; Silva, Fernando de C. da; Ferreira, Vitor F., E-mail: mdvargas@vm.uff.b [Universidade Federal Fluminense (UFF), Niteroi, RJ (Brazil). Inst. de Quimica; Casellato, Annelise [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Inst. de Quimica; Barbosa, Jussara P. [Instituto Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, RJ (Brazil); Pessoa, Claudia; Costa-Lotufo, Leticia V.; Marinho Filho, Jose D.B.; Moraes, Manoel O. de [Universidade Federal do Ceara (UFC), Fortaleza, CE (Brazil). Dept. de Fisiologia e Farmacologia; Mangrich, Antonio S. [Universidade Federal do Parana (UFPR), Curitiba, PR (Brazil). Dept. de Quimica

    2010-07-01

    DFT calculations using the B3LYP and PBE1PBE functionals with the standard 6-31G(d) and 6-311+G(2d,p) basis sets were carried out for the 3-(2-phenylhydrazone)-naphthalene-1,2,4-trione system in solution (dmso) and in the gas phase, and showed the keto-hydrazone forms (rotamers Ia and Ib) to be more stable than the enol-azo forms (rotamers IIa and IIb, by about 14 kcal mol-1) and III (by approximately 6 kcal mol-1), independently of the nature of the substituent in the phenylene ring. These results were confirmed by spectroscopic data on the derivatives HL1-HL13, obtained from 2-hydroxy-1,4-naphthoquinone and arylamines (R = 4-OMe, 4-N{sub 2}-C{sub 6}H{sub 5}, 4-Cl, 4-I, 3-I, 2-I, 4-COOH, 3-COOH, 4-CN, 3-CN, 4-NO{sub 2}, 3-NO{sub 2}, 2-NO{sub 2}). The in vitro antitumor (against SF-295, HCT-8, MDAMB-435 and HL-60 cancer cell lines) and antibacterial activities (Bacillus cereus, Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia and Pseudomonas aeruginosa) of compounds HL1-HL13 and of their respective copper(II) complexes, [Cu(L1-13){sub 2}], were tested. In general, these compounds exhibited low antibacterial activity, except for HL5 (R 3-I), more active than the control; however, the corresponding complex was inactive. In contrast, increased cytotoxicity was observed upon complexation. Complex [Cu(L13){sub 2}] (R = 3-NO{sub 2}) presented moderate cytotoxicity against human leukemia (HL-60). (author)

  4. Insights from Zebrafish and Mouse Models on the Activity and Safety of Ar-Turmerone as a Potential Drug Candidate for the Treatment of Epilepsy

    OpenAIRE

    Orellana-Paucar, Adriana Monserrath; Afrikanova, Tatiana; Thomas, Joice; Aibuldinov, Yelaman K; Dehaen, Wim; de Witte, Peter; Esguerra, Camila

    2013-01-01

    In a previous study, we uncovered the anticonvulsant properties of turmeric oil and its sesquiterpenoids (ar-turmerone, ?-, ?-turmerone and ?-atlantone) in both zebrafish and mouse models of chemically-induced seizures using pentylenetetrazole (PTZ). In this follow-up study, we aimed at evaluating the anticonvulsant activity of ar-turmerone further. A more in-depth anticonvulsant evaluation of ar-turmerone was therefore carried out in the i.v. PTZ and 6-Hz mouse models. The potential toxic ef...

  5. Recent developments of 2-aminothiazoles in medicinal chemistry.

    Science.gov (United States)

    Das, Debasis; Sikdar, Papiya; Bairagi, Moumita

    2016-02-15

    The 2-aminothiazole (2-AT) core is an active pharmacophore and used in medicinal chemistry and drug discovery research. A number of drugs with 2-AT core are in the market, e.g. Famotidine, Cefdinir, Meloxcam etc. Recently, 2-AT core has been explored for many more important therapeutic areas and identified new 2-aminothiazoles with anticancer, antitumor, antidiebatic and anticonvulsant activity. In this review, we discuss the newly identified and developed 2-aminothiazoles in recent years and their use in medicinal chemistry and pharmacology. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  6. Genetic variability of aryl hydrocarbon receptor (AhR)-mediated regulation of the human UDP glucuronosyltransferase (UGT) 1A4 gene

    Energy Technology Data Exchange (ETDEWEB)

    Erichsen, Thomas J; Ehmer, Ursula; Kalthoff, Sandra; Lankisch, Tim O; Mueller, Tordis M [Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Medical School, Hannover (Germany); Munzel, Peter A [Department of Toxicology, Institute of Pharmacology and Toxicology, University of Tubingen, Tubingen (Germany); Manns, Michael P [Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Medical School, Hannover (Germany); Strassburg, Christian P. [Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Medical School, Hannover (Germany)], E-mail: strassburg.christian@mh-hannover.de

    2008-07-15

    UDP glucuronosyltransferases (UGTs) play an important role for drug detoxification and toxicity. UGT function is genetically modulated by single nucleotide polymorphisms (SNPs) which lead to the expression of functionally altered protein, or altered expression levels. UGT1A4 activity includes anticonvulsants, antidepressants and environmental mutagens. In this study the induction of the human UGT1A4 gene and a potential influence of genetic variation in its promoter region were analyzed. SNPs at bp - 219 and - 163 occurred in 9% among 109 blood donors reducing UGT1A4 transcription by 40%. UGT1A4 transcription was dioxin inducible. Reporter gene experiments identified 2 xenobiotic response elements (XRE), which were functionally confirmed by mutagenesis analyses, and binding was demonstrated by electromobility shift assays. Constitutive human UGT1A4 gene expression and induction was aryl hydrocarbon receptor (AhR)-dependent, and reduced in the presence of SNPs at bp - 219 and - 163. AhR-mediated regulation of the human UGT1A4 gene by two XRE and a modulation by naturally occurring genetic variability by SNPs is demonstrated, which indicates gene-environment interaction with potential relevance for drug metabolism.

  7. Genetic variability of aryl hydrocarbon receptor (AhR)-mediated regulation of the human UDP glucuronosyltransferase (UGT) 1A4 gene

    International Nuclear Information System (INIS)

    Erichsen, Thomas J.; Ehmer, Ursula; Kalthoff, Sandra; Lankisch, Tim O.; Mueller, Tordis M.; Munzel, Peter A.; Manns, Michael P.; Strassburg, Christian P.

    2008-01-01

    UDP glucuronosyltransferases (UGTs) play an important role for drug detoxification and toxicity. UGT function is genetically modulated by single nucleotide polymorphisms (SNPs) which lead to the expression of functionally altered protein, or altered expression levels. UGT1A4 activity includes anticonvulsants, antidepressants and environmental mutagens. In this study the induction of the human UGT1A4 gene and a potential influence of genetic variation in its promoter region were analyzed. SNPs at bp - 219 and - 163 occurred in 9% among 109 blood donors reducing UGT1A4 transcription by 40%. UGT1A4 transcription was dioxin inducible. Reporter gene experiments identified 2 xenobiotic response elements (XRE), which were functionally confirmed by mutagenesis analyses, and binding was demonstrated by electromobility shift assays. Constitutive human UGT1A4 gene expression and induction was aryl hydrocarbon receptor (AhR)-dependent, and reduced in the presence of SNPs at bp - 219 and - 163. AhR-mediated regulation of the human UGT1A4 gene by two XRE and a modulation by naturally occurring genetic variability by SNPs is demonstrated, which indicates gene-environment interaction with potential relevance for drug metabolism

  8. miR-214-Dependent Increase of PHLPP2 Levels Mediates the Impairment of Insulin-Stimulated Akt Activation in Mouse Aortic Endothelial Cells Exposed to Methylglyoxal

    Directory of Open Access Journals (Sweden)

    Cecilia Nigro

    2018-02-01

    Full Text Available Evidence has been provided linking microRNAs (miRNAs and diabetic complications, by the regulation of molecular pathways, including insulin-signaling, involved in the pathophysiology of vascular dysfunction. Methylglyoxal (MGO accumulates in diabetes and is associated with cardiovascular complications. This study aims to analyze the contribution of miRNAs in the MGO-induced damaging effect on insulin responsiveness in mouse aortic endothelial cells (MAECs. miRNA modulation was performed by transfection of specific miRNA mimics and inhibitors in MAECs, treated or not with MGO. miRNA-target protein levels were evaluated by Western blot. PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2 regulation by miR-214 was tested by luciferase assays and by the use of a target protector specific for miR-214 on PHLPP2-3′UTR. This study reveals a 4-fold increase of PHLPP2 in MGO-treated MAECs. PHLPP2 levels inversely correlate with miR-214 modulation. Moreover, miR-214 overexpression is able to reduce PHLPP2 levels in MGO-treated MAECs. Interestingly, a direct regulation of PHLPP2 is proved to be dependent by miR-214. Finally, the inhibition of miR-214 impairs the insulin-dependent Akt activation, while its overexpression rescues the insulin effect on Akt activation in MGO-treated MAECs. In conclusion, this study shows that PHLPP2 is a target of miR-214 in MAECs, and identifies miR-214 downregulation as a contributing factor to MGO-induced endothelial insulin-resistance.

  9. Gastric cancer: the role of insulin-like growth factor 2 (IGF 2) and its receptors (IGF 1R and M6-P/IGF 2R).

    Science.gov (United States)

    Pavelić, Kresimir; Kolak, Toni; Kapitanović, Sanja; Radosević, Senka; Spaventi, Sime; Kruslin, Bozo; Pavelić, Jasminka

    2003-11-01

    Insulin-like growth factor 2 (IGF 2) appears to be involved in the progression of many tumours. It binds to at least two different types of receptor: IGF type 1 (IGF 1R) and mannose 6-phosphate/IGF type 2 (M6-P/IGF 2R). Ligand binding to IGF 1R provokes mitogenic and anti-apoptotic effects. M6-P/IGF 2R has a tumour suppressor function--it mediates IGF 2 degradation. Mutation of M6-P/IGF 2R causes both diminished growth suppression and augmented growth stimulation. The aim of this study was to investigate the role of IGF 2 and its receptors (IGF 1R and IGF 2R) in human gastric cancer. The expression of IGF 2 and its receptors was measured in order to analyse the possible correlation between the activity of these genes and cell proliferation in two different gastric tumour types: diffuse and intestinal. The effect of IGF 1 receptor blockage on cell proliferation and anchorage-independent cell growth was also examined. Increased expression of IGF 2 and IGF 1R genes (at the mRNA and protein level) was found in gastric cancer when compared with non-tumour tissue. Furthermore, there was a significant difference between IGF 2 expression in the more aggressive diffuse type and that in the intestinal type of gastric cancer. Moreover, the IGF 2 peptide level in the culture media obtained from the diffuse type of cancer cells was significantly higher when compared with the intestinal type. The level of IGF 2 peptide in the conditioned media strongly correlated with [3H]thymidine incorporation and cell proliferation. On the contrary, IGF 2R mRNA expression was much higher in the intestinal type of cancer than in the diffuse type. In addition, IGF 2R protein expression was substantially lower with progression of the diffuse cancer type to a higher stage. The alphaIR3 monoclonal antibody strongly inhibited [3H]thymidine incorporation and decreased the number of colonies in soft agar of cells overexpressing IGF 2. These findings suggest that members of the IGF family are involved

  10. Building a SuAVE browse interface to R2R's Linked Data

    Science.gov (United States)

    Clark, D.; Stocks, K. I.; Arko, R. A.; Zaslavsky, I.; Whitenack, T.

    2017-12-01

    The Rolling Deck to Repository program (R2R) is creating and evaluating a new browse portal based on the SuAVE platform and the R2R linked data graph. R2R manages the underway sensor data collected by the fleet of US academic research vessels, and provides a discovery and access point to those data at its website, www.rvdata.us. R2R has a database-driven search interface, but seeks a more capable and extensible browse interface that could be built off of the substantial R2R linked data resources. R2R's Linked Data graph organizes its data holdings around key concepts (e.g. cruise, vessel, device type, operator, award, organization, publication), anchored by persistent identifiers where feasible. The "Survey Analysis via Visual Exploration" or SuAVE platform (suave.sdsc.edu) is a system for online publication, sharing, and analysis of images and metadata. It has been implemented as an interface to diverse data collections, but has not been driven off of linked data in the past. SuAVE supports several features of interest to R2R, including faceted searching, collaborative annotations, efficient subsetting, Google maps-like navigation over an image gallery, and several types of data analysis. Our initial SuAVE-based implementation was through a CSV export from the R2R PostGIS-enabled PostgreSQL database. This served to demonstrate the utility of SuAVE but was static and required reloading as R2R data holdings grew. We are now working to implement a SPARQL-based ("RDF Query Language") service that directly leverages the R2R Linked Data graph and offers the ability to subset and/or customize output.We will show examples of SuAVE faceted searches on R2R linked data concepts, and discuss our experience to date with this work in progress.

  11. 2R and remodeling of vertebrate signal transduction engine

    Directory of Open Access Journals (Sweden)

    Huminiecki Lukasz

    2010-12-01

    Full Text Available Abstract Background Whole genome duplication (WGD is a special case of gene duplication, observed rarely in animals, whereby all genes duplicate simultaneously through polyploidisation. Two rounds of WGD (2R-WGD occurred at the base of vertebrates, giving rise to an enormous wave of genetic novelty, but a systematic analysis of functional consequences of this event has not yet been performed. Results We show that 2R-WGD affected an overwhelming majority (74% of signalling genes, in particular developmental pathways involving receptor tyrosine kinases, Wnt and transforming growth factor-β ligands, G protein-coupled receptors and the apoptosis pathway. 2R-retained genes, in contrast to tandem duplicates, were enriched in protein interaction domains and multifunctional signalling modules of Ras and mitogen-activated protein kinase cascades. 2R-WGD had a fundamental impact on the cell-cycle machinery, redefined molecular building blocks of the neuronal synapse, and was formative for vertebrate brains. We investigated 2R-associated nodes in the context of the human signalling network, as well as in an inferred ancestral pre-2R (AP2R network, and found that hubs (particularly involving negative regulation were preferentially retained, with high connectivity driving retention. Finally, microarrays and proteomics demonstrated a trend for gradual paralog expression divergence independent of the duplication mechanism, but inferred ancestral expression states suggested preferential subfunctionalisation among 2R-ohnologs (2ROs. Conclusions The 2R event left an indelible imprint on vertebrate signalling and the cell cycle. We show that 2R-WGD preferentially retained genes are associated with higher organismal complexity (for example, locomotion, nervous system, morphogenesis, while genes associated with basic cellular functions (for example, translation, replication, splicing, recombination; with the notable exception of cell cycle tended to be excluded. 2R

  12. Synthesis, characterization and biological behavior of some Schiff's and Mannich base derivatives of Lamotrigine

    Directory of Open Access Journals (Sweden)

    A.A. Kulkarni

    2017-02-01

    Full Text Available A series of various Schiff's and Mannich base derivatives (N1–2 & ND1–6 of Lamotrigine with isatin and substituted isatin were synthesized to get more potent anticonvulsant agents. The starting material for the synthesis of various new Schiff's and Mannich base derivatives was isatin (1H-indole- 2, 3-dione which in turn was prepared from substituted isonitrosoacetanilide using aniline. Lamotrigine reacts with isatin & substituted isatin gave Schiff's bases (N1–2 which on reaction with various secondary amines (dimethylamine, diethylamine, morpholine produced Mannich bases (ND1–6. The structures of newly synthesized compounds were characterized by using TLC, UV, FT-IR, 1HNMR and studied for their anticonvulsant activity. Anticonvulsant activity of all the derivatives was evaluated by MES method using phenobarbitone sodium & Lamotrigine as standard drugs and % reduction of time spent by animals in extension, flexion, clonus, and stupor phase were noted. Compounds ND-4 and ND-6 showed significant anticonvulsant activity when compared with that of standard drugs. The remaining all compounds show moderate activity. Biological activity data of the synthesized derivatives revealed that, the synthesized derivatives are good anticonvulsant agents as compared to Lamotrigine.

  13. R{sup 2} supergravity

    Energy Technology Data Exchange (ETDEWEB)

    Ferrara, Sergio [Physics Department, Theory Unit, CERN,CH 1211, Geneva 23 (Switzerland); INFN - Laboratori Nazionali di Frascati,Via Enrico Fermi 40, I-00044 Frascati (Italy); Department of Physics and Astronomy, University of California,Los Angeles, CA 90095-1547 (United States); Kehagias, Alex [Physics Division, National Technical University of Athens,15780 Zografou, Athens (Greece); Porrati, Massimo [Physics Department, Theory Unit, CERN,CH 1211, Geneva 23 (Switzerland); CCPP, Department of Physics,NYU 4 Washington Pl. New York NY 10003 (United States)

    2015-08-03

    We formulate R{sup 2} pure supergravity as a scale invariant theory built only in terms of superfields describing the geometry of curved superspace. The standard supergravity duals are obtained in both “old' and “new' minimal formulations of auxiliary fields. These theories have massless fields in de Sitter space as they do in their non supersymmetric counterpart. Remarkably, the dual theory of R{sup 2} supergravity in the new minimal formulation is an extension of the Freedman model, describing a massless gauge field and a massless chiral multiplet in de Sitter space, with inverse radius proportional to the Fayet-Iliopoulos term. This model can be interpreted as the “de-Higgsed' phase of the dual companion theory of R+R{sup 2} supergravity.

