WorldWideScience

Sample records for brain pharmacological characterization

  1. Pharmacological and immunochemical characterization of a2* nicotinic acetylcholine receptors (nAChRs) in mouse brain

    Institute of Scientific and Technical Information of China (English)

    Paul WHITEAKER; Jennifer A WILKING; Robert WB BROWN; Robert J BRENNAN; Allan C COLLINS; Jon M LINDSTROM; Jim BOULTER

    2009-01-01

    Aim: a2 nAChR subunit mRNA expression in mice is most intense in the olfactory bulbs and interpeduncular nucleus. We aimed to investigate the properties of a2* nAChRs in these mouse brain regions.Methods: a2 nAChR subunit-null mutant mice were engineered. Pharmacological and immunoprecipitation studies were used to determine the composition of a2 subunit-containing (a2*) nAChRs in these two regions.Results: [125I]Epibatidine (200 pmol/L) autoradiography and saturation binding demonstrated that al deletion reduces nAChR expression in both olfactory bulbs and interpeduncular nucleus (by 4.8±1.7 and 92卤26 fmol-mg"1 protein, respectively). Pharmacological characterization using the 02-selective drug A85380 to inhibit [125I]epibatidine binding proved inconclusive, so immunoprecipitation methods were used to further characterize a2* nAChRs. Protocols were established to immunoprecipitate 02 and 04 nAChRs. Immunoprecipitation specificity was ascertained using tissue from 02- and 04-null mutant mice, and efficacy was good (>90% of (32* and >80% of 04* nAChRs were routinely recovered). Conclusion: Immunoprecipitation experiments indicated that interpeduncular nucleus a2* nAChRs predominantly contain (32 subunits, while those in olfactory bulbs contain mainly 04 subunits. In addition, the immunoprecipitation evidence indicated that both nuclei, but especially the interpeduncular nucleus, express nAChR complexes containing both 02 and 04 subunits.

  2. Brain connectivity in pathological and pharmacological coma

    Directory of Open Access Journals (Sweden)

    Quentin Noirhomme

    2010-12-01

    Full Text Available Recent studies in patients with disorders of consciousness (DOC tend to support the view that awareness is not related to activity in a single brain region but to thalamo-cortical connectivity in the frontoparietal network. Functional neuroimaging studies have shown preserved albeit disconnected low level cortical activation in response to external stimulation in patients in a vegetative state or unresponsive wakefulness syndrome. While activation of these primary sensory cortices does not necessarily reflect conscious awareness, activation in higher order associative cortices in minimally conscious state patients seems to herald some residual perceptual awareness. PET studies have identified a metabolic dysfunction in a widespread fronto-parietal global neuronal workspace in DOC patients including the midline default mode network, ‘intrinsic’ system, and the lateral frontoparietal cortices or ‘extrinsic system’. Recent studies have investigated the relation of awareness to the functional connectivity within intrinsic and extrinsic networks, and with the thalami in both pathological and pharmacological coma. In brain damaged patients, connectivity in all default network areas was found to be non-linearly correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative, coma and brain dead patients. Anesthesia-induced loss of consciousness was also shown to correlate with a global decrease in cortico-cortical and thalamo-cortical connectivity in both intrinsic and extrinsic networks, but not in auditory or visual networks. In anesthesia, unconsciousness was also associated with a loss of cross-modal interactions between networks. These results suggest that conscious awareness critically depends on the functional integrity of thalamo-cortical and cortico-cortical frontoparietal connectivity within and between intrinsic and extrinsic brain networks.

  3. Characterization and pharmacology of the GHB receptor.

    Science.gov (United States)

    Ticku, Maharaj K; Mehta, Ashok K

    2008-10-01

    Radioligand binding using [(3)H]NCS-382, an antagonist of the GHB receptor, revealed specific binding sites in the rat cerebrocortical and hippocampal membranes. Scatchard analysis of saturation isotherms revealed two different populations of binding sites. NCS-382 was about 10 times more potent than GHB in inhibiting [(3)H]NCS-382 binding. A variety of ligands for other receptors did not affect [(3)H]NCS-382 binding. Quantitative autoradiographic analysis of [(3)H]NCS-382 binding revealed similar characteristics. Thus [(3)H]NCS-382, being more potent and selective, offers advantage over [(3)H]GHB as a radioligand. Unlike GHB, several analogues of GHB such as UMB68 (a tertiary alcohol analogue of GHB), UMB86 (4-hydroxy-4-napthylbutanoic acid, sodium salt), UMB72 [4-(3-phenylpropyloxy)butyric acid, sodium salt], UMB73 (4-benzyloxybutyric acid, sodium salt), UMB66 (3-chloropropanoic acid), gamma-hydroxyvaleric acid (that is, GHV, a 4-methyl-substituted analogue of GHB), 3-HPA (3-hydroxyphenylacetic acid), and ethers of 3-hydroxyphenylacetic acid (UMB108, UMB109, and UMB119) displaced [(3)H]NCS-382 without affecting [(3)H]GABA binding to GABA(B) receptor. Thus these compounds offer an advantage over GHB as an experimental tool. Our study, aimed at exploring the potential involvement of the GHB receptor in the pharmacology of ethanol, indicated that ethanol does not affect [(3)H]NCS-382 binding in the rat brain, thereby suggesting that ethanol does not interact directly with the GHB receptor. Our study, aimed at exploring the involvement of the GHB receptor in the pathology of succinate semialdehyde dehydrogenase deficiency, which is known to cause elevation of GHB levels, revealed no change in the affinity, receptor density or displacement potency as determined by using [(3)H]NCS-382 as a radioligand in Aldh5a1(-/-) vs. Aldh5a1(+/+) mouse brain.

  4. Effects of non-pharmacological or pharmacological interventions on cognition and brain plasticity of aging individuals

    Science.gov (United States)

    Pieramico, Valentina; Esposito, Roberto; Cesinaro, Stefano; Frazzini, Valerio; Sensi, Stefano L.

    2014-01-01

    Brain aging and aging-related neurodegenerative disorders are major health challenges faced by modern societies. Brain aging is associated with cognitive and functional decline and represents the favourable background for the onset and development of dementia. Brain aging is associated with early and subtle anatomo-functional physiological changes that often precede the appearance of clinical signs of cognitive decline. Neuroimaging approaches unveiled the functional correlates of these alterations and helped in the identification of therapeutic targets that can be potentially useful in counteracting age-dependent cognitive decline. A growing body of evidence supports the notion that cognitive stimulation and aerobic training can preserve and enhance operational skills in elderly individuals as well as reduce the incidence of dementia. This review aims at providing an extensive and critical overview of the most recent data that support the efficacy of non-pharmacological and pharmacological interventions aimed at enhancing cognition and brain plasticity in healthy elderly individuals as well as delaying the cognitive decline associated with dementia. PMID:25228860

  5. Characterization of technetium-99m-L,L-ECD for brain perfusion imaging, Part 1: Pharmacology of technetium-99m ECD in nonhuman primates

    Energy Technology Data Exchange (ETDEWEB)

    Walovitch, R.C.; Hill, T.C.; Garrity, S.T.; Cheesman, E.H.; Burgess, B.A.; O' Leary, D.H.; Watson, A.D.; Ganey, M.V.; Morgan, R.A.; Williams, S.J. (E.I. Du Pont de Nemours Co., Inc., No. Billerica, MA (USA))

    1989-11-01

    Technetium-99m ethyl cysteinate dimer (({sup 99m}Tc)ECD) is a neutral, lipophilic complex which rapidly crosses the blood-brain barrier. Brain retention and tissue metabolism of ({sup 99m}Tc)ECD is dependent upon the stereochemical configuration of the complex. While both L,L and D,D enantiomers are extracted by the brain, only the L,L but not the D,D form, is metabolized and retained in the monkey brain (4.7% injected dose initially, T 1/2 greater than 24 hr). Dynamic single photon emission computed tomography imaging studies in one monkey indicates {sup 99m}Tc-L,L-ECD to be distributed in a pattern consistent with regional cerebral blood flow for up to 16 hr postinjection. Dual-labeled {sup 99m}Tc-L,L-ECD and ({sup 14}C)iodoantipyrine autoradiography studies performed 1 hr after administration show cortical gray to white matter ratios of both isotopes to be equivalent (approximately 4-5:1). These data suggest that {sup 99m}Tc-L,L-ECD will be useful for the scintigraphic assessment of cerebral perfusion in humans.

  6. Cocaine is pharmacologically active in the nonhuman primate fetal brain

    DEFF Research Database (Denmark)

    Benveniste, Helene; Fowler, Joanna S; Rooney, William D;

    2010-01-01

    Cocaine use during pregnancy is deleterious to the newborn child, in part via its disruption of placental blood flow. However, the extent to which cocaine can affect the function of the fetal primate brain is still an unresolved question. Here we used PET and MRI and show that in third-trimester ......Cocaine use during pregnancy is deleterious to the newborn child, in part via its disruption of placental blood flow. However, the extent to which cocaine can affect the function of the fetal primate brain is still an unresolved question. Here we used PET and MRI and show that in third......-trimester pregnant nonhuman primates, cocaine at doses typically used by drug abusers significantly increased brain glucose metabolism to the same extent in the mother as in the fetus (approximately 100%). Inasmuch as brain glucose metabolism is a sensitive marker of brain function, the current findings provide...... are influenced by the state of pregnancy. Our findings have clinical implications because they imply that the adverse effects of prenatal cocaine exposure to the newborn child include not only cocaine's deleterious effects to the placental circulation, but also cocaine's direct pharmacological effect...

  7. Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats.

    Science.gov (United States)

    Gu, Xiaohuan; Wei, Zheng Zachory; Espinera, Alyssa; Lee, Jin Hwan; Ji, Xiaoya; Wei, Ling; Dix, Thomas A; Yu, Shan Ping

    2015-05-01

    Neonatal brain trauma is linked to higher risks of mortality and neurological disability. The use of mild to moderate hypothermia has shown promising potential against brain injuries induced by stroke and traumatic brain injury (TBI) in various experimental models and in clinical trials. Conventional methods of physical cooling, however, are difficult to use in acute treatments and in induction of regulated hypothermia. In addition, general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Our recent investigations demonstrate the potential therapeutic benefits of pharmacologically induced hypothermia (PIH) using the neurotensin receptor (NTR) agonist HPI201 (formerly known as ABS201) in stroke and TBI models of adult rodents. The present investigation explored the brain protective effects of HPI201 in a P14 rat pediatric model of TBI induced by controlled cortical impact. When administered via intraperitoneal (i.p.) injection, HPI201 induced dose-dependent reduction of body and brain temperature. A 6-h hypothermic treatment, providing an overall 2-3°C reduction of brain and body temperature, showed significant effect of attenuating the contusion volume versus TBI controls. Attenuation occurs whether hypothermia is initiated 15min or 2h after TBI. No shivering response was seen in HPI201-treated animals. HPI201 treatment also reduced TUNEL-positive and TUNEL/NeuN-colabeled cells in the contusion area and peri-injury regions. TBI-induced blood-brain barrier damage was attenuated by HPI201 treatment, evaluated using the Evans Blue assay. HPI201 significantly decreased MMP-9 levels and caspase-3 activation, both of which are pro-apototic, while it increased anti-apoptotic Bcl-2 gene expression in the peri-contusion region. In addition, HPI201 prevented the up-regulation of pro-inflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6. In sensorimotor activity assessments, rats in the HPI201

  8. Pharmacologic Management of Paroxysmal Sympathetic Hyperactivity After Brain Injury.

    Science.gov (United States)

    Samuel, Sophie; Allison, Teresa A; Lee, Kiwon; Choi, Huimahn A

    2016-04-01

    Paroxysmal sympathetic hyperactivity (PSH) is a result of acute brain injury that has been well known for many decades. However, the evidence for management of PSH is almost entirely anecdotal in nature. We reviewed case reports or series of pharmacotherapy management of PSH. These studies mentioned treatment options, but few studies exist to guide treatment strategies. For many years, the syndrome was not clearly understood; therefore, the therapy has focused on control of symptoms. In 2014, a Steering Committee came together to develop a conceptual definition and produced a consensus set of diagnostic criteria. Although understanding the diagnostic criteria is very well needed in management of patients with PSH, pharmacologic management is also crucial. Data describing the drug choices, dosing, and duration of therapy are also sparse. Recognition of appropriate medications is important because PSH is associated with morbidity, longer hospitalization, delaying transfer to rehabilitation units, and increasing cost. In this review article, we discussed the common medications used in the treatment of PSH. Treatment should target symptom abortion, prevention of symptoms, and refractory treatment. Symptom-abortive medications are indicated to control discrete breakthrough episodes, using medications such as morphine and short-acting benzodiazepines. Other medications used for prevention of symptoms and refractory treatment include long-acting benzodiazepines, nonselective β-blockers, α2 agonists, opioids, and GABA agonists. The mechanisms by which these agents improve symptoms of PSH remain speculative. However, a combination of medications from different classes seems the most effective approach in managing PSH symptoms. There is wide variability in clinical practice with regard to drug choices, dosing, and duration of therapy. Future research needs to be conducted using the new PSH assessment measure to appropriately apply drug management. PMID:26954919

  9. Effects of non-pharmacological or pharmacological interventions to promote cognition and brain plasticity in aging individuals

    Directory of Open Access Journals (Sweden)

    Valentina ePieramico

    2014-09-01

    Full Text Available Brain aging and aging-related neurodegenerative disorders are major health challenges faced by modern societies. Brain aging is associated with cognitive and functional decline and represents the favourable background for the onset and development of dementia. Brain aging is associated with early and subtle anatomo-functional physiological changes that often precede the appearance of clinical signs of cognitive decline. Neuroimaging approaches unveiled the functional correlates of these alterations and helped in the identification of therapeutic targets that can be potentially useful in counteracting age-dependent cognitive decline.A growing body of evidence supports the notion that cognitive stimulation and aerobic training can preserve and enhance operational skills in elderly individuals as well as reduce the incidence of dementia. This review aims at providing an extensive and critical overview of the most recent data that support the efficacy of non-pharmacological and pharmacological interventions aimed at enhancing cognition and brain plasticity in healthy elderly individuals as well as delaying the cognitive decline associated with dementia.

  10. Cocaine is pharmacologically active in the nonhuman primate fetal brain

    DEFF Research Database (Denmark)

    Benveniste, Helene; Fowler, Joanna S; Rooney, William D;

    2010-01-01

    -trimester pregnant nonhuman primates, cocaine at doses typically used by drug abusers significantly increased brain glucose metabolism to the same extent in the mother as in the fetus (approximately 100%). Inasmuch as brain glucose metabolism is a sensitive marker of brain function, the current findings provide......Cocaine use during pregnancy is deleterious to the newborn child, in part via its disruption of placental blood flow. However, the extent to which cocaine can affect the function of the fetal primate brain is still an unresolved question. Here we used PET and MRI and show that in third...... evidence that cocaine use by a pregnant mother will also affect the function of the fetal brain. We are also unique in showing that cocaine's effects in brain glucose metabolism differed in pregnant (increased) and nonpregnant (decreased) animals, which suggests that the psychoactive effects of cocaine...

  11. Pharmacological Neuroprotection after Perinatal Hypoxic-Ischemic Brain Injury

    NARCIS (Netherlands)

    Fan, Xiyong; Kavelaars, Annemieke; Heijnen, Cobi J.; Groenendaal, Floris; van Bel, Frank

    2010-01-01

    Perinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury. Recent progress in the search for neuroprotective compounds has provided us with several promising drugs to reduce perinatal HI-induced brain injury. In the early stage (first 6 hours after birth) therapies are concentra

  12. Cocaine is pharmacologically active in the nonhuman primate fetal brain

    OpenAIRE

    Benveniste, Helene; Fowler, Joanna S.; Rooney, William D; Scharf, Bruce A.; Backus, W. Walter; Izrailtyan, Igor; Knudsen, Gitte M; Hasselbalch, Steen G; Volkow, Nora D.

    2010-01-01

    Cocaine use during pregnancy is deleterious to the newborn child, in part via its disruption of placental blood flow. However, the extent to which cocaine can affect the function of the fetal primate brain is still an unresolved question. Here we used PET and MRI and show that in third-trimester pregnant nonhuman primates, cocaine at doses typically used by drug abusers significantly increased brain glucose metabolism to the same extent in the mother as in the fetus (∼100%). Inasmuch as brain...

  13. Pharmacologic resuscitation for hemorrhagic shock combined with traumatic brain injury

    DEFF Research Database (Denmark)

    Jin, Guang; Duggan, Michael; Imam, Ayesha;

    2012-01-01

    We have previously demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, can improve survival after hemorrhagic shock (HS), protect neurons from hypoxia-induced apoptosis, and attenuate the inflammatory response. We have also shown that administration of 6% hetastarch (Hextend [...... [Hex]) after traumatic brain injury (TBI) decreases brain swelling, without affecting size of the lesion. This study was performed to determine whether addition of VPA to Hex would decrease the lesion size in a clinically relevant large animal model of TBI + HS....

  14. Inclusion of terpenes in cyclodextrins: Preparation, characterization and pharmacological approaches.

    Science.gov (United States)

    Lima, Pollyana S S; Lucchese, Angélica M; Araújo-Filho, Heitor G; Menezes, Paula P; Araújo, Adriano A S; Quintans-Júnior, Lucindo J; Quintans, Jullyana S S

    2016-10-20

    Terpenes constitute the largest class of natural products and are important resources for the pharmaceutical, food and cosmetics industries. However, due to their low water solubility and poor bioavailability there has been a search for compounds that could improve their physicochemical properties. Cyclodextrins (natural and derived) have been proposed for this role and have been complexed with different types of terpenes. This complexation has been demonstrated by using analytical techniques for characterizing complexes such as DSC, NMR, XRD, FTIR, and TGA. The formation of inclusion complexes has been able to improve drug characteristics such as bioavailability, solubility and stability; and to enhance biological activity and efficacy. This review shows strong experimental evidence that cyclodextrins improve the pharmacological properties of terpenes, and therefore need to be recognized as being possible targets for clinical use. PMID:27474645

  15. A Narrative Review of Pharmacologic and Non-pharmacologic Interventions for Disorders of Consciousness Following Brain Injury in the Pediatric Population

    OpenAIRE

    Evanson, Nathan K.; Paulson, Andrea L.; Kurowski, Brad G.

    2016-01-01

    Traumatic brain injury (TBI) is the most common cause of long-term disability in the United States. A significant proportion of children who experience a TBI will have moderate or severe injuries, which includes a period of decreased responsiveness. Both pharmacological and non-pharmacological modalities are used for treating disorders of consciousness after TBI in children. However, the evidence supporting the use of potential therapies is relatively scant, even in adults, and overall, there...

  16. Synthesis, characterization and pharmacological evaluation of amide prodrugs of Flurbiprofen

    Energy Technology Data Exchange (ETDEWEB)

    Mishra, Ashutosh; Veerasamy, Ravichandran; Jain, Prateek Kumar; Dixit, Vinod Kumar; Agrawal, Ram Kishor [Dr. H. S. Gour Vishwavidyalaya, Sagar (India). Dept. of Pharmaceutical Sciences. Pharmaceutical Chemistry Research Lab.]. E-mail: dragrawal2001@yahoo.co.in

    2008-07-01

    Flurbiprofen (FB) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study was aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of FB were synthesized by amidation with ethyl esters of amino acids, namely, glycine, L-phenylalanine, L-tryptophan, L-valine, L-isoleucine, L-alanine, L-leucine, L-glutamic acid, L-aspartic acid and {beta} alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for bioavailability studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, antiinflammatory activities were obtained in all cases as compared to FB. Among synthesized prodrugs AR-9, AR-10 and AR-2 showing excellent pharmacological response and encouraging hydrolysis rate both in (Simulated Intestinal Fluid) SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent resulted in enhanced partition coefficient but diminished dissolution and hydrolysis rate. Such prodrugs can be considered for sustained release purpose. (author)

  17. Synthesis, characterization and pharmacological evaluation of amide prodrugs of Flurbiprofen

    International Nuclear Information System (INIS)

    Flurbiprofen (FB) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study was aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of FB were synthesized by amidation with ethyl esters of amino acids, namely, glycine, L-phenylalanine, L-tryptophan, L-valine, L-isoleucine, L-alanine, L-leucine, L-glutamic acid, L-aspartic acid and β alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for bioavailability studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, antiinflammatory activities were obtained in all cases as compared to FB. Among synthesized prodrugs AR-9, AR-10 and AR-2 showing excellent pharmacological response and encouraging hydrolysis rate both in (Simulated Intestinal Fluid) SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent resulted in enhanced partition coefficient but diminished dissolution and hydrolysis rate. Such prodrugs can be considered for sustained release purpose. (author)

  18. Pharmacological characterization of social isolation-induced hyperactivity

    DEFF Research Database (Denmark)

    Fabricius, Katrine; Helboe, Lone; Fink-Jensen, Anders;

    2011-01-01

    Social isolation (SI) of rats directly after weaning is a non-pharmacological, non-lesion animal model based on the neurodevelopmental hypothesis of schizophrenia. The model causes several neurobiological and behavioral alterations consistent with observations in schizophrenia.......Social isolation (SI) of rats directly after weaning is a non-pharmacological, non-lesion animal model based on the neurodevelopmental hypothesis of schizophrenia. The model causes several neurobiological and behavioral alterations consistent with observations in schizophrenia....

  19. Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity.

    Science.gov (United States)

    Ghanem, Carolina I; Pérez, María J; Manautou, José E; Mottino, Aldo D

    2016-07-01

    Acetaminophen (APAP) is a well-known analgesic and antipyretic drug. It is considered to be safe when administered within its therapeutic range, but in cases of acute intoxication, hepatotoxicity can occur. APAP overdose is the leading cause of acute liver failure in the northern hemisphere. Historically, studies on APAP toxicity have been focused on liver, with alterations in brain function attributed to secondary effects of acute liver failure. However, in the last decade the pharmacological mechanism of APAP as a cannabinoid system modulator has been documented and some articles have reported "in situ" toxicity by APAP in brain tissue at high doses. Paradoxically, low doses of APAP have been reported to produce the opposite, neuroprotective effects. In this paper we present a comprehensive, up-to-date overview of hepatic toxicity as well as a thorough review of both toxic and beneficial effects of APAP in brain. PMID:26921661

  20. Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.

    Science.gov (United States)

    Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

    2016-01-01

    MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results. PMID:26105141

  1. Comparison of [11C]cocaine binding at tracer and pharmacological doses of baboon brain: A PET study

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Fowler, J.S.; Logan, J. [Brookhaven National Lab., Upton, NY (United States)] [and others

    1994-05-01

    In vitro studies have shown that cocaine (C) binds to both high and low affinity sites on the dopamine transporter (DAT). We have previously characterized the binding of tracer doses of [{sup 11}C]cocaine (C*)to a high affinity site on the DAT. To assess if in vivo C also binds to low affinity sites we used PET to compare binding of tracer doses (17.8{plus_minus}12.2 {mu}g C) of C* to pharmacological doses (8 mg of C coadministered with C*). Sixteen paired studies were done to assess test/retest variability, specific versus non specific binding and to characterize binding profile. Dynamic scans were started immediately after injection of C* (5-8 mCi) for 50 min on the CTI-931 (6 x 6 x 6.5 mm FWHM). Time activity curves for tissue concentration and for unchanged tracer in plasma were used to calculate the transport constant between plasma and tissue (K1) and to obtain the distribution volume (DV). The ratio of the DV in striatum (ST) to that in cerebellum (CB) (which corresponds to Bmax/Kd-1) was used as model parameter. Peak brain uptake of C* was significantly higher for tracer than for pharmacological doses (0.041 versus 0.033 % dose/cc), as were the values for K1 (1.07{plus_minus}0.21 versus 0.68{plus_minus}0.26 (t=3.0 p<0.01)). Repeated measures were reproducible for tracer ({plus_minus}2%) and pharmacological doses of C* ({plus_minus}4%). Tracer dose C* showed highest binding and slowest clearance in ST which was reduced by C (0.5-2.0 mg/kg iv, -25 to -30%) and by drugs that inhibit DAT (2mg/kg nomifensine - 21%, 0.5 mg/kg methylphenidate -12%) and was increased by serotonin transporter inhibitors (5HT-Ti) (2 mg/kg citalopram +11%, 0.5 mg/kg fluoxetine +6%) and not changed by NE transporter inhibitors (0.5 mg/kg desipramine or 2 mg/kg tomoxetine). The increase with (5HT-Ti) may reflect neurotransmitter interactions or changes in bioavailability. At pharmacological doses C* showed homogeneous distribution and was not changed by C nor by any of the above drugs.