  14. CK2 phospho-dependent binding of R2TP complex to TEL2 is essential for mTOR and SMG1 stability.

    Science.gov (United States)

    Horejsí, Zuzana; Takai, Hiroyuki; Adelman, Carrie A; Collis, Spencer J; Flynn, Helen; Maslen, Sarah; Skehel, J Mark; de Lange, Titia; Boulton, Simon J

    2010-09-24

    TEL2 interacts with and is essential for the stability of all phosphatidylinositol 3-kinase-related kinases (PIKKs), but its mechanism of action remains unclear. Here, we show that TEL2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (CK2). Proteomic analyses establish that the CK2 phosphosite of TEL2 confers binding to the R2TP/prefoldin-like complex, which possesses chaperon/prefoldin activities required during protein complex assembly. The PIH1D1 subunit of the R2TP complex binds directly to the CK2 phosphosite of TEL2 in vitro and is required for the TEL2-R2TP/prefoldin-like complex interaction in vivo. Although the CK2 phosphosite mutant of TEL2 retains association with the PIKKs and HSP90 in cells, failure to interact with the R2TP/prefoldin-like complex results in instability of the PIKKs, principally mTOR and SMG1. We propose that TEL2 acts as a scaffold to coordinate the activities of R2TP/prefoldin-like and HSP90 chaperone complexes during the assembly of the PIKKs. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. Anticonvulsant effect of Uncaria rhynchophylla (Miq) Jack. in rats with kainic acid-induced epileptic seizure.

    Science.gov (United States)

    Hsieh, C L; Chen, M F; Li, T C; Li, S C; Tang, N Y; Hsieh, C T; Pon, C Z; Lin, J G

    1999-01-01

    This study investigated the anticonvulsant effect of Uncaria rhynchophylla (UR) and the physiological mechanisms of its action in rats. A total of 70 male Sprague-Dawley (SD) rats were selected for study. Thirty four of these rats were divided into 5 groups as follows: 1) CONTROL GROUP (n = 6): received intraperitoneal injection (i.p.) of kainic acid (KA, 12 mg/kg); 2) UR1000 group (n = 10), 3) UR500 group (n = 6) 4) UR250 group, received UR 1000, 500, 250 mg/kg i.p. 30 min prior to KA administration, respectively; 5) Contrast group: received carbamazepine 20 mg/kg i.p. 30 min prior to KA administration. Behavior and EEG were monitored from 15 min prior to drug administration to 3 hours after KA administration. The number of wet dog shakes were counted at 10 min intervals throughout the experimental course. The remaining 36 rats were used to measure the lipid peroxide level in the cerebral cortex one hour after KA administration. These rats were divided into 6 groups of 6 rats as follows: 1) Normal group: no treatment was given; 2) CONTROL GROUP: received KA (12 mg/kg) i.p.; 3) UR1000 group, 4) UR500 group, 5) UR250 group, received UR 1000, 500, 250 mg/kg i.p. 30 min prior to KA administration, respectively; 6) Contrast group: received carbamazepine 20 mg/kg i.p. 30 min prior to KA administration. Our results indicated that both UR 1000 and 500 mg/kg decreased the incidence of KA-induced wet dog shakes, no similar effect was observed in the UR 250 mg/kg and carbamazepine 20 mg/kg group. Treatment with UR 1000 mg/kg, 500 mg/kg, or 250 mg/kg and carbamazepine 20 mg/kg decreased KA-induced lipid peroxide level in the cerebral cortex and was dose-dependent. These findings suggest that the anticonvulsant effect of UR possibly results from its suppressive effect on lipid peroxidation in the brain.

  16. Early life status epilepticus and stress have distinct and sex-specific effects on learning, subsequent seizure outcomes, including anticonvulsant response to phenobarbital.

    Science.gov (United States)

    Akman, Ozlem; Moshé, Solomon L; Galanopoulou, Aristea S

    2015-02-01

    Neonatal status epilepticus (SE) is often associated with adverse cognitive and epilepsy outcomes. We investigate the effects of three episodes of kainic acid-induced SE (3KA-SE) and maternal separation in immature rats on subsequent learning, seizure susceptibility, and consequences, and the anticonvulsant effects of phenobarbital, according to sex, type, and age at early life (EL) event. 3KA-SE or maternal separation was induced on postnatal days (PN) 4-6 or 14-16. Rats were tested on Barnes maze (PN16-19), or lithium-pilocarpine SE (PN19) or flurothyl seizures (PN32). The anticonvulsant effects of phenobarbital (20 or 40 mg/kg/rat, intraperitoneally) pretreatment were tested on flurothyl seizures. FluoroJadeB staining assessed hippocampal injury. 3KA-SE or separation on PN4-6 caused more transient learning delays in males and did not alter lithium-pilocarpine SE latencies, but aggravated its outcomes in females. Anticonvulsant effects of phenobarbital were preserved and potentiated in specific groups depending on sex, type, and age at EL event. Early life 3KA-SE and maternal separation cause more but transient cognitive deficits in males but aggravate the consequences of subsequent lithium-pilocarpine SE in females. In contrast, on flurothyl seizures, EL events showed either beneficial or no effect, depending on gender, type, and age at EL events. © 2014 John Wiley & Sons Ltd.

  17. Comparison of the efficacy of two anticonvulsants, phenytoin and valproate to improve PCP and d-amphetamine induced deficits in a reversal learning task in the rat

    Directory of Open Access Journals (Sweden)

    Nagi F Idris

    2009-06-01

    Full Text Available Recent studies in our laboratory have shown that PCP (phencyclidine and d-amphetamine induce a cognitive deficit in rats, in a paradigm of potential relevance for the pathology of schizophrenia. Atypical, but not classical antipsychotics and the anticonvulsant, lamotrigine have been shown to prevent a selective reversal learning deficit induced by PCP. In contrast, only haloperidol reversed the d-amphetamine-induced deficit. The present study aimed to explore the ability of two anticonvulsants with differing mechanism of action, valproate and phenytoin to attenuate the cognitive deficits induced by PCP and d-amphetamine in the reversal learning paradigm. PCP at 1.5mg/kg and d-amphetamine at 0.5mg/kg both produced a selective and significant reduction in performance of the reversal phase with no effect on the initial phase of the task in female-hooded Lister rats. Valproate (25-200mg/kg and phenytoin (25-50mg/kg had no effect on performance when administered alone. Valproate (100-200mg/kg, whose principle action is thought to be the enhancement of GABA transmission, was unable to prevent the cognitive deficit induced by either PCP or d-amphetamine. Conversely, phenytoin (50mg/kg, a use-dependent sodium channel inhibitor, significantly prevented the deficit induced by PCP, but not d-amphetamine. These results add to our earlier work with lamotrigine, and suggest that sodium channel blockade may be a mechanism by which some anticonvulsant drugs can prevent the PCP-induced deficit. These data have implications for the use of anticonvulsant drugs in the treatment of cognitive or psychotic disorders.

  18. Fgf signaling controls pharyngeal taste bud formation through miR-200 and Delta-Notch activity.

    Science.gov (United States)

    Kapsimali, Marika; Kaushik, Anna-Lila; Gibon, Guillaume; Dirian, Lara; Ernest, Sylvain; Rosa, Frederic M

    2011-08-01

    Taste buds, the taste sensory organs, are conserved in vertebrates and composed of distinct cell types, including taste receptor, basal/presynaptic and support cells. Here, we characterize zebrafish taste bud development and show that compromised Fgf signaling in the larva results in taste bud reduction and disorganization. We determine that Fgf activity is required within pharyngeal endoderm for formation of Calb2b(+) cells and reveal miR-200 and Delta-Notch signaling as key factors in this process. miR-200 knock down shows that miR-200 activity is required for taste bud formation and in particular for Calb2b(+) cell formation. Compromised delta activity in mib(-/-) dramatically reduces the number of Calb2b(+) cells and increases the number of 5HT(+) cells. Conversely, larvae with increased Notch activity and ascl1a(-/-) mutants are devoid of 5HT(+) cells, but have maintained and increased Calb2b(+) cells, respectively. These results show that Delta-Notch signaling is required for intact taste bud organ formation. Consistent with this, Notch activity restores Calb2b(+) cell formation in pharyngeal endoderm with compromised Fgf signaling, but fails to restore the formation of these cells after miR-200 knock down. Altogether, this study provides genetic evidence that supports a novel model where Fgf regulates Delta-Notch signaling, and subsequently miR-200 activity, in order to promote taste bud cell type differentiation.

  19. Glucose utilization in the brain during acute seizure is a useful biomarker for the evaluation of anticonvulsants: effect of methyl ethyl ketone in lithium-pilocarpine status epilepticus rats

    International Nuclear Information System (INIS)

    Yamada, Akifumi; Momosaki, Sotaro; Hosoi, Rie; Abe, Kohji; Yamaguchi, Masatoshi; Inoue, Osamu

    2009-01-01

    Enhancement of glucose utilization in the brain has been well known during acute seizure in various kinds of animal model of epilepsy. This enhancement of glucose utilization might be related to neural damage in these animal models. Recently, we found that methyl ethyl ketone (MEK) had both anticonvulsive and neuroprotective effects in lithium-pilocapine (Li-pilo) status epilepticus (SE) rat. In this article, we measured the uptake of [ 14 C]2-deoxyglucose ([ 14 C]DG) in the Li-pilo SE and Li-pilo SE with MEK rat brain in order to assess whether the glucose utilization was a useful biomarker for the detection of efficacy of anticonvulsive compounds. Significant increase of [ 14 C]DG uptake (45 min after the injection) in the cerebral cortex, hippocampus, amygdala and thalamus during acute seizure induced by Li-pilo were observed. On the other hand, the initial uptake of [ 14 C]DG (1 min after the injection) in the Li-pilo SE rats was not different from the control rats. Therefore, the enhancement of glucose metabolism during acute seizure was due to the facilitation of the rate of phosphorylation process of [ 14 C]DG in the brain. Pretreatment with MEK (8 mmol/kg) completely abolished the enhancement of glucose utilization in the Li-pilo SE rats. The present results indicated that glucose utilization in the brain during acute seizure might be a useful biomarker for the evaluation of efficacy of anticonvulsive compounds.

  20. Glucose utilization in the brain during acute seizure is a useful biomarker for the evaluation of anticonvulsants: effect of methyl ethyl ketone in lithium-pilocarpine status epilepticus rats

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Akifumi [Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka, 565-0871 (Japan); Momosaki, Sotaro; Hosoi, Rie [Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka, 565-0871 (Japan); Abe, Kohji [Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka, 565-0871 (Japan); Developmental Research Laboratories, Shionogi and Co., Ltd., Toyonaka, Osaka, 561-0825 (Japan); Yamaguchi, Masatoshi [Faculty of Pharmaceutical Sciences, Fukuoka University, Johnan, Fukuoka 814-0180 (Japan); Inoue, Osamu [Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka, 565-0871 (Japan)

    2009-11-15

    Enhancement of glucose utilization in the brain has been well known during acute seizure in various kinds of animal model of epilepsy. This enhancement of glucose utilization might be related to neural damage in these animal models. Recently, we found that methyl ethyl ketone (MEK) had both anticonvulsive and neuroprotective effects in lithium-pilocapine (Li-pilo) status epilepticus (SE) rat. In this article, we measured the uptake of [{sup 14}C]2-deoxyglucose ([{sup 14}C]DG) in the Li-pilo SE and Li-pilo SE with MEK rat brain in order to assess whether the glucose utilization was a useful biomarker for the detection of efficacy of anticonvulsive compounds. Significant increase of [{sup 14}C]DG uptake (45 min after the injection) in the cerebral cortex, hippocampus, amygdala and thalamus during acute seizure induced by Li-pilo were observed. On the other hand, the initial uptake of [{sup 14}C]DG (1 min after the injection) in the Li-pilo SE rats was not different from the control rats. Therefore, the enhancement of glucose metabolism during acute seizure was due to the facilitation of the rate of phosphorylation process of [{sup 14}C]DG in the brain. Pretreatment with MEK (8 mmol/kg) completely abolished the enhancement of glucose utilization in the Li-pilo SE rats. The present results indicated that glucose utilization in the brain during acute seizure might be a useful biomarker for the evaluation of efficacy of anticonvulsive compounds.

  1. Mechanism of Metal Ion Activation of the Diphtheria Toxin Repressor DtxR

    Energy Technology Data Exchange (ETDEWEB)

    D' Aquino,J.; Tetenbaum-Novatt, J.; White, A.; Berkovitch, F.; Ringe, D.

    2005-01-01

    The diphtheria toxin repressor (DtxR) is a metal ion-activated transcriptional regulator that has been linked to the virulence of Corynebacterium diphtheriae. Structure determination has shown that there are two metal ion binding sites per repressor monomer, and site-directed mutagenesis has demonstrated that binding site 2 (primary) is essential for recognition of the target DNA repressor, leaving the role of binding site 1 (ancillary) unclear. Calorimetric techniques have demonstrated that although binding site 1 (ancillary) has high affinity for metal ion with a binding constant of 2 x 10{sup -7}, binding site 2 (primary) is a low-affinity binding site with a binding constant of 6.3 x 10{sup -4}. These two binding sites act in an independent fashion, and their contribution can be easily dissected by traditional mutational analysis. Our results clearly demonstrate that binding site 1 (ancillary) is the first one to be occupied during metal ion activation, playing a critical role in stabilization of the repressor. In addition, structural data obtained for the mutants Ni-DtxR(H79A, C102D), reported here, and the previously reported DtxR(H79A) have allowed us to propose a mechanism of metal activation for DtxR.

  2. Use of the accelerating rotarod for assessment of motor performance decrement induced by potential anticonvulsant compounds in nerve agent poisoning. (Reannouncement with new availability information)

    Energy Technology Data Exchange (ETDEWEB)

    Capacio, B.R.; Harris, L.W.; Anderson, D.R.; Lennox, W.J.; Gales, V.

    1992-12-31

    The accelerating rotarod was used to assess motor performance decrement in rats after administration of candidate anticonvulsant compounds (acetazolamide, amitriptyline, chlordiazepoxide, diazepan, diazepam-lysine, lorazepam, loprazolam, midazolam, phenobarbital and scopolamine) against nerve agent poisoning. AH compounds were tested as the commercially available injectable preparation except for diazepam-lysine and loprazolam, which are not FDA approved. A peak effect time, as well as a dose to decrease performance time by 50% from control (PDD50), was determined. The calculated PDD50 (micrometer ol/kg) values and peak effect tunes were midazolam, 1.16 at 15 min; loprazolam, 1.17 at 15 min; diazepam-lysine, 4.17 at 30 min; lorazepwn, 4.98 at 15 min; diazepam, 5.27 at 15 min; phenobarbital, 101.49 at 45 min; chlordiazepoxide, 159.21 at 30 min; scopolamine, amitriptyline and acetazolamide did not demonstrate a performance decrement at any of the doses tested. The PDD50 values were compared with doses which have been utilized against nerve agent-induced convulsions or published ED50 values from standard anticonvulsant screening tests (maximal electroshock MES and subcutaneous pentylenetetrazol (scMET)). I serve agents, anticonvulsants, diazepam, accelerating rotarod, motor performance.

  3. Analysis of various types of single-polypeptide-chain (sc) heterodimeric A{sub 2A}R/D{sub 2}R complexes and their allosteric receptor–receptor interactions

    Energy Technology Data Exchange (ETDEWEB)

    Kamiya, Toshio, E-mail: kamiya@z2.keio.jp [Department of Molecular Cell Signaling, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526 (Japan); Department of Neurology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526 (Japan); Cell Biology Laboratory, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502 (Japan); Yoshioka, Kazuaki; Nakata, Hiroyasu [Department of Molecular Cell Signaling, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526 (Japan)

    2015-01-09

    Highlights: • Various scA{sub 2A}R/D{sub 2}R constructs, with spacers between the two receptors, were created. • Using whole cell binding assay, constructs were examined for their binding activity. • Although the apparent ratio of A{sub 2A}R to D{sub 2}R binding sites should be 1, neither was 1. • Counter agonist-independent binding cooperativity occurred in context of scA{sub 2A}R/D{sub 2}R. - Abstract: Adenosine A{sub 2A} receptor (A{sub 2A}R) heteromerizes with dopamine D{sub 2} receptor (D{sub 2}R). However, these class A G protein-coupled receptor (GPCR) dimers are not fully formed, but depend on the equilibrium between monomer and dimer. In order to stimulate the heteromerization, we have previously shown a successful design for a fusion receptor, single-polypeptide-chain (sc) heterodimeric A{sub 2A}R/D{sub 2}R complex. Here, using whole cell binding assay, six more different scA{sub 2A}R/D{sub 2}R constructs were examined. Not only in scA{sub 2A}R/D{sub 2}R ‘liberated’ with longer spacers between the two receptors, which confer the same configuration as the prototype, the A{sub 2A}R-odr4TM-D{sub 2L}R, but differ in size (Forms 1–3), but also in scA{sub 2A}R/D{sub 2L}R (Form 6) fused with a transmembrane (TM) of another type II TM protein, instead of odr4TM, neither of their fixed stoichiometry (the apparent ratios of A{sub 2A}R to D{sub 2}R binding sites) was 1, suggesting their compact folding. This suggests that type II TM, either odr4 or another, facilitates the equilibrial process of the dimer formation between A{sub 2A}R and D{sub 2L}R, resulting in the higher-order oligomer formation from monomer of scA{sub 2A}R/D{sub 2L}R itself. Also, in the reverse type scA{sub 2A}R/D{sub 2L}R, i.e., the D{sub 2L}R-odr4TM-A{sub 2A}R, counter agonist-independent binding cooperativity (cooperative folding) was found to occur (Forms 4 and 5). In this way, the scA{sub 2A}R/D{sub 2L}R system has unveiled the cellular phenomenon as a snapshot of the

  4. Modeling and protein engineering studies of active and inactive states of human dopamine D2 receptor (D2R) and investigation of drug/receptor interactions.

    Science.gov (United States)

    Salmas, Ramin Ekhteiari; Yurtsever, Mine; Stein, Matthias; Durdagi, Serdar

    2015-05-01

    Homology model structures of the dopamine D2 receptor (D2R) were generated starting from the active and inactive states of β2-adrenergic crystal structure templates. To the best of our knowledge, the active conformation of D2R was modeled for the first time in this study. The homology models are built and refined using MODELLER and ROSETTA programs. Top-ranked models have been validated with ligand docking simulations and in silico Alanine-scanning mutagenesis studies. The derived extra-cellular loop region of the protein models is directed toward the binding site cavity which is often involved in ligand binding. The binding sites of protein models were refined using induced fit docking to enable the side-chain refinement during ligand docking simulations. The derived models were then tested using molecular modeling techniques on several marketed drugs for schizophrenia. Alanine-scanning mutagenesis and molecular docking studies gave similar results for marketed drugs tested. We believe that these new D2 receptor models will be very useful for a better understanding of the mechanisms of action of drugs to be targeted to the binding sites of D2Rs and they will contribute significantly to drug design studies involving G-protein-coupled receptors in the future.

  5. Activity of R(+ limonene against Anisakis larvae

    Directory of Open Access Journals (Sweden)

    Filippo Giarratana

    2015-12-01

    Full Text Available The aim of this work is to evaluate the activity of R(+ limonene of against Anisakidae larvae. Its effectiveness was tested in vitro. The results obtained showing a significant activity of the compound against Anisakis larvae, suggesting further investigation on its potential use in the industrial marinating process. In this regard, the use of R(+ limonene in seafood products could be interesting, also due the sensory attributes resulting from its use and its relatively safe status.

  6. Composition and crystallization kinetics of R2O-Al2O3-SiO2 glass-ceramics

    International Nuclear Information System (INIS)

    Xiong, Dehua; Cheng, Jinshu; Li, Hong

    2010-01-01

    The crystallization behavior and microstructure of R 2 O-Al 2 O 3 -SiO 2 (R means K, Na and Li) glass were investigated by means of differential scanning calorimeter (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM). The crystallization kinetic parameters including the crystallization apparent activation energy (E a ), the Avrami parameter (n), glass transition temperature (T g ) and the activity energy of glass transition (E t ) were also measured with different methods. The results have shown that: the DSC traces of composition A parent glass have two different precipitation crystallization peaks corresponding to E a1 (A) = 151.4 kJ/mol (Li 2 SiO 3 ) and E a2 (A) = 623.1 kJ/mol (Li 2 Si 2 O 5 ), the average value of n = 1.70 (Li 2 Si 2 O 5 ) for the surface crystallization and E t (A) = 202.8 kJ/mol. And E a (B) = 50.7 kJ/mol (Li 2 SiO 3 ), the average value of n = 3.89 (Li 2 SiO 3 ) for the bulk crystallization and E t (B) = 220.4 kJ/mol for the composition B parent glass. Because of the content of R 2 O is bigger than composition A, composition B parent glass has a lower E a , T g and a larger n, E t .

  7. An Improved Method for P2X7R Antagonist Screening.

    Directory of Open Access Journals (Sweden)

    Rômulo José Soares-Bezerra

    Full Text Available ATP physiologically activates the P2X7 receptor (P2X7R, a member of the P2X ionotropic receptor family. When activated by high concentrations of ATP (i.e., at inflammation sites, this receptor is capable of forming a pore that allows molecules of up to 900 Da to pass through. This receptor is upregulated in several diseases, particularly leukemia, rheumatoid arthritis and Alzheimer's disease. A selective antagonist of this receptor could be useful in the treatment of P2X7R activation-related diseases. In the present study, we have evaluated several parameters using in vitro protocols to validate a high-throughput screening (HTS method to identify P2X7R antagonists. We generated dose-response curves to determine the EC50 value of the known agonist ATP and the ICs50 values for the known antagonists Brilliant Blue G (BBG and oxidized ATP (OATP. The values obtained were consistent with those found in the literature (0.7 ± 0.07 mM, 1.3-2.6 μM and 173-285 μM for ATP, BBG and OATP, respectively [corrected].The Z-factor, an important statistical tool that can be used to validate the robustness and suitability of an HTS assay, was 0.635 for PI uptake and 0.867 for LY uptake. No inter-operator variation was observed, and the results obtained using our improved method were reproducible. Our data indicate that our assay is suitable for the selective and reliable evaluation of P2X7 activity in multiwell plates using spectrophotometry-based methodology. This method might improve the high-throughput screening of conventional chemical or natural product libraries for possible candidate P2X7R antagonist or agonist.

  8. Ursodeoxycholic Acid Can Improve Liver Transaminase Quantities in Children with Anticonvulsant Drugs Hepatotoxicity: a Pilot Study.

    Directory of Open Access Journals (Sweden)

    Masoumeh Asgarshirazi

    2015-06-01

    Full Text Available The present study has been directed to investigate Ursodeoxycholic Acid (UDCA effect in children, to reduce the high Liver transaminases induced by Anticonvulsant drugs (drug induced hepatitis. This idea has been driven from Cytoprotective and antioxidant properties of UDCA to be used in drug induced inflammation in Liver. Twenty two epileptic patients aged between 4 mo - 3 yr whom were under anticonvulsant therapy with drugs such as valperoic acid, primidone, levetiracetam, Phenobarbital or any combination of them and had shown Liver transaminases rise , after rule out of Viral-Autoimmune, Metabolic and Anatomic causes, have been prescribed UDCA in dose of 10-15 mg/kg/day, at least for 6 months. Any patient who have shown confusing factors such as genetic disorders with liver involvement or spontaneous decline in enzymes or had not treatment compliance has been excluded from the study. Transaminases range changes as well as Probable side effects of the drug have been monitored. The results indicated that UDCA is effective and well tolerable in the children with drug induced hyper transaminasemia. No side effect has been seen and recorded in this study. Based on this study and its results, we recommend UDCA as a safe and effective choice in drug induced hepatotoxicities.

  9. Multiple Copies of a Simple MYB-Binding Site Confers Trans-regulation by Specific Flavonoid-Related R2R3 MYBs in Diverse Species

    Directory of Open Access Journals (Sweden)

    Cyril Brendolise

    2017-10-01

    Full Text Available In apple, the MYB transcription factor MYB10 controls the accumulation of anthocyanins. MYB10 is able to auto-activate its expression by binding its own promoter at a specific motif, the R1 motif. In some apple accessions a natural mutation, termed R6, has more copies of this motif within the MYB10 promoter resulting in stronger auto-activation and elevated anthocyanins. Here we show that other anthocyanin-related MYBs selected from apple, pear, strawberry, petunia, kiwifruit and Arabidopsis are able to activate promoters containing the R6 motif. To examine the specificity of this motif, members of the R2R3 MYB family were screened against a promoter harboring the R6 mutation. Only MYBs from subgroups 5 and 6 activate expression by binding the R6 motif, with these MYBs sharing conserved residues in their R2R3 DNA binding domains. Insertion of the apple R6 motif into orthologous promoters of MYB10 in pear (PcMYB10 and Arabidopsis (AtMY75 elevated anthocyanin levels. Introduction of the R6 motif into the promoter region of an anthocyanin biosynthetic enzyme F3′5′H of kiwifruit imparts regulation by MYB10. This results in elevated levels of delphinidin in both tobacco and kiwifruit. Finally, an R6 motif inserted into the promoter the vitamin C biosynthesis gene GDP-L-Gal phosphorylase increases vitamin C content in a MYB10-dependent manner. This motif therefore provides a tool to re-engineer novel MYB-regulated responses in plants.

  10. Structural and vibrational properties of oxcarbazepine, an anticonvulsant substance by using DFT and SCRF calculations

    Science.gov (United States)

    Ladetto, María F.; Márquez, María B.; Brandán, Silvia A.

    2014-10-01

    In this work, we have presented a structural and vibrational study on the properties in gas and aqueous solution phases of oxcarbazepine, a polymorphic anticonvulsant substance, combining the available IR and Raman spectra with Density Functional Theory (DFT) calculations. Two stable C1 and C2 forms for the title molecule were theoretically determined by using the hybrid B3LYP/6-31G* method. The integral equation formalism variant polarised continuum model (IEFPCM) was employed to study the solvent effects by means of the self-consistent reaction field (SCRF) method. The vibrational spectra for the two forms of oxcarbazepine were completely assigned together with two dimeric species also observed in the solid phase. The presences of the two C1 and C2 forms together with the two dimeric species are supported by the IR and Raman bands between 1424 and 125 cm-1. Here, the properties for both forms of oxcarbazepine are compared and discussed.

  11. Estrogenic and AhR activities in dissolved phase and suspended solids from wastewater treatment plants.

    Science.gov (United States)

    Dagnino, Sonia; Gomez, Elena; Picot, Bernadette; Cavaillès, Vincent; Casellas, Claude; Balaguer, Patrick; Fenet, Hélène

    2010-05-15

    The distribution of estrogen receptor (ERalpha) and Aryl Hydrocarbon Receptor (AhR) activities between the dissolved phase and suspended solids were investigated during wastewater treatment. Three wastewater treatment plants with different treatment technologies (waste stabilization ponds (WSPs), trickling filters (TFs) and activated sludge supplemented with a biofilter system (ASB)) were sampled. Estrogenic and AhR activities were detected in both phases in influents and effluents. Estrogenic and AhR activities in wastewater influents ranged from 41.8 to 79 ng/L E(2) Eq. and from 37.9 to 115.5 ng/L TCDD Eq. in the dissolved phase and from 5.5 to 88.6 ng/g E(2) Eq. and from 15 to 700 ng/g TCDD Eq. in the suspended solids. For both activities, WSP showed greater or similar removal efficiency than ASB and both were much more efficient than TF which had the lowest removal efficiency. Moreover, our data indicate that the efficiency of removal of ER and AhR activities from the suspended solid phase was mainly due to removal of suspended solids. Indeed, ER and AhR activities were detected in the effluent suspended solid phase indicating that suspended solids, which are usually not considered in these types of studies, contribute to environmental contamination by endocrine disrupting compounds and should therefore be routinely assessed for a better estimation of the ER and AhR activities released in the environment. Copyright 2010 Elsevier B.V. All rights reserved.

  12. Multinational Exploration of Acquired R&D Activities

    DEFF Research Database (Denmark)

    Gammelgaard, Jens

    2004-01-01

    R&D. This paper establishes the connection between amultinational corporation that follows a capability-motivated acquisition strategy and theR&D role new subsidiaries should play in order for the acquired resources to be utilizedcorporation-wide. Statistical findings reveal the need to follow......This paper presents the results of a survey of 54 Danish multinational corporations that haveacquired activities abroad. The role of the acquired R&D units was the focus of the survey,particularly with respect to the schism between basic and applied R&D, and the schismbetween autonomous and network...

  13. BENZYLIDENESALICYLOYLHYDRAZINATO- N,OTIN(IV] (R = OCH3, Br, N(CH32 AND THEIR ANTI-INFLAMMATORY ACTIVITY

    Directory of Open Access Journals (Sweden)

    N. V. Shmatkova

    2014-11-01

    Full Text Available The complexes [SnCl4(2-OH-HB-4R-b] ·CH3CN (R = 4-OCH3 (І, 4-Br(II were obtained by interaction of SnCl4 with salicyloylhydrazones 4–R- benzaldehydes (2-OH-HB-4R-b in acetonitrile. The composition and structure (O(C=O-N(CH=N – the coordination of ligand’s amide form were established by element analysis methods, conductometry, thermogravimetry and IR spectroscopy. It was studied the anti-inflammatory activity of (I, II and previously synthesized, structurally characterized [SnCl4(2-OH-HB-4R-b∙H] (R=N (CH32 (III in model of aseptic carrageenan induced swelling, and it is shown that compound (II demonstrates the highest activity.

  14. Acoplamiento molecular y actividad antibacteriana de las tioureas (R,R-N,N´-bis(1-ciclohexiletiltiourea y (R,R-N,N´-bis(1-feniletiltiourea

    Directory of Open Access Journals (Sweden)

    Fabían Martínez Flores

    2013-05-01

    Full Text Available Las tioureas, son compuestos resultantes de sustituir el átomo de oxígeno de la urea (NH2CONH2 por un átomo de azufre (NH2CSNH2. Actualmente se ha visto que las tioureas presentan diversas actividades biológicas, dentro de las que se encuentra la antimicrobiana. En el presente estudio se evaluó la actividad antibacteriana mediante acoplamiento molecular entre la enzima DNA girasa (receptor y las tioureas (R, R-N,N´-bis(1 ciclohexiletiltiourea (CYTU1 y (R,R-N,N´-bis(1-feniletiltiourea (CYTU2 como ligando en busca del posible mecanismo de acción de estos compuestos, los resultados muestran que existe interacción entre la enzima y ambas tioureas en el sitio activo. Por otro lado, también se evaluó la actividad antibacteriana frente a cepas de Sthapylococcus aureus, Escherichia coli y Pseudomonas fluorescens, mediante el método de microdilución en caldo con la adición de bromuro de 3-(4,5-dimetil-2-tiazolil-2,5-difeniltetrazolium (MTT, como parte del ensayo de viabilidad, mostrando una disminución de la misma sólo contra las bacterias gram negativas, siendo la tiourea CYTU2 la que mostró mejor actividad antibacteriana. Molecular docking and antibacterial activity thioureas (R,R-N,N´-bis(1-cyclohexyethylthiourea and (R,R-N,N´-bis(1-phenylethylthiourea Abstract Thioureas are resultant compounds of substitute the oxygen atom from urea (NH2CONH2 for a sulfur atom (NH2CSNH2. There are evidential that show the biological activity of thioureas, within which are antibacterial activity. We studied the antibacterial activity of two thioureas (R,R-N,N´-bis(1 cyclohexylethylthiourea (CYTU1 y (R,R-N,N´-bis(1 phenylethylthiourea (CYTU2 in silico using Molecular Docking between the DNA gyrase enzyme (receptor and the two thioureas (ligand. The results showed interaction between DNA girase and both thioureas on the pocket of the enzyme. By other hand, the biological activity was evaluated against the following bacterial strains: Sthapylococcus

  15. The anticonvulsant levetiracetam for the treatment of pain in polyneuropathy: A randomized, placebo-controlled, cross-over trial

    DEFF Research Database (Denmark)

    Holbech, Jakob Vormstrup; Otto, Marit; Bach, Flemming W

    2011-01-01

    of this study was to test the analgesic effect of levetiracetam in painful polyneuropathy. METHODS: This was a randomized, double-blind, placebo-controlled, cross-over trial with levetiracetam 3000mg/day versus placebo (6-week treatment periods). Patients with diagnosed polyneuropathy and symptoms for more than......-three patients were screened for participation and 39 patients entered the study. Thirty-five patients were included in the data analysis. There were no differences in the ratings of pain relief (levetiracetam 2.29 versus placebo 2.28, p=0.979), total pain intensity (levetiracetam 5.5 versus placebo 5.3, p=0......Levetiracetam is an anticonvulsant which is assumed to act by modulating neurotransmitter release via binding to the vesicle protein SV2A. This could have an impact on signaling in the nociceptive system, and a pilot study indicated relief of neuropathic pain with levetiracetam. OBJECTIVES: The aim...

  16. Crystallization and preliminary X-ray study of a (2R,3R)-2,3-butanediol dehydrogenase from Bacillus coagulans 2-6.

    Science.gov (United States)

    Miao, Xiangzhi; Huang, Xianhui; Zhang, Guofang; Zhao, Xiufang; Zhu, Xianming; Dong, Hui

    2013-10-01

    (2R,3R)-2,3-Butanediol dehydrogenase (R,R-BDH) from Bacillus coagulans 2-6 is a zinc-dependent medium-chain alcohol dehydrogenase. Recombinant R,R-BDH with a His6 tag at the C-terminus was expressed in Escherichia coli BL21 (DE3) cells and purified by Ni2+-chelating affinity and size-exclusion chromatography. Crystals were grown by the hanging-drop vapour-diffusion method at 289 K. The crystallization condition consisted of 8%(v/v) Tacsimate pH 4.6, 18%(w/v) polyethylene glycol 3350. The crystal diffracted to 2.8 Å resolution in the orthorhombic space group P222₁, with unit-cell parameters a=88.35, b=128.73, c=131.03 Å.

  17. CYP2R1 mutations causing vitamin D-deficiency rickets.

    Science.gov (United States)

    Thacher, Tom D; Levine, Michael A

    2017-10-01

    CYP2R1 is the principal hepatic 25-hydroxylase responsible for the hydroxylation of parent vitamin D to 25-hydroxyvitamin D [25(OH)D]. Serum concentrations of 25(OH)D reflect vitamin D status, because 25(OH)D is the major circulating metabolite of vitamin D. The 1α-hydroxylation of 25(OH)D in the kidney by CYP27B1 generates the fully active vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25(OH) 2 D). The human CYP2R1 gene, located at 11p15.2, has five exons, coding for an enzyme with 501 amino acids. In Cyp2r1-/- knockout mice, serum 25(OH)D levels were reduced by more than 50% compared wild-type mice. Genetic polymorphisms of CYP2R1 account for some of the individual variability of circulating 25(OH)D values in the population. We review the evidence that inactivating mutations in CYP2R1 can lead to a novel form of vitamin D-deficiency rickets resulting from impaired 25-hydroxylation of vitamin D. We sequenced the promoter, exons and intron-exon flanking regions of the CYP2R1 gene in members of 12 Nigerian families with rickets in more than one family member. We found missense mutations (L99P and K242N) in affected members of 2 of 12 families. The L99P mutation had previously been reported as a homozygous defect in an unrelated child of Nigerian origin with rickets. In silico analyses predicted impaired CYP2R1 folding or reduced interaction with substrate vitamin D by L99P and K242N mutations, respectively. In vitro studies of the mutant CYP2R1 proteins in HEK293 cells confirmed normal expression levels but completely absent or markedly reduced 25-hydroxylase activity by the L99P and K242N mutations, respectively. Heterozygous subjects had more moderate biochemical and clinical features of vitamin D deficiency than homozygous subjects. After an oral bolus dose of 50,000 IU of vitamin D 2 or vitamin D 3 , heterozygous subjects had lower increases in serum 25(OH)D than control subjects, and homozygous subjects had minimal increases, supporting a semidominant

  18. Low-Concentration Tributyltin Decreases GluR2 Expression via Nuclear Respiratory Factor-1 Inhibition.

    Science.gov (United States)

    Ishida, Keishi; Aoki, Kaori; Takishita, Tomoko; Miyara, Masatsugu; Sakamoto, Shuichiro; Sanoh, Seigo; Kimura, Tomoki; Kanda, Yasunari; Ohta, Shigeru; Kotake, Yaichiro

    2017-08-11

    Tributyltin (TBT), which has been widely used as an antifouling agent in paints, is a common environmental pollutant. Although the toxicity of high-dose TBT has been extensively reported, the effects of low concentrations of TBT are relatively less well studied. We have previously reported that low-concentration TBT decreases α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptor subunit 2 ( GluR2 ) expression in cortical neurons and enhances neuronal vulnerability to glutamate. However, the mechanism of this TBT-induced GluR2 decrease remains unknown. Therefore, we examined the effects of TBT on the activity of transcription factors that control GluR2 expression. Exposure of primary cortical neurons to 20 nM TBT for 3 h to 9 days resulted in a decrease in GluR2 mRNA expression. Moreover, TBT inhibited the DNA binding activity of nuclear respiratory factor-1 (NRF-1), a transcription factor that positively regulates the GluR2 . This result indicates that TBT inhibits the activity of NRF-1 and subsequently decreases GluR2 expression. In addition, 20 nM TBT decreased the expression of genes such as cytochrome c, cytochrome c oxidase (COX) 4, and COX 6c, which are downstream of NRF-1. Our results suggest that NRF-1 inhibition is an important molecular action of the neurotoxicity induced by low-concentration TBT.