  2. 2-(/sup 125/I)iodomelatonin binding sites in hamster brain membranes: pharmacological characteristics and regional distribution

    Energy Technology Data Exchange (ETDEWEB)

    Duncan, M.J.; Takahashi, J.S.; Dubocovich, M.L.

    1988-05-01

    Studies in a variety of seasonally breeding mammals have shown that melatonin mediates photoperiodic effects on reproduction. Relatively little is known, however, about the site(s) or mechanisms of action of this hormone for inducing reproductive effects. Although binding sites for (3H)melatonin have been reported previously in bovine, rat, and hamster brain, the pharmacological selectivity of these sites was never demonstrated. In the present study, we have characterized binding sites for a new radioligand, 2-(125I)iodomelatonin, in brains from a photoperiodic species, the Syrian hamster. 2-(125I)Iodomelatonin labels a high affinity binding site in hamster brain membranes. Specific binding of 2-(125I)iodomelatonin is rapid, stable, saturable, and reversible. Saturation studies demonstrated that 2-(125I)iodomelatonin binds to a single class of sites with an affinity constant (Kd) of 3.3 +/- 0.5 nM and a total binding capacity (Bmax) of 110.2 +/- 13.4 fmol/mg protein (n = 4). The Kd value determined from kinetic analysis (3.1 +/- 0.9 nM; n = 5) was very similar to that obtained from saturation experiments. Competition experiments showed that the relative order of potency of a variety of indoles for inhibition of 2-(125I)iodomelatonin binding site to hamster brain membranes was as follows: 6-chloromelatonin greater than or equal to 2-iodomelatonin greater than N-acetylserotonin greater than or equal to 6-methoxymelatonin greater than or equal to melatonin greater than 6-hydroxymelatonin greater than or equal to 6,7-dichloro-2-methylmelatonin greater than 5-methoxytryptophol greater than 5-methoxytryptamine greater than or equal to 5-methoxy-N,N-dimethyltryptamine greater than N-acetyltryptamine greater than serotonin greater than 5-methoxyindole (inactive).

  3. 2-[125I]iodomelatonin binding sites in hamster brain membranes: pharmacological characteristics and regional distribution

    International Nuclear Information System (INIS)

    Studies in a variety of seasonally breeding mammals have shown that melatonin mediates photoperiodic effects on reproduction. Relatively little is known, however, about the site(s) or mechanisms of action of this hormone for inducing reproductive effects. Although binding sites for [3H]melatonin have been reported previously in bovine, rat, and hamster brain, the pharmacological selectivity of these sites was never demonstrated. In the present study, we have characterized binding sites for a new radioligand, 2-[125I]iodomelatonin, in brains from a photoperiodic species, the Syrian hamster. 2-[125I]Iodomelatonin labels a high affinity binding site in hamster brain membranes. Specific binding of 2-[125I]iodomelatonin is rapid, stable, saturable, and reversible. Saturation studies demonstrated that 2-[125I]iodomelatonin binds to a single class of sites with an affinity constant (Kd) of 3.3 +/- 0.5 nM and a total binding capacity (Bmax) of 110.2 +/- 13.4 fmol/mg protein (n = 4). The Kd value determined from kinetic analysis (3.1 +/- 0.9 nM; n = 5) was very similar to that obtained from saturation experiments. Competition experiments showed that the relative order of potency of a variety of indoles for inhibition of 2-[125I]iodomelatonin binding site to hamster brain membranes was as follows: 6-chloromelatonin greater than or equal to 2-iodomelatonin greater than N-acetylserotonin greater than or equal to 6-methoxymelatonin greater than or equal to melatonin greater than 6-hydroxymelatonin greater than or equal to 6,7-dichloro-2-methylmelatonin greater than 5-methoxytryptophol greater than 5-methoxytryptamine greater than or equal to 5-methoxy-N,N-dimethyltryptamine greater than N-acetyltryptamine greater than serotonin greater than 5-methoxyindole (inactive)

  4. Synthesis and pharmacological characterization of certain baclofen analogues

    DEFF Research Database (Denmark)

    Attia, M.I.; Herdeis, C.; Bräuner-Osborne, Hans

    2013-01-01

    (RS)-4-Amino-3-(4-chlorophenyl)butanoic acid (baclofen, 2) is the prototypic selective GABAR agonist and is used clinically for the treatment of spasticity associated with brain and spinal cord injuries. Synthesis and GABA receptor agonist activity of certain amino acids structurally related...

  5. Pharmacological characterization of a novel antiglaucoma agent, Bimatoprost (AGN 192024).

    Science.gov (United States)

    Woodward, D F; Krauss, A H-P; Chen, J; Liang, Y; Li, C; Protzman, C E; Bogardus, A; Chen, R; Kedzie, K M; Krauss, H A; Gil, D W; Kharlamb, A; Wheeler, L A; Babusis, D; Welty, D; Tang-Liu, D D-S; Cherukury, M; Andrews, S W; Burk, R M; Garst, M E

    2003-05-01

    Replacement of the carboxylic acid group of prostaglandin (PG) F(2alpha) with a nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel PGF(2alpha) analog, where the carboxylic acid is replaced by a neutral ethylamide substituent. Bimatoprost potently contracted the feline lung parenchymal preparation (EC(50) value of 35-55 nM) but exhibited no meaningful activity in a variety of PG-sensitive tissue and cell preparations. Its activity seemed unrelated to FP receptor stimulation according to the following evidence. 1) Bimatoprost exhibited no meaningful activity in tissues and cells containing functional FP receptors. 2) Bimatoprost activity in the cat lung parenchyma is not species-specific because its potent activity in this preparation could not be reproduced in cells stably expressing the feline FP receptor. 3) Radioligand binding studies using feline and human recombinant FP receptors exhibited minimal competition versus [(3)H]17-phenyl PGF(2a) for Bimatoprost. 4) Bimatoprost pretreatment did not attenuate PGF(2alpha)-induced Ca(2+) signals in Swiss 3T3 cells. 5) Regional differences were apparent for Bimatoprost but not FP agonist effects in the cat lung. Bimatoprost reduced intraocular pressure in ocular normotensive and hypertensive monkeys over a 0.001 to 0.1% dose range. A single-dose and multiple-dose ocular distribution/metabolism studies using [(3)H]Bimatoprost (0.1%) were performed. Within the globe, bimatoprost concentrations were 10- to 100-fold higher in anterior segment tissues compared with the aqueous humor. Bimatoprost was overwhelmingly the predominant molecular species identified at all time points in ocular tissues, indicating that the intact molecule reduces intraocular pressure.

  6. Pharmacological Preventions of Brain Injury Following Experimental Germinal Matrix Hemorrhage: an Up-to-Date Review.

    Science.gov (United States)

    Tang, Jun; Tao, Yihao; Jiang, Bing; Chen, Qianwei; Hua, Feng; Zhang, John; Zhu, Gang; Chen, Zhi

    2016-02-01

    Germinal matrix hemorrhage (GMH) is defined as the rupture of immature blood vessels in the subependymal zone of premature infants with significant mortality and morbidity. Considering the notable social and ecological stress brought by GMH-induced brain injury and sequelae, safe and efficient pharmacological preventions are badly needed. Currently, several appropriate animal models are available to mimic the clinical outcomes of GMH in human patients. In the long run, hemorrhagic strokes are the research target. Previously, we found that minocycline was efficient to alleviate GMH-induced brain edema and posthemorrhagic hydrocephalus (PHH) in rats, which may be closely related to the activation of cannabinoid receptor 2 (CB2R). However, how the two molecules correlate and the underlined molecular pathway remain unknown. To extensively understand current experimental GMH treatment, this literature review critically evaluates existing therapeutic strategies, potential treatments, and potentially involved molecular mechanisms. Each strategy has its own advantages and disadvantages. Some of the mechanisms are still controversial, requiring an increasing number of animal experiments before the therapeutic strategy would be widely accepted.

  7. Pain facilitation brain regions activated by nalbuphine are revealed by pharmacological fMRI.

    Directory of Open Access Journals (Sweden)

    Robert Gear

    Full Text Available Nalbuphine, an agonist-antagonist kappa-opioid, produces brief analgesia followed by enhanced pain/hyperalgesia in male postsurgical patients. However, it produces profound analgesia without pain enhancement when co-administration with low dose naloxone. To examine the effect of nalbuphine or nalbuphine plus naloxone on activity in brain regions that may explain these differences, we employed pharmacological magnetic resonance imaging (phMRI in a double blind cross-over study with 13 healthy male volunteers. In separate imaging sessions subjects were administered nalbuphine (5 mg/70 kg preceded by either saline (Sal-Nalb or naloxone 0.4 mg (Nalox-Nalb. Blood oxygen level-dependent (BOLD activation maps followed by contrast and connectivity analyses revealed marked differences. Sal-Nalb produced significantly increased activity in 60 brain regions and decreased activity in 9; in contrast, Nalox-Nalb activated only 14 regions and deactivated only 3. Nalbuphine, like morphine in a previous study, attenuated activity in the inferior orbital cortex, and, like noxious stimulation, increased activity in temporal cortex, insula, pulvinar, caudate, and pons. Co-administration/pretreatment of naloxone selectively blocked activity in pulvinar, pons and posterior insula. Nalbuphine induced functional connectivity between caudate and regions in the frontal, occipital, temporal, insular, middle cingulate cortices, and putamen; naloxone co-admistration reduced all connectivity to non-significant levels, and, like phMRI measures of morphine, increased activation in other areas (e.g., putamen. Naloxone pretreatment to nalbuphine produced changes in brain activity possess characteristics of both analgesia and algesia; naloxone selectively blocks activity in areas associated with algesia. Given these findings, we suggest that nalbuphine interacts with a pain salience system, which can modulate perceived pain intensity.

  8. Molecular cloning, tissue distribution, and pharmacological characterization of melanocortin-4 receptor in spotted scat, Scatophagus argus.

    Science.gov (United States)

    Li, Jian-Tao; Yang, Zhao; Chen, Hua-Pu; Zhu, Chun-Hua; Deng, Si-Ping; Li, Guang-Li; Tao, Ya-Xiong

    2016-05-01

    Melanocortin-4 receptor (MC4R) plays an important role in the regulation of food intake and energy expenditure in mammals. The functions of the MC4R in fish have not been investigated extensively. We herein reported on the cloning, tissue distribution, and pharmacological characterization of spotted scat (Scatophagus argus) MC4R (SAMC4R). It consisted of a 984bp open reading frame predicted to encode a protein of 327 amino acids. Sequence analysis revealed that SAMC4R was highly homologous (>80%) at amino acid levels to several teleost MC4Rs. Phylogenetic analyses showed that SAMC4R was closely related to piscine MC4R. Using RT-PCR, we showed that in addition to brain, pituitary, and gonads, mc4r mRNA was also widely expressed in peripheral tissues of spotted scat in sexually divergent pattern. With human MC4R (hMC4R) as a control, several agonists including α-melanocyte stimulating hormone (α-MSH), [Nle(4), D-Phe(7)]-α-MSH (NDP-MSH), adrenocorticotropic hormone (ACTH) and THIQ (N-[(3R)-1,2,3,4-tetrahydroisoquinolinium3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl]-2-oxoethylamine), were used to investigate the binding and signaling properties of SAMC4R. The results showed that SAMC4R bound NDP-MSH with the highest affinity followed by ACTH (1-24) and α-MSH. Similar ranking was also found for hMC4R, although SAMC4R had two to five-fold higher affinities for these ligands. THIQ did not displace NDP-MSH from SAMC4R, different from hMC4R. α-MSH, NDP-MSH, and ACTH (1-24) were identified as potent agonists to stimulate cAMP generation followed by THIQ in SAMC4R. The availability of SAMC4R and its pharmacological characteristics will facilitate the investigation of its function in regulating diverse physiological processes in spotted scat. PMID:27080551

  9. Connexin and pannexin hemichannels in brain glial cells: properties, pharmacology and roles

    Directory of Open Access Journals (Sweden)

    Christian eGiaume

    2013-07-01

    Full Text Available Functional interaction between neurons and glia is an exciting field that has expanded tremendously during the past decade. Such partnership has multiple impacts on neuronal activity and survival. Indeed, numerous findings indicate that glial cells interact tightly with neurons in physiological as well as pathological situations. One typical feature of glial cells is their high expression level of gap junction protein subunits, named connexins (Cxs, thus the membrane channels they form may contribute to neuroglial interaction that impacts neuronal activity and survival. While the participation of gap junction channels in neuroglia interactions has been regularly reviewed in the past, the other channel function of Cxs, i.e. hemichannels located at the cell surface, has only recently received attention. While gap junction channels provide the basis for a unique direct cell-to-cell communication, Cx hemichannels allow the exchange of ions and signaling molecules between the cytoplasm and the extracellular medium, thus supporting autocrine and paracrine communication through a process referred to as gliotransmission, as well as uptake and release of metabolites. More recently, another family of proteins, termed pannexins (Panxs, has been identified. These proteins share similar membrane topology but no sequence homology with Cxs. They form multimeric membrane channels with pharmacology somewhat overlapping with that of Cx hemichannels. Such duality has led to several controversies in the literature concerning the identification of the molecular channel constituents (Cxs versus Panxs in glia. In the present review, we up-date and discuss the knowledge of Cx hemichannels and Panx channels in glia, their properties and pharmacology, as well as the understanding of their contribution to neuroglia interactions in healthy and diseased brain.

  10. Formulations for Intranasal Delivery of Pharmacological Agents to Combat Brain Disease: A New Opportunity to Tackle GBM?

    Directory of Open Access Journals (Sweden)

    Stefaan W. van Gool

    2013-08-01

    Full Text Available Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of patients diagnosed with glioblastoma multiforme does not exceed 15 months. Infiltration of glioma cells into the brain parenchyma, and the blood-brain barrier are important hurdles to further increase the efficacy of classic therapeutic tools. Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events. The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain. This route will bypass the blood-brain barrier and limit systemic side effects. Upon presentation at the nasal cavity, pharmacological agents reach the brain via the olfactory and trigeminal nerves. Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles. In this review, the focus will be on formulations of pharmacological agents, which increase the nasal permeation of hydrophilic agents to the brain, improve delivery at a constant and slow release rate, protect therapeutics from degradation along the pathway, increase mucoadhesion, and facilitate overall nasal transport. A mounting body of evidence is accumulating that the underexplored intranasal delivery route might represent a major breakthrough to combat glioblastoma.

  11. Synthesis, Characterization, and Pharmacological Evaluation of Selected Aromatic Amines

    Directory of Open Access Journals (Sweden)

    Hammad Ismail

    2015-01-01

    Full Text Available Aromatic amines 1-amino-4-phenoxybenzene (A-1A, 2-(4-aminophenoxy naphthalene (A-2A, and 1-(4-aminophenoxy naphthalene (A-3A were synthesized by the reduction of corresponding nitroaromatics with hydrazine monohydrate and Pd/C 5% (w/w. The newly synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR, UV-visible spectrophotometer, and mass spectrometry and their biological activities were investigated along with structurally similar 4-(4-aminophenyloxy biphenyl (A-A. Results of brine shrimp cytotoxicity assay showed that almost all of the compounds had LD50 values <1 μg/mL. The compounds also showed significant antitumor activity with IC50 values ranging from 67.45 to 12.2 µgmL−1. The cytotoxicity and antitumor studies correlate the results which suggests the anticancerous nature of compounds. During the interaction study of these compounds with DNA, all of the compounds showed hyperchromic effect indicating strong interaction through binding with the grooves of DNA. Moreover, A-3A also showed decrease in λmax confirming higher propensity for DNA groove binding. In DPPH free radical scavenging assay, all the compounds showed potential antioxidant capability. The compounds were highly active in protecting DNA against hydroxyl free radicals. DNA interaction and antioxidant results back up each other indicating that these compounds have potential to be used as cancer chemopreventive agents. Additionally, one compound (A-1A showed significant antibacterial and antifungal activity as well.

  12. The pharmacological effects of ginkgo biloba, a plant extract, on the brain of dementia patients in comparison with tacrine.

    Science.gov (United States)

    Itil, T M; Eralp, E; Ahmed, I; Kunitz, A; Itil, K Z

    1998-01-01

    In 1994, a standardized dry extract of Ginkgo biloba leaves (SeGb), has been approved by German health authorities for the treatment of primary degenerative dementia and vascular dementia. More than 24 different brands of Ginkgo biloba extract are sold in the United States. Tacrine, also known as tetrahydroaminoacrine (THA), and donepezil are currently the only drugs approved in the United States for the treatment of Alzheimer's disease. Previous studies demonstrated that SeGb and tacrine induce significant pharmacological effects on the brains of young, healthy human males, as determined by bioelectrical activity measurements obtained using the quantitative pharmaco-electroencephalogram (QPEEG) method. The type of central nervous system (CNS) effects we have seen on computer-analyzed EEGs (CEEGs) after administration of tacrine or EGb suggests both are "cognitive activators" which are, as a class of products, characterized by a (prepost) relative increase of 7.5 to 13 Hz ("alpha") and decrease of 1.3 to 7.5 Hz ("delta" and "theta") activity. To determine whether EGb or tacrine had noticeable pharmacological effects on elderly subjects diagnosed with possible or probable Alzheimer's, the present open, uncontrolled trial was conducted. Data from 18 subjects (11 males, 7 females) at an average age of 67.4 years with light to moderate dementia (Mini Mental mean score = 23.7, ranges: 15-29 [Geriatric Depression Scale mean scores = 3.7; range: 3.2-5.4]) were analyzed for this presentation. Each subject was randomly administered a single oral "Test-Dose" of either 40 mg of tacrine or 240 mg of EGb2 in two separate sessions within 3- to 7-day intervals. Before drug administration and at 1- and 3-hour intervals after drug administration, CEEGs were recorded for a minimum of 10 minutes. The CEEGs were analyzed using Period Analysis programs we developed for QPEEG. The results indicated that both EGb and, to a lesser degree, tacrine induced pharmacological effects, as

  13. The pharmacological effects of ginkgo biloba, a plant extract, on the brain of dementia patients in comparison with tacrine.

    Science.gov (United States)

    Itil, T M; Eralp, E; Ahmed, I; Kunitz, A; Itil, K Z

    1998-01-01

    In 1994, a standardized dry extract of Ginkgo biloba leaves (SeGb), has been approved by German health authorities for the treatment of primary degenerative dementia and vascular dementia. More than 24 different brands of Ginkgo biloba extract are sold in the United States. Tacrine, also known as tetrahydroaminoacrine (THA), and donepezil are currently the only drugs approved in the United States for the treatment of Alzheimer's disease. Previous studies demonstrated that SeGb and tacrine induce significant pharmacological effects on the brains of young, healthy human males, as determined by bioelectrical activity measurements obtained using the quantitative pharmaco-electroencephalogram (QPEEG) method. The type of central nervous system (CNS) effects we have seen on computer-analyzed EEGs (CEEGs) after administration of tacrine or EGb suggests both are "cognitive activators" which are, as a class of products, characterized by a (prepost) relative increase of 7.5 to 13 Hz ("alpha") and decrease of 1.3 to 7.5 Hz ("delta" and "theta") activity. To determine whether EGb or tacrine had noticeable pharmacological effects on elderly subjects diagnosed with possible or probable Alzheimer's, the present open, uncontrolled trial was conducted. Data from 18 subjects (11 males, 7 females) at an average age of 67.4 years with light to moderate dementia (Mini Mental mean score = 23.7, ranges: 15-29 [Geriatric Depression Scale mean scores = 3.7; range: 3.2-5.4]) were analyzed for this presentation. Each subject was randomly administered a single oral "Test-Dose" of either 40 mg of tacrine or 240 mg of EGb2 in two separate sessions within 3- to 7-day intervals. Before drug administration and at 1- and 3-hour intervals after drug administration, CEEGs were recorded for a minimum of 10 minutes. The CEEGs were analyzed using Period Analysis programs we developed for QPEEG. The results indicated that both EGb and, to a lesser degree, tacrine induced pharmacological effects, as

  14. Pharmacological doses of gamma-hydroxybutyrate (GHB) potentiate histone acetylation in the rat brain by histone deacetylase inhibition.

    Science.gov (United States)

    Klein, Christian; Kemmel, Véronique; Taleb, Omar; Aunis, Dominique; Maitre, Michel

    2009-08-01

    Several small chain fatty acids, including butyrate, valproate, phenylbutyrate and its derivatives, inhibit several HDAC activities in the brain at a several hundred micromolar concentration. Gamma-hydroxy-butyrate (GHB), a natural compound found in the brain originating from the metabolism of GABA, is structurally related to these fatty acids. The average physiological tissue concentration of GHB in the brain is below 50 microM, but when GHB is administered or absorbed for therapeutic or recreative purposes, its concentration reaches several hundred micromolars. In the present scenario, we demonstrate that pharmacological concentrations of GHB significantly induce brain histone H3 acetylation with a heterogeneous distribution in the brain and reduce in vitro HDAC activity. The degree of HDAC inhibition was also different according to the region of the brain considered. Taking into account the multiple physiological and functional roles attributed to the modification of histone acetylation and its consequences at the level of gene expression, we propose that part of the therapeutic or toxic effects of high concentrations of GHB in the brain after therapeutic administration of the drug could be partly due to GHB-induced epigenetic factors. In addition, we hypothesize that GHB, being naturally synthesized in the cytosolic compartment of certain neurons, could penetrate into the nuclei and may reach sufficient levels that could significantly modulate histone acetylation and may participate in the epigenetic modification of gene expression.

  15. Plausible antioxidant biomechanics and anticonvulsant pharmacological activity of brain-targeted β-carotene nanoparticles.