  19. Low-Concentration Tributyltin Decreases GluR2 Expression via Nuclear Respiratory Factor-1 Inhibition

    Science.gov (United States)

    Ishida, Keishi; Aoki, Kaori; Takishita, Tomoko; Miyara, Masatsugu; Sakamoto, Shuichiro; Sanoh, Seigo; Kimura, Tomoki; Kanda, Yasunari; Ohta, Shigeru; Kotake, Yaichiro

    2017-01-01

    Tributyltin (TBT), which has been widely used as an antifouling agent in paints, is a common environmental pollutant. Although the toxicity of high-dose TBT has been extensively reported, the effects of low concentrations of TBT are relatively less well studied. We have previously reported that low-concentration TBT decreases α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptor subunit 2 (GluR2) expression in cortical neurons and enhances neuronal vulnerability to glutamate. However, the mechanism of this TBT-induced GluR2 decrease remains unknown. Therefore, we examined the effects of TBT on the activity of transcription factors that control GluR2 expression. Exposure of primary cortical neurons to 20 nM TBT for 3 h to 9 days resulted in a decrease in GluR2 mRNA expression. Moreover, TBT inhibited the DNA binding activity of nuclear respiratory factor-1 (NRF-1), a transcription factor that positively regulates the GluR2. This result indicates that TBT inhibits the activity of NRF-1 and subsequently decreases GluR2 expression. In addition, 20 nM TBT decreased the expression of genes such as cytochrome c, cytochrome c oxidase (COX) 4, and COX 6c, which are downstream of NRF-1. Our results suggest that NRF-1 inhibition is an important molecular action of the neurotoxicity induced by low-concentration TBT. PMID:28800112

  20. (2S,4R-2-[(1R-1-(4-Bromophenyl-2-nitroethyl]-4-ethylcyclohexanone

    Directory of Open Access Journals (Sweden)

    Chi-Xiao Zhang

    2013-02-01

    Full Text Available The crystal structure of the title compound, C16H20BrNO3, contains three chiral centers in the configuration 1R,2S,6R. The cyclohexane ring is in a chair conformation. In the crystal, molecules are linked by weak C—H...O interactions, forming chains along the a-axis direction.

  1. Synthesis of carbasugars from aldonolactones, part III - A study on the allylic substitution of (1R,5R,8R)- and (1R,5R,8S)-8-hydroxy-2-oxabicyclo[3.3.0]oct-6-en-3-one derivatives - Preparation of (1S,2R,3R)-9-[2-hydroxy-3-(2-hydroxyethyl)cyclopent-4-en-1-yl]-9H-adenine

    DEFF Research Database (Denmark)

    Johansen, Steen Karsk; Lundt, Inge

    2001-01-01

    The palladium-catalyzed substitution of acylated (1R,5R,8R)- and (1R,SR,8S)-8-hydroxy-2-oxabicyclo[3.3.0] ones has been studied using a number of C- and N-nucleophiles, In all cases, the exo derivatives (8R) were found to be more reactive than the corresponding endo derivatives (8S). The reaction...... with these nucleophiles. Additionally, Mitsunobu substitution of (1R,5R,8R)-8-hydroxy-2-oxabicyclo[3.3.0]oct-B-en-3-one (3) with 6-chloropurine, followed by reduction of the lactone moiety and treatment with Liquid ammonia, gave the carbocyclic nucleoside (1S,2R,3R)-9-[2-hydroxy-3-(2-hydroxyethyl)cyclopent-4-en-1-yl]-9H...

  2. MGluR5 mediates the interaction between late-LTP, network activity, and learning.

    Directory of Open Access Journals (Sweden)

    Arthur Bikbaev

    2008-05-01

    Full Text Available Hippocampal synaptic plasticity and learning are strongly regulated by metabotropic glutamate receptors (mGluRs and particularly by mGluR5. Here, we investigated the mechanisms underlying mGluR5-modulation of these phenomena. Prolonged pharmacological blockade of mGluR5 with MPEP produced a profound impairment of spatial memory. Effects were associated with 1 a reduction of mGluR1a-expression in the dentate gyrus; 2 impaired dentate gyrus LTP; 3 enhanced CA1-LTP and 4 suppressed theta (5-10 Hz and gamma (30-100 Hz oscillations in the dentate gyrus. Allosteric potentiation of mGluR1 after mGluR5 blockade significantly ameliorated dentate gyrus LTP, as well as suppression of gamma oscillatory activity. CA3-lesioning prevented MPEP effects on CA1-LTP, suggesting that plasticity levels in CA1 are driven by mGluR5-dependent synaptic and network activity in the dentate gyrus. These data support the hypothesis that prolonged mGluR5-inactivation causes altered hippocampal LTP levels and network activity, which is mediated in part by impaired mGluR1-expression in the dentate gyrus. The consequence is impairment of long-term learning.

  3. An R2R3-MYB gene, LeAN2, positively regulated the thermo-tolerance in transgenic tomato.

    Science.gov (United States)

    Meng, Xia; Wang, Jie-Ru; Wang, Guo-Dong; Liang, Xiao-Qing; Li, Xiao-Dong; Meng, Qing-Wei

    2015-03-01

    LeAN2 is an anthocyanin-associated R2R3-MYB transcription factor, but little is known about its function in imparting thermo-tolerance to higher plants. To examine the function of LeAN2 in the regulation of heat stress in tomato, LeAN2 was isolated and transgenic tomato plants were obtained. Overexpression of LeAN2 under the control of the CaMV35S promoter in tomato induced the up-regulation of several structural genes in the anthocyanin biosynthetic pathway as well as anthocyanin accumulation in transgenic tomato plants. Transgenic tomato plants showed enhanced tolerance to heat stress by maintaining higher fresh weight (FW), net photosynthetic rate (Pn) and maximal photochemical efficiency of photosystem II (PSII) (Fv/Fm) compared with wild-type (WT) plants. Furthermore, transgenic plants showed higher non-enzymatic antioxidant activity, lower levels of reactive oxygen species (ROS), and higher contents of D1 protein than that in WT plants under heat stress. These results indicate that LeAN2 had an important function in heat stress resistance. Copyright © 2014 Elsevier GmbH. All rights reserved.

  4. Overview of TBM R and D activities in India

    Energy Technology Data Exchange (ETDEWEB)

    Rajendra Kumar, E., E-mail: rajendrakumare@gmail.com [Institute for Plasma Research, Bhat, Gandhinagar 382428 (India); Jayakumar, T. [Indira Gandhi Centre for Atomic Research, Kalpakkam 603102 (India); Suri, A.K. [Materials Group, Bhabha Atomic Research Centre, Mumbai 400085 (India)

    2012-08-15

    In India, development of Lead-Lithium Ceramic Breeder (LLCB) blanket is being performed as the primary candidate of Test Blanket Module (TBM) towards DEMO reactor. The LLCB TBM will be tested from the first phase of ITER operation (H-H phase) in one-half of an ITER port no. 2. The Indian TBM R and D program is focused on the development of blanket materials and critical technologies: structural material (IN-RAFMS), breeding materials (Pb-Li, Li{sub 2}TiO{sub 3}), development of technologies for Lead-Lithium cooling system (LLCS), helium cooling system (HCS), tritium extraction system (TES) and TBM related fabrication technologies. This paper will provide an overview of LLCB TBM R and D activities under progress in India.

  5. Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (-)-HA-966 is a potent gamma-butyrolactone-like sedative

    International Nuclear Information System (INIS)

    Singh, L.; Donald, A.E.; Foster, A.C.; Hutson, P.H.; Iversen, L.L.; Iversen, S.D.; Kemp, J.A.; Leeson, P.D.; Marshall, G.R.; Oles, R.J.; Priestley, T.; Thorn, L.; Tricklebank, M.D.; Vass, C.A.; Williams, B.J.

    1990-01-01

    The antagonist effect of ±-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-aspartate (NMDA) receptor occurs through a selective interaction with the glycine modulatory site within the receptor complex. When the enantiomers of ±-HA-966 were resolved, the (R)-(+)-enantiomer was found to be a selective glycine/NMDA receptor antagonist, a property that accounts for its anticonvulsant activity in vivo. In contrast, the (S)-(-)-enantiomer was only weakly active as an NMDA-receptor antagonist, but nevertheless it possessed a marked sedative and muscle relaxant action in vivo. In radioligand binding experiments, (+)-HA-966 inhibited strychnine-insensitive [ 3 H]glycine binding to rat cerebral cortex synaptic membranes with an IC 50 of 12.5 μM, whereas (-)-HA-966 had an IC 50 value of 339 μM. In mice, (+)-HA-966 antagonized sound and N-methyl-DL-aspartic acid (NMDLA)-induced seizures. The coadministration of D-serine dose-dependently antagonized the anticonvulsant effect of a submaximal dose of (+)-HA-966 against NMDLA-induced seizures. The sedative/ataxic effect of racemic HA-966 was mainly attributable to the (-)-enantiomer. It is suggested that, as in the case of the sedative γ-butyrolactone, disruption of striatal dopaminergic mechanisms may be responsible for this action

  6. Evaluation of role 2 (R2) medical resources in the Afghanistan combat theater: Initial review of the joint trauma system R2 registry.

    Science.gov (United States)

    Mann-Salinas, Elizabeth A; Le, Tuan D; Shackelford, Stacy A; Bailey, Jeffrey A; Stockinger, Zsolt T; Spott, Mary Ann; Wirt, Michael D; Rickard, Rory; Lane, Ian B; Hodgetts, Timothy; Cardin, Sylvain; Remick, Kyle N; Gross, Kirby R

    2016-11-01

    A Role 2 registry (R2R) was developed in 2008 by the US Joint Trauma System (JTS). The purpose of this project was to undertake a preliminary review of the R2R to understand combat trauma epidemiology and related interventions at these facilities to guide training and optimal use of forward surgical capability in the future. A retrospective review of available JTS R2R records; the registry is a convenience sample entered voluntarily by members of the R2 units. Patients were classified according to basic demographics, affiliation, region where treatment was provided, mechanism of injury, type of injury, time and method of transport from point of injury (POI) to R2 facility, interventions at R2, and survival. Analysis included trauma patients aged ≥18 years or older wounded in year 2008 to 2014, and treated in Afghanistan. A total of 15,404 patients wounded and treated in R2 were included in the R2R from February 2008 to September 2014; 12,849 patients met inclusion criteria. The predominant patient affiliations included US Forces, 4,676 (36.4%); Afghan Forces, 4,549 (35.4%); and Afghan civilians, 2,178 (17.0%). Overall, battle injuries predominated (9,792 [76.2%]). Type of injury included penetrating, 7,665 (59.7%); blunt, 4,026 (31.3%); and other, 633 (4.9%). Primary mechanism of injury included explosion, 5,320 (41.4%); gunshot wounds, 3,082 (24.0%); and crash, 1,209 (9.4%). Of 12,849 patients who arrived at R2, 167 (1.3%) were dead; of 12,682 patients who were alive upon arrival, 342 (2.7%) died at R2. This evaluation of the R2R describes the patient profiles of and common injuries treated in a sample of R2 facilities in Afghanistan. Ongoing and detailed analysis of R2R information may provide evidence-based guidance to military planners and medical leaders to best prepare teams and allocate R2 resources in future operations. Given the limitations of the data set, conclusions must be interpreted in context of other available data and analyses, not in isolation

  7. A R2R3-MYB transcription factor from Epimedium sagittatum regulates the flavonoid biosynthetic pathway.

    Directory of Open Access Journals (Sweden)

    Wenjun Huang

    Full Text Available Herba epimedii (Epimedium, a traditional Chinese medicine, has been widely used as a kidney tonic and antirheumatic medicine for thousands of years. The bioactive components in herba epimedii are mainly prenylated flavonol glycosides, end-products of the flavonoid pathway. Epimedium species are also used as garden plants due to the colorful flowers and leaves. Many R2R3-MYB transcription factors (TFs have been identified to regulate the flavonoid and anthocyanin biosynthetic pathways. However, little is known about the R2R3-MYB TFs involved in regulation of the flavonoid pathway in Epimedium. Here, we reported the isolation and functional characterization of the first R2R3-MYB TF (EsMYBA1 from Epimedium sagittatum (Sieb. Et Zucc. Maxim. Conserved domains and phylogenetic analysis showed that EsMYBA1 belonged to the subgroup 6 clade (anthocyanin-related MYB clade of R2R3-MYB family, which includes Arabidopsis AtPAP1, apple MdMYB10 and legume MtLAP1. EsMYBA1 was preferentially expressed in leaves, especially in red leaves that contain higher content of anthocyanin. Alternative splicing of EsMYBA1 resulted in three transcripts and two of them encoded a MYB-related protein. Yeast two-hybrid and transient luciferase expression assay showed that EsMYBA1 can interact with several bHLH regulators of the flavonoid pathway and activate the promoters of dihydroflavonol 4-reductase (DFR and anthocyanidin synthase (ANS. In both transgenic tobacco and Arabidopsis, overexpression of EsMYBA1 induced strong anthocyanin accumulation in reproductive and/or vegetative tissues via up-regulation of the main flavonoid-related genes. Furthermore, transient expression of EsMYBA1 in E. sagittatum leaves by Agrobacterium infiltration also induced anthocyanin accumulation in the wounded area. This first functional characterization of R2R3-MYB TFs in Epimedium species will promote further studies of the flavonoid biosynthesis and regulation in medicinal plants.

  8. A R2R3-MYB transcription factor from Epimedium sagittatum regulates the flavonoid biosynthetic pathway.

    Science.gov (United States)

    Huang, Wenjun; Sun, Wei; Lv, Haiyan; Luo, Ming; Zeng, Shaohua; Pattanaik, Sitakanta; Yuan, Ling; Wang, Ying

    2013-01-01

    Herba epimedii (Epimedium), a traditional Chinese medicine, has been widely used as a kidney tonic and antirheumatic medicine for thousands of years. The bioactive components in herba epimedii are mainly prenylated flavonol glycosides, end-products of the flavonoid pathway. Epimedium species are also used as garden plants due to the colorful flowers and leaves. Many R2R3-MYB transcription factors (TFs) have been identified to regulate the flavonoid and anthocyanin biosynthetic pathways. However, little is known about the R2R3-MYB TFs involved in regulation of the flavonoid pathway in Epimedium. Here, we reported the isolation and functional characterization of the first R2R3-MYB TF (EsMYBA1) from Epimedium sagittatum (Sieb. Et Zucc.) Maxim. Conserved domains and phylogenetic analysis showed that EsMYBA1 belonged to the subgroup 6 clade (anthocyanin-related MYB clade) of R2R3-MYB family, which includes Arabidopsis AtPAP1, apple MdMYB10 and legume MtLAP1. EsMYBA1 was preferentially expressed in leaves, especially in red leaves that contain higher content of anthocyanin. Alternative splicing of EsMYBA1 resulted in three transcripts and two of them encoded a MYB-related protein. Yeast two-hybrid and transient luciferase expression assay showed that EsMYBA1 can interact with several bHLH regulators of the flavonoid pathway and activate the promoters of dihydroflavonol 4-reductase (DFR) and anthocyanidin synthase (ANS). In both transgenic tobacco and Arabidopsis, overexpression of EsMYBA1 induced strong anthocyanin accumulation in reproductive and/or vegetative tissues via up-regulation of the main flavonoid-related genes. Furthermore, transient expression of EsMYBA1 in E. sagittatum leaves by Agrobacterium infiltration also induced anthocyanin accumulation in the wounded area. This first functional characterization of R2R3-MYB TFs in Epimedium species will promote further studies of the flavonoid biosynthesis and regulation in medicinal plants.

  9. Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors.

    Science.gov (United States)

    Wang, Lei; de Kloet, Annette D; Pati, Dipanwita; Hiller, Helmut; Smith, Justin A; Pioquinto, David J; Ludin, Jacob A; Oh, S Paul; Katovich, Michael J; Frazier, Charles J; Raizada, Mohan K; Krause, Eric G

    2016-06-01

    Over-activation of the brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme 2 (ACE2) inhibits RAS activity by converting angiotensin-II, the effector peptide of RAS, to angiotensin-(1-7), which activates the Mas receptor (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that ACE2 reduces anxiety-like behavior by activating central MasR. To identify the brain circuits mediating these effects, we measured Fos, a marker of neuronal activation, subsequent to EPM exposure and found that ACE2 KI mice had decreased Fos in the bed nucleus of stria terminalis but had increased Fos in the basolateral amygdala (BLA). Within the BLA, we determined that ∼62% of GABAergic neurons contained MasR mRNA and expression of MasR mRNA was upregulated by ACE2 overexpression, suggesting that ACE2 may influence GABA neurotransmission within the BLA via MasR activation. Indeed, ACE2 overexpression was associated with increased frequency of spontaneous inhibitory postsynaptic currents (indicative of presynaptic release of GABA) onto BLA pyramidal neurons and central infusion of A-779 eliminated this effect. Collectively, these results suggest that ACE2 may reduce anxiety-like behavior by activating central MasR that facilitate GABA release onto pyramidal neurons within the

  10. [Lithium and anticonvulsants in bipolar depression].