    Science.gov (United States)

    Yusuf, Mohammad; Khan, Riaz A; Khan, Maria; Ahmed, Bahar

    2012-01-01

    β-Carotene has been established as a known free radical scavenger with chain-breaking antioxidant properties. It has been documented for the treatment of epileptic convulsions at a 200 mg/kg body weight dose. The reported pathogenesis for epileptic convulsions is oxidative stress. Hence, experimental epileptic convulsions via oxidative stress was induced in albino mice epileptic models (maximal electroshock seizure and pentylenetetrazole [PTZ]). A dose concentration equivalent to 2 mg/kg was efficaciously administered in the form of brain-targeted polysorbate-80-coated poly(d,l-lactide-co-glycolide) nanoparticles. The nanoparticles were prepared by solvent evaporation technique and further characterized for their physical parameters, in-vitro release kinetics, and in-vivo brain release via various standard methods. Normal β-carotene nanoparticles (BCNP) and polysorbate-80-coated β-carotene nanoparticles (P-80-BCNP) of 169.8 ± 4.8 nm and 176.3 ± 3.2 nm in size, respectively, were formulated and characterized. Their zeta potential and polydispersity index were subsequently evaluated after 5 months of storage to confirm stability. In vivo activity results showed that a 2 mg unformulated β-carotene dose was ineffective as an anticonvulsant. However, salutary response was reported from BCNP at the same dose, as the hind limb duration decreased significantly in maximal electroshock seizure to 9.30 ± 0.86 seconds, which further decreased with polysorbate-80 coating to 2.10 ± 1.16 seconds as compared to normal control (15.8 ± 1.49 seconds) and placebo control (16.50 ± 1.43 seconds). In the PTZ model, the duration of general tonic-clonic seizures reduced significantly to 2.90 ± 0.98 seconds by the use of BCNP and was further reduced on P-80-BCNP to 1.20 ± 0.20 seconds as compared to PTZ control and PTZ-placebo control (8.09 ± 0.26 seconds). General tonic-clonic seizures latency was increased significantly to 191.0 ± 9.80 seconds in BCNP and was further

  16. Plausible antioxidant biomechanics and anticonvulsant pharmacological activity of brain-targeted β-carotene nanoparticles

    Directory of Open Access Journals (Sweden)

    Yusuf M

    2012-08-01

    Full Text Available Mohammad Yusuf,1 Riaz A Khan,3 Maria Khan,2 Bahar Ahmed11Department of Pharmaceutical Chemistry, 2Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Hamdard University, New Delhi, India; 3Department of Chemistry, Manav Rachna International University, National Capital Region, Aravali Hills, Faridabad, IndiaAbstract: β-Carotene has been established as a known free radical scavenger with chain-breaking antioxidant properties. It has been documented for the treatment of epileptic convulsions at a 200 mg/kg body weight dose. The reported pathogenesis for epileptic convulsions is oxidative stress. Hence, experimental epileptic convulsions via oxidative stress was induced in albino mice epileptic models (maximal electroshock seizure and pentylenetetrazole [PTZ]. A dose concentration equivalent to 2 mg/kg was efficaciously administered in the form of brain-targeted polysorbate-80-coated poly(d,l-lactide-co-glycolide nanoparticles. The nanoparticles were prepared by solvent evaporation technique and further characterized for their physical parameters, in-vitro release kinetics, and in-vivo brain release via various standard methods. Normal β-carotene nanoparticles (BCNP and polysorbate-80-coated β-carotene nanoparticles (P-80-BCNP of 169.8 ± 4.8 nm and 176.3 ± 3.2 nm in size, respectively, were formulated and characterized. Their zeta potential and polydispersity index were subsequently evaluated after 5 months of storage to confirm stability. In vivo activity results showed that a 2 mg unformulated β-carotene dose was ineffective as an anticonvulsant. However, salutary response was reported from BCNP at the same dose, as the hind limb duration decreased significantly in maximal electroshock seizure to 9.30 ± 0.86 seconds, which further decreased with polysorbate-80 coating to 2.10 ± 1.16 seconds as compared to normal control (15.8 ± 1.49 seconds and placebo control (16.50 ± 1.43 seconds. In the PTZ model, the duration of

  17. Pharmacological characterization of emerging synthetic cannabinoids in HEK293T cells and hippocampal neurons.

    Science.gov (United States)

    Costain, Willard J; Tauskela, Joseph S; Rasquinha, Ingrid; Comas, Tanya; Hewitt, Melissa; Marleau, Vincent; Soo, Evelyn C

    2016-09-01

    There has been a worldwide proliferation of synthetic cannabinoids that have become marketed as legal alternatives to cannabis (marijuana). Unfortunately, there is a dearth of information about the pharmacological effects of many of these emerging synthetic cannabinoids (ESCs), which presents a challenge for regulatory authorities that need to take such scientific evidence into consideration in order to regulate ECSs as controlled substances. We aimed to characterize the pharmacological properties of ten ESCs using two cell based assays that enabled the determination of potency and efficacy relative to a panel of well-characterized cannabinoids. Agonist-mediated inhibition of forskolin-stimulated cyclic adenosine monophosphate (cAMP) levels was monitored in live HEK293T cells transfected with human cannabinoid receptor 1 gene (CNR1) and pGloSensor-22F. Pharmacological analysis of this data indicated that all of the ESCs tested were full agonists, with the following rank order of potency: Win 55212-2≈5F-PB-22≈AB-PINACA≈EAM-2201≈MAM-2201>JWH-250≈ PB-22>AKB48 N-(5FP)>AKB-48≈STS-135>XLR-11. Assessment of agonist-stimulated depression of Ca(2+) transients was also used to confirm the efficacy of five ESCs (XLR-11, JWH-250, AB-PINACA, 5F-PB-22, and MAM-2201) in cultured primary hippocampal neurons. This work aims to help inform decisions made by regulatory agencies concerned with the profusion of these poorly characterized recreational drugs. PMID:27260125

  18. Pharmacological characterization of a selective agonist for Bombesin Receptor Subtype - 3

    OpenAIRE

    Zhang, Li; Nothacker, Hans-Peter; Wang, Zhiwei; Bohn, Laura M.; Civelli, Olivier

    2009-01-01

    Bombesin receptor subtype-3 (BRS-3) is an orphan G protein-coupled receptor in the bombesin receptor family that still awaits identification of its natural ligand. BRS-3 deficient mice develop a mild late-onset obesity with metabolic defects, implicating BRS-3 plays a role in feeding and metabolism. We describe here the pharmacological characterization of a synthetic compound, 16a, which serves as a potent agonist for BRS-3. This compound is selective for BRS-3 as it does not activate neurome...

  19. Pharmacological characterization of β2-adrenoceptor in PGT-β mouse pineal gland tumour cells

    OpenAIRE

    Suh, Byung-Chang; Chae, Hee-Don; Chung, Joo-Ho; Kim, Kyong-Tai

    1999-01-01

    The adrenoceptor in a mouse pineal gland tumour cell line (PGT-β) was identified and characterized using pharmacological and physiological approaches.Adrenaline and noradrenaline, adrenoceptor agonists, stimulated cyclic AMP generation in a concentration-dependent manner, but had no effect on inositol 1,4,5-trisphosphate production. Adrenaline was a more potent activator of cyclic AMP generation than noradrenaline, with half maximal-effective concentrations (EC50) seen at 175±22 nM and 18±2 μ...

  20. Acute pharmacologically induced shifts in serotonin availability abolish emotion-selective responses to negative face emotions in distinct brain networks

    DEFF Research Database (Denmark)

    Grady, Cheryl Lynn; Siebner, Hartwig R; Hornboll, Bettina;

    2013-01-01

    Pharmacological manipulation of serotonin availability can alter the processing of facial expressions of emotion. Using a within-subject design, we measured the effect of serotonin on the brain's response to aversive face emotions with functional MRI while 20 participants judged the gender...... enhanced the neural response of this set of regions to angry faces, relative to Control, and CIT also enhanced activity for neutral faces. The net effect of these changes in both networks was to abolish the selective response to fearful expressions. These results suggest that a normal level of serotonin...

  1. Biochemical and pharmacological characterization of irradiated crotamine by gamma rays of 60Co

    International Nuclear Information System (INIS)

    The serum production in Brazil, the only effective treatment in cases of snakebites, uses horses that although large size, have reduced l lifespan compared with horses not immunized. Ionizing radiation has been shown as an excellent tool in reducing the toxicity of venoms and toxins isolated, and promote the achievement of better immunogens for serum production, and contributing to the welfare of serum-producing animals. It is known, however, that the effects of ionizing radiation on protein are characterized by various chemical modifications, such as fragmentation, cross-linking due to aggregation and oxidation products generated by water radiolysis. However, the action of gamma radiation on toxins is not yet fully understood structurally and pharmacologically, a fact that prevents the application of this methodology in the serum production process. So we proposed in this paper the characterization of crotamine, an important protein from the venom of Crotalus durissus terrificus species, irradiated with 60Co gamma rays. After isolating the toxin by chromatographic techniques and testing to prove the obtaining of pure crotamine, it was irradiated with gamma rays and subjected to structural analysis, Fluorescence and Circular Dichroism. Using high hydrostatic pressure tests were also conducted in order to verify that the conformational changes caused by radiation suffer modifications under high pressures. From the pharmacological point of view, muscle contraction tests were conducted with the objective of limiting the action of crotamine in smooth muscle as well as the change in the action of toxin caused structural changes to the front. Analysis of Circular Dichroism and Fluorescence showed changes in structural conformation of crotamine when subjected to gamma radiation and that such changes possibly occurring in the secondary and tertiary structure of the protein. The observed in pharmacological tests showed that the irradiated crotamine was less effective in

  2. P03.09PHARMACOLOGICAL MODULATION OF BLOOD-BRAIN BARRIER: FUTURE STRATEGY FOR TREATMENT OF BRAIN TUMORS

    OpenAIRE

    Sardi, I.; Cardellicchio, S.; Iorio, A.L.; da Ros, M.; la Marca, G.; Giunti, L.; Massimino, M.; L. Genitori

    2014-01-01

    A prerequisite for the efficacy of chemotherapy is that it reaches the tumor mass at a therapeutic concentration. In brain tumors this phenomenon is hampered by the presence of the blood brain barrier (BBB) which limits the spread of chemotherapeutic agents within the brain. It is lately emerged as this Multi Drug Resistance (MDR) phenomenon is explained through the cooperation of P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2), two “gatekeeper" transporters th...

  3. Human CRF2 α and β splice variants: pharmacological characterization using radioligand binding and a luciferase gene expression assay

    International Nuclear Information System (INIS)

    Corticotropin releasing factor (CRF) receptors belong to the super-family of G protein-coupled receptors. These receptors are classified into two subtypes (CRF1 and CRF2). Both receptors are positively coupled to adenylyl cyclase but they have a distinct pharmacology and distribution in brain. Two isoforms belonging to the CRF2 subtype receptors, CRF2α and CRF2β, have been identified in rat and man. The neuropeptides CRF and urocortin mediate their actions through this CRF G protein-coupled receptor family. In this report, we describe the pharmacological characterization of the recently identified hCRF2β receptor. We have used radioligand binding with [125I]-tyr0-sauvagine and a gene expression assay in which the firefly luciferase gene expression is under the control of cAMP responsive elements. Association kinetics of [125I]-tyr0-sauvagine binding to the hCRF2β receptor were monophasic while dissociation kinetics were biphasic, in agreement with the kinetics results obtained with the hCRF2α receptor. Saturation binding analysis revealed two affinity states in HEK 293 cells with binding parameters in accord with those determined kinetically and with parameters obtained with the hCRF2α receptor. A non-hydrolysable GTP analog, Gpp(NH)p, reduced the high affinity binding of [125I]-tyr0-sauvagine to both hCRF2 receptor isoforms in a similar manner. The rank order of potency of CRF agonist peptides in competition experiments was identical for both hCRF2α-helical CRF(9-41)oCRF). Similarly, agonist potency was similar for the two isoforms when studied using the luciferase gene reporter system. The peptide antagonist α-helical CRF(9-41) exhibited a non-competitive antagonism of urocortin-stimulated luciferase expression with both hCRF2 receptor isoforms. Taken together, these results indicate that the pharmacological profiles of the CRF2 splice variants are identical. This indicates that the region of the N-terminus that varies between the receptors is probably

  4. Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot.

    Science.gov (United States)

    Veronese, Mattia; Zanotti-Fregonara, Paolo; Rizzo, Gaia; Bertoldo, Alessandra; Innis, Robert B; Turkheimer, Federico E

    2016-04-15

    PET studies allow in vivo imaging of the density of brain receptor species. The PET signal, however, is the sum of the fraction of radioligand that is specifically bound to the target receptor and the non-displaceable fraction (i.e. the non-specifically bound radioligand plus the free ligand in tissue). Therefore, measuring the non-displaceable fraction, which is generally assumed to be constant across the brain, is a necessary step to obtain regional estimates of the specific fractions. The nondisplaceable binding can be directly measured if a reference region, i.e. a region devoid of any specific binding, is available. Many receptors are however widely expressed across the brain, and a true reference region is rarely available. In these cases, the nonspecific binding can be obtained after competitive pharmacological blockade, which is often contraindicated in humans. In this work we introduce the genomic plot for estimating the nondisplaceable fraction using baseline scans only. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen brain atlas are used as a surrogate measure of the specific binding. Thus, the genomic plot allows the calculation of the specific and nondisplaceable components of radioligand uptake without the need of pharmacological blockade. We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of seven different neuroreceptor radioligands, where nonspecific fractions were either obtained separately using drug displacement or available from a true reference region. The population nondisplaceable fractions estimated by the genomic plot were very close to those measured by actual human blocking studies (mean relative difference between 2% and 7%). However, these estimates were valid only when mRNA expressions were predictive of protein levels (i

  5. Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot

    Science.gov (United States)

    Veronese, Mattia; Zanotti-Fregonara, Paolo; Rizzo, Gaia; Bertoldo, Alessandra; Innis, Robert B.; Turkheimer, Federico E.

    2016-01-01

    PET studies allow in vivo imaging of the density of brain receptor species. The PET signal, however, is the sum of the fraction of radioligand that is specifically bound to the target receptor and the non-displaceable fraction (i.e. the non-specifically bound radioligand plus the free ligand in tissue). Therefore, measuring the non-displaceable fraction, which is generally assumed to be constant across the brain, is a necessary step to obtain regional estimates of the specific fractions. The nondisplaceable binding can be directly measured if a reference region, i.e. a region devoid of any specific binding, is available. Many receptors are however widely expressed across the brain, and a true reference region is rarely available. In these cases, the nonspecific binding can be obtained after competitive pharmacological blockade, which is often contraindicated in humans. In this work we introduce the genomic plot for estimating the nondisplaceable fraction using baseline scans only. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen brain atlas are used as a surrogate measure of the specific binding. Thus, the genomic plot allows the calculation of the specific and nondisplaceable components of radioligand uptake without the need of pharmacological blockade. We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of seven different neuroreceptor radioligands, where nonspecific fractions were either obtained separately using drug displacement or available from a true reference region. The population nondisplaceable fractions estimated by the genomic plot were very close to those measured by actual human blocking studies (mean relative difference between 2% and 7%). However, these estimates were valid only when mRNA expressions were predictive of protein levels (i

  6. Ictal brain SPET during seizures pharmacologically provoked with pentylenetetrazol: a new diagnostic procedure in drug-resistant epileptic patients

    Energy Technology Data Exchange (ETDEWEB)

    Calcagni, Maria Lucia; Giordano, Alessandro; Bruno, Isabella; Di Giuda, Daniela; De Rossi, Giuseppe; Troncone, Luigi [Department of Nuclear Medicine, Universita Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Roma (Italy); Parbonetti, Giovanni; Colicchio, Gabriella [Department of Neurosurgery, Universita Cattolica del Sacro Cuore, Roma (Italy)

    2002-10-01

    Functional brain imaging plays an important role in seizure focus localisation. However, truly ictal single-photon emission tomography (SPET) studies are not routinely performed owing to technical problems associated with the use of tracers and methodological and logistical difficulties. In this study we tried to resolve both of these issues by means of a new procedure: technetium-99m ethyl cysteinate dimer (ECD) brain SPET performed during seizures pharmacologically provoked with pentylenetetrazol, a well-known central and respiratory stimulant. We studied 33 drug-resistant epileptic patients. All patients underwent anamnestic evaluation, neuropsychological and psychodynamic assessment, magnetic resonance imaging, interictal and ictal video-EEG monitoring, and interictal and ictal SPET with {sup 99m}Tc-ECD. In order to obtain truly ictal SPET, 65 mg of pentylenetetrazol was injected every 2 minutes and, immediately the seizure began, 740 MBq of {sup 99m}Tc-ECD was injected. The scintigraphic findings were considered abnormal if a single area of hyperperfusion was present and corresponded to the site of a single area of hypoperfusion at interictal SPET: the ''hypo-hyperperfusion'' SPET pattern. In 27 of the 33 patients (82%), interictal-ictal SPET showed the hypo-hyperperfusion SPET pattern. Video-EEG showed a single epileptogenic zone in 21/33 patients (64%), and MRI showed anatomical lesions in 19/33 patients (57%). Twenty-two of the 27 patients with hypo-hyperperfusion SPET pattern underwent ablative or palliative surgery and were seizure-free at 3 years of follow-up. No adverse effects were noted during pharmacologically provoked seizure. It is concluded that ictal brain SPET performed during pharmacologically provoked seizure provides truly ictal images because {sup 99m}Tc-ECD is injected immediately upon seizure onset. Using this feasible procedure it is possible to localise the focus, to avoid the limitations due to the unpredictability

  7. Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.

    Science.gov (United States)

    Castilla-Ortega, Estela; Blanco, Eduardo; Serrano, Antonia; Ladrón de Guevara-Miranda, David; Pedraz, María; Estivill-Torrús, Guillermo; Pavón, Francisco Javier; Rodríguez de Fonseca, Fernando; Santín, Luis J

    2016-05-01

    We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model. PMID:25870909

  8. Effect of pharmacologic resuscitation on the brain gene expression profiles in a swine model of traumatic brain injury and hemorrhage

    DEFF Research Database (Denmark)

    Dekker, Simone E; Bambakidis, Ted; Sillesen, Martin;

    2014-01-01

    per group). Following 6 hours of observation, brain RNA was isolated, and gene expression profiles were measured using a Porcine Gene ST 1.1 microarray (Affymetrix, Santa Clara, CA). Pathway analysis was done using network analysis tools Gene Ontology, Ingenuity Pathway Analysis, and Parametric Gene...

  9. Differential pharmacological effects on brain reactivity and plasticity in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Anna-Katharine eBrem

    2013-10-01

    Full Text Available Acetylcholinesterase inhibitors (AChEI are the most commonly prescribed monotherapeutic medications for Alzheimer’s disease (AD. However, their underlying neurophysiological effects remain largely unknown.We investigated the effects of monotherapy (AChEI and combination therapy (AChEI and memantine on brain reactivity and plasticity. Patients treated with monotherapy (AChEI (N=7 were compared to patients receiving combination therapy (COM (N=9 and a group of age-matched, healthy controls (HC (N=13. Cortical reactivity and plasticity of the motor cortex (MC were examined using transcranial magnetic stimulation (TMS. Cognitive functions were assessed with the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog, activities of daily living with the ADCS-ADL. In addition we assessed the degree of brain atrophy by measuring brain-scalp distances in seven different brain areas.Patient groups differed in resting motor threshold and brain atrophy, with COM showing a lower motor threshold but less atrophy than AChEI. COM showed similar plasticity effects as the HC group, while plasticity was reduced in AChEI. Long-interval intracortical inhibition (LICI was impaired in both patient groups when compared to HC. ADAS-Cog scores were positively correlated with LICI measures and with brain atrophy, specifically in the left IPL.AD patients treated with mono- or combination therapy show distinct neurophysiological patterns. Further studies should investigate whether these measures might serve as biomarkers of treatment response and whether they could guide other therapeutic interventions.

  10. The pharmacology of neurotrophic treatment with Cerebrolysin: brain protection and repair to counteract pathologies of acute and chronic neurological disorders.

    Science.gov (United States)

    Masliah, E; Díez-Tejedor, E

    2012-04-01

    Neurotrophic factors are considered as part of the therapeutic strategy for neurological disorders like dementia, stroke and traumatic brain injury. Cerebrolysin is a neuropeptide preparation which mimics the action of endogenous neurotrophic factors on brain protection and repair. In dementia models, Cerebrolysin decreases β-amyloid deposition and microtubule-associated protein tau phosphorylation by regulating glycogen synthase kinase-3β and cyclin-dependent kinase 5 activity, increases synaptic density and restores neuronal cytoarchitecture. These effects protect integrity of the neuronal circuits and thus result in improved cognitive and behavioral performance. Furthermore, Cerebrolysin enhances neurogenesis in the dentate gyrus, the basis for neuronal replacement therapy in neurodegenerative diseases. Experimental studies in stroke animal models have shown that Cerebrolysin stabilizes the structural integrity of cells by inhibition of calpain and reduces the number of apoptotic cells after ischemic lesion. Cerebrolysin induces restorative processes, decreases infarct volume and edema formation and promotes functional recovery. Stroke-induced neurogenesis in the subventricular zone was also promoted by Cerebrolysin, thus supporting the brain's self-repair after stroke. Both, traumatic brain and spinal cord injury conditions stimulate the expression of natural neurotrophic factors to promote repair and regeneration processes -axonal regeneration, neuronal plasticity and neurogenesis- that is considered to be crucial for the future recovery. Neuroprotective effects of Cerebrolysin on experimentally induced traumatic spinal cord injury have shown that Cerebrolysin prevents apoptosis of lesioned motoneurons and promotes functional recovery. This section summarizes the most relevant data on the pharmacology of Cerebrolysin obtained from in vitro assays (biochemical and cell cultures) and in vivo animal models of acute and chronic neurological disorders. PMID

  11. The pharmacology of neurotrophic treatment with Cerebrolysin: brain protection and repair to counteract pathologies of acute and chronic neurological disorders.

    Science.gov (United States)

    Masliah, E; Díez-Tejedor, E

    2012-04-01

    Neurotrophic factors are considered as part of the therapeutic strategy for neurological disorders like dementia, stroke and traumatic brain injury. Cerebrolysin is a neuropeptide preparation which mimics the action of endogenous neurotrophic factors on brain protection and repair. In dementia models, Cerebrolysin decreases β-amyloid deposition and microtubule-associated protein tau phosphorylation by regulating glycogen synthase kinase-3β and cyclin-dependent kinase 5 activity, increases synaptic density and restores neuronal cytoarchitecture. These effects protect integrity of the neuronal circuits and thus result in improved cognitive and behavioral performance. Furthermore, Cerebrolysin enhances neurogenesis in the dentate gyrus, the basis for neuronal replacement therapy in neurodegenerative diseases. Experimental studies in stroke animal models have shown that Cerebrolysin stabilizes the structural integrity of cells by inhibition of calpain and reduces the number of apoptotic cells after ischemic lesion. Cerebrolysin induces restorative processes, decreases infarct volume and edema formation and promotes functional recovery. Stroke-induced neurogenesis in the subventricular zone was also promoted by Cerebrolysin, thus supporting the brain's self-repair after stroke. Both, traumatic brain and spinal cord injury conditions stimulate the expression of natural neurotrophic factors to promote repair and regeneration processes -axonal regeneration, neuronal plasticity and neurogenesis- that is considered to be crucial for the future recovery. Neuroprotective effects of Cerebrolysin on experimentally induced traumatic spinal cord injury have shown that Cerebrolysin prevents apoptosis of lesioned motoneurons and promotes functional recovery. This section summarizes the most relevant data on the pharmacology of Cerebrolysin obtained from in vitro assays (biochemical and cell cultures) and in vivo animal models of acute and chronic neurological disorders.

  12. Isolation and characterization of halophilic Bacillussp. BS3 able to produce pharmacologically important biosurfactants

    Institute of Scientific and Technical Information of China (English)

    MBS Donio; SFA Ronica; V Thanga Viji; S Velmurugan; J Adlin Jenifer; M Michaelbabu; T Citarasu

    2013-01-01

    Objective:To characterize the pharmacological importance of biosurfactants isolated from halophilicBacillus spBS3.Methods:HalophilicBacillus sp.BS3 was isolated from solar salt works, identified by16S rRNA sequencing and was used for screening their biosurfactant production.Characters of the biosurfactant and their anticancer activity were analyzed and performed in mammary epithelial carcinoma cell at different concentrations.Results:The biosurfactant were characterized byTLC,FTIR andGC-MS analysis and identified as lipopeptide type.GC-MS analysis revealed that, the biosurfactant had various compounds including13-Docosenamide,(Z);Mannosamine,9- andN,N,N',N'-tetramethyl.Surprisingly the antiviral activity was found against shrimp white spot syndrome virus(WSSV) by suppressing the viral replication and significantly raised shrimp survival(P<0.01).Anticancer activity performed in the mammary epithelial carcinoma cell at different concentrations of biosurfactants, among the various concentrations of biosurfactants such as0.00025,0.0025,0.025,0.25 and2.5μg, the 0.25 μg concentration suppressed the cells significantly(P<0.05) to24.8%.Conclusions:Based on the findings, the present study concluded that, there is a possibility to develop eco-friendly antimicrobial and anticancer drugs from the extremophilic origin.

  13. Chemistry and pharmacology of triaminedithiol technetium-based brain perfusion agents

    Energy Technology Data Exchange (ETDEWEB)

    Watson, A.D.; Walovitch, R.C.; Belonga, B.Q.; Cheesman, E.H.

    We have examined the effects of converting the technetium(V)oxo core to the technetium nitrido core in technetium complexes based on amine derivatives of the quadridentate ligand N,N'-bis(2',2'-dimethyl-2'-mercaptoethyl)-2,2-dimethylethylenediamine. Five neutral complexes containing the technetium (V) oxo core were prepared and brain uptake indices and biodistributions were carried out in rats.

  14. Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

    Science.gov (United States)

    Swedberg, Michael D B

    2016-01-01

    Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit

  15. Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

    Science.gov (United States)

    Swedberg, Michael D B

    2016-01-01

    Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit

  16. Ghrelin and the brain-gut axis as a pharmacological target for appetite control.

    Science.gov (United States)

    Seim, Inge; El-Salhy, Magdy; Hausken, Trygve; Gundersen, Doris; Chopin, Lisa

    2012-01-01

    Appetite regulation is highly complex and involves a large number of orexigenic and anorexigenic peptide hormones. These are small, processed, secreted peptides derived from larger prepropeptide precursors. These peptides are important targets for the development of therapeutics for obesity, a global health epidemic. As a case study, we consider the ghrelin axis. The ghrelin axis is likely to be a particularly useful drug target, as it also plays a role in energy homeostasis, adipogenesis, insulin regulation and reward associated with food intake. Ghrelin is the only known circulating gut orexigenic peptide hormone. As it appears to play a role in diet-induced obesity, blocking the action of ghrelin is likely to be effective for treating and preventing obesity. The ghrelin peptide has been targeted using a number of approaches, with ghrelin mirror-image oligonucleotides (Spiegelmers) and immunotherapy showing some promise. The ghrelin receptor, the growth hormone secretagogue receptor, may also provide a useful target and a number of antagonists and inverse agonists have been developed. A particularly promising new target is the enzyme which octanoylates ghrelin, ghrelin O-acyltransferase (GOAT), and drugs that inhibit GOAT are likely to circumvent pharmacological issues associated with approaches that directly target ghrelin or its receptor.

  17. Dopaminergic 3H-agonist receptors in rat brain: new evidence on localization and pharmacology

    Energy Technology Data Exchange (ETDEWEB)

    Bacopoulos, N.G.

    1984-01-23

    Recent methodological advances have allowed the reliable assay of specific dopaminergic 3H-agonist binding sites in rat striatum. Lesions of dopamine(DA) terminals or drugs which deplete DA levels prevent the preincubation-induced increase in binding, and this effect is completely reversible by preincubation with added DA. It is concluded that the evidence supporting the existence of presynaptic D-3 sites is artefactual and that 3H-DA binding sites are more likely related to post-synaptic receptors. 3H-DA binding involves two sites, one of which has pharmacologic properties similar to D-1 receptors, whereas the other resembles D-2 receptors. The affinity of 15 antipsychotic drugs for 3H-haloperidol binding sites was highly correlated (R = 0.94) with their inhibitory potency at a subset of 3H-DA binding sites. However, the inhibition of 3H-DA binding by antipsychotic drugs was noncompetitive. These findings can be explained by an allosteric model, whereby antagonists bind to a site different from but allosterically linked to a high-affinity 3H-DA binding site.

  18. Pharmacological and structural characterization of conformationally restricted (S)-glutamate analogues at ionotropic glutamate receptors

    DEFF Research Database (Denmark)

    Juknaite, Lina; Venskutonyte, Raminta; Assaf, Zeinab;

    2012-01-01

    at NMDA receptors, where the introduction of the carbocyclic ring is expected to lead to a steric clash with binding site residues. CBG-IV was demonstrated to be an agonist at both GluA2 and the kainate receptor GluK1. CBG-IV showed high affinity binding to GluK1 compared to GluA2, GluK2 and GluK3, which......Conformationally restricted glutamate analogues have been pharmacologically characterized at AMPA and kainate receptors and the crystal structures have been solved of the ligand (2S,1'R,2'S)-2-(2'-carboxycyclobutyl)glycine (CBG-IV) in complex with the ligand binding domains of the AMPA receptor Glu......A2 and the kainate receptor GluK3. These structures show that CBG-IV interacts with the binding pocket in the same way as (S)-glutamate. The binding affinities reveal that CBG-IV has high affinity at the AMPA and kainate receptor subtypes. Appreciable binding affinity of CBG-IV was not observed...

  19. Pharmacological characterization and neutralization of the venoms used in the production of Bothropic antivenom in Brazil.

    Science.gov (United States)

    Camey, Kyoko U; Velarde, David T; Sanchez, Eladio F

    2002-05-01

    Some pharmacological effects of the venoms of five different Brazilian Bothrops species and a pool of these venoms (AgB) were quantified. The ability of polyspecific Bothropic antivenom produced at Fundação Ezequiel Dias (FUNED, Brazil) to neutralize the principal toxic and enzymatic activities was studied using in vivo and in vitro assays. The lethality, hemorrhagic, necrotizing, proteolytic, phospholipase, coagulant and fibrinolytic activities were measured for each of these venoms. Comparison of protein electrophoretic patterns showed significant differences such as the presence of common and also unique components. Furthermore, experimental studies revealed differences in their biological properties among individual samples. It was found that the Bothrops antivenom was highly effective in the neutralization of the toxic activities of all venoms tested. In addition, indirect ELISA was used to compare the antigenic cross-reactivity for each of the five Bothrops venoms as well as the venoms of B. atrox, B. leucurus and B. erythromelas which were not included in the antigenic pool (AgB). Therefore, the characterization of several toxic activities of snake venoms is necessary, if toxicity is to be properly evaluated. Results indicate that the Brazilian antivenom prepared at FUNED against Bothrops snakes is effective in neutralizing the main toxic effects of Bothrops venoms. PMID:11821121

  20. The nature of the destructive, compensatory and regenerative processes in the brain of rats after experimental moderate traumatic brain injury and the possibility of their pharmacological correction

    Directory of Open Access Journals (Sweden)

    Mamytova E.M.

    2016-06-01

    analysis showed a reduction in the bulk density of the nucleus is 7, and 21 days of experimental traumatic brain injury in the group without treatment. In Cerebrolysin group on day 14 and 21, the bulk density of the nucleus closer to the control parameters. The same trend was observed in relation to the bulk density of ribosomes and neurofibrillary. In case of injury of moderate severity in the group without a neuroprotectant during the entire study period there is a diffuse lesion of the brain studied departments mostly damaged hemisphere, which appeared resistant dystrophic and destructive changes of the neurons without significant signs of pronounced reparative regeneration in the regenerative posttraumatic period. Conclusion. When using a neuroprotectant cerebrolysin marked increase in intact neurons, which was celebrated not only in the injured, but also in the contralateral hemisphere on the day 21st of the experiment. In this case an increase amount of glial cells was also seen. Citation: Mamytova EM. [The nature of the destructive, compensatory and regenerative processes in the brain of rats after experimental moderate traumatic brain injury and the possibility of their pharmacological correction]. Morphologia. 2016;10(2:18-22. Russian.

  1. Immunochemical characterization of rat brain protein kinase

    International Nuclear Information System (INIS)

    Polyclonal antibodies against rat brain protein kinase C (the Ca2+/phospholipid-dependent enzyme) were raised in goat. These antibodies can neutralize completely the kinase activity in purified enzyme preparation as well as that in the crude homogenate. Immunoblot analysis of the purified and the crude protein kinase C preparations revealed a major immunoreactive band of 80 kDa. The antibodies also recognize the same enzyme from other rat tissues. Neuronal tissues (cerebral cortex, cerebellum, hypothalamus, and retina) and lymphoid organs (thymus and spleen) were found to be enriched in protein kinase C, whereas lung, kidney, liver, heart, and skeletal muscle contained relatively low amounts of this kinase. Limited proteolysis of the purified rat brain protein kinase C with trypsin results in an initial degradation of the kinase into two major fragments of 48 and 38 kDa. Both fragments are recognized by the antibodies. However, further digestion of the 48-kDa fragment to 45 kDa and the 38-kDa fragment to 33 kDa causes a loss of the immunoreactivity. Upon incubation of the cerebellar extract with Ca2+, the 48-kDa fragment was also identified as a major proteolytic product of protein kinase C. Proteolytic degradation of protein kinase C converts the Ca2+/phospholipid-dependent kinase to an independent form without causing a large impairment of the binding of [3H]phorbol 12,13-dibutyrate. The two major proteolytic fragments were separated by ion exchange chromatography and one of them (45-48 kDa) was identified as a protein kinase and the other (33-38 kDa) as a phorbol ester-binding protein. These results demonstrate that rat brain protein kinase C is composed of two functionally distinct units, namely, a protein kinase and a Ca2+-independent/phospholipid-dependent phorbol ester-binding protein

  2. Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys.

    Science.gov (United States)

    Kimmel, Heather L; Negus, S Stevens; Wilcox, Kristin M; Ewing, Sarah B; Stehouwer, Jeffrey; Goodman, Mark M; Votaw, John R; Mello, Nancy K; Carroll, F Ivy; Howell, Leonard L

    2008-09-01

    Although inhibition of dopamine transporters (DAT) and the subsequent increase in dopamine clearly play a role in the effects of psychomotor stimulants, the reinforcing effectiveness of DAT inhibitors varies. Previous studies suggest that pharmacokinetic and pharmacodynamic properties of these drugs account for this variability. The present studies compared the time course and behavioral effects of five phenyltropane analogs of cocaine with high affinity for DAT and varying time courses of action in rhesus monkeys. The rate of drug uptake in putamen was measured using positron emission tomography neuroimaging. The rank order of the time to peak drug uptake was cocaineCocaine and all five analogs fully substituted for the cocaine cue in animals trained to discriminate cocaine from saline. All of the drugs were self-administered under a progressive-ratio schedule of drug self-administration and reinstated previously extinguished self-administration maintained under a second-order schedule. The time to peak drug uptake corresponded closely with the time to peak discriminative stimulus effects, and there was a trend for the time of peak drug uptake to correspond negatively with the peak number of drug infusions. Collectively, these results indicate that the rate of drug entry in brain can play an important role in the behavioral pharmacology of psychomotor stimulants. PMID:18468667

  3. Ibuprofen inhibits rat brain deamidation of anandamide at pharmacologically relevant concentrations. Mode of inhibition and structure-activity relationship.

    Science.gov (United States)

    Fowler, C J; Tiger, G; Stenström, A

    1997-11-01

    The ability of rat brain (minus cerebellum) homogenates to deamidate arachidonyl ethanolamide (anandamide) was determined with a custom-synthesized substrate, arachidonyl ethanolamide-[1-3H] ([3H]anandamide). Conditions whereby initial velocities were measured were established. The homogenates deamidated anandamide with a Km value of 0.8 microM and a Vmax value of 1.73 nmol . (mg protein)-1 . min-1. The deamidation of 2 microM -3H-anandamide was inhibited by phenylmethylsulfonyl fluoride and arachidonyl trifluoromethyl ketone with IC50 values of 3.7 and 0.23 microM, respectively. Ibuprofen inhibited anandamide deamidation in a mixed fashion, with Ki and K'i values of 82 and 1420 microM. At an anandamide concentration of 2 microM, the IC50 values (in microM) of a series of compounds related in structure to ibuprofen were as follows: suprofen, 170; ibuprofen, 270; fenoprofen, 480; naproxen, 550; ketoprofen, 650; diclofenac, approximately 1000. Sulindac produced 27% inhibition at a concentration of 1000 microM, whereas isobutyric acid, hydrocinnamic acid, acetylsalicylic acid and acetaminophen were essentially inactive at concentrations pharmacologically relevant concentrations and that there is some specificity to the inhibition produced by ibuprofen and suprofen. PMID:9353392

  4. Pharmacological characterization of the rat metabotropic glutamate receptor type 8a revealed strong similarities and slight differences with the type 4a receptor.

    Science.gov (United States)

    De Colle, C; Bessis, A S; Bockaert, J; Acher, F; Pin, J P

    2000-04-01

    In the brain, group-III metabotropic glutamate (mGlu) receptors mGlu(4), mGlu(7) and mGlu(8) receptors play a critical role in controlling the release process at many glutamatergic synapses. The pharmacological profile of mGlu(4) receptor has been studied extensively, allowing us to propose a pharmacophore model for this receptor subtype. Surprisingly, the activity of only a few compounds have been reported on mGlu(7) and mGlu(8) receptors. In order to identify new possibilities for the design of selective compounds able to discriminate between the members of the group-III mGlu receptors, we have undertaken a complete pharmacological characterization of mGlu(8) receptor and compared it with that of mGlu(4) receptor, using the same expression system, and the same read out. The activities of 32 different molecules revealed that these two mGlu receptors subtypes share a similar pharmacological profile. Only small differences were noticed in addition to that previously reported with S-carboxyglutamate (S-Gla) being a partial agonist at mGlu(4) receptor and a full antagonist at mGlu(8) receptor. These include: a slightly higher relative potency of the agonists 1S,3R and 1S,3S-aminocyclopentane-1,3-dicarboxylic acid (ACPD), S-4-carboxyphenylglycine (S-4CPG) and S-4-carboxy-3-hydroxyphenylglycine (S-4C3HPG), and a slightly higher potency of the antagonists 2-aminobicyclo[3.1.0]hexane-2, 6-dicarboxylic acid (LY354740) and RS-alpha-methyl-4-phosphonophenylglycine (MPPG) on mGlu(8) receptor. When superimposed on the mGlu(4) receptor pharmacophore model, these molecules revealed three regions that may be different between the ligand binding sites of mGlu(8) and mGlu(4) receptors. PMID:10771029

  5. Principles of Safety Pharmacology

    OpenAIRE

    Pugsley, M. K.; Authier, S; Curtis, M J

    2008-01-01

    Safety Pharmacology is a rapidly developing discipline that uses the basic principles of pharmacology in a regulatory-driven process to generate data to inform risk/benefit assessment. The aim of Safety Pharmacology is to characterize the pharmacodynamic/pharmacokinetic (PK/PD) relationship of a drug's adverse effects using continuously evolving methodology. Unlike toxicology, Safety Pharmacology includes within its remit a regulatory requirement to predict the risk of rare lethal events. Thi...

  6. Characterization of tyramine and octopamine receptors in the insect (Locusta migratoria migratorioides) brain.

    Science.gov (United States)

    Hiripi, L; Juhos, S; Downer, R G

    1994-01-01

    The kinetic and pharmacological properties of [3H]tyramine and [3H]octopamine binding to membrane preparations of locust (Locusta migratoria migratorioides) brain were studied to characterize the tyramine and octopamine receptors. [3H]Tyramine and [3H]octopamine bind specifically and reversibly to the locust brain membrane with equilibrium achieved after 20 min. The dissociation of [3H]tyramine is monophasic while that of the [3H]octopamine shows a biphasic tendency. Scatchard analysis of the saturation curves reveals a single high affinity binding site for each of tyramine and octopamine. The mean (+/- S.E.M.) values of Kd and Bmax are 6.11 +/- 0.71 nM and 21.45 +/- 3.0 fmol/mg tissue for tyramine and 5.65 +/- 0.91 nM and 15.0 +/- 2.4 fmol/mg tissue for octopamine, respectively. Pharmacological analysis of the binding suggests the presence of both tyramine and octopamine receptors in the locust brain. alpha-Adrenergic agonists and antagonists have a high affinity to the octopamine but not the tyramine receptor whereas dopaminergic drugs have a higher affinity to the tyramine receptor than the octopamine receptor. No highly effective inhibitors of tyramine binding were identified. The serotonergic blockers, mianserin, LSD, BOL are effective blockers for both tyramine and octopamine receptors, whereas the serotonergic antagonist gramine is more active against the octopamine than the serotonin receptor. The results suggest that a G-protein binding mechanism is involved in the expression of both the tyramine and octopamine effects. PMID:7907928

  7. Molecular and pharmacological characterization of two D(1)-like dopamine receptors in the Lyme disease vector, Ixodes scapularis.

    Science.gov (United States)

    Meyer, Jason M; Ejendal, Karin F K; Watts, Val J; Hill, Catherine A

    2011-08-01

    Advancements in tick neurobiology may impact the development of acaricides to control those species that transmit human and animal diseases. Here, we report the first cloning and pharmacological characterization of two neurotransmitter binding G protein-coupled receptors in the Lyme disease (blacklegged) tick, Ixodes scapularis. The genes IscaGPRdop1 and IscaGPRdop2 were identified in the I. scapularis genome assembly and predicted as orthologs of previously characterized D(1)-like dopamine receptors in the fruit fly Drosophila melanogaster and honeybee Apis mellifera. Heterologous expression in HEK 293 cells demonstrated that each receptor functioned as a D(1)-like dopamine receptor because significant increases in levels of intracellular cyclic adenosine monophosphate (cAMP) were detected following dopamine treatment. Importantly, the receptors were distinct in their pharmacological properties regarding concentration-dependent response to dopamine, constitutive activity, and response to other biogenic amines. Exposure to a variety of dopamine receptor agonists and antagonists further demonstrated a D(1)-like pharmacology of these dopamine receptors and highlighted their differential activities in vitro. PMID:21457782

  8. Characterization and pharmacological properties of a novel multifunctional Kunitz inhibitor from Erythrina velutina seeds.

    Directory of Open Access Journals (Sweden)

    Richele J A Machado

    Full Text Available Inhibitors of peptidases isolated from leguminous seeds have been studied for their pharmacological properties. The present study focused on purification, biochemical characterization and anti-inflammatory and anticoagulant evaluation of a novel Kunitz trypsin inhibitor from Erythrina velutina seeds (EvTI. Trypsin inhibitors were purified by ammonium sulfate (30-60%, fractionation followed by Trypsin-Sepharose affinity chromatography and reversed-phase high performance liquid chromatography. The purified inhibitor showed molecular mass of 19,210.48 Da. Furthermore, a second isoform with 19,228.16 Da was also observed. The inhibitor that showed highest trypsin specificity and enhanced recovery yield was named EvTI (P2 and was selected for further analysis. The EvTI peptide fragments, generated by trypsin and pepsin digestion, were further analyzed by MALDI-ToF-ToF mass spectrometry, allowing a partial primary structure elucidation. EvTI exhibited inhibitory activity against trypsin with IC50 of 2.2×10(-8 mol.L(-1 and constant inhibition (Ki of 1.0×10(-8 mol.L(-1, by a non-competitive mechanism. In addition to inhibit the activity of trypsin, EvTI also inhibited factor Xa and neutrophil elastase, but do not inhibit thrombin, chymotrypsin or peptidase 3. EvTI was investigated for its anti-inflammatory and anti-coagulant properties. Firstly, EvTI showed no cytotoxic effect on human peripheral blood cells. Nevertheless, the inhibitor was able to prolong the clotting time in a dose-dependent manner by using in vitro and in vivo models. Due to anti-inflammatory and anticoagulant EvTI properties, two sepsis models were here challenged. EvTI inhibited leukocyte migration and specifically acted by inhibiting TNF-α release and stimulating IFN-α and IL-12 synthesis. The data presented clearly contribute to a better understanding of the use of Kunitz inhibitors in sepsis as a bioactive agent capable of interfering in blood coagulation and inflammation.

  9. Characterization and pharmacological modulation of intestinal inflammation induced by ionizing radiation

    International Nuclear Information System (INIS)

    The use of radiation therapy to treat abdominal and pelvic malignancies inevitably involves exposure of healthy intestinal tissues which are very radiosensitive. As a result, most patients experience symptoms such as abdominal pain, nausea and diarrhea. Such symptoms are associated with acute damage to intestine mucosa including radio-induced inflammatory processes. With a rat model of colorectal fractionated radiation, we have shown a gradual development of a colonic inflammation during radiation planning, without evident tissue injury. This radio-induced inflammation is characterized not only by the sur expressions of pro-inflammatory cytokines and chemokines, a NF-kB activation, but also by a repression of anti-inflammatory cytokines and the nuclear receptors PPARa and RXRa, both involved in inflammation control. This early inflammation is associated with a discreet neutrophil recruitment and a macrophage accumulation. Macrophages are still abnormally numerous in tissue 27 weeks after the last day of irradiation. Inflammatory process is the most often related to a specific immune profile, either a type Th1 leading to a cellular immune response, or a type Th2 for humoral immunity. According to our studies, a unique abdominal radiation in the rat induces an ileum inflammation and an immune imbalance resulting in a Th2-type profile. Inhibiting this profile is important as its persistence promotes chronic inflammation, predisposition to bacterial infections and fibrosis which is the main delayed side-effect of radiotherapy. The treatment of rats with an immuno-modulator compound, the caffeic acid phenethyl ester (C.A.P.E.), have the potential to both reduce ileal mucosal inflammation and inhibit the radio-induced Th2 status. In order to search new therapeutic molecular target, we has been interested in the PPARg nuclear receptor involved in the maintenance of colon mucosal integrity. In our abdominal irradiation model, we have demonstrated that the prophylactic

  10. Synthesis and pharmacological characterization at glutamate receptors of the four enantiopure isomers of tricholomic acid

    DEFF Research Database (Denmark)

    Pinto, Andrea; Conti, Paola; De Amici, Marco;

    2008-01-01

    The two enantiomeric pairs of erythro- and threo-amino-(3'-hydroxy-4',5'-dihydro-isoxazol-5'-yl)-acetic acids were synthesized via the 1,3-dipolar cycloaddition of bromonitrile oxide to ( R)- or ( S)-3-( tert-butoxycarbonyl)-2,2-dimethyl-4-vinyloxazolidine. The pharmacological profiles of the stu...

  11. Characterizing the concept of activity pacing as a non-pharmacological intervention in rheumatology care

    DEFF Research Database (Denmark)

    Cuperus, N; Vliet Vlieland, Tpm; Brodin, N;

    2016-01-01

    OBJECTIVE: To develop a consensual list of the most important aspects of activity pacing (AP) as an intervention within the context of non-pharmacological rheumatology care. METHOD: An international, multidisciplinary expert panel comprising 60 clinicians and/or healthcare providers experienced i...

  12. Characterization and comparison of sodium-glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects.

    Science.gov (United States)

    Tahara, Atsuo; Takasu, Toshiyuki; Yokono, Masanori; Imamura, Masakazu; Kurosaki, Eiji

    2016-03-01

    The sodium-glucose cotransporter (SGLT) 2 offer a novel approach to treating type 2 diabetes by reducing hyperglycaemia via increased urinary glucose excretion. In the present study, the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six SGLT2 inhibitors commercially available in Japan were investigated and compared. Based on findings in normal and diabetic mice, the six drugs were classified into two categories, long-acting: ipragliflozin and dapagliflozin, and intermediate-acting: tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. Long-acting SGLT2 inhibitors exerted an antihyperglycemic effect with lower variability of blood glucose level via a long-lasting increase in urinary glucose excretion. In addition, ipragliflozin and luseogliflozin exhibited superiority over the others with respect to fast onset of pharmacological effect. Duration and onset of the pharmacologic effects seemed to be closely correlated with the pharmacokinetic properties of each SGLT2 inhibitor, particularly with respect to high distribution and long retention in the target organ, the kidney. While all six SGLT2 inhibitors were significantly effective in increasing urinary glucose excretion and reducing hyperglycemia, our findings suggest that variation in the quality of daily blood glucose control associated with duration and onset of pharmacologic effects of each SGLT2 inhibitor might cause slight differences in rates of improvement in type 2 diabetes. PMID:26970780

  13. Studies in neuroendocrine pharmacology

    Science.gov (United States)

    Maickel, R. P.

    1976-01-01

    The expertise and facilities available within the Medical Sciences Program section on Pharmacology were used along with informational input from various NASA sources to study areas relevant to the manned space effort. Topics discussed include effects of drugs on deprivation-induced fluid consumption, brain biogenic amines, biochemical responses to stressful stimuli, biochemical and behavioral pharmacology of amphetamines, biochemical and pharmacological studies of analogues to biologically active indole compounds, chemical pharmacology: drug metabolism and disposition, toxicology, and chemical methodology. Appendices include a bibliography, and papers submitted for publication or already published.

  14. Pharmacological characterization of venoms from three theraphosid spiders: Poecilotheria regalis, Ceratogyrus darlingi and Brachypelma epicureanum

    OpenAIRE

    García-Arredondo, Alejandro; Rodríguez-Rios, Luis; Díaz-Peña, Luis Fernando; Vega-Ángeles, Ricardo

    2015-01-01

    Background Tarantulas (Theraphosidae) represent an important source of novel biologically active compounds that target a variety of ion channels and cell receptors in both insects and mammals. In this study, we evaluate and compare the pharmacological activity of venoms from three taxonomically different theraphosid spiders bred in captivity: Poecilotheria regalis, an aggressive arboreal tarantula from southeastern India; Ceratogyrus darlingi, an aggressive tarantula from southern Africa; and...

  15. A High Rate Tension Device for Characterizing Brain Tissue

    CERN Document Server

    Rashid, Badar; Gilchrist, Michael; 10.1177/1754337112436900

    2013-01-01

    The mechanical characterization of brain tissue at high loading velocities is vital for understanding and modeling Traumatic Brain Injury (TBI). The most severe form of TBI is diffuse axonal injury (DAI) which involves damage to individual nerve cells (neurons). DAI in animals and humans occurs at strains > 10% and strain rates > 10/s. The mechanical properties of brain tissues at these strains and strain rates are of particular significance, as they can be used in finite element human head models to accurately predict brain injuries under different impact conditions. Existing conventional tensile testing machines can only achieve maximum loading velocities of 500 mm/min, whereas the Kolsky bar apparatus is more suitable for strain rates > 100/s. In this study, a custom-designed high rate tension device is developed and calibrated to estimate the mechanical properties of brain tissue in tension at strain rates < 90/s, while maintaining a uniform velocity. The range of strain can also be extended to 100% de...

  16. Temporal and pharmacological characterization of angiostatin release and generation by human platelets: implications for endothelial cell migration.