    Science.gov (United States)

    Samalin, L; Nourry, A; Llorca, P-M

    2011-12-01

    For decades, lithium and anticonvulsants have been widely used in the treatment of bipolar disorder. Their efficacy in the treatment of mania is recognized. These drugs have been initially evaluated in old and methodologically heterogeneous studies. Their efficacy in bipolar depression has not always been confirmed in more recent and methodologically more reliable studies. Thus, lithium's efficacy as monotherapy was challenged by the study of Young (2008) that showed a lack of efficacy compared with placebo in the treatment of bipolar depression. In two recent meta-analyses, valproate has shown a modest efficacy in the treatment of bipolar depression. As for lithium, valproate appeared to have a larger antimanic effect for acute phase and prophylaxis of bipolar disorder. In contrast, lamotrigine is more effective on the depressive pole of bipolar disorder with better evidence for the prevention of depressive recurrences. The guidelines include these recent studies and recommend lamotrigine as a first-line treatment of bipolar depression and for maintenance treatment. Because of more discordant data concerning lithium and valproate, these two drugs are placed either as first or as second line treatment of bipolar depression. The different safety/efficacy ratios of mood stabilizers underlie the complementarity and the importance of combination between them, or with some second-generation antipsychotics, in the treatment of patients with bipolar disorder. Copyright © 2011 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.

  11. Monkey liver cytochrome P450 2C19 is involved in R- and S-warfarin 7-hydroxylation.

    Science.gov (United States)

    Hosoi, Yoshio; Uno, Yasuhiro; Murayama, Norie; Fujino, Hideki; Shukuya, Mitsunori; Iwasaki, Kazuhide; Shimizu, Makiko; Utoh, Masahiro; Yamazaki, Hiroshi

    2012-12-15

    Cynomolgus monkeys are widely used as primate models in preclinical studies. However, some differences are occasionally seen between monkeys and humans in the activities of cytochrome P450 enzymes. R- and S-warfarin are model substrates for stereoselective oxidation in humans. In this current research, the activities of monkey liver microsomes and 14 recombinantly expressed monkey cytochrome P450 enzymes were analyzed with respect to R- and S-warfarin 6- and 7-hydroxylation. Monkey liver microsomes efficiently mediated both R- and S-warfarin 7-hydroxylation, in contrast to human liver microsomes, which preferentially catalyzed S-warfarin 7-hydroxylation. R-Warfarin 7-hydroxylation activities in monkey liver microsomes were not inhibited by α-naphthoflavone or ketoconazole, and were roughly correlated with P450 2C19 levels and flurbiprofen 4-hydroxylation activities in microsomes from 20 monkey livers. In contrast, S-warfarin 7-hydroxylation activities were not correlated with the four marker drug oxidation activities used. Among the 14 recombinantly expressed monkey P450 enzymes tested, P450 2C19 had the highest activities for R- and S-warfarin 7-hydroxylations. Monkey P450 3A4 and 3A5 slowly mediated R- and S-warfarin 6-hydroxylations. Kinetic analysis revealed that monkey P450 2C19 had high V(max) and low K(m) values for R-warfarin 7-hydroxylation, comparable to those for monkey liver microsomes. Monkey P450 2C19 also mediated S-warfarin 7-hydroxylation with V(max) and V(max)/K(m) values comparable to those for recombinant human P450 2C9. R-warfarin could dock favorably into monkey P450 2C19 modeled. These results collectively suggest high activities for monkey liver P450 2C19 toward R- and S-warfarin 6- and 7-hydroxylation in contrast to the saturation kinetics of human P450 2C9-mediated S-warfarin 7-hydroxylation. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Enterovirus 71 antagonizes the antiviral activity of host STAT3 and IL-6R with partial dependence on virus-induced miR-124.

    Science.gov (United States)

    Chang, Zhangmei; Wang, Yan; Bian, Liang; Liu, Qingqing; Long, Jian-Er

    2017-12-01

    Enterovirus 71 (EV71) has caused major outbreaks of hand, foot and mouth disease. EV71 infections increase the production of many host cytokines and pro-inflammatory factors, including interleukin (IL)-6, IL-10 and COX-2. Some of these molecules could stimulate the signal transducer and activator of transcription 3 (STAT3), which plays a key role in regulating host immune responses and several viral diseases. However, the role of STAT3 in EV71 infection remains unknown. This study found that the phosphorylation levels of STAT3 (p Y705 -STAT3) are closely related to EV71 infection. Further experiments revealed that STAT3 exerts an anti-EV71 activity. However, the antiviral activity of STAT3 is partially antagonized by EV71-induced miR-124, which directly targets STAT3 mRNA. Similarly, IL-6R, the α-subunit of the IL-6 receptor complex, exhibits anti-EV71 activity and is directly targeted by the virus-induced miR-124. These results indicate that EV71 can evade host IL-6R- and STAT3-mediated antiviral activities by EV71-induced miR-124. This suggests that controlling miR-124 and the downstream targets, IL-6R and STAT3, might benefit the antiviral treatment of EV71 infection.

  13. Functional Characterization of a Novel R2R3-MYB Transcription Factor Modulating the Flavonoid Biosynthetic Pathway from Epimedium sagittatum

    Directory of Open Access Journals (Sweden)

    Wenjun Huang

    2017-07-01

    Full Text Available Epimedium species have been widely used both as traditional Chinese medicinal plants and ornamental perennials. Both flavonols, acting as the major bioactive components (BCs and anthocyanins, predominantly contributing to the color diversity of Epimedium flowers belong to different classes of flavonoids. It is well-acknowledged that flavonoid biosynthetic pathway is predominantly regulated by R2R3-MYB transcription factor (TF as well as bHLH TF and WD40 protein at the transcriptional level. MYB TFs specifically regulating anthocyanin or flavonol biosynthetic pathway have been already isolated and functionally characterized from Epimedium sagittatum, but a R2R3-MYB TF involved in regulating both these two pathways has not been functionally characterized to date in Epimedium plants. In this study, we report the functional characterization of EsMYB9, a R2R3-MYB TF previously isolated from E. sagittatum. The previous study indicated that EsMYB9 belongs to a small subfamily of R2R3-MYB TFs containing grape VvMYB5a and VvMYB5b TFs, which regulate flavonoid biosynthetic pathway. The present studies show that overexpression of EsMYB9 in tobacco leads to increased transcript levels of flavonoid pathway genes and increased contents of anthocyanins and flavonols. Yeast two-hybrid assay indicates that the C-terminal region of EsMYB9 contributes to the autoactivation activity, and EsMYB9 interacts with EsTT8 or AtTT8 bHLH regulator. Transient reporter assay shows that EsMYB9 slightly activates the expression of EsCHS (chalcone synthase promoter in transiently transformed leaves of Nicotiana benthamiana, but the addition of AtTT8 or EsTT8 bHLH regulator strongly enhances the transcriptional activation of EsMYB9 against five promoters of the flavonoid pathway genes except EsFLS (flavonol synthase. In addition, co-transformation of EsMYB9 and EsTT8 in transiently transfected tobacco leaves strongly induces the expressions of flavonoid biosynthetic genes. The

  14. Initial mass function in R-associations CMaR1, Mon R1 and Mon R2 from radiodata

    International Nuclear Information System (INIS)

    Pyatunina, T.B.

    1985-01-01

    Results of search for compact radiosources in R-associations CMa R1 and Mon R1 carried out with the radiotelescope RATAN-600 at the 7.6-cm wavelength are given. The number of sources found in the association Mon R1 is approximately equal to the expected number of background extragalactic radiosources. In the association CMa R1 seven radiosources of small angular diameter with the flux greater than 30 mJy are found, two of which probably are background sources. A comparison of optical and radiodata on the association CMa R1 and previously published data on the association Mon R2 make it possible to estimate the initial mass function for associations under study: xi(M) infinity Msup(-2.7+-0.7) for stars with M approximately 10Msub(Sun)

  15. miR398 and miR395 are involved in response to SO2 stress in Arabidopsis thaliana.

    Science.gov (United States)

    Li, Lihong; Yi, Huilan; Xue, Meizhao; Yi, Min

    2017-11-01

    Sulfur dioxide (SO 2 ) is a common air pollutant that has adverse effects on plants. MicroRNAs (miRNAs) are small noncoding RNA that play critical roles in plant development and stress response. In this study, we found that two miRNAs, miR398 and miR395, were differentially expressed in Arabidopsis shoots under SO 2 stress. The expression of miR398 was down-regulated, and the transcript levels of its target genes, Cu/Zn superoxide dismutases (CSD1 and CSD2), were increased during SO 2 exposure. The activity of superoxide dismutase (SOD), one of the major antioxidant enzymes, was enhanced with the increase in the CSD transcript level, suggesting an important role of miR398 in response to SO 2 -induced oxidative stress. Meanwhile, the expression of miR395 was increased, and the transcript levels of its target genes, ATP sulfurylases (APS3 and APS4) and a low-affinity sulfate transporter (SULTR2;1), were decreased in Arabidopsis shoots, showing that miR395 played important roles in the regulation of sulfate assimilation and translocation during SO 2 exposure. The content of glutathione (GSH), an important sulfur-containing antioxidant, was enhanced with the changes in sulfur metabolism in Arabidopsis shoots under SO 2 stress. These results showed that both miR398 and miR395 were involved in protecting plants from oxidative damage during SO 2 exposure. Many stress-responsive cis-elements were found in the promoter regions of MIR398 and MIR395, suggesting that these miRNAs might respond to various environmental conditions, including SO 2 stress. Overall, our study provides an insight into the regulatory roles of miRNAs in response to SO 2 stress in plants, and highlights the molecular mechanisms of plant adaptation to environmental stress.

  16. Comparing consistency of R2* and T2*-weighted BOLD analysis of resting state fetal fMRI

    Science.gov (United States)

    Seshamani, Sharmishtaa; Blazejewska, Anna I.; Gatenby, Christopher; Mckown, Susan; Caucutt, Jason; Dighe, Manjiri; Studholme, Colin

    2015-03-01

    Understanding when and how resting state brain functional activity begins in the human brain is an increasing area of interest in both basic neuroscience and in the clinical evaluation of the brain during pregnancy and after premature birth. Although fMRI studies have been carried out on pregnant women since the 1990's, reliable mapping of brain function in utero is an extremely challenging problem due to the unconstrained fetal head motion. Recent studies have employed scrubbing to exclude parts of the time series and whole subjects from studies in order to control the confounds of motion. Fundamentally, even after correction of the location of signals due to motion, signal intensity variations are a fundamental limitation, due to coil sensitivity and spin history effects. An alternative technique is to use a more parametric MRI signal derived from multiple echoes that provides a level of independence from basic MRI signal variation. Here we examine the use of R2* mapping combined with slice based multi echo geometric distortion correction for in-utero studies. The challenges for R2* mapping arise from the relatively low signal strength of in-utero data. In this paper we focus on comparing activation detection in-utero using T2W and R2* approaches. We make use a subset of studies with relatively limited motion to compare the activation patterns without the additional confound of significant motion. Results at different gestational ages indicate comparable agreement in many activation patterns when limited motion is present, and the detection of some additional networks in the R2* data, not seen in the T2W results.

  17. Ginsenoside 25-OCH3-PPD promotes activity of LXRs to ameliorate P2X7R-mediated NLRP3 inflammasome in the development of hepatic fibrosis.

    Science.gov (United States)

    Han, Xin; Song, Jian; Lian, Li-Hua; Yao, You-Li; Shao, Dan-Yang; Fan, Ying; Hou, Li-Shuang; Wang, Ge; Zheng, Shuang; Wu, Yan-Ling; Nan, Ji-Xing

    2018-06-22

    Ginseng is widely used in energy drinks, dietary supplements and herbal medicines, and its pharmacological actions are related with energy metabolism. As an important modulating energy metabolism pathway, liver X receptors (LXRs) can promote the resolving of hepatic fibrosis and inflammation. The present study aims to evaluate the regulation of 25-OCH3-PPD, a ginsenoside isolated from Panax ginseng, against hepatic fibrosis and inflammation in thioacetamide (TAA)-stimulated mice by activating LXRs pathway. 25-OCH3-PPD decreases serum ALT/AST levels and improves the histological pathology of liver in TAA-induced mice; attenuates transcripts of pro-fibrogenic markers associated with hepatic stellate cell activation; attenuates the levels of pro-Inflammatory cytokines and blocks apoptosis happened in liver; inhibits NLRP3 inflammasome by affecting P2X7R activation; regulates PI3K/Akt and LKB1/AMPK-SIRT1. 25-OCH3-PPD also facilitates LX25Rs and FXR activities decreased by TAA stimulation. 25-OCH3-PPD also decreases α-SMA via regulation of LXRs and P2X7R-NLRP3 in vitro. Our data suggest the possibility that 25-OCH3-PPD promotes activity of LXRs to ameliorate P2X7R-mediated NLRP3 inflammasome in the development of hepatic fibrosis.

  18. Quantitative Contribution of IL2Rγ to the Dynamic Formation of IL2-IL2R Complexes.

    Directory of Open Access Journals (Sweden)

    Luis F Ponce

    Full Text Available Interleukin-2 (IL2 is a growth factor for several immune cells and its function depends on its binding to IL2Rs in the cell membrane. The most accepted model for the assembling of IL2-IL2R complexes in the cell membrane is the Affinity Conversion Model (ACM. This model postulates that IL2R receptor association is sequential and dependent on ligand binding. Most likely free IL2 binds first to IL2Rα, and then this complex binds to IL2Rβ, and finally to IL2Rγ (γc. However, in previous mathematical models representing this process, the binding of γc has not been taken into account. In this work, the quantitative contribution of the number of IL2Rγ chain to the IL2-IL2R apparent binding affinity and signaling is studied. A mathematical model of the affinity conversion process including the γ chain in the dynamic, has been formulated. The model was calibrated by fitting it to experimental data, specifically, Scatchard plots obtained using human cell lines. This paper demonstrates how the model correctly explains available experimental observations. It was estimated, for the first time, the value of the kinetic coefficients of IL2-IL2R complexes interaction in the cell membrane. Moreover, the number of IL2R components in different cell lines was also estimated. It was obtained a variable distribution in the number of IL2R components depending on the cell type and the activation state. Of most significance, the study predicts that not only the number of IL2Rα and IL2Rβ, but also the number of γc determine the capacity of the cell to capture and retain IL2 in signalling complexes. Moreover, it is also showed that different cells might use different pathways to bind IL2 as consequence of its IL2R components distribution in the membrane.

  19. Total Synthesis of (R, R, R)-gamma-Tocopherol through Cu-Catalyzed Asymmetric 1,2-Addition

    NARCIS (Netherlands)

    Wu, Zhongtao; Harutyunyan, Syuzanna R.; Minnaard, Adriaan J.

    2014-01-01

    Based on the asymmetric copper-catalyzed 1,2-addition of Grignard reagents to ketones, (R,R,R)--tocopherol has been synthesized in 36% yield over 12 steps (longest linear sequence). The chiral center in the chroman ring was constructed with 73% ee by the 1,2-addition of a phytol-derived Grignard

  20. (E-2-((4R,5R-5-((Benzyloxymethyl-2,2-dimethyl-1,3-dioxolan-4-ylbut-2-ene-1,4-diol

    Directory of Open Access Journals (Sweden)

    Carlos R. Carreras

    2010-04-01

    Full Text Available The synthesis of (E-2-((4R,5R-5-((benzyloxymethyl-2,2-dimethyl-1,3-dioxolan-4-ylbut-2-ene-1,4-diol by a one-step reduction of the appropriate 2-substituted butenolide is reported. Product characterization was carried out by IR, 1H NMR, 13C NMR, MS, elemental analysis and optical rotation.

  1. Structure and Mechanism of Receptoe Sharing by the IL-10R2 Common Chain

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Sung-il; Jones, Brandi C.; Logsdon, Naomi J.; Harris, Bethany D.; Deshpande, Ashlesha; Radaeva, Svetlana; Halloran, Brian A.; Gao, Bin; Walter, Mark R. (NIH); (UAB)

    2010-06-14

    IL-10R2 is a shared cell surface receptor required for the activation of five class 2 cytokines (IL-10, IL-22, IL-26, IL-28, and IL-29) that play critical roles in host defense. To define the molecular mechanisms that regulate its promiscuous binding, we have determined the crystal structure of the IL-10R2 ectodomain at 2.14 {angstrom} resolution. IL-10R2 residues required for binding were identified by alanine scanning and used to derive computational models of IL-10/IL-10R1/IL-10R2 and IL-22/IL-22R1/IL-10R2 ternary complexes. The models reveal a conserved binding epitope that is surrounded by two clefts that accommodate the structural and chemical diversity of the cytokines. These results provide a structural framework for interpreting IL-10R2 single nucleotide polymorphisms associated with human disease.

  2. Structure and Mechanism of Receptor Sharing by the IL-10R2 Common Chain

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Sung-il; Jones, Brandi C.; Logsdon, Naomi J.; Harris, Bethany D.; Deshpande, Ashlesha; Radaeva, Svetlana; Halloran, Brian A.; Gao, Bin; Walter, Mark R. (NIH); (UAB)

    2010-07-19

    IL-10R2 is a shared cell surface receptor required for the activation of five class 2 cytokines (IL-10, IL-22, IL-26, IL-28, and IL-29) that play critical roles in host defense. To define the molecular mechanisms that regulate its promiscuous binding, we have determined the crystal structure of the IL-10R2 ectodomain at 2.14 {angstrom} resolution. IL-10R2 residues required for binding were identified by alanine scanning and used to derive computational models of IL-10/IL-10R1/IL-10R2 and IL-22/IL-22R1/IL-10R2 ternary complexes. The models reveal a conserved binding epitope that is surrounded by two clefts that accommodate the structural and chemical diversity of the cytokines. These results provide a structural framework for interpreting IL-10R2 single nucleotide polymorphisms associated with human disease.