    Directory of Open Access Journals (Sweden)

    Aneta Radziwon-Balicka

    Full Text Available Platelets play an important role in thrombosis and in neo-vascularisation as they release and produce factors that both promote and suppress angiogenesis. Amongst these factors is the angiogenesis inhibitor angiostatin, which is released during thrombus formation. The impact of anti-thrombotic agents and the kinetics of platelet angiostatin release are unknown. Hence, our objectives were to characterize platelet angiostatin release temporally and pharmacologically and to determine how angiostatin release influences endothelial cell migration, an early stage of angiogenesis. We hypothesized anti-platelet agents would suppress angiostatin release but not generation by platelets. Human platelets were aggregated and temporal angiostatin release was compared to vascular endothelial growth factor (VEGF. Immuno-gold electron microscopy and immunofluorescence microscopy identified α-granules as storage organelles of platelet angiostatin. Acetylsalicylic acid, MRS2395, GPIIb/IIIa blocking peptide, and aprotinin were used to characterize platelet angiostatin release and generation. An endothelial cell migration assay was performed under hypoxic conditions to determine the effects of pharmacological platelet and angiostatin inhibition. Compared to VEGF, angiostatin generation and release from α-granules occurred later temporally during platelet aggregation. Consequently, collagen-activated platelet releasates stimulated endothelial cell migration more potently than maximally-aggregated platelets. Platelet inhibitors prostacyclin, S-nitroso-glutathione, acetylsalicylic acid, and GPIIb/IIIa blocking peptide, but not a P2Y12 inhibitor, suppressed angiostatin release but not generation. Suppression of angiostatin generation in the presence of acetylsalicylic acid enhanced platelet-stimulated endothelial migration. Hence, the temporal and pharmacological modulation of platelet angiostatin release may have significant consequences for neo

  17. Characterization of senescence-accelerated mouse prone 6 (SAMP6) as an animal model for brain research.

    Science.gov (United States)

    Niimi, Kimie; Takahashi, Eiki

    2014-01-01

    The senescence-accelerated mouse (SAM) was developed by selective breeding of the AKR/J strain, based on a graded score for senescence, which led to the development of both senescence-accelerated prone (SAMP), and senescence-accelerated resistant (SAMR) strains. Among the SAMP strains, SAMP6 is well characterized as a model of senile osteoporosis, but its brain and neuronal functions have not been well studied. We therefore decided to characterize the central nervous system of SAMP6, in combination with different behavioral tests and analysis of its biochemical and pharmacological properties. Multiple behavioral tests revealed higher motor activity, reduced anxiety, anti-depressant activity, motor coordination deficits, and enhanced learning and memory in SAMP6 compared with SAMR1. Biochemical and pharmacological analyses revealed several alterations in the dopamine and serotonin systems, and in long-term potentiation (LTP)-related molecules. In this review, we discuss the possibility of using SAMP6 as a model of brain function. PMID:24521858

  18. Cloning, expression and pharmacological characterization of rabbit adenosine A1 and A3 receptors.

    Science.gov (United States)

    Hill, R J; Oleynek, J J; Hoth, C F; Kiron, M A; Weng, W; Wester, R T; Tracey, W R; Knight, D R; Buchholz, R A; Kennedy, S P

    1997-01-01

    The role of adenosine A1 and A3 receptors in mediating cardioprotection has been studied predominantly in rabbits, yet the pharmacological characteristics of rabbit adenosine A1 and A3 receptor subtypes are unknown. Thus, the rabbit adenosine A3 receptor was cloned and expressed, and its pharmacology was compared with that of cloned adenosine A1 receptors. Stable transfection of rabbit A1 or A3 cDNAs in Chinese hamster ovary-K1 cells resulted in high levels of expression of each of the receptors, as demonstrated by high-affinity binding of the A1/A3 adenosine receptor agonist N6-(4-amino-3-[125I]iodobenzyl)adenosine (125I-ABA). For both receptors, binding of 125I-ABA was inhibited by the GTP analog 5'-guanylimidodiphosphate, and forskolin-stimulated cyclic AMP accumulation was inhibited by the adenosine receptor agonist (R)-phenylisopropyladenosine. The rank orders of potency of adenosine receptor agonists for inhibition of 125I-ABA binding were as follows: rabbit A1, N6-cyclopentyladenosine = (R)-phenylisopropyladenosine > N-ethylcarboxamidoadenosine > or = I-ABA > or = N6-2-(4-aminophenyl) ethyladenosine > > N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide > N6-(4-amino-3-benzyl)adenosine; rabbit A3, N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide > or = I-ABA > > N-ethylcarboxamidoadenosine > N6-2-(4-aminophenyl) ethyladenosine = N6-cyclopentyladenosine = (R)-phenylisopropyladenosine > N6-(4-amino-3-benzyl)adenosine. The adenosine receptor antagonist rank orders were as follow: rabbit A1, 8-cyclopentyl-1,3-dipropylxanthine > 1,3- dipropyl-8-(4-acrylate)phenylxanthine > or = xanthine amine congener > > 8-(p-sulfophenyl)theophylline; rabbit A3, xanthine amine congener > 1,3-dipropyl-8-(4-acrylate)phenylxanthine > or = 8-cyclopentyl-1,3-dipropylxanthine > > 8-(p-sulfophenyl)theophylline. These observations confirm the identity of the expressed proteins as A1 and A3 receptors. The results will facilitate further in-depth studies of the roles of A1 and A3 receptors in

  19. Genetic and Pharmacological Inhibition of PDK1 in Cancer Cells: Characterization of a Selective Allosteric Kinase Inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Nagashima, Kumiko; Shumway, Stuart D.; Sathyanarayanan, Sriram; Chen, Albert H.; Dolinski, Brian; Xu, Youyuan; Keilhack, Heike; Nguyen, Thi; Wiznerowicz, Maciej; Li, Lixia; Lutterbach, Bart A.; Chi, An; Paweletz, Cloud; Allison, Timothy; Yan, Youwei; Munshi, Sanjeev K.; Klippel, Anke; Kraus, Manfred; Bobkova, Ekaterina V.; Deshmukh, Sujal; Xu, Zangwei; Mueller, Uwe; Szewczak, Alexander A.; Pan, Bo-Sheng; Richon, Victoria; Pollock, Roy; Blume-Jensen, Peter; Northrup, Alan; Andersen, Jannik N. (Merck)

    2013-11-20

    Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases and has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 as a therapeutic target, pharmacological support is lacking due to the prevalence of nonspecific inhibitors. Here, we benchmark literature and newly developed inhibitors and conduct parallel genetic and pharmacological queries into PDK1 function in cancer cells. Through kinase selectivity profiling and x-ray crystallographic studies, we identify an exquisitely selective PDK1 inhibitor (compound 7) that uniquely binds to the inactive kinase conformation (DFG-out). In contrast to compounds 1-5, which are classical ATP-competitive kinase inhibitors (DFG-in), compound 7 specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), supporting its unique binding mode. Interfering with PDK1 activity has minimal antiproliferative effect on cells growing as plastic-attached monolayer cultures (i.e. standard tissue culture conditions) despite reduced phosphorylation of AKT, RSK, and S6RP. However, selective PDK1 inhibition impairs anchorage-independent growth, invasion, and cancer cell migration. Compound 7 inhibits colony formation in a subset of cancer cell lines (four of 10) and primary xenograft tumor lines (nine of 57). RNAi-mediated knockdown corroborates the PDK1 dependence in cell lines and identifies candidate biomarkers of drug response. In summary, our profiling studies define a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems.

  20. Localization and pharmacological characterization of voltage dependent calcium channels in cultured neocortical neurons

    DEFF Research Database (Denmark)

    Timmermann, D B; Lund, T M; Belhage, B;

    2001-01-01

    in cytosolic calcium concentration. The results of this investigation demonstrate that pharmacologically distinct types of voltage dependent calcium channels are differentially localized in cell bodies, neurites and nerve terminals of mouse cortical neurons but that the Q-type calcium channel appears......The physiological significance and subcellular distribution of voltage dependent calcium channels was defined using calcium channel blockers to inhibit potassium induced rises in cytosolic calcium concentration in cultured mouse neocortical neurons. The cytosolic calcium concentration was measured...... using the fluorescent calcium chelator fura-2. The types of calcium channels present at the synaptic terminal were determined by the inhibitory action of calcium channel blockers on potassium-induced [3H]GABA release in the same cell preparation. L-, N-, P-, Q- and R-/T-type voltage dependent calcium...

  1. Molecular cloning and pharmacological characterization of giant panda (Ailuropoda melanoleuca) melanocortin-4 receptor.

    Science.gov (United States)

    Wang, Zhi-Qiang; Wang, Wei; Shi, Lin; Chai, Ji-Tian; Zhang, Xin-Jun; Tao, Ya-Xiong

    2016-04-01

    The melanocortin-4 receptor (MC4R) is critical in regulating mammalian food intake and energy expenditure. Giant panda (Ailuropoda melanoleuca), famous as the living fossil, is an endangered species endemic to China. We are interested in exploring the functions of the giant panda MC4R (amMC4R) in regulating energy homeostasis and report herein the molecular cloning and pharmacology of the amMC4R. Sequence analysis revealed that amMC4R was highly homologous (>88%) at nucleotide and amino acid sequences to several mammalian MC4Rs. Western blot revealed that the expression construct myc-amMC4R in pcDNA3.1 was successfully constructed and expressed in HEK293T cells. With human MC4R (hMC4R) as a control, pharmacological characteristics of amMC4R were analyzed with binding and signaling assays. Four agonists, including [Nle(4), D-Phe(7)]-α-melanocyte stimulating hormone (NDP-MSH), α- and β-MSH, and a small molecule agonist, THIQ, were used in binding and signaling assays. We showed that amMC4R bound NDP-MSH with the highest affinity followed by THIQ, α-MSH, and β-MSH, with the same ranking order as hMC4R. Treatment of HEK293T cells expressing amMC4R with different concentrations of agonists resulted in dose-dependent increase of intracellular cAMP levels, with similar EC50s for the four agonists. The results suggested that the cloned amMC4R encoded a functional MC4R. The availability of amMC4R and its binding and signaling properties will facilitate the investigation of amMC4R in regulating food intake and energy homeostasis. PMID:26896843

  2. Single subject pharmacological-MRI (phMRI study: Modulation of brain activity of psoriatic arthritis pain by cyclooxygenase-2 inhibitor

    Directory of Open Access Journals (Sweden)

    Chialvo DR

    2005-11-01

    Full Text Available Abstract We use fMRI to examine brain activity for pain elicited by palpating joints in a single patient suffering from psoriatic arthritis. Changes in these responses are documented when the patient ingested a single dose of a selective cyclooxygenase-2 inhibitor (COX-2i. We show that mechanical stimulation of the painful joints exhibited a cortical activity pattern similar to that reported for acute pain, with activity primarily localized to the thalamus, insular, primary and secondary somatosensory cortices and the mid anterior cingulum. COX-2i resulted in significant decreased in reported pain intensity and in brain activity after 1 hour of administration. The anterior insula and SII correlated with pain intensity, however no central activation site for the drug was detected. We demonstrate the similarity of the activation pattern for palpating painful joints to brain activity in normal subjects in response to thermal painful stimuli, by performing a spatial conjunction analysis between these maps, where overlap is observed in the insula, thalamus, secondary somatosensory cortex, and anterior cingulate. The results demonstrate that one can study effects of pharmacological manipulations in a single subject where the brain activity for a clinical condition is delineated and its modulation by COX-2i demonstrated. This approach may have diagnostic and prognostic utility.

  3. Characterization and Pharmacological Activities of Jellyfish, Chrysaora hysoscella Captured in Bushehr Port, Iran

    Directory of Open Access Journals (Sweden)

    Somayyeh Gharibi

    2016-08-01

    Full Text Available Background: Cutaneous reactions like pruritus and erythema are common in warm months of the year in Bushehr Port, Persian Gulf, Iran due to jellyfish envenomation. This study reports isolation of the Chrysaora hysoscella nematocysts and evaluating its pharmacological activities during a bloom in 2013. Methods: The venom of C. hysoscella captured in Jofre area in Bushehr port was analyzed. The electrophoretic profile was assessed by SDS-PAGE (12.5% and the crude sample was analyzed using reverse phase HPLC. Caseinase activity was also determined. Results: After separation of tentacles and isolation of their nematocysts, three different major protein components were revealed at 72-250 kDa with SDS-PAGE, signifying the presence of peptides in its venom. Two major peaks at 8.62 and 11.23 min were observed in reverse phase HPLC of the crude venom denoting protease peptide structural identities. Caseinase activity of C. hysoscella's venom was extremely low as compared with other jellyfish venoms. Conclusion: This was the first report on the structural examination of jellyfish in Persian Gulf and may pave the way for determination and separation of destructive enzymes inducing cutaneous reactions in fishermen and swimmers.

  4. Interleukin-1 receptors in mouse brain: Characterization and neuronal localization

    International Nuclear Information System (INIS)

    The cytokine interleukin-1 (IL-1) has a variety of effects in brain, including induction of fever, alteration of slow wave sleep, and alteration of neuroendocrine activity. To examine the potential sites of action of IL-1 in brain, we used iodine-125-labeled recombinant human interleukin-1 [( 125I]IL-1) to identify and characterize IL-1 receptors in crude membrane preparations of mouse (C57BL/6) hippocampus and to study the distribution of IL-1-binding sites in brain using autoradiography. In preliminary homogenate binding and autoradiographic studies, [125I]IL-1 alpha showed significantly higher specific binding than [125I]IL-1 beta. Thus, [125I]IL-1 alpha was used in all subsequent assays. The binding of [125I]IL-1 alpha was linear over a broad range of membrane protein concentrations, saturable, reversible, and of high affinity, with an equilibrium dissociation constant value of 114 +/- 35 pM and a maximum number of binding sites of 2.5 +/- 0.4 fmol/mg protein. In competition studies, recombinant human IL-1 alpha, recombinant human IL-1 beta, and a weak IL-1 beta analog. IL-1 beta +, inhibited [125I]IL-1 alpha binding to mouse hippocampus in parallel with their relative bioactivities in the T-cell comitogenesis assay, with inhibitory binding affinity constants of 55 +/- 18, 76 +/- 20, and 2940 +/- 742 pM, respectively; rat/human CRF and human tumor necrosis factor showed no effect on [125I]IL-1 alpha binding. Autoradiographic localization studies revealed very low densities of [125I]IL-1 alpha-binding sites throughout the brain, with highest densities present in the molecular and granular layers of the dentate gyrus of the hippocampus and in the choroid plexus. Quinolinic acid lesion studies demonstrated that the [125I]IL-1 alpha-binding sites in the hippocampus were localized to intrinsic neurons

  5. [Pharmacological influences on the brain level and transport of GABA. II) Effect of various psychoactive drugs on brain level and uptake of GABA].

    Science.gov (United States)

    Gabana, M A; Varotto, M; Saladini, M; Zanchin, G; Battistin, L

    1981-04-30

    The effects of some psychoactive drugs on the level and uptake of GABA in the mouse brain was studied using well standardized procedures, mainely the silica-gel cromatography for determining the GABA content and the brain slices for measuring GABA uptake. It was found that levomepromazine, sulpiride, haloperidol and amytryptiline were without effects on the cerebral level of GABA; it was also found that these drugs do not influence the rates of uptake of GABA by mouse brain slices. Such results do indicate that the psychoactive drugs studied are without effects on the level and uptake of GABA in the brain. PMID:7272066

  6. Pharmacological characterization of an imidazolopyrazole as novel selective androgen receptor modulator.

    Science.gov (United States)

    Zhang, Xuqing; Allan, George F; Tannenbaum, Pamela; Sbriscia, Tifanie; Linton, Olivia; Lai, Muh-Tsann; Haynes-Johnson, Donna; Bhattacharjee, Sheela; Lundeen, Scott G; Sui, Zhihua

    2013-03-01

    Selective androgen receptor modulators (SARMs) are androgens with tissue-selective activity. SARMs that have anabolic activity on muscle while having minimal stimulatory activity on prostate are classified as SARM agonists. They can be used to prevent the loss of lean body mass that is associated with cancer, immunodeficiency, renal disease and aging. They may also have anabolic activity on bone; thus, unlike estrogens, they may reverse the loss of bone strength associated with aging or hypogonadism. Our in-house effort on SARM program discovers a nonsteroidal androgen receptor ligand with a unique imidazolopyrazole moiety in its structure. In vitro, this compound is a weak androgen receptor binder and a weak androgen agonist. Despite this, in orchidectomized mature rats it is an effective SARM agonist, with an ED(50) on levator ani muscle of 3.3mg/kg and an ED(50) on ventral prostate of >30mg/kg. It has its maximal effect on muscle at the dose of 10mg/kg. In addition, this compound has mixed agonistic and antagonistic activities on prostate, reducing the weight of that tissue in intact rats by 22% at 10mg/kg. The compound does not have significant effect on gonadotropin levels or testosterone levels in both orchidectomized and intact male rats. It does not have notable progestin, estrogen or glucocorticoid agonistic or antagonistic activity in rats. In a female sexual behavior model, it improves the sexual desire of ovariectomized female rats for sexually mature intact males over nonsexually ovariectomized females. Overall, the imidazolopyrazole is a potent prostate-sparing candidate for development as a SARM agonist with an appropriate pharmacological profile for clinical benefit in muscle-wasting conditions and female sexual function disorders.

  7. Pharmacological characterization of cultivated neuronal networks: relevance to synaptogenesis and synaptic connectivity.

    Science.gov (United States)

    Verstraelen, Peter; Pintelon, Isabel; Nuydens, Rony; Cornelissen, Frans; Meert, Theo; Timmermans, Jean-Pierre

    2014-07-01

    Mental disorders, such as schizophrenia or Alzheimer's disease, are associated with impaired synaptogenesis and/or synaptic communication. During development, neurons assemble into neuronal networks, the primary supracellular mediators of information processing. In addition to the orchestrated activation of genetic programs, spontaneous electrical activity and associated calcium signaling have been shown to be critically involved in the maturation of such neuronal networks. We established an in vitro model that recapitulates the maturation of neuronal networks, including spontaneous electrical activity. Upon plating, mouse primary hippocampal neurons grow neurites and interconnect via synapses to form a dish-wide neuronal network. Via live cell calcium imaging, we identified a limited period of time in which the spontaneous activity synchronizes across neurons, indicative of the formation of a functional network. After establishment of network activity, the neurons grow dendritic spines, the density of which was used as a morphological readout for neuronal maturity and connectivity. Hence, quantification of neurite outgrowth, synapse density, spontaneous neuronal activity, and dendritic spine density allowed to study neuronal network maturation from the day of plating until the presence of mature neuronal networks. Via acute pharmacological intervention, we show that synchronized network activity is mediated by the NMDA-R. The balance between kynurenic and quinolinic acid, both neuro-active intermediates in the tryptophan/kynurenine pathway, was shown to be decisive for the maintenance of network activity. Chronic modulation of the neurotrophic support influenced the network formation and revealed the extreme sensitivity of calcium imaging to detect subtle alterations in neuronal physiology. Given the reproducible cultivation in a 96-well setup in combination with fully automated analysis of the calcium recordings, this approach can be used to build a high

  8. Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression

    Science.gov (United States)

    Haenisch, Britta; Bilkei-Gorzo, Andras; Caron, Marc G.; Bönisch, Heinz

    2009-01-01

    Diverse factors such as changes in neurotrophins and brain plasticity have been proposed to be involved in the actions of antidepressant drugs (ADs). However, in mouse models of depression based on chronic stress, it is still unclear whether simultaneous changes in behavior and neurotrophin expression occur and whether these changes can be corrected or prevented comparably by chronic administration of ADs or genetic manipulations that produce antidepressant-like effects such as the knockout (KO) of the norepinephrine transporter (NET) gene. Here we show that chronic restraint or social defeat stress induce comparable effects on behavior and changes in the expression of neurotrophins in depression-related brain regions. Chronic stress caused down-regulation of BDNF, NGF and NT-3 in hippocampus and cerebral cortex and up-regulation of these targets in striatal regions. In wild-type mice, these effects could be prevented by concomitant chronic administration of five pharmacologically diverse ADs. In contrast, NETKO mice were resistant to stress-induced depressive-like changes in behavior and brain neurotrophin expression. Thus, the resistance of the NETKO mice to the stress-induced depression-associated behaviors and biochemical changes highlight the importance of noradrenergic pathways in the maintenance of mood. In addition, these mice represent a useful model to study depression-resistant behaviors, and they might help to provide deeper insights into the identification of downstream targets involved in the mechanisms of antidepressants. PMID:19694905

  9. Electrophysiological and pharmacological characterization of K+-currents in muscle fibres isolated from the ventral sucker of Fasciola hepatica.

    Science.gov (United States)

    Kumar, D; White, C; Fairweather, I; McGeown, J G

    2004-12-01

    Fibres isolated from the ventral sucker of Fasciola hepatica were identified as muscle on the basis of their contractility, and their actin and myosin staining. They were voltage-clamped at a holding potential of -40 mV and depolarization-activated outward currents were characterized both electrophysiologically and pharmacologically. Activation was well fitted by a Boltzmann equation with a half-maximal potential of + 9 mV and a slope factor of -14.3 mV, and the kinetics of activation and deactivation were voltage-sensitive. Tail current analysis showed that the reversal potential was shifted by +46+/-3 mV when E(K) was increased by 52 mV, confirming that this was a K+-current with electrophysiological characteristics similar to delayed rectifier and Ca2+-activated K+-currents in other tissues. The peak current at + 60 mV was inhibited by 76+/-6% by tetrapentylammonium chloride (1 mM) and by 84+/-7% by Ba2+ (3 mM), but was completely resistant to block by tetraethylammonium (30 mM), 3,4-diaminopyridine (100 microM) and 4-aminopyridine (10 mM). Penitrem A, a blocker of high-conductance Ca2+-activated K+-channels reduced the current at +60 mV by 23+/-5%. When the effects of Ca2+-channel blocking agents were tested, the peak outward current at + 60 mV was reduced by 71+/-7% by verapamil (30 microM) and by 59+/-4% by nimodipine (30 microM). Superfusion with BAPTA-AM (50 microM), which is hydrolysed intracellularly to release the Ca2+-buffer BAPTA, also decreased the current by 44+/-16%. We conclude that voltage-and Ca2+-sensitive K+-channels are expressed in this tissue, but that their pharmacology differs considerably from equivalent channels in other phyla. PMID:15648701

  10. Pharmacological characterization of a novel gastrodin derivative as a potential anti-migraine agent.

    Science.gov (United States)

    Wang, Ping-Han; Zhao, Li-Xue; Wan, Jing-Yu; Zhang, Liang; Mao, Xiao-Na; Long, Fang-Yi; Zhang, Shuang; Chen, Chu; Du, Jun-Rong

    2016-03-01

    Migraine is a highly prevalent neurovascular disorder in the brain. An optimal therapy for migraine has not yet been developed. Gastrodin (Gas), the main effective constitute from Gastrodiae Rhizoma (Tianma in Chinese), has been indicated for migraine treatment and prophylaxis more than 30 years, with demonstrated safety. However, Gas is a phenolic glycoside, with relatively low concentrations and weak efficacy in the central nervous system. To develop more effective anti-migraine agents, we synthesized a novel Gas derivative (Gas-D). In the present study, comparative pharmacodynamic evaluations of Gas and Gas-D were performed in a model of nitroglycerin (NTG)-induced migraine in rats and the hot-plate test in mice. Following behavioral testing in this migraine model, external jugular vein blood and the trigeminal nucleus caudalis (TNC) were collected to analyze plasma nitric oxide (NO) and calcitonin gene-related peptide (CGRP) concentrations and c-Fos expression in the TNC. The acute oral toxicity of Gas and Gas-D was also examined. We found that Gas-D had potent anti-migraine effects, likely attributable to inhibition of both trigeminal nerve activation at central sites and the peripheral release of CGRP following NO scavenging. Additionally, Gas-D exerted significant anti-nociceptive effect in response to thermal pain compared with Gas. Furthermore, a single dose of 2.048 g/kg Gas or Gas-D presented no acute oral toxicity in mice. Altogether, the potent anti-migraine and anti-hyperalgesic effects of Gas-D suggest that it might be a potentially novel drug candidate for migraine treatment or prophylaxis.

  11. Pharmacological characterization of the novel anxiolytic beta-carboline abecarnil in rodents and primates.

    Science.gov (United States)

    Ozawa, M; Nakada, Y; Sugimachi, K; Yabuuchi, F; Akai, T; Mizuta, E; Kuno, S; Yamaguchi, M

    1994-03-01

    beta-Carboline abecarnil was behaviorally and biochemically characterized as a new anxiolytic agent in rodents and primates in comparison with the benzodiazepine (BZ) anxiolytics. Oral treatment with abecarnil (0.5-10 mg/kg) showed a potent anticonflict activity in the water-lick test in rats. The minimal effective dose was lower than those of BZ anxiolytics, such as etizolam, diazepam, clotiazepam and tofisopam. Abecarnil also showed taming effects to suppress fighting and aggressive behaviors in mice and monkeys with little sedative and ataxic effects, in contrast to the BZ anxiolytics producing marked sedative and ataxic effects. Furthermore, abecarnil suppressed both the sedative and ataxic effects induced by diazepam. Abecarnil bound to rat cerebellar BZ1 receptors (Ki = 0.24 nM) with higher affinity than to rat spinal cord BZ2 receptors (Ki = 1.3 nM), whereas BZ derivatives bound to both the receptors with a low and equal affinity. GABA-ratios of abecarnil were 1.9 for the BZ1 receptors and 2.8 for the BZ2 receptors, and they were smaller than those of diazepam and flunitrazepam. Thus, in contrast to the BZ derivatives, abecarnil may act as a selective partial agonist at central BZ1 receptors, resulting in its potent anticonflict and taming effects with little sedative and ataxic effects. PMID:7912751

  12. Pharmacological profile of brain-derived neurotrophic factor (BDNF) splice variant translation using a novel drug screening assay: a "quantitative code".