  3. An R2R3 MYB transcription factor associated with regulation of the anthocyanin biosynthetic pathway in Rosaceae (on linr)

    NARCIS (Netherlands)

    Wang, Kui-Lin; Bolitho, Karen; Grafton, Karryn; Kortstee, A.J.; Karunairetnam, Sakuntala; McGhie, T.K.; Espley, R.V.; Hellens, R.P.; Allan, A.C.

    2010-01-01

    Background - The control of plant anthocyanin accumulation is via transcriptional regulation of the genes encoding the biosynthetic enzymes. A key activator appears to be an R2R3 MYB transcription factor. In apple fruit, skin anthocyanin levels are controlled by a gene called MYBA or MYB1, while the

  4. Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q.

    Science.gov (United States)

    Marinovic-Terzic, Ivana; Yoshioka-Yamashita, Atsuko; Shimodaira, Hideki; Avdievich, Elena; Hunton, Irina C; Kolodner, Richard D; Edelmann, Winfried; Wang, Jean Y J

    2008-09-16

    Mismatch repair (MMR) corrects replication errors during DNA synthesis. The mammalian MMR proteins also activate cell cycle checkpoints and apoptosis in response to persistent DNA damage. MMR-deficient cells are resistant to cisplatin, a DNA cross-linking agent used in chemotherapy, because of impaired activation of apoptotic pathways. It is shown that postmeiotic segregation 2 (PMS2), an MMR protein, is required for cisplatin-induced activation of p73, a member of the p53 family of transcription factors with proapoptotic activity. The human PMS2 is highly polymorphic, with at least 12 known nonsynonymous codon changes identified. We show here that the PMS2(R20Q) variant is defective in activating p73-dependent apoptotic response to cisplatin. When expressed in Pms2-deficient mouse fibroblasts, human PMS2(R20Q) but not PMS2 interfered with the apoptotic response to cisplatin. Correspondingly, PMS2 but not PMS2(R20Q) enhanced the cytotoxic effect of cisplatin measured by clonogenic survival. Because PMS2(R20Q) lacks proapoptotic activity, this polymorphic allele may modulate tumor responses to cisplatin among cancer patients.

  5. ChR2 transgenic animals in peripheral sensory system: Sensing light as various sensations.

    Science.gov (United States)

    Ji, Zhi-Gang; Wang, Hongxia

    2016-04-01

    Since the introduction of Channelrhodopsin-2 (ChR2) to neuroscience, optogenetics technology was developed, making it possible to activate specific neurons or circuits with spatial and temporal precision. Various ChR2 transgenic animal models have been generated and are playing important roles in revealing the mechanisms of neural activities, mapping neural circuits, controlling the behaviors of animals as well as exploring new strategy for treating the neurological diseases in both central and peripheral nervous system. An animal including humans senses environments through Aristotle's five senses (sight, hearing, smell, taste and touch). Usually, each sense is associated with a kind of sensory organ (eyes, ears, nose, tongue and skin). Is it possible that one could hear light, smell light, taste light and touch light? When ChR2 is targeted to different peripheral sensory neurons by viral vectors or generating ChR2 transgenic animals, the animals can sense the light as various sensations such as hearing, touch, pain, smell and taste. In this review, we focus on ChR2 transgenic animals in the peripheral nervous system. Firstly the working principle of ChR2 as an optogenetic actuator is simply described. Then the current transgenic animal lines where ChR2 was expressed in peripheral sensory neurons are presented and the findings obtained by these animal models are reviewed. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. New anisotropic rare earth fluorides BaR2F8(R=Y,Dy-Lu): growth and characterization

    International Nuclear Information System (INIS)

    Kaminskii, A.A.; Butashin, A.V.; Sulyanov, S.N.; Bagayev, S.N.; Eichler, H.J.; Findeisen, J.; Liu, B.; Taeuber, U.; Peuser, P.

    1998-01-01

    Polymorphism of BaR 2 F 8 compounds is analyzed, and some peculiarities of the crystal growth from the melt are discussed. We report on the orthorhombic BaLu 2 F 8 crystal with ordered structure, a new crystalline material for generating Ln 3+ activator ions. Spectroscopic and laser characteristics of Nd 3+ - and Er 3+ -doped BaLu 2 F 8 samples are discussed as representative examples. Besides, we pay special attention to monoclinic BaY 2 F 8 :Er 3+ crystals, as active media for highly efficient CW 3 μm laser-diode pumped lasers. (orig.)

  7. Regulation of protease-activated receptor 1 signaling by the adaptor protein complex 2 and R4 subfamily of regulator of G protein signaling proteins.

    Science.gov (United States)

    Chen, Buxin; Siderovski, David P; Neubig, Richard R; Lawson, Mark A; Trejo, Joann

    2014-01-17

    The G protein-coupled protease-activated receptor 1 (PAR1) is irreversibly proteolytically activated by thrombin. Hence, the precise regulation of PAR1 signaling is important for proper cellular responses. In addition to desensitization, internalization and lysosomal sorting of activated PAR1 are critical for the termination of signaling. Unlike most G protein-coupled receptors, PAR1 internalization is mediated by the clathrin adaptor protein complex 2 (AP-2) and epsin-1, rather than β-arrestins. However, the function of AP-2 and epsin-1 in the regulation of PAR1 signaling is not known. Here, we report that AP-2, and not epsin-1, regulates activated PAR1-stimulated phosphoinositide hydrolysis via two different mechanisms that involve, in part, a subset of R4 subfamily of "regulator of G protein signaling" (RGS) proteins. A significantly greater increase in activated PAR1 signaling was observed in cells depleted of AP-2 using siRNA or in cells expressing a PAR1 (420)AKKAA(424) mutant with defective AP-2 binding. This effect was attributed to AP-2 modulation of PAR1 surface expression and efficiency of G protein coupling. We further found that ectopic expression of R4 subfamily members RGS2, RGS3, RGS4, and RGS5 reduced activated PAR1 wild-type signaling, whereas signaling by the PAR1 AKKAA mutant was minimally affected. Intriguingly, siRNA-mediated depletion analysis revealed a function for RGS5 in the regulation of signaling by the PAR1 wild type but not the AKKAA mutant. Moreover, activation of the PAR1 wild type, and not the AKKAA mutant, induced Gαq association with RGS3 via an AP-2-dependent mechanism. Thus, AP-2 regulates activated PAR1 signaling by altering receptor surface expression and through recruitment of RGS proteins.

  8. Isobolographic analysis of the mechanisms of action of anticonvulsants from a combination effect.

    Science.gov (United States)

    Matsumura, Nobuko; Nakaki, Toshio

    2014-10-15

    The nature of the pharmacodynamic interactions of drugs is influenced by the drugs׳ mechanisms of action. It has been hypothesized that drugs with different mechanisms are likely to interact synergistically, whereas those with similar mechanisms seem to produce additive interactions. In this review, we describe an extensive investigation of the published literature on drug combinations of anticonvulsants, the nature of the interaction of which has been evaluated by type I and II isobolographic analyses and the subthreshold method. The molecular targets of antiepileptic drugs (AEDs) include Na(+) and Ca(2+) channels, GABA type-A receptor, and glutamate receptors such as NMDA and AMPA/kainate receptors. The results of this review indicate that the nature of interactions evaluated by type I isobolographic analyses but not by the two other methods seems to be consistent with the above hypothesis. Type I isobolographic analyses may be used not only for evaluating drug combinations but also for predicting the targets of new drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Human amniotic epithelial cells inhibit CD4+ T cell activation in acute kidney injury patients by influencing the miR-101-c-Rel-IL-2 pathway.

    Science.gov (United States)

    Liu, Junfeng; Hua, Rong; Gong, Zhangbin; Shang, Bin; Huang, Yongyi; Guo, Lihe; Liu, Te; Xue, Jun

    2017-01-01

    In the pathogenesis of acute kidney injury (AKI), the release of multiple interleukins can lead to increased kidney damage. Human amniotic epithelial cells (HuAECs) can inhibit immune cell activation in vivo and in vitro. We hypothesized that HuAECs could weaken patient-derived peripheral blood CD4+ T-cell activation and decreasing the ability of these cells to express and release IL-2. -Cell proliferation assay revealed that under the same culture conditions, activated AKI patient-derived CD4+ T cells had a significantly reduced proliferation rate when were co-cultured with HuAECs. And the level of IL-2 released was also significantly reduced. Western blot and qRT-PCR assays showed that the expression of c-Rel in the CD4+ T cells was also significantly reduced. However, the expression level of endogenous miR-101 in the CD4+ T cells co-cultured with HuAECs was significantly increased. Luciferase reporter assay results suggested that miR-101 could bind to a specific site in the c-Rel 3' UTR and induce the post-transcriptional silencing of c-Rel. Subsequently, we over-expressed miR-101 in AKI patient-derived CD4+ T cells. The qRT-PCR and western blot assay results revealed that the expression of endogenous c-Rel was significantly reduced, while the ELISA results indicated that the level of IL-2 released was also significantly decreased. Finally, ChIP-PCR assay results showed that the miR-101-overexpressing CD4+ T-cell group and the HuAEC co-culture CD4+ T-cell group exhibited significantly decreased binding capacities between the 'c-Rel-NFκB' complex and the IL-2 gene promoter, and the transcriptional activity of IL-2 was also significantly decreased. Therefore, we confirmed that HuAECs can stimulate miR-101 expression in AKI patient-derived peripheral blood CD4+ T cells, thus inhibiting the expression of the miR-101 target gene c-Rel and leading to a reduction in IL-2 expression and release. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Detection of maltodextrin and its discrimination from sucrose are independent of the T1R2 + T1R3 heterodimer.

    Science.gov (United States)

    Smith, Kimberly R; Spector, Alan C

    2017-10-01

    Maltodextrins, such as Maltrin and Polycose, are glucose polymer mixtures of varying chain lengths that are palatable to rodents. Although glucose and other sugars activate the T1R2 + T1R3 "sweet" taste receptor, recent evidence from T1R2- or T1R3-knockout (KO) mice suggests that maltodextrins, despite their glucose polymer composition, activate a separate receptor mechanism to generate a taste percept qualitatively distinguishable from that of sweeteners. However, explicit discrimination of maltodextrins from prototypical sweeteners has not yet been psychophysically tested in any murine model. Therefore, mice lacking T1R2 + T1R3 and wild-type controls were tested in a two-response taste discrimination task to determine whether maltodextrins are 1 ) detectable when both receptor subunits are absent and 2 ) perceptually distinct from that of sucrose irrespective of viscosity, intensity, and hedonics. Most KO mice displayed similar Polycose sensitivity as controls. However, some KO mice were only sensitive to the higher Polycose concentrations, implicating potential allelic variation in the putative polysaccharide receptor or downstream pathways unmasked by the absence of T1R2 + T1R3. Varied Maltrin and sucrose concentrations of approximately matched viscosities were then presented to render the oral somatosensory features, intensity, and hedonic value of the solutions irrelevant. Although both genotypes competently discriminated Maltrin from sucrose, performance was apparently driven by the different orosensory percepts of the two stimuli in control mice and the presence of a Maltrin but not sucrose orosensory cue in KO mice. These data support the proposed presence of an orosensory receptor mechanism that gives rise to a qualitatively distinguishable sensation from that of sucrose. Copyright © 2017 the American Physiological Society.

  11. EGF-R is Expressed and AP-1 and NF-κ:B Are Activated in Stromal Myofibroblasts Surrounding Colon Adenocarcinomas Paralleling Expression of COX-2 and VEGF

    Directory of Open Access Journals (Sweden)

    Panagiotis A. Konstantinopoulos

    2007-01-01

    Full Text Available Background: COX-2 and VEGF are important triggers of colon cancer growth, metastasis and angiogenesis. Cox-2 promoter contains transcriptional regulatory elements for AP-1 and NF-κ:B transcription factors whilst vegf is a known AP-1 downstream target gene. We investigated whether stromal myofibroblasts surrounding colon adenocarcinomas express COX-2 and VEGF and whether activation of AP-1 and NF-κ:B, as well as expression of EGF-R parallel expression of COX-2 and VEGF in these cells. Methods: Immunohistochemical methodology was performed on archival sections from 40 patients with colon adenocarcinomas. We evaluated c-FOS, p-c-JUN (phosphorylated c-JUN, p-Iκ:B-α (phosphorylated Iκ:B-α, EGF-R, COX-2, NF-κ:B and VEGF expression in stromal myofibroblasts surrounding colon adenocarcinomas. Double immunostaining with a-smooth muscle actin and each antibody was done to verify the expression of these molecules in stromal myofibroblasts. Results: VEGF, p-Iκ:B-α, NF-κ:B, c-FOS, p-c-JUN, EGF-R and COX-2 were expressed in stromal myofibroblasts surrounding colon adenocarcinomas in the majority of cases. EGF-R, p-Iκ:B-α, NF-κ:B, c-FOS and p-c-JUN correlated positively with COX-2 and VEGF expression. Conclusion: Stromal myofibroblasts surrounding colon adenocarcinomas are an important source of VEGF and COX-2 production, while AP-1 and NF-κ:B transcription factors are activated and EGF-R is expressed in these cells and associated with COX-2 and VEGF production.

  12. Characterization of the Sweet Taste Receptor Tas1r2 from an Old World Monkey Species Rhesus Monkey and Species-Dependent Activation of the Monomeric Receptor by an Intense Sweetener Perillartine.

    Directory of Open Access Journals (Sweden)

    Chenggu Cai

    Full Text Available Sweet state is a basic physiological sensation of humans and other mammals which is mediated by the broadly acting sweet taste receptor-the heterodimer of Tas1r2 (taste receptor type 1 member 2 and Tas1r3 (taste receptor type 1 member 3. Various sweeteners interact with either Tas1r2 or Tas1r3 and then activate the receptor. In this study, we cloned, expressed and functionally characterized the taste receptor Tas1r2 from a species of Old World monkeys, the rhesus monkey. Paired with the human TAS1R3, it was shown that the rhesus monkey Tas1r2 could respond to natural sugars, amino acids and their derivates. Furthermore, similar to human TAS1R2, rhesus monkey Tas1r2 could respond to artificial sweeteners and sweet-tasting proteins. However, the responses induced by rhesus monkey Tas1r2 could not be inhibited by the sweet inhibitor amiloride. Moreover, we found a species-dependent activation of the Tas1r2 monomeric receptors of human, rhesus monkey and squirrel monkey but not mouse by an intense sweetener perillartine. Molecular modeling and sequence analysis indicate that the receptor has the conserved domains and ligand-specific interactive residues, which have been identified in the characterized sweet taste receptors up to now. This is the first report of the functional characterization of sweet taste receptors from an Old World monkey species.

  13. Characterization of the Sweet Taste Receptor Tas1r2 from an Old World Monkey Species Rhesus Monkey and Species-Dependent Activation of the Monomeric Receptor by an Intense Sweetener Perillartine.

    Science.gov (United States)

    Cai, Chenggu; Jiang, Hua; Li, Lei; Liu, Tianming; Song, Xuejie; Liu, Bo

    2016-01-01

    Sweet state is a basic physiological sensation of humans and other mammals which is mediated by the broadly acting sweet taste receptor-the heterodimer of Tas1r2 (taste receptor type 1 member 2) and Tas1r3 (taste receptor type 1 member 3). Various sweeteners interact with either Tas1r2 or Tas1r3 and then activate the receptor. In this study, we cloned, expressed and functionally characterized the taste receptor Tas1r2 from a species of Old World monkeys, the rhesus monkey. Paired with the human TAS1R3, it was shown that the rhesus monkey Tas1r2 could respond to natural sugars, amino acids and their derivates. Furthermore, similar to human TAS1R2, rhesus monkey Tas1r2 could respond to artificial sweeteners and sweet-tasting proteins. However, the responses induced by rhesus monkey Tas1r2 could not be inhibited by the sweet inhibitor amiloride. Moreover, we found a species-dependent activation of the Tas1r2 monomeric receptors of human, rhesus monkey and squirrel monkey but not mouse by an intense sweetener perillartine. Molecular modeling and sequence analysis indicate that the receptor has the conserved domains and ligand-specific interactive residues, which have been identified in the characterized sweet taste receptors up to now. This is the first report of the functional characterization of sweet taste receptors from an Old World monkey species.

  14. Five percent CO2 is a potent, fast-acting inhalation anticonvulsant

    Czech Academy of Sciences Publication Activity Database

    Tolner, E. A.; Hochman, D. W.; Hassinen, P.; Otáhal, Jakub; Gaily, E.; Haglund, M. M.; Kubová, Hana; Schuchmann, S.; Vanhatalo, S.; Kaila, K.

    2011-01-01

    Roč. 52, č. 1 (2011), s. 104-114 ISSN 0013-9580 R&D Projects: GA AV ČR(CZ) 1QS501210509; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : pH * hypercarbia * epilepsy * human * electroencephalogram Subject RIV: FH - Neurology Impact factor: 3.961, year: 2011

  15. Steviamine, a new class of indolizidine alkaloid [(1R,2S,3R,5R,8aR-3-hydroxymethyl-5-methyloctahydroindolizine-1,2-diol hydrobromide

    Directory of Open Access Journals (Sweden)

    Amber L. Thompson

    2009-11-01

    Full Text Available X-ray crystallographic analysis of the title hydrobromide salt, C10H20N+·Br−, of (1R,2S,3R,5R,8aR-3-hydroxymethyl-5-methyloctahydroindolizine-1,2-diol defines the absolute and relative stereochemistry at the five chiral centres in steviamine, a new class of polyhydroxylated indolizidine alkaloid isolated from Stevia rebaudiana (Asteraceae leaves. In the crystal structure, molecules are linked by intermolecular O—H...Br and N—H...Br hydrogen bonds, forming double chains around the twofold screw axes along the b-axis direction. Intramolecular O—H...O interactions occur.