    Science.gov (United States)

    Vaghi, Valentina; Polacchini, Alessio; Baj, Gabriele; Pinheiro, Vera L M; Vicario, Annalisa; Tongiorgi, Enrico

    2014-10-01

    The neurotrophin brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal development and plasticity. BDNF is a major pharmaceutical target in neurodevelopmental and psychiatric disorders. However, pharmacological modulation of this neurotrophin is challenging because BDNF is generated by multiple, alternatively spliced transcripts with different 5'- and 3'UTRs. Each BDNF mRNA variant is transcribed independently, but translation regulation is unknown. To evaluate the translatability of BDNF transcripts, we developed an in vitro luciferase assay in human neuroblastoma cells. In unstimulated cells, each BDNF 5'- and 3'UTR determined a different basal translation level of the luciferase reporter gene. However, constructs with either a 5'UTR or a 3'UTR alone showed poor translation modulation by BDNF, KCl, dihydroxyphenylglycine, AMPA, NMDA, dopamine, acetylcholine, norepinephrine, or serotonin. Constructs consisting of the luciferase reporter gene flanked by the 5'UTR of one of the most abundant BDNF transcripts in the brain (exons 1, 2c, 4, and 6) and the long 3'UTR responded selectively to stimulation with the different receptor agonists, and only transcripts 2c and 6 were increased by the antidepressants desipramine and mirtazapine. We propose that BDNF mRNA variants represent "a quantitative code" for regulated expression of the protein. Thus, to discriminate the efficacy of drugs in stimulating BDNF synthesis, it is appropriate to use variant-specific in vitro screening tests.

  13. Spinal cord transection-induced allodynia in rats--behavioral, physiopathological and pharmacological characterization.

    Directory of Open Access Journals (Sweden)

    Saïd M'Dahoma

    Full Text Available In humans, spinal cord lesions induce not only major motor and neurovegetative deficits but also severe neuropathic pain which is mostly resistant to classical analgesics. Better treatments can be expected from precise characterization of underlying physiopathological mechanisms. This led us to thoroughly investigate (i mechanical and thermal sensory alterations, (ii responses to acute treatments with drugs having patent or potential anti-allodynic properties and (iii the spinal/ganglion expression of transcripts encoding markers of neuronal injury, microglia and astrocyte activation in rats that underwent complete spinal cord transection (SCT. SCT was performed at thoracic T8-T9 level under deep isoflurane anaesthesia, and SCT rats were examined for up to two months post surgery. SCT induced a marked hyper-reflexia at hindpaws and strong mechanical and cold allodynia in a limited (6 cm2 cutaneous territory just rostral to the lesion site. At this level, pressure threshold value to trigger nocifensive reactions to locally applied von Frey filaments was 100-fold lower in SCT- versus sham-operated rats. A marked up-regulation of mRNAs encoding ATF3 (neuronal injury and glial activation markers (OX-42, GFAP, P2×4, P2×7, TLR4 was observed in spinal cord and/or dorsal root ganglia at T6-T11 levels from day 2 up to day 60 post surgery. Transcripts encoding the proinflammatory cytokines IL-1β, IL-6 and TNF-α were also markedly but differentially up-regulated at T6-T11 levels in SCT rats. Acute treatment with ketamine (50 mg/kg i.p., morphine (3-10 mg/kg s.c. and tapentadol (10-20 mg/kg i.p. significantly increased pressure threshold to trigger nocifensive reaction in the von Frey filaments test, whereas amitriptyline, pregabalin, gabapentin and clonazepam were ineffective. Because all SCT rats developed long lasting, reproducible and stable allodynia, which could be alleviated by drugs effective in humans, thoracic cord transection might be a

  14. Cl- conduction of GABA(A)-receptor complex of synaptic membranes of rat brain cortex after development of chronic epileptization of the brain (pharmacological kindling).

    Science.gov (United States)

    Rebrov, I G; Karpova, M N; Andreev, A A; Klishina, N Y; Kalinina, M V; Kusnetzova, L V

    2008-03-01

    Experiments on Wistar rats showed that basal and muscimol-induced 36Cl- entry into synaptoneurosomes isolated from the brain cortex decreased after kindling (30 mg/kg pentylenetetrazole intraperitoneally for 30 days) in animals with seizure severity score 4-5. Changes in Cl- conduction during kindling are discussed.

  15. Functional characterization of transmembrane adenylyl cyclases from the honeybee brain.

    Science.gov (United States)

    Balfanz, Sabine; Ehling, Petra; Wachten, Sebastian; Jordan, Nadine; Erber, Joachim; Mujagic, Samir; Baumann, Arnd

    2012-06-01

    The second messenger cAMP has a pivotal role in animals' physiology and behavior. Intracellular concentrations of cAMP are balanced by cAMP-synthesizing adenylyl cyclases (ACs) and cAMP-cleaving phosphodiesterases. Knowledge about ACs in the honeybee (Apis mellifera) is rather limited and only an ortholog of the vertebrate AC3 isoform has been functionally characterized, so far. Employing bioinformatics and functional expression we characterized two additional honeybee genes encoding membrane-bound (tm)ACs. The proteins were designated AmAC2t and AmAC8. Unlike the common structure of tmACs, AmAC2t lacks the first transmembrane domain. Despite this unusual topography, AmAC2t-activity could be stimulated by norepinephrine and NKH477 with EC(50s) of 0.07 μM and 3 μM. Both ligands stimulated AmAC8 with EC(50s) of 0.24 μM and 3.1 μM. In brain cryosections, intensive staining of mushroom bodies was observed with specific antibodies against AmAC8, an expression pattern highly reminiscent of the Drosophila rutabaga AC. In a current release of the honeybee genome database we identified three additional tmAC- and one soluble AC-encoding gene. These results suggest that (1) the AC-gene family in honeybees is comparably large as in other species, and (2) based on the restricted expression of AmAC8 in mushroom bodies, this enzyme might serve important functions in honeybee behavior. PMID:22426196

  16. Biochemical and pharmacological characterization of the human lymphocyte antigen B-associated transcript 5 (BAT5/ABHD16A.

    Directory of Open Access Journals (Sweden)

    Juha R Savinainen

    Full Text Available Human lymphocyte antigen B-associated transcript 5 (BAT5, also known as ABHD16A is a poorly characterized 63 kDa protein belonging to the α/β-hydrolase domain (ABHD containing family of metabolic serine hydrolases. Its natural substrates and biochemical properties are unknown.Amino acid sequence comparison between seven mammalian BAT5 orthologs revealed that the overall primary structure was highly (≥95% conserved. Activity-based protein profiling (ABPP confirmed successful generation of catalytically active human (h and mouse (m BAT5 in HEK293 cells, enabling further biochemical characterization. A sensitive fluorescent glycerol assay reported hBAT5-mediated hydrolysis of medium-chain saturated (C14:0, long-chain unsaturated (C18:1, C18:2, C20:4 monoacylglycerols (MAGs and 15-deoxy-Δ12,14-prostaglandin J2-2-glycerol ester (15d-PGJ2-G. In contrast, hBAT5 possessed only marginal diacylglycerol (DAG, triacylglycerol (TAG, or lysophospholipase activity. The best MAG substrates were 1-linoleylglycerol (1-LG and 15d-PGJ2-G, both exhibiting low-micromolar Km values. BAT5 had a neutral pH optimum and showed preference for the 1(3- vs. 2-isomers of MAGs C18:1, C18:2 and C20:4. Inhibitor profiling revealed that β-lactone-based lipase inhibitors were nanomolar inhibitors of hBAT5 activity (palmostatin B > tetrahydrolipstatin > ebelactone A. Moreover, the hormone-sensitive lipase inhibitor C7600 (5-methoxy-3-(4-phenoxyphenyl-3H-[1], [3], [4]oxadiazol-2-one was identified as a highly potent inhibitor (IC50 8.3 nM. Phenyl and benzyl substituted analogs of C7600 with increased BAT5 selectivity were synthesized and a preliminary SAR analysis was conducted to obtain initial insights into the active site dimensions.This study provides an initial characterization of BAT5 activity, unveiling the biochemical and pharmacological properties with in vitro substrate preferences and inhibitor profiles. Utilization of glycerolipid substrates and sensitivity to

  17. Biochemical and Pharmacological Characterization of the Human Lymphocyte Antigen B-Associated Transcript 5 (BAT5/ABHD16A)

    Science.gov (United States)

    Savinainen, Juha R.; Patel, Jayendra Z.; Parkkari, Teija; Navia-Paldanius, Dina; Marjamaa, Joona J. T.; Laitinen, Tuomo; Nevalainen, Tapio; Laitinen, Jarmo T.

    2014-01-01

    Background Human lymphocyte antigen B-associated transcript 5 (BAT5, also known as ABHD16A) is a poorly characterized 63 kDa protein belonging to the α/β-hydrolase domain (ABHD) containing family of metabolic serine hydrolases. Its natural substrates and biochemical properties are unknown. Methodology/Principal Findings Amino acid sequence comparison between seven mammalian BAT5 orthologs revealed that the overall primary structure was highly (≥95%) conserved. Activity-based protein profiling (ABPP) confirmed successful generation of catalytically active human (h) and mouse (m) BAT5 in HEK293 cells, enabling further biochemical characterization. A sensitive fluorescent glycerol assay reported hBAT5-mediated hydrolysis of medium-chain saturated (C14∶0), long-chain unsaturated (C18∶1, C18∶2, C20∶4) monoacylglycerols (MAGs) and 15-deoxy-Δ12,14-prostaglandin J2-2-glycerol ester (15d-PGJ2-G). In contrast, hBAT5 possessed only marginal diacylglycerol (DAG), triacylglycerol (TAG), or lysophospholipase activity. The best MAG substrates were 1-linoleylglycerol (1-LG) and 15d-PGJ2-G, both exhibiting low-micromolar Km values. BAT5 had a neutral pH optimum and showed preference for the 1(3)- vs. 2-isomers of MAGs C18∶1, C18∶2 and C20∶4. Inhibitor profiling revealed that β-lactone-based lipase inhibitors were nanomolar inhibitors of hBAT5 activity (palmostatin B > tetrahydrolipstatin > ebelactone A). Moreover, the hormone-sensitive lipase inhibitor C7600 (5-methoxy-3-(4-phenoxyphenyl)-3H-[1], [3], [4]oxadiazol-2-one) was identified as a highly potent inhibitor (IC50 8.3 nM). Phenyl and benzyl substituted analogs of C7600 with increased BAT5 selectivity were synthesized and a preliminary SAR analysis was conducted to obtain initial insights into the active site dimensions. Conclusions/Significance This study provides an initial characterization of BAT5 activity, unveiling the biochemical and pharmacological properties with in vitro substrate preferences and

  18. Short-term selective breeding for High and Low prepulse inhibition of the acoustic startle response; pharmacological characterization and QTL mapping in the selected lines

    OpenAIRE

    Hitzemann, Robert; Malmanger, Barry; Belknap, John; Darakjian, Priscila; McWeeney, Shannon

    2008-01-01

    Selective breeding offers several important advantages over using inbred strain panels in detecting genetically correlated traits to the selection phenotype. The purpose of the current study was to selectively breed for prepulse inhibition (PPI) of the acoustic startle response (ASR), to pharmacologically and behaviorally characterize the selected lines and to use the lines for quantitative trait loci (QTL) mapping. Starting with heterogeneous stock mice formed by crossing the C57BL/6J, DBA/2...

  19. The pharmacological characterization of attentional processes using a two-lever choice reaction time task in rats.

    Science.gov (United States)

    Mishima, Kenichi; Fujii, Megumi; Aoo, Naoya; Yoshikawa, Tetsuya; Fukue, Yoshihiko; Honda, Yoko; Egashira, Nobuaki; Iwasaki, Katsunori; Shoyama, Yukihiro; Fujiwara, Michihiro

    2002-12-01

    Activating the noradrenergic and cholinergic systems is known to enhance attentional processes, while stimulating dopaminergic, serotonergic, and GABAergic systems suppresses them. The objective of the present study was to investigate the pharmacological characterization in the attentional processes of a two-lever choice reaction time (CRT) task using different centrally acting drugs. We designed seven parameters in this task: the correct response (CR) rate; error response rate; nonresponse (NR) rate; differential reinforcement of other behavior (DRO) responses; number of incorrect lever pressings during both the intertrial interval and DRO periods; the mean CRT of CR; and activity during 30 trials. The compounds produced different profiles at each dose. 1) Facilitative and disruptive effects on attentional processes occurred with changes in CRT alone. Scopolamine (0.1 mg/kg) and prazosin (0.3-1 mg/kg) prolonged the CRT, whereas methamphetamine (0.3 mg/kg) shortened the CRT. 2) Attentional deficits occurred with abnormal behavior showing premature response or perseverative behavior. Scopolamine (0.2-1 mg/kg), methamphetamine (3 mg/kg), delta(9)-tetrahydrocannabinol (10 mg/kg), and MK-801 (0.1-0.3 mg/kg) produced a marked increase in the number of total lever pressings. 3) Motor function deficits rather than attentional deficits occurred. 8-OH DPAT (1 mg/kg) and muscimol (1 mg/kg) produced a decrease in CR and an increase in NR with a marked decrease in activity and prolonged the CRT. Activating noradrenergic alpha(1) receptors was found to enhance the attentional processes, while blocking muscarinic receptors, alpha(1) receptors, and NMDA receptors, and stimulating cannabinoid receptors and the dopaminergic systems impaired the attentional processes in the two-lever CRT task.

  20. Am5-HT7: molecular and pharmacological characterization of the first serotonin receptor of the honeybee (Apis mellifera).

    Science.gov (United States)

    Schlenstedt, Jana; Balfanz, Sabine; Baumann, Arnd; Blenau, Wolfgang

    2006-09-01

    The biogenic amine serotonin (5-HT) plays a key role in the regulation and modulation of many physiological and behavioural processes in both vertebrates and invertebrates. These functions are mediated through the binding of serotonin to its receptors, of which 13 subtypes have been characterized in vertebrates. We have isolated a cDNA from the honeybee Apis mellifera (Am5-ht7) sharing high similarity to members of the 5-HT(7) receptor family. Expression of the Am5-HT(7) receptor in HEK293 cells results in an increase in basal cAMP levels, suggesting that Am5-HT(7) is expressed as a constitutively active receptor. Serotonin application to Am5-ht7-transfected cells elevates cyclic adenosine 3',5'-monophosphate (cAMP) levels in a dose-dependent manner (EC(50) = 1.1-1.8 nm). The Am5-HT(7) receptor is also activated by 5-carboxamidotryptamine, whereas methiothepin acts as an inverse agonist. Receptor expression has been investigated by RT-PCR, in situ hybridization, and western blotting experiments. Receptor mRNA is expressed in the perikarya of various brain neuropils, including intrinsic mushroom body neurons, and in peripheral organs. This study marks the first comprehensive characterization of a serotonin receptor in the honeybee and should facilitate further analysis of the role(s) of the receptor in mediating the various central and peripheral effects of 5-HT. PMID:16945110

  1. Combining non-pharmacological treatments with pharmacotherapies for neurological disorders: a unique interface of the brain, drug-device, and intellectual property.

    Science.gov (United States)

    Bulaj, Grzegorz

    2014-01-01

    Mobile medical applications (mHealth), music, and video games are being developed and tested for their ability to improve pharmacotherapy outcomes and medication adherence. Pleiotropic mechanism of music and gamification engages an intrinsic motivation and the brain reward system, supporting therapies in patients with neurological disorders, including neuropathic pain, depression, anxiety, or neurodegenerative disorders. Based on accumulating results from clinical trials, an innovative combination treatment of epilepsy seizures, comorbidities, and the medication non-adherence can be designed, consisting of antiepileptic drugs and disease self-management software delivering clinically beneficial music. Since creative elements and art expressed in games, music, and software are copyrighted, therefore clinical and regulatory challenges in developing copyrighted, drug-device therapies may be offset by a value proposition of the exclusivity due to the patent-independent protection, which can last for over 70 years. Taken together, development of copyrighted non-pharmacological treatments (e-therapies), and their combinations with pharmacotherapies, offer incentives to chronically ill patients and outcome-driven health care industries. PMID:25071711

  2. Combining Non-pharmacological Treatments with Pharmacotherapies for Neurological Disorders: a Unique Interface of the Brain, Drug-Device and Intellectual Property

    Directory of Open Access Journals (Sweden)

    Grzegorz eBulaj

    2014-07-01

    Full Text Available Mobile medical applications (mHealth, music and video games are being developed and tested for their ability to improve pharmacotherapy outcomes and medication adherence. Pleiotropic mechanism of music and gamification engage an intrinsic motivation and the brain reward system, supporting therapies in patients with neurological disorders, including neuropathic pain, depression, anxiety, or neurodegenerative disorders. Based on accumulating results from clinical trials, an innovative combination treatment of epilepsy seizures, comorbidities and the medication non-adherence can be designed, consisting of antiepileptic drugs and disease self-management software delivering clinically beneficial music. Since creative elements and art expressed in games, music and software are copyrighted, therefore clinical and regulatory challenges in developing copyrighted, drug-device therapies may be offset by a value proposition of the exclusivity due to the patent-independent protection which can last for over 70 years. Taken together, development of copyrighted non-pharmacological treatments (e-therapies, and their combinations with pharmacotherapies, offers incentives to chronically-ill patients and outcome-driven health care industries.

  3. Combining Non-Pharmacological Treatments with Pharmacotherapies for Neurological Disorders: A Unique Interface of the Brain, Drug–Device, and Intellectual Property

    Science.gov (United States)

    Bulaj, Grzegorz

    2014-01-01

    Mobile medical applications (mHealth), music, and video games are being developed and tested for their ability to improve pharmacotherapy outcomes and medication adherence. Pleiotropic mechanism of music and gamification engages an intrinsic motivation and the brain reward system, supporting therapies in patients with neurological disorders, including neuropathic pain, depression, anxiety, or neurodegenerative disorders. Based on accumulating results from clinical trials, an innovative combination treatment of epilepsy seizures, comorbidities, and the medication non-adherence can be designed, consisting of antiepileptic drugs and disease self-management software delivering clinically beneficial music. Since creative elements and art expressed in games, music, and software are copyrighted, therefore clinical and regulatory challenges in developing copyrighted, drug–device therapies may be offset by a value proposition of the exclusivity due to the patent–independent protection, which can last for over 70 years. Taken together, development of copyrighted non-pharmacological treatments (e-therapies), and their combinations with pharmacotherapies, offer incentives to chronically ill patients and outcome-driven health care industries. PMID:25071711

  4. Histone deacetylase activity and brain-derived neurotrophic factor (BDNF levels in a pharmacological model of mania

    Directory of Open Access Journals (Sweden)

    Laura Stertz

    2014-03-01

    Full Text Available Objective: In the present study, we aimed to examine the effects of repeated D-amphetamine (AMPH exposure, a well-accepted animal model of acute mania in bipolar disorder (BD, and histone deacetylase (HDAC inhibitors on locomotor behavior and HDAC activity in the prefrontal cortex (PFC and peripheral blood mononuclear cells (PBMCs of rats. Moreover, we aimed to assess brain-derived neurotrophic factor (BDNF protein and mRNA levels in these samples. Methods: We treated adult male Wistar rats with 2 mg/kg AMPH or saline intraperitoneally for 14 days. Between the 8th and 14th days, rats also received 47.5 mg/kg lithium (Li, 200 mg/kg sodium valproate (VPT, 2 mg/kg sodium butyrate (SB, or saline. We evaluated locomotor activity in the open-field task and assessed HDAC activity in the PFC and PBMCs, and BDNF levels in the PFC and plasma. Results: AMPH significantly increased locomotor activity, which was reversed by all drugs. This hyperactivity was associated with increased HDAC activity in the PFC, which was partially reversed by Li, VPT, and SB. No differences were found in BDNF levels. Conclusion: Repeated AMPH administration increases HDAC activity in the PFC without altering BDNF levels. The partial reversal of HDAC increase by Li, VPT, and SB may account for their ability to reverse AMPH-induced hyperactivity.

  5. Anatomical characterization of cytoglobin and neuroglobin mRNA and protein expression in the mouse brain

    DEFF Research Database (Denmark)

    Hundahl, Christian Ansgar; Allen, Gregg C; Hannibal, Jens;

    2010-01-01

    The present study aimed at characterizing the anatomical and subcellular localization of cytoglobin (Cygb) and neuroglobin (Ngb) in the mouse brain by use of in situ hybridisation, immunohistochemistry and immunoelectron microscopy. Cygb and Ngb were only found in distinct brain areas and often in...

  6. Pharmacological characterization of human excitatory amino acid transporters EAAT1, EAAT2 and EAAT3 in a fluorescence-based membrane potential assay

    DEFF Research Database (Denmark)

    Jensen, Anders A.; Bräuner-Osborne, Hans

    2004-01-01

    (FMP) assay. The K(m) and K(i) values obtained for 12 standard EAAT ligands at EAAT1, EAAT2 and EAAT3 in the FMP assay correlated well with the K(i) values obtained in the [(3) H]-d-aspartate assay (r(2) values of 0.92, 0.92, and 0.95, respectively). Furthermore, the pharmacological characteristics......We have expressed the human excitatory amino acid transporters EAAT1, EAAT2 and EAAT3 stably in HEK293 cells and characterized the transporters pharmacologically in a conventional [(3) H]-d-aspartate uptake assay and in a fluorescence-based membrane potential assay, the FLIPR Membrane Potential...... conventional electrophysiology set-ups might be superior in terms of studying sophisticated kinetic aspects of the uptake process, the FMP assay enables the collection of considerable amounts of highly reproducible data with relatively little labor. Furthermore, considering that the number of EAAT ligands...

  7. Pharmacologic Neuroimaging of the Ontogeny of Dopamine Receptor Function

    OpenAIRE

    Chen, Y. Iris; Choi, Ji-Kyung; Xu, Haibo; Ren, Jiaqian; Andersen, Susan L.; Jenkins, Bruce G.

    2010-01-01

    Characterization of the ontogeny of the cerebral dopaminergic system is crucial for gaining a greater understanding of normal brain development and its alterations in response to drugs of abuse or conditions such as attention-deficit hyperactivity disorder. Pharmacological MRI (phMRI) was used to determine the response to dopamine transporter (DAT) blockers cocaine and methylphenidate (MPH), the dopamine releaser D-amphetamine (AMPH), the selective D1 agonist dihydrexidine, and the D2/D3 agon...

  8. Characterizing dynamic local functional connectivity in the human brain.

    Science.gov (United States)

    Deng, Lifu; Sun, Junfeng; Cheng, Lin; Tong, Shanbao

    2016-01-01

    Functional connectivity (FC), obtained from functional magnetic resonance imaging (fMRI), brings insights into the functional organization of the brain. Recently, rich and complex behaviour of brain has been revealed by the dynamic fluctuation of FC, which had previously been regarded as confounding 'noise'. While the dynamics of long-distance, inter-regional FC has been extensively studied, the dynamics of local FC within a few millimetres in space remains largely unexplored. In this study, the local FC was depicted by regional homogeneity (ReHo), and the dynamics of local FC was obtained using sliding windows method. We observed a robust positive correlation between ReHo and its temporal variability, which was shown to be an intrinsic feature of the brain rather than a pure stochastic effect. Furthermore, fluctuation of ReHo was associated with global functional organization: (i) brain regions with higher centrality of inter-regional FC tended to possess higher ReHo variability; (ii) coherence of ReHo fluctuation was higher within brain's functional modules. Finally, we observed alteration of ReHo variability during a motor task compared with resting-state. Our findings associated the temporal fluctuation of ReHo with brain function, opening up the possibility of dynamic local FC study in the future. PMID:27231194

  9. Brain

    Science.gov (United States)

    ... will return after updating. Resources Archived Modules Updates Brain Cerebrum The cerebrum is the part of the ... the outside of the brain and spinal cord. Brain Stem The brain stem is the part of ...

  10. Characterizing Multiscale Mechanical Properties of Brain Tissue Using Atomic Force Microscopy, Impact Indentation, and Rheometry.