  16. CB1R-Mediated Activation of Caspase-3 Causes Epigenetic and Neurobehavioral Abnormalities in Postnatal Ethanol-Exposed Mice

    Directory of Open Access Journals (Sweden)

    Shivakumar Subbanna

    2018-02-01

    Full Text Available Alcohol exposure can affect brain development, leading to long-lasting behavioral problems, including cognitive impairment, which together is defined as fetal alcohol spectrum disorder (FASD. However, the fundamental mechanisms through which this occurs are largely unknown. In this study, we report that the exposure of postnatal day 7 (P7 mice to ethanol activates caspase-3 via cannabinoid receptor type-1 (CB1R in neonatal mice and causes a reduction in methylated DNA binding protein (MeCP2 levels. The developmental expression of MeCP2 in mice is closely correlated with synaptogenesis and neuronal maturation. It was shown that ethanol treatment of P7 mice enhanced Mecp2 mRNA levels but reduced protein levels. The genetic deletion of CB1R prevented, and administration of a CB1R antagonist before ethanol treatment of P7 mice inhibited caspase-3 activation. Additionally, it reversed the loss of MeCP2 protein, cAMP response element binding protein (CREB activation, and activity-regulated cytoskeleton-associated protein (Arc expression. The inhibition of caspase-3 activity prior to ethanol administration prevented ethanol-induced loss of MeCP2, CREB activation, epigenetic regulation of Arc expression, long-term potentiation (LTP, spatial memory deficits and activity-dependent impairment of several signaling molecules, including MeCP2, in adult mice. Collectively, these results reveal that the ethanol-induced CB1R-mediated activation of caspase-3 degrades the MeCP2 protein in the P7 mouse brain and causes long-lasting neurobehavioral deficits in adult mice. This CB1R-mediated instability of MeCP2 during active synaptic maturation may disrupt synaptic circuit maturation and lead to neurobehavioral abnormalities, as observed in this animal model of FASD.

  17. Synthesis, physical-chemical properties of 2-((4-R-5-(thiophene-2-ylmethyl-4H-1,2,4-triazole-3-ylthioacetohydrazides

    Directory of Open Access Journals (Sweden)

    O. A. Suhak

    2017-04-01

    Full Text Available Aim. Analysis of the scientific literature over the past decade has shown that large synthetic possibilities towards creating new and effective drug substances have heterocyclic compounds, in particular the derivatives of 1,2,4-triazole. 1,2,4-Triazole is a structural fragment of many synthetic drugs. The special interest cause ylidene hydrazides of 2-(5-R-1,2,4-triazole-3-ylthioacetic acids as potential biologically active compounds, among which highly effective medicines can be found. With the aim of finding new biologically active compounds the derivatives of 2-((4-R-5-(thiophene-2-ylmethyl-4H-1,2,4-triazole-3-ylthioaceticohydrazides have been synthesized, their physical-chemical properties have been studied with the use of modern methods, namely elemental analysis, IR,1H-NMR spectroscopy, and their individuality by HPLC-MS. Materials and methods. N'-R1-еden-2-((4-R-5-(thiophene-2-ylmethyl-4H-1,2,4-triazole-3-ylthioaceticohydrazides were received by adding aromatic (2-BrC6H4, 2,3-(OCH32C6H3, 3,5-(OCH32C6H3, 4-N(CH32C6H4, 3,4-F2C6H3, 2-NO2C6H4,4-NO2C6H4, 4-OHC6H4, 2-OHC6H4, 4-FC6H4, 2-CI-6-FC6H3 or heterocyclic (2-SC4H3, 5-NO2-2-C4H2O aldehyde to an equivalent amount of the appropriate 2-((4-R-5-(thiophene-2-ylmethyl-4H-1,2,4-triazole-3-ylthioaceticohydrazide in the acetic acid medium. The study of physical-chemical properties of obtained compounds was carried out according to the methods outlined in SPU. Chromato-mass-spectral studies were performed on hazarding chromatograph Agilent 1260 Infinity HPLC equipped with mass spectrometer Agilent 6120 with ionization in electro-spray (ESI. Conclusion. This suggests the possibility for further study of biological action of the synthesized compounds. As a result of studies the N'-R1-eden-2-((4-R-5-(thiophene-2-ylmethyl-4H-1,2,4-triazole-3-ylthioaceticohydrazides have been synthesized and their physical-chemical properties have been studied.

  18. Antihypoxic activity of benzylidenhydrazides of 4-R-5- (thiophene-2-ylmethyl-1,2,4-triazol-3-ilthioacetic acid

    Directory of Open Access Journals (Sweden)

    O. A. Suhak

    2017-08-01

    Full Text Available In recent years we see significant increase of natural and technogenic situations that lead to disorders of functional and metabolic processes of central nervous system and cardiovascular diseases, including acute cerebrovascular accident. The leading factor in vascular brain pathology is hypoxia. Currently all body states, in which we see any reason decrease of oxygen delivery to tissues is considered as hypoxia. Paying into account the fact that available pharmacotherapeutic agents for the oxygen deficiency treatment tend to have limited efficacy, narrow range of active doses and often cause undesirable side effects, the special attention is paid to drugs that have an antihypoxic action and exclude the above mentioned effects. Aim. To study antihypoxic actions for the first time synthesized derivatives of 1,2,4-triazoles and to find the "structure - action" dependence. Materials and methods. Antihypoxic activity of 1,2,4-triazoles derivatives was studied at modeling hypoxia with hypercapnia. Rats were placed in same volume (1330 ml sealed up jars, then overturned them down and put in a cell with water to prevent the flow of air. As a comparison drug in the study we used mexidol 100 mg / kg. Results. The study has identified three compounds that extend the comparison drug mexidol and prolong the life expectancy of 59.94 %, 47.79% and 53.31% (compounds 1, 2, 5, respectively. While mexidol was 42.54%. After analyzing the data and chemical structure of the synthesized compounds we have established some relative patterns between chemical structure and antihypoxic actions of 1,2,4-triazoles derivatives. Conclusions. As the result of the study, we have discovered the compound that exceeds the referent drug mexidol on 17.4%. In the study of the acute toxicity of 1,2,4-triazoles derivatives it was found that all compounds belong to IV Class of toxicity (LD50 = 331-770 mg / kg. The presence of two halogen atoms in the molecules of benzylidenhydrazides

  19. Activation of the Ca2+-sensing receptors increases currents through inward rectifier K+ channels via activation of phosphatidylinositol 4-kinase.

    Science.gov (United States)

    Liu, Chung-Hung; Chang, Hsueh-Kai; Lee, Sue-Ping; Shieh, Ru-Chi

    2016-11-01

    Inward rectifier K + channels are important for maintaining normal electrical function in many cell types. The proper function of these channels requires the presence of membrane phosphoinositide 4,5-bisphosphate (PIP 2 ). Stimulation of the Ca 2+ -sensing receptor CaR, a pleiotropic G protein-coupled receptor, activates both G q/11 , which decreases PIP 2 , and phosphatidylinositol 4-kinase (PI-4-K), which, conversely, increases PIP 2 . How membrane PIP 2 levels are regulated by CaR activation and whether these changes modulate inward rectifier K + are unknown. In this study, we found that activation of CaR by the allosteric agonist, NPSR568, increased inward rectifier K + current (I K1 ) in guinea pig ventricular myocytes and currents mediated by Kir2.1 channels exogenously expressed in HEK293T cells with a similar sensitivity. Moreover, using the fluorescent PIP 2 reporter tubby-R332H-cYFP to monitor PIP 2 levels, we found that CaR activation in HEK293T cells increased membrane PIP 2 concentrations. Pharmacological studies showed that both phospholipase C (PLC) and PI-4-K are activated by CaR stimulation with the latter played a dominant role in regulating membrane PIP 2 and, thus, Kir currents. These results provide the first direct evidence that CaR activation upregulates currents through inward rectifier K + channels by accelerating PIP 2 synthesis. The regulation of I K1 plays a critical role in the stability of the electrical properties of many excitable cells, including cardiac myocytes and neurons. Further, synthetic allosteric modulators that increase CaR activity have been used to treat hyperparathyroidism, and negative CaR modulators are of potential importance in the treatment of osteoporosis. Thus, our results provide further insight into the roles played by CaR in the cardiovascular system and are potentially valuable for heart disease treatment and drug safety.

  20. The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors

    Science.gov (United States)

    Zvejniece, L; Vavers, E; Svalbe, B; Vilskersts, R; Domracheva, I; Vorona, M; Veinberg, G; Misane, I; Stonans, I; Kalvinsh, I; Dambrova, M

    2014-01-01

    Background and Purpose Here, we describe the in vitro and in vivo effects of (4R,5S)-2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide (E1R), a novel positive allosteric modulator of sigma-1 receptors. Experimental Approach E1R was tested for sigma receptor binding activity in a [3H](+)-pentazocine assay, in bradykinin (BK)-induced intracellular Ca2+ concentration ([Ca2+]i) assays and in an electrically stimulated rat vas deferens model. E1R's effects on cognitive function were tested using passive avoidance (PA) and Y-maze tests in mice. A selective sigma-1 receptor antagonist (NE-100), was used to study the involvement of the sigma-1 receptor in the effects of E1R. The open-field test was used to detect the effects of E1R on locomotion. Key Results Pretreatment with E1R enhanced the selective sigma-1 receptor agonist PRE-084's stimulating effect during a model study employing electrically stimulated rat vasa deferentia and an assay measuring the BK-induced [Ca2+]i increase. Pretreatment with E1R facilitated PA retention in a dose-related manner. Furthermore, E1R alleviated the scopolamine-induced cognitive impairment during the PA and Y-maze tests in mice. The in vivo and in vitro effects of E1R were blocked by treatment with the selective sigma-1 receptor antagonist NE-100. E1R did not affect locomotor activity. Conclusion and Implications E1R is a novel 4,5-disubstituted derivative of piracetam that enhances cognition and demonstrates efficacy against scopolamine-induced cholinergic dysfunction in mice. These effects are attributed to its positive modulatory action on the sigma-1 receptor and this activity may be relevant when developing new drugs for treating cognitive symptoms related to neurodegenerative diseases. PMID:24490863

  1. Coronal Activity in the R CrA T Association

    Science.gov (United States)

    Patten, Brian M.; Oliversen, Ronald J. (Technical Monitor)

    2005-01-01

    Brian Patten is the Principal Investigator of the NASA ROSS-ADP project Coronal Activity in the R CrA T Association. For this project we have extracted net counts and variability information for all of the X-ray sources found in 23 archival ROSAT PSPC and HRI images in the region of the R CrA T association. These data have been merged with an extensive database of optical and near-infrared photometry, optical spectroscopy, and parallax data. These data have been used to (1) identify new association members and clarify the membership status of a number of previously suspected members of the association, and (2) derive, for the first time, an accurate coronal luminosity function for the T Tauri members of this T association and make direct comparisons between the coronal luminosity functions for other T associations and those of large clusters. We have used our survey data to assess (a) the importance of the star-formation environment in initial coronal activity levels, (b) the effects of PMS evolution on dynamo activity as a function of mass and age, and (c) the level of contamination by field post-T Tauri stars on association membership surveys.

  2. Clarified Açaí (Euterpe oleracea Juice as an Anticonvulsant Agent: In Vitro Mechanistic Study of GABAergic Targets

    Directory of Open Access Journals (Sweden)

    Gabriela P. F. Arrifano

    2018-01-01

    Full Text Available Seizures affect about 50 million people around the world. Approximately 30% of seizures are refractory to the current pharmacological arsenal, so, the pursuit of new therapeutic alternatives is essential. Clarified Euterpe oleracea (EO juice showed anticonvulsant properties similar to diazepam in an in vivo model with pentylenetetrazol, a GABAA receptor blocker. This study investigated the effects of EO on the main GABAergic targets for anticonvulsant drugs, analyzing the effect on the GABA receptor’s benzodiazepine and picrotoxinin binding sites and the GABA uptake. Primary cultures of cortical neurons and astrocytes were treated with EO (0–25% for up to 90 min. [3H]Flunitrazepam and [3H]TBOB binding, [3H]GABA uptake, cell viability, and morphology were assayed. Nonlethal concentrations of EO increased agonist binding and decreased antagonist binding in cortical neurons. Low concentrations significantly inhibited GABA uptake, especially in astrocytes, suggesting an accumulation of endogenous GABA in the synaptic cleft. The results demonstrate, for the first time, that EO can improve GABAergic neurotransmission via interactions with GABAA receptor and modulation of GABA uptake. Understanding these molecular mechanisms will help in the treatment of seizures and epilepsy, especially in developing countries where geographic isolation and low purchasing power are the main barriers to access to adequate treatment.

  3. Psychotropic and Anticonvulsant Drug Usage in Early Childhood Special Education Programs I. Phase One: A Preliminary Report: Prevalence, Attitude, Training, and Problems.

    Science.gov (United States)

    Gadow, Kenneth D.

    As part of a three phase study designed to survey the teachers and parents of children receiving psychotropic and anticonvulsant drugs, 208 teachers of preschool special education children on medication were mailed questionnaires. The Early Childhood Medication Questionnaire used in the survey included items relating to teacher, program, and…

  4. An ODIP effort to map R2R ocean data terms to international vocabularies

    Science.gov (United States)

    Ferreira, Renata; Stocks, Karen; Arko, Robert

    2014-05-01

    The heterogeneity of terminology used in describing data creates a barrier to the efficient discovery and re-use of data, particularly across institutional, programmatic, and disciplinary boundaries. Here we explore the outcomes of a student project to crosswalk terms between the Rolling Deck to Repository (R2R) program and other international systems, as part of the Ocean Data Interoperability Platform (ODIP). R2R is a US program developing and implementing an information management system to preserve and provide access to routine underway data collected by U.S academic research vessels. R2R participates in ODIP, an international forum for improving the interoperability and effective sharing of marine data resources through technical workshops and joint prototypes. The vocabulary mapping effort lays a foundation for future ocean data portals through which users search and access international ocean data using familiar terms. R2R describes its data with a suite of controlled vocabularies (http://www.rvdata.us/voc) some of which were developed locally or are specific to the US. The goal of this student project is to crosswalk local/national vocabularies to authoritative international vocabularies, where they exist, or to vocabularies widely used by ODIP partners. Specifically, R2R developed the following crosswalks: R2R science party names to ORCID person identifiers, UNOLS ports to SeaDataNet Ports Gazetteer, R2R Device Models to NVS SeaVoX Device Catalog, and R2R Organizations to the European Directory of Marine Organizations (EDMO). Mappings were done in simple spreadsheets using synonymy relationships only, and will be published as part of the R2R Linked Data resources. The level of success in crosswalking was variable. The majority of ports were successfully mapped. Differences in the character sets (i.e. whether diacritic marks were used) caused automated matching to fail occasionally, but the number of ports was small enough that these could be manually

  5. MHD control experiments in the Extrap T2R Reversed Field Pinch

    Science.gov (United States)

    Marrelli, L.; Bolzonella, T.; Brunsell, P.; Cecconello, M.; Drake, J.; Franz, P.; Gregoratto, D.; Manduchi, G.; Martin, P.; Ortolani, S.; Paccagnella, R.; Piovesan, P.; Spizzo, G.; Yadikin, D.; Zanca, P.

    2004-11-01

    We report here on MHD active control experiments performed in the Extrap T2R device, which has been recently equipped with a set of 32 feedback controlled saddle coils couples. Experiments aiming at selectively exciting a resonant resistive instability in order to actively induce Quasi Single Helicity states will be presented. Open loop experiments have in fact shown that a spectrum with one dominant mode can be excited in a high aspect ratio device like T2R. In addition, evidences of controlled braking of tearing modes, which spontaneously rotate in T2R, have been gathered, allowing the determination of a threshold for mode wall locking. Different feedback control schemes have been implemented. In particular, mode suppression schemes proved successful in delaying resistive wall modes growth and in increasing the discharge duration: this suggests a hybrid mode control scenario, in which RWM are suppressed and QSH is induced. Radiation imaging and internal magnetic field reconstructions performed with the ORBIT code will be presented.

  6. Biological Activities of Hydrazone Derivatives

    Directory of Open Access Journals (Sweden)

    S. Güniz Küçükgüzel

    2007-08-01

    Full Text Available There has been considerable interest in the development of novel compounds with anticonvulsant, antidepressant, analgesic, antiinflammatory, antiplatelet, antimalarial, antimicrobial, antimycobacterial, antitumoral, vasodilator, antiviral and antischistosomiasis activities. Hydrazones possessing an azometine -NHN=CH- proton constitute an important class of compounds for new drug development. Therefore, many researchers have synthesized these compounds as target structures and evaluated their biological activities. These observations have been guiding for the development of new hydrazones that possess varied biological activities.

  7. Expeditious syntheses of stable and radioactive isotope-labeled anticonvulsant agent, JNJ-26990990, and its metabolites.

    Science.gov (United States)

    Lin, Ronghui; Weaner, Larry E; Hoerr, David C; Salter, Rhys; Gong, Yong

    2013-01-01

    Syntheses of stable and radioactive isotope-labeled anticonvulsant agent, JNJ-26990990, that is, N-(benzo[b]thien-3-ylmethyl)-sulfamide and its metabolites are described. [(13)C(15)N]Benzo[b]thiophene-3-carbonitrile was first prepared by coupling of 3-bromo-benzo[b]thiophene with [(13)C(15)N]-copper cyanide. The resultant [(13)C(15)N]benzo[b]thiophene-3-carbonitrile was reduced with lithium aluminum deuteride to give [(13)CD2(15)N]benzo[b]thiophen-3-yl-methylamine; which was then coupled with sulfamide to afford [(13)CD2(15)N]-N-(benzo[b]thien-3-ylmethyl)-sulfamide, the stable isotope-labeled compound with four stable isotope atoms. Direct oxidation of [(13)CD2(15)N]-N-(benzo[b]thien-3-ylmethyl)-sulfamide with hydrogen peroxide and peracetic acid gave the stable isotope-labeled sulfoxide and sulfone metabolites. On the other hand, radioactive (14)C-labeled N-(benzo[b]thien-3-ylmethyl)-sulfamide was prepared conveniently by sequential coupling of 3-bromo-benzo[b]thiophene with [(14)C]-copper cyanide, reduction of the carbonitrile to carboxaldehyde, and reductive amination with sulfamide. Copyright © 2013 John Wiley & Sons, Ltd.