    Science.gov (United States)

    Canovic, Elizabeth Peruski; Qing, Bo; Mijailovic, Aleksandar S; Jagielska, Anna; Whitfield, Matthew J; Kelly, Elyza; Turner, Daria; Sahin, Mustafa; Van Vliet, Krystyn J

    2016-01-01

    To design and engineer materials inspired by the properties of the brain, whether for mechanical simulants or for tissue regeneration studies, the brain tissue itself must be well characterized at various length and time scales. Like many biological tissues, brain tissue exhibits a complex, hierarchical structure. However, in contrast to most other tissues, brain is of very low mechanical stiffness, with Young's elastic moduli E on the order of 100s of Pa. This low stiffness can present challenges to experimental characterization of key mechanical properties. Here, we demonstrate several mechanical characterization techniques that have been adapted to measure the elastic and viscoelastic properties of hydrated, compliant biological materials such as brain tissue, at different length scales and loading rates. At the microscale, we conduct creep-compliance and force relaxation experiments using atomic force microscope-enabled indentation. At the mesoscale, we perform impact indentation experiments using a pendulum-based instrumented indenter. At the macroscale, we conduct parallel plate rheometry to quantify the frequency dependent shear elastic moduli. We also discuss the challenges and limitations associated with each method. Together these techniques enable an in-depth mechanical characterization of brain tissue that can be used to better understand the structure of brain and to engineer bio-inspired materials. PMID:27684097

  11. A novel glutamate dehydrogenase from bovine brain: purification and characterization.

    Science.gov (United States)

    Lee, J; Kim, S W; Cho, S W

    1995-08-01

    A soluble form of novel glutamate dehydrogenase has been purified from bovine brain. The preparation was homogeneous on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and composed of six identical subunits having a subunit size of 57,500 Da. The biochemical properties of glutamate dehydrogenase such as N-terminal amino acids sequences, kinetic parameters, amino acids analysis, and optimum pH were examined in both reductive amination of alpha-ketoglutarate and oxidative deamination of glutamate. N-terminal amino acid sequences of the bovine brain enzyme showed the significant differences in the first 5 amino acids compared to other glutamate dehydrogenases from various sources. These results indicate that glutamate dehydrogenase isolated from bovine brain is a novel polypeptide.

  12. CHARACTERIZATION OF EXTRACELLULAR GABA IN THE SUBSTANTIA-NIGRA-RETICULATA BY MEANS OF BRAIN MICRODIALYSIS

    NARCIS (Netherlands)

    TIMMERMAN, W; ZWAVELING, J; WESTERINK, BHC

    1992-01-01

    Brain microdialysis was used to characterize extracellular gamma-aminobutyric acid (GABA) in the substantia nigra reticulata (SNR) of freely moving rats. The extracellular GABA in the SNR was characterized using acutely implanted probes (4-8 h after surgery; day 1) and chronically implanted probes (

  13. Brain signature characterizing the body-brain-mind axis of transsexuals.

    Directory of Open Access Journals (Sweden)

    Hsiao-Lun Ku

    Full Text Available Individuals with gender identity disorder (GID, who are commonly referred to as transsexuals (TXs, are afflicted by negative psychosocial stressors. Central to the psychological complex of TXs is the conviction of belonging to the opposite sex. Neuroanatomical and functional brain imaging studies have demonstrated that the GID is associated with brain alterations. In this study, we found that TXs identify, when viewing male-female couples in erotic or non-erotic ("neutral" interactions, with the couple member of the desired gender in both situations. By means of functional magnetic resonance imaging, we found that the TXs, as opposed to controls (CONs, displayed an increased functional connectivity between the ventral tegmental area, which is associated with dimorphic genital representation, and anterior cingulate cortex subregions, which play a key role in social exclusion, conflict monitoring and punishment adjustment. The neural connectivity pattern suggests a brain signature of the psychosocial distress for the gender-sex incongruity of TXs.

  14. A novel radioligand for glycine transporter 1: characterization and use in autoradiographic and in vivo brain occupancy studies

    Energy Technology Data Exchange (ETDEWEB)

    Zeng Zhizhen [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States)], E-mail: zhizhen_zeng@merck.com; O' Brien, Julie A. [Sleep and Psychiatric Disorders, Merck Research Laboratories, West Point, PA 19486 (United States); Lemaire, Wei [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); O' Malley, Stacey S.; Miller, Patricia J. [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States); Zhao Zhijian [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); Wallace, Michael A. [Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065 (United States); Raab, Conrad [Drug Metabolism, Merck Research Laboratories, West Point, PA 19486 (United States); Lindsley, Craig W. [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); Departments of Pharmacology and Chemistry, Vanderbilt University, Nashville, TN 37232 (United States); Sur, Cyrille; Williams, David L. [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States)

    2008-04-15

    Introduction: In an effort to develop agents to test the NMDA hypofunction hypothesis of schizophrenia, benchmark compounds from a program to discover potent, selective, competitive glycine transporter 1 (GlyT1) inhibitors were radiolabeled in order to further study the detailed pharmacology of these inhibitors and the distribution of GlyT1 in brain. We here report the in vitro characterization of [{sup 35}S](S)-2-amino-4-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl) ethyl)benzamide ([{sup 35}S]ACPPB), a radiotracer developed from a potent and selective non-sarcosine-derived GlyT1 inhibitor, its use in autoradiographic studies to localize (S)-2-amino-6-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl)ethyl) benzamide (ACPPB) binding sites in rat and rhesus brain and for in vivo occupancy assays of competitive GlyT1 inhibitors. Methods: Functional potencies of unlabeled compounds were characterized by [{sup 14}C]glycine uptake into JAR (human placental choriocarcinoma) cells and synaptosomes. Radioligand binding studies were performed with tissue homogenates. Autoradiographic studies were performed on tissue slices. Results: ACPPB is a potent (K{sub d}=1.9 nM), selective, GlyT1 inhibitor that, when radiolabeled with [{sup 35}S], is a well-behaved radioligand with low nondisplaceable binding. Autoradiographic studies of rat and rhesus brain slices with this ligand showed that specific binding sites were plentiful and nonhomogeneously distributed, with high levels of binding in the brainstem, cerebellar white matter, thalamus, cortical white matter and spinal cord gray matter. In vivo studies demonstrate displaceable binding of [{sup 35}S]ACPPB in rat brain tissues following iv administration of this radioligand. Conclusions: This is the first report of detailed anatomical localization of GlyT1 using direct radioligand binding, and the first demonstration that an in vivo occupancy assay is feasible, suggesting that it may also be feasible to develop

  15. Biochemical and pharmacological characterization of irradiated crotamine by gamma rays of {sup 60}Co; Caracterizacao bioquimica e farmacologica da crotamina irradiada por raios gama de {sup 60}Co

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, Karina Corleto

    2014-07-01

    The serum production in Brazil, the only effective treatment in cases of snakebites, uses horses that although large size, have reduced l lifespan compared with horses not immunized. Ionizing radiation has been shown as an excellent tool in reducing the toxicity of venoms and toxins isolated, and promote the achievement of better immunogens for serum production, and contributing to the welfare of serum-producing animals. It is known, however, that the effects of ionizing radiation on protein are characterized by various chemical modifications, such as fragmentation, cross-linking due to aggregation and oxidation products generated by water radiolysis. However, the action of gamma radiation on toxins is not yet fully understood structurally and pharmacologically, a fact that prevents the application of this methodology in the serum production process. So we proposed in this paper the characterization of crotamine, an important protein from the venom of Crotalus durissus terrificus species, irradiated with {sup 60}Co gamma rays. After isolating the toxin by chromatographic techniques and testing to prove the obtaining of pure crotamine, it was irradiated with gamma rays and subjected to structural analysis, Fluorescence and Circular Dichroism. Using high hydrostatic pressure tests were also conducted in order to verify that the conformational changes caused by radiation suffer modifications under high pressures. From the pharmacological point of view, muscle contraction tests were conducted with the objective of limiting the action of crotamine in smooth muscle as well as the change in the action of toxin caused structural changes to the front. Analysis of Circular Dichroism and Fluorescence showed changes in structural conformation of crotamine when subjected to gamma radiation and that such changes possibly occurring in the secondary and tertiary structure of the protein. The observed in pharmacological tests showed that the irradiated crotamine was less effective

  16. Characterization of brain inflammation during primary amoebic meningoencephalitis.

    Science.gov (United States)

    Cervantes-Sandoval, Isaac; Serrano-Luna, José de Jesús; García-Latorre, Ethel; Tsutsumi, Víctor; Shibayama, Mineko

    2008-09-01

    Naegleria fowleri is a free-living amoeba and the etiologic agent of primary amoebic meningoencephalitis (PAM). Trophozoites reach the brain by penetrating the olfactory epithelium, and invasion of the olfactory bulbs results in an intense inflammatory reaction. The contribution of the inflammatory response to brain damage in experimental PAM has not been delineated. Using both optical and electron microscopy, we analyzed the morphologic changes in the brain parenchyma due to inflammation during experimental PAM. Several N. fowleri trophozoites were observed in the olfactory bulbs 72 h post-inoculation, and the number of amoebae increased rapidly over the next 24 h. Eosinophils and neutrophils surrounding the amoebae were then noted at later times during infection. Electron microscopic examination of the increased numbers of neutrophils and the interactions with trophozoites indicated an active attempt to eliminate the amoebae. The extent of inflammation increased over time, with a predominant neutrophil response indicating important signs of damage and necrosis of the parenchyma. These data suggest a probable role of inflammation in tissue damage. To test the former hypothesis, we used CD38-/- knockout mice with deficiencies in chemotaxis to compare the rate of mortality with the parental strain, C57BL/6J. The results showed that inflammation and mortality were delayed in the knockout mice. Based on these results, we suggest that the host inflammatory response and polymorphonuclear cell lysis contribute to a great extent to the central nervous system tissue damage.

  17. Pharmacological characterization of nanoparticle-induced platelet microaggregation using quartz crystal microbalance with dissipation: comparison with light aggregometry

    Science.gov (United States)

    Santos-Martinez, Maria J; Tomaszewski, Krzysztof A; Medina, Carlos; Bazou, Despina; Gilmer, John F; Radomski, Marek W

    2015-01-01

    Background Engineered nanoparticles (NPs) can induce platelet activation and aggregation, but the mechanisms underlying these interactions are not well understood. This could be due in part to use of devices that study platelet function under quasi-static conditions with low sensitivity to measure platelet microaggregation. Therefore, in this study we investigated the pharmacological pathways and regulators of NP-induced platelet microaggregation under flow conditions at nanoscale using quartz crystal microbalance with dissipation (QCM-D) and compared the data thus obtained with those generated by light aggregometry. Methods Blood was collected from healthy volunteers, and platelet-rich plasma was obtained. Thrombin receptor-activating peptide, a potent stimulator of platelet function, and pharmacological inhibitors were used to modulate platelet microaggregation in the presence/absence of silica (10 nm and 50 nm) and polystyrene (23 nm) NPs. Light aggregometry was used to study platelet aggregation in macroscale. Optical, immunofluorescence, and scanning electron microscopy were also used to visualize platelet aggregates. Results Platelet microaggregation was enhanced by thrombin receptor-activating peptide, whereas prostacyclin, nitric oxide donors, acetylsalicylic acid, and phenanthroline, but not adenosine diphosphate (ADP) blockers, were able to inhibit platelet microaggregation. NPs caused platelet microaggregation, an effect not detectable by light aggregometry. NP-induced microaggregation was attenuated by platelet inhibitors. Conclusion NP-induced platelet microaggregation appears to involve classical proaggregatory pathways (thromboxane A2-mediated and matrix metalloproteinase-2-mediated) and can be regulated by endogenous (prostacyclin) and pharmacological (acetylsalicylic acid, phenanthroline, and nitric oxide donors) inhibitors of platelet function. Quartz crystal microbalance with dissipation, but not light aggregometry, is an appropriate method for

  18. Pharmacologic inhibition of MLK3 kinase activity blocks the in vitro migratory capacity of breast cancer cells but has no effect on breast cancer brain metastasis in a mouse xenograft model.

    Directory of Open Access Journals (Sweden)

    Kun Hyoe Rhoo

    Full Text Available Brain metastasis of breast cancer is an important clinical problem, with few therapeutic options and a poor prognosis. Recent data have implicated mixed lineage kinase 3 (MLK3 in controlling the in vitro migratory capacity of breast cancer cells, as well as the metastasis of MDA-MB-231 breast cancer cells from the mammary fat pad to distant lymph nodes in a mouse xenograft model. We therefore set out to test whether MLK3 plays a role in brain metastasis of breast cancer cells. To address this question, we used a novel, brain penetrant, MLK3 inhibitor, URMC099. URMC099 efficiently inhibited the migration of breast cancer cells in an in vitro cell monolayer wounding assay, and an in vitro transwell migration assay, but had no effect on in vitro cell growth. We also tested the effect of URMC099 on tumor formation in a mouse xenograft model of breast cancer brain metastasis. This analysis showed that URMC099 had no effect on the either the frequency or size of breast cancer brain metastases. We conclude that pharmacologic inhibition of MLK3 by URMC099 can reduce the in vitro migratory capacity of breast cancer cells, but that it has no effect on either the frequency or size of breast cancer brain metastases, in a mouse xenograft model.

  19. A Comparative Study of Theoretical Graph Models for Characterizing Structural Networks of Human Brain

    Directory of Open Access Journals (Sweden)

    Xiaojin Li

    2013-01-01

    Full Text Available Previous studies have investigated both structural and functional brain networks via graph-theoretical methods. However, there is an important issue that has not been adequately discussed before: what is the optimal theoretical graph model for describing the structural networks of human brain? In this paper, we perform a comparative study to address this problem. Firstly, large-scale cortical regions of interest (ROIs are localized by recently developed and validated brain reference system named Dense Individualized Common Connectivity-based Cortical Landmarks (DICCCOL to address the limitations in the identification of the brain network ROIs in previous studies. Then, we construct structural brain networks based on diffusion tensor imaging (DTI data. Afterwards, the global and local graph properties of the constructed structural brain networks are measured using the state-of-the-art graph analysis algorithms and tools and are further compared with seven popular theoretical graph models. In addition, we compare the topological properties between two graph models, namely, stickiness-index-based model (STICKY and scale-free gene duplication model (SF-GD, that have higher similarity with the real structural brain networks in terms of global and local graph properties. Our experimental results suggest that among the seven theoretical graph models compared in this study, STICKY and SF-GD models have better performances in characterizing the structural human brain network.

  20. A digital atlas to characterize the mouse brain transcriptome.

    Directory of Open Access Journals (Sweden)

    James P Carson

    2005-09-01

    Full Text Available Massive amounts of data are being generated in an effort to represent for the brain the expression of all genes at cellular resolution. Critical to exploiting this effort is the ability to place these data into a common frame of reference. Here we have developed a computational method for annotating gene expression patterns in the context of a digital atlas to facilitate custom user queries and comparisons of this type of data. This procedure has been applied to 200 genes in the postnatal mouse brain. As an illustration of utility, we identify candidate genes that may be related to Parkinson disease by using the expression of a dopamine transporter in the substantia nigra as a search query pattern. In addition, we discover that transcription factor Rorb is down-regulated in the barrelless mutant relative to control mice by quantitative comparison of expression patterns in layer IV somatosensory cortex. The semi-automated annotation method developed here is applicable to a broad spectrum of complex tissues and data modalities.

  1. Niosomal approach to brain delivery: Development, characterization and in vitro toxicological studies.

    Science.gov (United States)

    Ingallina, C; Rinaldi, F; Bogni, A; Ponti, J; Passeri, D; Reggente, M; Rossi, M; Kinsner-Ovaskainen, A; Mehn, D; Rossi, F; Botta, B; Carafa, M; Marianecci, C

    2016-09-25

    The majority of active agents do not readily permeate into brain due to the presence of the blood-brain barrier and blood-cerebrospinal fluid barrier. Currently, the most innovative and promising non-invasive strategy in brain delivery is the design and preparation of nanocarriers, which can move through the brain endothelium. Niosomes can perform brain delivery, in fact polysorbates, can act as an anchor for apolipoprotein E from blood plasma. The particles mimic LDL and interact with the LDL receptor leading to the endothelial cells uptake. The efficacy of niosomes for anticancer therapeutic applications was correlated to their physicochemical and drug delivery properties. Dimensions and ζ-potential were characterized using dynamic light scattering and asymmetric flow-field fractionation system. Lipid bilayer was characterized measuring the fluidity, polarity and microviscosity by fluorescent probe spectra evaluation. Morphology and homogeneity were characterized using atomic force microscopy. Physicochemical stability and serum stability (45% v/v fetal bovine and human serum) were evaluated as a function of time using dynamic light scattering. U87-MG human glioblastoma cells were used to evaluate vesicle cytotoxicity and internalisation efficiency. From the obtained data, the systems appear useful to perform a prolonged (modified) release of biological active substances to the central nervous system. PMID:27498282

  2. Hierarchical non-negative matrix factorization to characterize brain tumor heterogeneity using multi-parametric MRI

    NARCIS (Netherlands)

    Sauwen, Nicolas; Sima, Diana M.; Van Cauter, Sofie; Veraart, Jelle; Leemans, Alexander; Maes, Frederik; Himmelreich, Uwe; Van Huffel, Sabine

    2015-01-01

    Tissue characterization in brain tumors and, in particular, in high-grade gliomas is challenging as a result of the co-existence of several intra-tumoral tissue types within the same region and the high spatial heterogeneity. This study presents a method for the detection of the relevant tumor subst

  3. G protein-linked receptors labeled by [3H]histamine in guinea pig cerebral cortex. I. Pharmacological characterization [corrected].

    Science.gov (United States)

    Sinkins, W G; Kandel, M; Kandel, S I; Schunack, W; Wells, J W

    1993-04-01

    Binding of histamine to washed membranes from guinea pig cerebral cortex can be described empirically as two classes of distinct and independent sites (log IP1 = -8.45 +/- 0.02, R1;t = 98 +/- 6 pmol/g of protein; log KP2 = -6.34 +/- 0.22, R2.t = 990 +/- 60 pmol/g of protein). At 1.4 nm [3H]histamine, the kinetics of association and dissociation are biexponential. The values of k-Pj/k+Pj calculated for parallel one-step processes agree well with the corresponding values of KPj. Both k-p1 and k-P2 are increased by 0.1 mM guanylylimidodiphosphate; apparent capacity at equilibrium is reduced for both classes of sites, with little or no change in KP1 or KP2. Twenty-six H2 and H3 agonists and antagonists block access of [3H]histamine to the same sites, and the binding patterns reveal either one or two hyperbolic terms [i.e., sigma nj = 1 F' jKj/(Kj+[L])]. Two terms are required for six agonists and six antagonists, and F'2 varies widely from ligand to ligand. Also, the quantity log (K2/K1) is correlated with F'1 among agonists but with F'2 among antagonists (K1 < K2). The pharmacological selectivity is suggestive of both H2 and H3 receptors. An H2 specificity emerges from the appropriate values of Kj for 12 H2 agonists (i.e., K1 when n = 1 and K2 when n = 2; p = 0.00045), although a specificity distinct from that of H2 receptors is found with H2 antagonists. An H3 specificity emerges from the inhibitory potencies (IC50) of eight H3 agonists (p = 0.00025) and eight H3 antagonists (p = 0.0019); also, the sites labeled by [3H]histamine resemble H3 receptors reportedly labeled by N alpha-[3H]methylhistamine and (R)-alpha-[3H]methylhistamine. Ligand-dependent differences in F'2 are inconsistent with the notion of distinct and independent sites, and the tendency of antagonists to promote the sites of weaker affinity (F'2) argues against a ligand-regulated equilibrium between two states. The physical significance of the binding parameters is therefore unclear. The failure to

  4. Medial plantar nerve ligation as a novel model of neuropathic pain in mice: pharmacological and molecular characterization

    Science.gov (United States)

    Sant’Anna, Morena B.; Kusuda, Ricardo; Bozzo, Tiago A.; Bassi, Gabriel S.; Alves-Filho, José C.; Cunha, Fernando Q.; Ferreira, Sergio H.; Souza, Guilherme R.; Cunha, Thiago M.

    2016-01-01

    Peripheral neuropathic pain is a consequence of an injury/disease of the peripheral nerves. The mechanisms involved in its pathophysiology are not entirely understood. To better understand the mechanisms involved in the development of peripheral nerve injury-induced neuropathic pain, more experimental models are required. Here, we developed a novel peripheral neuropathic pain model in mice by using a minimally invasive surgery and medial plantar nerve ligation (MPNL). After MPNL, mechanical allodynia was established, and mice quickly recovered from the surgery without any significant motor impairment. MPNL causes an increased expression of ATF-3 in the sensory neurons. At 14 days after surgery, gabapentin was capable of reversing the mechanical allodynia, whereas anti-inflammatory drugs and opioids were ineffective. MPNL-induced neuropathic pain was mediated by glial cells activation and the production of TNF-α and IL-6 in the spinal cord. These results indicate MPNL as a reasonable animal model for the study of peripheral neuropathic pain, presenting analgesic pharmacological predictivity to clinically used drugs. The results also showed molecular phenotypic changes similar to other peripheral neuropathic pain models, with the advantage of a lack of motor impairment. These features indicate that MPNL might be more appropriate for the study of neuropathic pain than classical models. PMID:27230787

  5. Pharmacological characterization of the dermorphin analog [Dmt(1)]DALDA, a highly potent and selective mu-opioid peptide.

    Science.gov (United States)

    Neilan, C L; Nguyen, T M; Schiller, P W; Pasternak, G W

    2001-05-01

    The dermorphin-derived peptide [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH(2)), labels mu-opioid receptors with high affinity and selectivity in receptor binding assays. In mouse, radiant heat tail-flick assay [Dmt(1)]DALDA produced profound spinal and supraspinal analgesia, being approximately 5000- and 100-fold more potent than morphine on a molar basis, respectively. When administered systemically, [Dmt(1)]DALDA was over 200-fold more potent than morphine. Pharmacologically, [Dmt(1)]DALDA was distinct from morphine. [Dmt(1)]DALDA displayed no cross-tolerance to morphine in the model used and it retained supraspinal analgesic activity in morphine-insensitive CXBK mice. Supraspinally, it also differed from morphine in its lack of sensitivity towards naloxonazine. Finally, in antisense mapping studies, [Dmt(1)]DALDA was insensitive to MOR-1 exon probes that reduced morphine analgesia, implying a distinct receptor mechanism of action. Thus, [Dmt(1)]DALDA is an interesting and extraordinarily potent, systemically active peptide analgesic, raising the possibility of novel approaches in the design of clinically useful drugs.

  6. A "genome-to-lead" approach for insecticide discovery: pharmacological characterization and screening of Aedes aegypti D(1-like dopamine receptors.

    Directory of Open Access Journals (Sweden)

    Jason M Meyer

    2012-01-01

    Full Text Available BACKGROUND: Many neglected tropical infectious diseases affecting humans are transmitted by arthropods such as mosquitoes and ticks. New mode-of-action chemistries are urgently sought to enhance vector management practices in countries where arthropod-borne diseases are endemic, especially where vector populations have acquired widespread resistance to insecticides. METHODOLOGY/PRINCIPAL FINDINGS: We describe a "genome-to-lead" approach for insecticide discovery that incorporates the first reported chemical screen of a G protein-coupled receptor (GPCR mined from a mosquito genome. A combination of molecular and pharmacological studies was used to functionally characterize two dopamine receptors (AaDOP1 and AaDOP2 from the yellow fever mosquito, Aedes aegypti. Sequence analyses indicated that these receptors are orthologous to arthropod D(1-like (Gα(s-coupled receptors, but share less than 55% amino acid identity in conserved domains with mammalian dopamine receptors. Heterologous expression of AaDOP1 and AaDOP2 in HEK293 cells revealed dose-dependent responses to dopamine (EC(50: AaDOP1 = 3.1±1.1 nM; AaDOP2 = 240±16 nM. Interestingly, only AaDOP1 exhibited sensitivity to epinephrine (EC(50 = 5.8±1.5 nM and norepinephrine (EC(50 = 760±180 nM, while neither receptor was activated by other biogenic amines tested. Differential responses were observed between these receptors regarding their sensitivity to dopamine agonists and antagonists, level of maximal stimulation, and constitutive activity. Subsequently, a chemical library screen was implemented to discover lead chemistries active at AaDOP2. Fifty-one compounds were identified as "hits," and follow-up validation assays confirmed the antagonistic effect of selected compounds at AaDOP2. In vitro comparison studies between AaDOP2 and the human D(1 dopamine receptor (hD(1 revealed markedly different pharmacological profiles and identified amitriptyline and doxepin as AaDOP2

  7. Synthesis, spectral characterization, and pharmacological screening of some 4-[{1-(aryl)methylidene}-amino]-3-(4-pyridyl)-5-mercapto-4H-1,2,4-triazole derivatives

    OpenAIRE

    Anees A. Siddiqui; Ravinesh Mishra; Rajiv Kumar; Mohd Rashid; Somila Khaidem

    2010-01-01

    Background : Pain is an unpleasant and subjective sensation that results from a harmful sensorial stimulation, which alerts the body about current or potential damage to its tissues and organs. Fever is a complex physiological response triggered by infections or aseptic stimuli. Elevation in body temperature occurs when the concentration of prostaglandin E 2 (PGE 2 ) increases within parts of the brain. Triazole derivatives have been found to possess various pharmacological and biological act...