  8. Amino methylation of 2-R-6-R_1-imidazo-[2.1-B]-1.3.4-thiadiazole

    International Nuclear Information System (INIS)

    Saidov, D.K.; Rakhmonov, R.O.; Khodzhiboev, Yu.; Kukaniev, M.A.; Bandaev, S.

    2015-01-01

    Present article is devoted to amino methylation of 2-R-6-R_1-imidazo-[2.1-B]-1.3.4-thiadiazole. The reaction of new modifications of derivatives of imidazo-[2.1-B]-1.3.4-thiadiazoles-2-bromine-6-p-bromophenyl and 2-alkyl alkylene sulfonyl-6-phenyl imidazo--[2.1-B]-1.3.4-thiadiazole on Mannich with secondary and heterocyclic amines was studied.

  9. Reactivity-worth estimates of the OSMOSE samples in the MINERVE reactor R1-MOX, R2-UO2 and MORGANE/R configurations.

    Energy Technology Data Exchange (ETDEWEB)

    Zhong, Z.; Klann, R. T.; Nuclear Engineering Division

    2007-08-03

    An initial series of calculations of the reactivity-worth of the OSMOSE samples in the MINERVE reactor with the R2-UO2 and MORGANE/R core configuration were completed. The calculation model was generated using the lattice physics code DRAGON. In addition, an initial comparison of calculated values to experimental measurements was performed based on preliminary results for the R1-MOX configuration.

  10. The Copper Homeostasis Transcription Factor CopR Is Involved in H2O2 Stress in Lactobacillus plantarum CAUH2

    Directory of Open Access Journals (Sweden)

    Yang Yang

    2017-10-01

    Full Text Available Transcriptional factors (TFs play important roles in the responses to oxidative, acid, and other environmental stresses in Gram-positive bacteria, but the regulatory mechanism of TFs involved in oxidative stress remains unknown in lactic acid bacteria. In the present work, homologous overexpression strains with 43 TFs were constructed in the Lactobacillus plantarum CAUH2 parent strain. The strain overexpressing CopR displayed the highest sensitivity and a 110-fold decrease in survival rate under H2O2 challenge. The importance of CopR in the response to H2O2 stress was further confirmed by a 10.8-fold increase in the survival of a copR insertion mutant. In silico analysis of the genes flanking copR revealed putative CopR-binding “cop box” sequences in the promoter region of the adjacent gene copB encoding a Cu2+-exporting ATPase. Electrophoretic mobility shift assay (EMSA analysis demonstrated the specific binding of CopR with copB in vitro, suggesting copB is a target gene of CopR in L. plantarum. The role of CopB involved in oxidative stress was verified by the significantly decreased survival in the copB mutant. Furthermore, a growth defect in copper-containing medium demonstrated that CopB functions as an export ATPase for copper ions. Furthermore, EMSAs revealed that CopR functions as a regulator that negatively regulates copB gene and Cu2+ serves as inducer of CopR to activate the expression of CopB in response to H2O2 stress in L. plantarum CAUH2. Our findings indicated that CopR plays an important role in enhancing oxidative resistance by regulating copB to modulate copper homeostasis.

  11. Partial synthesis of (3R,6'R)-alpha-cryptoxanthin and (3R)-beta-cryptoxanthin from (3R,3'R,6'R)-lutein.

    Science.gov (United States)

    Khachik, Frederick; Chang, An-Ni; Gana, Audry; Mazzola, Eugene

    2007-02-01

    (3R,3'R,6'R)-Lutein (1), (3R,3'R)-zeaxanthin (2), (3R,6'R)-alpha-cryptoxanthin (3), and (3R)-beta-cryptoxanthin (4) are among dietary hydroxycarotenoids that have been identified in human serum, milk, and ocular tissues. While 1 containing 6% of 2 is commercially available, industrial production of optically active 3 and 4 has not yet been accomplished. Several processes have been developed that transform 1 into 3, 4, and minor quantities of (3R,5'RS,6'R)-3',4'-didehydro-5',6'-dihydro-beta,beta-caroten-3-ol (5) (a regioisomer of 3). In one process, lutein (1) was cleanly deoxygenated to 3 in the presence of trifluoroacetic acid (TFA) and Me3N.BH3 in CH2Cl2 at ambient temperature in nearly 90% yield. Reaction of lutein (1) with a Lewis acid (AlCl3, ZnBr2, ZnI2) and a hydride donor (Me3N.BH3, Na[BH3(OCOCF3)], NaCNBH3) in solvents such as CH2Cl2, THF, and TBME produced similar results. In a two-step process, high-temperature acid-catalyzed dehydration of 1 (propanol/water/acid, 90 degrees C) gave a mixture of anhydroluteins 6, 7, and 8 in 86% yield. In the second step, these dehydration products underwent ionic hydrogenation with TFA/Me3N.BH3 in CH2Cl2 to afford a mixture of 3 and 4 in nearly 80% yield that contained only 1% of 5.

  12. Synthesis and biological characterization of (3R,4R)-4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol and its stereoisomers for monoamine transporters

    Science.gov (United States)

    Kharkar, Prashant S.; Batman, Angela M.; Zhen, Juan; Beardsley, Patrick M.; Reith, Maarten E. A.

    2012-01-01

    In this report we describe synthesis and biological evaluation of a series of asymmetric 4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol based dihydroxy compounds where the hydroxy groups are located both on the piperidine ring and also on the N-phenylethyl side chain exo-cyclically. In vitro uptake inhibition data indicates high affinity of these molecules for the dopamine transporter (DAT) in addition to their moderate to high affinity for the norepinephrine transporter (NET). Interestingly, compounds 9b and 9d exhibited affinities for all three monoamine transporters with highest potency at DAT and NET and moderate potency at the serotonin transporter (SERT) (Ki 2.29, 78.4 and 155 nM for 9b and 1.55, 14.1 and 259 nM for 9d, respectively). Selected compounds, 9a, 9d and 9d’ were tested for their locomotor activity effects in mice, and for their ability to occasion the cocaine discriminative stimulus in rats. These test compounds generally exhibited a much longer duration of action than cocaine for elevating locomotor activity, and dose-dependently completely generalized the cocaine discriminative stimulus. PMID:19449323

  13. The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action.

    Science.gov (United States)

    Griveau, A; Devailly, G; Eberst, L; Navaratnam, N; Le Calvé, B; Ferrand, M; Faull, P; Augert, A; Dante, R; Vanacker, J M; Vindrieux, D; Bernard, D

    2016-09-22

    Little is known about the biological role of the phospholipase A2 receptor (PLA2R1) transmembrane protein. In recent years, PLA2R1 has been shown to have an important role in regulating tumor-suppressive responses via JAK2 activation, but the underlying mechanisms are largely undeciphered. In this study, we observed that PLA2R1 increases the mitochondrial content, judged by increased levels of numerous mitochondrial proteins, of the mitochondrial structural component cardiolipin, of the mitochondrial DNA content, and of the mitochondrial DNA replication and transcription factor TFAM. This effect of PLA2R1 relies on a transcriptional program controlled by the estrogen-related receptor alpha1 (ERRα) mitochondrial master regulator. Expression of ERRα and of its nucleus-encoded mitochondrial targets is upregulated upon PLA2R1 ectopic expression, and this effect is mediated by JAK2. Conversely, downregulation of PLA2R1 decreases the level of ERRα and of its nucleus-encoded mitochondrial targets. Finally, blocking the ERRα-controlled mitochondrial program largely inhibits the PLA2R1-induced tumor-suppressive response. Together, our data document ERRα and its mitochondrial program as downstream effectors of the PLA2R1-JAK2 pathway leading to oncosuppression.

  14. Andra - R and D activity report 2015

    International Nuclear Information System (INIS)

    2016-09-01

    The National Radioactive Waste Management Agency (Andra), created in 1979 within the CEA, was established by the December 1991 Waste Act as a public body in charge of the long-term management of all radioactive waste, under the supervision of the Ministry of Ecology, Energy, Sustainable Development and the Sea (formerly the Ministry of Industry and the Ministry of Environment), and the Ministry of Research. Its 3 basic missions were extended and their funding secured through the 2006 Planning Act: - a R and D mission to propose safe long-term solution for radioactive waste without current disposal system; this mission includes long-term storage, since the 2006 Planning Act, in order to propose interim solutions while final ones are being studied, - an industrial mission concerning, on one hand, waste acceptance criteria and control and, on the other hand, siting, construction, operation, closure and monitoring of repositories, - an information mission, notably through the regular publication of the National Inventory of radioactive materials and waste. This document is the 2015 annual activity report of the Andra for the R and D mission. It presents: the 2015 R and D highlights, the R and D at the service of Andra's projects and activities (towards Cigeo's industrial development, main R and D results for a key step of the low level-long living wastes project, R and D at the service of surface facilities operation), the Andra partnership with the scientific community (mobilization, PhDs, projects investment, conference and workshops participation), and the restructuring of the scientific governance of the Andra. The patents issued by the Andra and the defended PhD Theses are listed in the appendix

  15. R2 Cognitive Computing

    Data.gov (United States)

    National Aeronautics and Space Administration — Robonaut 2, a crew assistant robotic prototype, will be integrated with IBM’s Watson. R2 will embody the artificial intelligence to enable new levels of robotic...

  16. SPoRT's Participation in the GOES-R Proving Ground Activity

    Science.gov (United States)

    Jedlovec, Gary; Fuell, Kevin; Smith, Matthew; Stano, Geoffrey; Molthan, Andrew

    2011-01-01

    The next generation geostationary satellite, GOES-R, will carry two new instruments with unique atmospheric and surface observing capabilities, the Advanced Baseline Imager (ABI) and the Geostationary Lightning Mapper (GLM), to study short-term weather processes. The ABI will bring enhanced multispectral observing capabilities with frequent refresh rates for regional and full disk coverage to geostationary orbit to address many existing and new forecast challenges. The GLM will, for the first time, provide the continuous monitoring of total lightning flashes over a hemispherical region from space. NOAA established the GOES-R Proving Ground activity several years ago to demonstrate the new capabilities of these instruments and to prepare forecasters for their day one use. Proving Ground partners work closely with algorithm developers and the end user community to develop and transition proxy data sets representing GOES-R observing capabilities. This close collaboration helps to maximize refine algorithms leading to the delivery of a product that effectively address a forecast challenge. The NASA Short-term Prediction Research and Transition (SPoRT) program has been a participant in the NOAA GOES-R Proving Ground activity by developing and disseminating selected GOES-R proxy products to collaborating WFOs and National Centers. Established in 2002 to demonstrate the weather and forecasting application of real-time EOS measurements, the SPoRT program has grown to be an end-to-end research to operations activity focused on the use of advanced NASA modeling and data assimilation approaches, nowcasting techniques, and unique high-resolution multispectral data from EOS satellites to improve short-term weather forecasts on a regional and local scale. Participation in the Proving Ground activities extends SPoRT s activities and taps its experience and expertise in diagnostic weather analysis, short-term weather forecasting, and the transition of research and experimental

  17. R2R - software to speed the depiction of aesthetic consensus RNA secondary structures

    Directory of Open Access Journals (Sweden)

    Weinberg Zasha

    2011-01-01

    Full Text Available Abstract Background With continuing identification of novel structured noncoding RNAs, there is an increasing need to create schematic diagrams showing the consensus features of these molecules. RNA structural diagrams are typically made either with general-purpose drawing programs like Adobe Illustrator, or with automated or interactive programs specific to RNA. Unfortunately, the use of applications like Illustrator is extremely time consuming, while existing RNA-specific programs produce figures that are useful, but usually not of the same aesthetic quality as those produced at great cost in Illustrator. Additionally, most existing RNA-specific applications are designed for drawing single RNA molecules, not consensus diagrams. Results We created R2R, a computer program that facilitates the generation of aesthetic and readable drawings of RNA consensus diagrams in a fraction of the time required with general-purpose drawing programs. Since the inference of a consensus RNA structure typically requires a multiple-sequence alignment, the R2R user annotates the alignment with commands directing the layout and annotation of the RNA. R2R creates SVG or PDF output that can be imported into Adobe Illustrator, Inkscape or CorelDRAW. R2R can be used to create consensus sequence and secondary structure models for novel RNA structures or to revise models when new representatives for known RNA classes become available. Although R2R does not currently have a graphical user interface, it has proven useful in our efforts to create 100 schematic models of distinct noncoding RNA classes. Conclusions R2R makes it possible to obtain high-quality drawings of the consensus sequence and structural models of many diverse RNA structures with a more practical amount of effort. R2R software is available at http://breaker.research.yale.edu/R2R and as an Additional file.

  18. R2R - software to speed the depiction of aesthetic consensus RNA secondary structures

    Science.gov (United States)

    2011-01-01

    Background With continuing identification of novel structured noncoding RNAs, there is an increasing need to create schematic diagrams showing the consensus features of these molecules. RNA structural diagrams are typically made either with general-purpose drawing programs like Adobe Illustrator, or with automated or interactive programs specific to RNA. Unfortunately, the use of applications like Illustrator is extremely time consuming, while existing RNA-specific programs produce figures that are useful, but usually not of the same aesthetic quality as those produced at great cost in Illustrator. Additionally, most existing RNA-specific applications are designed for drawing single RNA molecules, not consensus diagrams. Results We created R2R, a computer program that facilitates the generation of aesthetic and readable drawings of RNA consensus diagrams in a fraction of the time required with general-purpose drawing programs. Since the inference of a consensus RNA structure typically requires a multiple-sequence alignment, the R2R user annotates the alignment with commands directing the layout and annotation of the RNA. R2R creates SVG or PDF output that can be imported into Adobe Illustrator, Inkscape or CorelDRAW. R2R can be used to create consensus sequence and secondary structure models for novel RNA structures or to revise models when new representatives for known RNA classes become available. Although R2R does not currently have a graphical user interface, it has proven useful in our efforts to create 100 schematic models of distinct noncoding RNA classes. Conclusions R2R makes it possible to obtain high-quality drawings of the consensus sequence and structural models of many diverse RNA structures with a more practical amount of effort. R2R software is available at http://breaker.research.yale.edu/R2R and as an Additional file. PMID:21205310

  19. R2R--software to speed the depiction of aesthetic consensus RNA secondary structures.

    Science.gov (United States)

    Weinberg, Zasha; Breaker, Ronald R

    2011-01-04

    With continuing identification of novel structured noncoding RNAs, there is an increasing need to create schematic diagrams showing the consensus features of these molecules. RNA structural diagrams are typically made either with general-purpose drawing programs like Adobe Illustrator, or with automated or interactive programs specific to RNA. Unfortunately, the use of applications like Illustrator is extremely time consuming, while existing RNA-specific programs produce figures that are useful, but usually not of the same aesthetic quality as those produced at great cost in Illustrator. Additionally, most existing RNA-specific applications are designed for drawing single RNA molecules, not consensus diagrams. We created R2R, a computer program that facilitates the generation of aesthetic and readable drawings of RNA consensus diagrams in a fraction of the time required with general-purpose drawing programs. Since the inference of a consensus RNA structure typically requires a multiple-sequence alignment, the R2R user annotates the alignment with commands directing the layout and annotation of the RNA. R2R creates SVG or PDF output that can be imported into Adobe Illustrator, Inkscape or CorelDRAW. R2R can be used to create consensus sequence and secondary structure models for novel RNA structures or to revise models when new representatives for known RNA classes become available. Although R2R does not currently have a graphical user interface, it has proven useful in our efforts to create 100 schematic models of distinct noncoding RNA classes. R2R makes it possible to obtain high-quality drawings of the consensus sequence and structural models of many diverse RNA structures with a more practical amount of effort. R2R software is available at http://breaker.research.yale.edu/R2R and as an Additional file.

  20. An R2R3-MYB transcription factor, OjMYB1, functions in anthocyanin biosynthesis in Oenanthe javanica.

    Science.gov (United States)

    Feng, Kai; Xu, Zhi-Sheng; Que, Feng; Liu, Jie-Xia; Wang, Feng; Xiong, Ai-Sheng

    2018-02-01

    This study showed that an R2R3-MYB transcription factor, OjMYB1, is involved in anthocyanin biosynthesis and accumulation in Oenanthe javanica. Anthocyanins can be used as safe natural food colorants, obtained from many plants. R2R3-MYB transcription factors (TFs) play important roles in anthocyanins biosynthesis during plant development. Oenanthe javanica is a popular vegetable with high nutritional values and numerous medical functions. O. javanica has purple petioles that are mainly due to anthocyanins accumulation. In the present study, the gene encoding an R2R3-MYB TF, OjMYB1, was isolated from purple O. javanica. Sequencing results showed that OjMYB1 contained a 912-bp open reading frame encoding 303 amino acids. Sequence alignments revealed that OjMYB1 contained bHLH-interaction motif ([DE]Lx2[RK]x3Lx6Lx3R) and ANDV motif ([A/G]NDV). Phylogenetic analysis indicated that the OjMYB1 classified into the anthocyanins biosynthesis clade. Subcellular localization assay showed that OjMYB1 was a nuclear protein in vivo. The heterologous expression of OjMYB1 in Arabidopsis could enhance the anthocyanins content and up-regulate the expression levels of the structural genes-related anthocyanins biosynthesis. Yeast two-hybrid assay indicated that OjMYB1 could interact with AtTT8 and AtEGL3 proteins. Enzymatic analysis revealed that overexpression of OjMYB1 gene up-regulated the enzyme activity of 3-O-glycosyltransferase encoded by AtUGT78D2 in transgenic Arabidopsis. Our results provided a comprehensive understanding of the structure and function of OjMYB1 TF in O. javanica.