  8. Method for isolation and molecular characterization of extracellular microvesicles released from brain endothelial cells

    Directory of Open Access Journals (Sweden)

    Haqqani Arsalan S

    2013-01-01

    Full Text Available Abstract Background In addition to possessing intracellular vesicles, eukaryotic cells also produce extracellular microvesicles, ranging from 50 to 1000 nm in diameter that are released or shed into the microenvironment under physiological and pathological conditions. These membranous extracellular organelles include both exosomes (originating from internal vesicles of endosomes and ectosomes (originating from direct budding/shedding of plasma membranes. Extracellular microvesicles contain cell-specific collections of proteins, glycoproteins, lipids, nucleic acids and other molecules. These vesicles play important roles in intercellular communication by acting as carrier for essential cell-specific information to target cells. Endothelial cells in the brain form the blood–brain barrier, a specialized interface between the blood and the brain that tightly controls traffic of nutrients and macromolecules between two compartments and interacts closely with other cells forming the neurovascular unit. Therefore, brain endothelial cell extracellular microvesicles could potentially play important roles in ‘externalizing’ brain-specific biomarkers into the blood stream during pathological conditions, in transcytosis of blood-borne molecules into the brain, and in cell-cell communication within the neurovascular unit. Methods To study cell-specific molecular make-up and functions of brain endothelial cell exosomes, methods for isolation of extracellular microvesicles using mass spectrometry-compatible protocols and the characterization of their signature profiles using mass spectrometry -based proteomics were developed. Results A total of 1179 proteins were identified in the isolated extracellular microvesicles from brain endothelial cells. The microvesicles were validated by identification of almost 60 known markers, including Alix, TSG101 and the tetraspanin proteins CD81 and CD9. The surface proteins on isolated microvesicles could potentially

  9. Factors characterizing access and latency to first pharmacological treatment in Italian patients with schizophrenia, mood, and anxiety spectrum disorders.

    Science.gov (United States)

    Dell'Osso, Bernardo; Cremaschi, Laura; Palazzo, Carlotta; Suardi, Neva; Spagnolin, Gregorio; Camuri, Giulia; Benatti, Beatrice; Oldani, Lucio; Dobrea, Cristina; Arici, Chiara; Pace, Giovanna; Tiseo, Alessandra; Nahum, Ester Sembira; Castellano, Filippo; D'Urso, Nazario; Clerici, Massimo; Primavera, Diego; Carpiniello, Bernardo; Altamura, A Carlo

    2015-01-01

    Latency to first pharmacological treatment [duration of untreated illness (DUI)] in psychiatric disorders can be measured in years, with differences across diagnostic areas and relevant consequences in terms of socio-occupational functioning and outcome. Within the psychopathological onset of a specific disorder, many factors influence access and latency to first pharmacotherapy and the present study aimed to investigate such factors, through an ad-hoc developed questionnaire, in a sample of 538 patients with diagnoses of schizophrenia-spectrum disorder (SZ), mood disorder (MD), and anxiety disorder (AD). Patients with SZs showed earlier ages at onset, first diagnosis and treatment, as well as shorter DUI compared with other patients (43.17 months vs. 58.64 and 80.43 months in MD and AD; F=3.813, P=0.02). Patients with MD and AD reported more frequently onset-related stressful events, benzodiazepines as first treatment, and autonomous help seeking compared with patients with SZs. In terms of first therapist, psychiatrist referral accounted for 43.6% of the cases, progressively decreasing from SZ to MD and AD (57.6, 41.8, and 38.3%, respectively). The opposite phenomenon was observed for nonpsychiatrist clinician referrals, whereas psychologist referrals remained constant. The present findings confirm the presence of a relevant DUI in a large sample of Italian patients with different psychiatric disorders (5 years, on average), pointing out specific differences, in terms of treatment access and latency, between psychotic and affective patients. Such aspects are relevant for detection of at-risk patients and implement early intervention programs.

  10. Pharmacologic characterization and autoradiographic distribution of binding sites for iodinated tachykinins in the rat central nervous system

    Energy Technology Data Exchange (ETDEWEB)

    Buck, S.H.; Helke, C.J.; Burcher, E.; Shults, C.W.; O' Donohue, T.L.

    1986-11-01

    P-type, E-type, and K-type tachykinin binding sites have been identified in the mammalian CNS. These sites may be tachykinin receptors for which the mammalian neuropeptides substance P, neuromedin K, and substance K are the preferred natural agonists, respectively. In the present investigation, we have compared the pharmacology and the autoradiographic distribution of CNS binding sites for the iodinated (/sup 125/I-Bolton-Hunter reagent) tachykinins substance P, eledoisin, neuromedin K, and substance K. Iodinated eledoisin and neuromedin K exhibited an E-type binding pattern in cortical membranes. Iodinated eledoisin, neuromedin K, and substance K each labeled sites that had a similar distribution but one that was considerably different from that of sites labeled by iodinated substance P. CNS regions where there were detectable densities of binding sites for iodinated eledoisin, neuromedin K, and substance K and few or no sites for iodinated substance P included cortical layers IV-VI, mediolateral septum, supraoptic and paraventricular nuclei, interpeduncular nucleus, ventral tegmental area, and substantia nigra pars compacta. Binding sites for SP were generally more widespread in the CNS. CNS regions where there was a substantial density of binding sites for iodinated substance P and few or no sites for iodinated eledoisin, neuromedin K, and substance K included cortical layers I and II, olfactory tubercle, nucleus accumbens, caudate-putamen, globus pallidus, medial and lateral septum, endopiriform nucleus, rostral thalamus, medial and lateral preoptic nuclei, arcuate nucleus, dorsal raphe nucleus, dorsal parabrachial nucleus, parabigeminal nucleus, cerebellum, inferior olive, nucleus ambiguus, retrofacial and reticular nuclei, and spinal cord autonomic and somatic motor nuclei.

  11. Characterization of task-free and task-performance brain states via functional connectome patterns.

    Science.gov (United States)

    Zhang, Xin; Guo, Lei; Li, Xiang; Zhang, Tuo; Zhu, Dajiang; Li, Kaiming; Chen, Hanbo; Lv, Jinglei; Jin, Changfeng; Zhao, Qun; Li, Lingjiang; Liu, Tianming

    2013-12-01

    Both resting state fMRI (R-fMRI) and task-based fMRI (T-fMRI) have been widely used to study the functional activities of the human brain during task-free and task-performance periods, respectively. However, due to the difficulty in strictly controlling the participating subject's mental status and their cognitive behaviors during R-fMRI/T-fMRI scans, it has been challenging to ascertain whether or not an R-fMRI/T-fMRI scan truly reflects the participant's functional brain states during task-free/task-performance periods. This paper presents a novel computational approach to characterizing and differentiating the brain's functional status into task-free or task-performance states, by which the functional brain activities can be effectively understood and differentiated. Briefly, the brain's functional state is represented by a whole-brain quasi-stable connectome pattern (WQCP) of R-fMRI or T-fMRI data based on 358 consistent cortical landmarks across individuals, and then an effective sparse representation method was applied to learn the atomic connectome patterns (ACPs) of both task-free and task-performance states. Experimental results demonstrated that the learned ACPs for R-fMRI and T-fMRI datasets are substantially different, as expected. A certain portion of ACPs from R-fMRI and T-fMRI data were overlapped, suggesting some subjects with overlapping ACPs were not in the expected task-free/task-performance brain states. Besides, potential outliers in the T-fMRI dataset were further investigated via functional activation detections in different groups, and our results revealed unexpected task-performances of some subjects. This work offers novel insights into the functional architectures of the brain.

  12. Eye-position recording during brain MRI examination to identify and characterize steps of glioma diagnosis

    Science.gov (United States)

    Cavaro-Ménard, Christine; Tanguy, Jean-Yves; Le Callet, Patrick

    2010-02-01

    MRI is an essential tool for brain glioma diagnosis thanks to its ability to produce images in any layout plan and to its numerous sequences adapted to both anatomic and functional imaging. In this paper, we investigate the use of an eyetracking system to explore relationships between visual scanning patterns and the glioma diagnostic process during brain MRI analysis. We divide the analyzed screen into Areas of Interest (AOIs), each AOI corresponding to one sequence. Analyzing temporal organization of fixation location intra AOI and inter AOI splits the diagnostic process into different steps. The analysis of saccadic amplitudes reveals clear delineation of three sequential steps. During the first step (characterized by large saccades), a radiologist performs a short review on all sequences and on the patient report. In the second step (characterized by short saccades), a radiologist sequentially and systematically scans all the slices of each sequence. The fixation duration in one AOI depends on the number of slices, on the lesion subtlety and on the lesion contrast in the sequence to be analyzed. In order to improve the detection, localization and characterization of the glioma, the radiologist compares sequences during the third step (characterized by large saccades). Eye-position recording enables one to identify each elementary task implemented during diagnostic process of glioma detection and characterization on brain MRI. Total dwell time associated with one MRI sequence (one AOI) and contrast in primary lesion area enable one to estimate the amount and subtleties of diagnosis criteria provided by the sequence. From this information, one could establish some rules to optimize brain MRI compression (depending on the sequence to be compressed).

  13. Brain network characterization of high-risk preterm-born school-age children.

    Science.gov (United States)

    Fischi-Gomez, Elda; Muñoz-Moreno, Emma; Vasung, Lana; Griffa, Alessandra; Borradori-Tolsa, Cristina; Monnier, Maryline; Lazeyras, François; Thiran, Jean-Philippe; Hüppi, Petra S

    2016-01-01

    Higher risk for long-term cognitive and behavioral impairments is one of the hallmarks of extreme prematurity (EP) and pregnancy-associated fetal adverse conditions such as intrauterine growth restriction (IUGR). While neurodevelopmental delay and abnormal brain function occur in the absence of overt brain lesions, these conditions have been recently associated with changes in microstructural brain development. Recent imaging studies indicate changes in brain connectivity, in particular involving the white matter fibers belonging to the cortico-basal ganglia-thalamic loop. Furthermore, EP and IUGR have been related to altered brain network architecture in childhood, with reduced network global capacity, global efficiency and average nodal strength. In this study, we used a connectome analysis to characterize the structural brain networks of these children, with a special focus on their topological organization. On one hand, we confirm the reduced averaged network node degree and strength due to EP and IUGR. On the other, the decomposition of the brain networks in an optimal set of clusters remained substantially different among groups, talking in favor of a different network community structure. However, and despite the different community structure, the brain networks of these high-risk school-age children maintained the typical small-world, rich-club and modularity characteristics in all cases. Thus, our results suggest that brain reorganizes after EP and IUGR, prioritizing a tight modular structure, to maintain the small-world, rich-club and modularity characteristics. By themselves, both extreme prematurity and IUGR bear a similar risk for neurocognitive and behavioral impairment, and the here defined modular network alterations confirm similar structural changes both by IUGR and EP at school age compared to control. Interestingly, the combination of both conditions (IUGR + EP) does not result in a worse outcome. In such cases, the alteration in network

  14. Brain network characterization of high-risk preterm-born school-age children

    Directory of Open Access Journals (Sweden)

    Elda Fischi-Gomez

    2016-01-01

    Full Text Available Higher risk for long-term cognitive and behavioral impairments is one of the hallmarks of extreme prematurity (EP and pregnancy-associated fetal adverse conditions such as intrauterine growth restriction (IUGR. While neurodevelopmental delay and abnormal brain function occur in the absence of overt brain lesions, these conditions have been recently associated with changes in microstructural brain development. Recent imaging studies indicate changes in brain connectivity, in particular involving the white matter fibers belonging to the cortico-basal ganglia-thalamic loop. Furthermore, EP and IUGR have been related to altered brain network architecture in childhood, with reduced network global capacity, global efficiency and average nodal strength. In this study, we used a connectome analysis to characterize the structural brain networks of these children, with a special focus on their topological organization. On one hand, we confirm the reduced averaged network node degree and strength due to EP and IUGR. On the other, the decomposition of the brain networks in an optimal set of clusters remained substantially different among groups, talking in favor of a different network community structure. However, and despite the different community structure, the brain networks of these high-risk school-age children maintained the typical small-world, rich-club and modularity characteristics in all cases. Thus, our results suggest that brain reorganizes after EP and IUGR, prioritizing a tight modular structure, to maintain the small-world, rich-club and modularity characteristics. By themselves, both extreme prematurity and IUGR bear a similar risk for neurocognitive and behavioral impairment, and the here defined modular network alterations confirm similar structural changes both by IUGR and EP at school age compared to control. Interestingly, the combination of both conditions (IUGR + EP does not result in a worse outcome. In such cases, the alteration

  15. Synthesis, spectral characterization, and pharmacological screening of some 4-[{1-(arylmethylidene}-amino]-3-(4-pyridyl-5-mercapto-4H-1,2,4-triazole derivatives

    Directory of Open Access Journals (Sweden)

    Anees A Siddiqui

    2010-01-01

    Full Text Available Background : Pain is an unpleasant and subjective sensation that results from a harmful sensorial stimulation, which alerts the body about current or potential damage to its tissues and organs. Fever is a complex physiological response triggered by infections or aseptic stimuli. Elevation in body temperature occurs when the concentration of prostaglandin E 2 (PGE 2 increases within parts of the brain. Triazole derivatives have been found to possess various pharmacological and biological activities, such as, anti-inflammatory, analgesics, antipyretic, and antifungal. Materials and Methods : Various 4-[{1-(arylmethylidene}-amino]-3-(4-pyridyl-5-mercapto-4H-1,2,4-triazole derivatives were synthesized by a sequence of reactions starting from isonicotinic acid hydrazide. The synthesized compounds were screened for in-vivo analgesic by the tail-flick method and anti-pyretic activities at a dose of 25 and 100 mg/kg body weight respectively. The antipyretic activity was evaluated using Brewer′s yeast induced pyrexia in rats. Fever was induced by subcutaneously injecting 20 ml/kg of 20% aqueous suspension of Brewer′s yeast in normal saline. Results and Discussion : The analgesic screening results revealed that the compounds 3b, 3c, and 3d exhibited excellent analgesic activity at 60 and 90 minutes compared to the standard drug (Analgin. Results revealed that the compounds 3a, 3e, and 3f significantly decreased the temperature of pyretic (P<0.001 rats at one, three and six hours after compound administration as compared to Aspirin (standard drug. Conclusion : Compounds 3b, 3c, and 3d exhibited significant analgesic activity comparable with the standard drug analgin, using the tail flick model. Compounds 3a, 3e, and 3f showed significant anti-pyretic activities comparable with the standard drug aspirin using the yeast-induced pyrexia model.

  16. Synthesis, spectral characterization, molecular structure and pharmacological studies of N'-(1, 4-naphtho-quinone-2yl) isonicotinohyWdrazide

    Science.gov (United States)

    Kavitha Rani, P. R.; Fernandez, Annette; George, Annie; Remadevi, V. K.; Sudarsanakumar, M. R.; Laila, Shiny P.; Arif, Muhammed

    2015-01-01

    A simple and efficient procedure was employed for the synthesis of N'-(1,4-naphtho-quinone-2-yl) isonicotinohydrazide (NIH) by the reaction of 2-hydroxy-1,4-naphthaquinone (lawsone) and isonicotinoyl hydrazine in methanol using ultrasonic irradiation. Lawsone is the principal dye, isolated from the leaves of henna (Lawsonia inermis). Structural modification was done on the molecule aiming to get a more active derivative. The structure of the parent compound and the derivative was characterized by elemental analyses, infrared, electronic, 1H, 13C NMR and GC-MS spectra. The fluorescence spectral investigation of the compound was studied in DMSO and ethanol. Single crystal X-ray diffraction studies reveal that NIH crystallizes in monoclinic space group. The DNA cleavage study was monitored by gel electrophoresis method. The synthesized compound was found to have significant antioxidant activity against DPPH radical (IC50 = 58 μM). The in vitro cytotoxic studies of the derivative against two human cancer cell lines MCF-7 (human breast cancer) and HCT-15 (human colon carcinoma cells) using MTT assay revealed that the compound exhibited higher cytotoxic activity with a lower IC50 value indicating its efficiency in killing the cancer cells even at low concentrations. These results suggest that the structural modifications performed on lawsone could be considered a good strategy to obtain a more active drug.

  17. Pharmacological Characterization of a Potent Inhibitor of Autotaxin in Animal Models of Inflammatory Bowel Disease and Multiple Sclerosis.

    Science.gov (United States)

    Thirunavukkarasu, Kannan; Tan, Bailin; Swearingen, Craig A; Rocha, Guilherme; Bui, Hai H; McCann, Denis J; Jones, Spencer B; Norman, Bryan H; Pfeifer, Lance A; Saha, Joy K

    2016-10-01

    Autotaxin is a secreted enzyme that catalyzes the conversion of lysophosphatidyl choline into the bioactive lipid mediator lysophosphatidic acid (LPA). It is the primary enzyme responsible for LPA production in plasma. It is upregulated in inflammatory conditions and inhibition of autotaxin may have anti-inflammatory activity in a variety of inflammatory diseases. To determine the role of autotaxin and LPA in the pathophysiology of inflammatory disease states, we used a potent and orally bioavailable inhibitor of autotaxin that we have recently identified, and characterized it in mouse models of inflammation, inflammatory bowel disease (IBD), multiple sclerosis (MS), and visceral pain. Compound-1, a potent inhibitor of autotaxin with an IC50 of ∼2 nM, has good oral pharmacokinetic properties in mice and results in a substantial inhibition of plasma LPA that correlates with drug exposure levels. Treatment with the inhibitor resulted in significant anti-inflammatory and analgesic effects in the carrageenan-induced paw inflammation and acetic acid-induced visceral pain tests, respectively. Compound-1 also significantly inhibited disease activity score in the dextran sodium sulfate-induced model of IBD, and in the experimental autoimmune encephalomyelitis model of MS. In conclusion, the present study demonstrates the anti-inflammatory and analgesic properties of a novel inhibitor of autotaxin that may serve as a therapeutic option for IBD, MS, and pain associated with inflammatory states.

  18. Characterization of a cell-free protein synthesizing system isolated from rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Rajagopalan, L.E.; Harper, A.E.

    1987-05-01

    The authors have characterized a cell-free preparation from rat brain that can initiate translation of endogenous mRNAs in vitro and maintain protein synthesis for at least 90 minutes at an optimum temperature of 37C. The essential component of this system is a postmitochondrial supernate (PMS) obtained by centrifuging a whole brain homogenate at 10,000 x g for 10 minutes at 4C. In the presence of phosphocreatine (PC), ATP and GTP there is active incorporation of (TVS)methionine into trichloroacetic acid precipitable protein. Incorporation is sensitive to the concentrations of PC, magnesium and potassium ions and spermidine and is inhibited 50-60% in the presence of 7-methylguanosine 5'-monophosphate, a specific inhibitor of polypeptide chain initiation. The proteolysis of brain protein that occurs when the system is incubated for more than 60 min. can be minimized by adding bovine serum albumin. The addition of 3.0 mM 5'-guanylimidodiphosphate a non-hydrolyzable analog of GTP, blocks incorporation entirely. The phosphocreatine requirement for maintaining an optimum endogenous concentration of GTP is lowered from 10.0 mM to 5.0 mM in the presence of 2.0 mM NADPH. The system that initiates protein synthesis in vitro can be used to study changes in brain protein synthesis as a result of various treatments, and the mechanisms underlying such changes.

  19. Serum levels of brain-derived neurotrophic factor in major depressive disorder : state-trait issues, clinical features and pharmacological treatment

    NARCIS (Netherlands)

    Molendijk, M. L.; Bus, B. A. A.; Spinhoven, Ph; Penninx, B. W. J. H.; Kenis, G.; Prickaerts, J.; Voshaar, R. C. Oude; Elzinga, B. M.

    2011-01-01

    Recent evidence supports 'the neurotrophin hypothesis of depression' in its prediction that brain-derived neurotrophic factor (BDNF) is involved in depression. However, some key questions remain unanswered, including whether abnormalities in BDNF persist beyond the clinical state of depression, whet

  20. Dual-porosity poroviscoelasticity and quantitative hydromechanical characterization of the brain tissue with experimental hydrocephalus data.

    Science.gov (United States)

    Mehrabian, Amin; Abousleiman, Younane N; Mapstone, Timothy B; El-Amm, Christian A

    2015-11-01

    Hydromechanical brain models often involve constitutive relations which must account for soft tissue deformation and creep, together with the interstitial fluid movement and exchange through capillaries. The interaction of rather unknown mechanisms which produce, absorb, and circulate the cerebrospinal fluid within the central nervous system can further add to their complexity. Once proper models for these phenomena or processes are selected, estimation of the associated parameters could be even more challenging. This paper presents the results of a consistent, coupled poroviscoelastic modeling and characterization of the brain tissue as a dual-porosity system. The model draws from Biot's theory of poroviscoelasticity, and adopts the generalized Kelvin's rheological description of the viscoelastic tissue behavior. While the interstitial space serves as the primary porosity through which the bulk flow of the interstitial fluid occurs, a secondary porosity network comprising the capillaries and venous system allows for its partial absorption into the blood. The correspondence principle is used in deriving a time-dependent analytical solution to the proposed model. It allows for identical poroelastic formulation of the original poroviscoelastic problem in the Laplace transform space. Hydrocephalus generally refers to a class of medical conditions which share the ventricles enlargement as a common feature. A set of published data from induced hydrocephalus and follow-up perfusion of cats' brains is used for quantitative characterization of the proposed model. A selected portion of these data including the ventricular volume and rate of fluid absorption from the perfused brain, together with the forward model solution, is utilized via an inverse problem technique to find proper estimations of the model parameters. Results show significant improvement in model predictions of the experimental data. The convoluted and coupled solution results are presented through the time

  1. Combining Non-Pharmacological Treatments with Pharmacotherapies for Neurological Disorders: A Unique Interface of the Brain, Drug–Device, and Intellectual Property

    OpenAIRE

    Grzegorz eBulaj

    2014-01-01

    Mobile medical applications (mHealth), music, and video games are being developed and tested for their ability to improve pharmacotherapy outcomes and medication adherence. Pleiotropic mechanism of music and gamification engages an intrinsic motivation and the brain reward system, supporting therapies in patients with neurological disorders, including neuropathic pain, depression, anxiety, or neurodegenerative disorders. Based on accumulating results from clinical trials, an innovative combin...

  2. A new pyrrolyl-quinoxalinedione series of non-NMDA glutamate receptor antagonists: pharmacological characterization and comparison with NBQX and valproate in the kindling model of epilepsy.

    Science.gov (United States)

    Löscher, W; Lehmann, H; Behl, B; Seemann, D; Teschendorf, H J; Hofmann, H P; Lubisch, W; Höger, T; Lemaire, H G; Gross, G

    1999-01-01

    Antagonists at the ionotropic non-NMDA [AMPA (amino-methyl proprionic acid)/kainate] type of glutamate receptors have been suggested to possess several advantages compared to NMDA (N-methyl-D-aspartate) receptor antagonists, particularly in terms of risk/benefit ratio, but the non-NMDA receptor antagonists available so far have not fulfilled this promise. From a large series of pyrrolyl-quinoxalinedione derivatives, we selected six new competitive non-NMDA receptor antagonists. The basis of selection was high potency and selectivity for AMPA and/or kainate receptors, high in vivo potency after systemic administration, and an acceptable ratio between neuroprotective or anticonvulsant effects and adverse effects. Pharmacological characteristics of these novel compounds are described in this study with special emphasis on their effects in the kindling model of temporal lobe epilepsy, the most common type of epilepsy in humans. In most experiments, NBQX and the major antiepileptic drug valproate were used for comparison with the novel compounds. The novel non-NMDA receptor antagonists markedly differed in their AMPA and kainate receptor affinities from NBQX. Thus, while NBQX essentially did not bind to kainate receptors at relevant concentrations, several of the novel compounds exhibited affinity to rat brain kainate receptors or recombinant kainate receptor subtypes in addition to AMPA receptors. One compound, LU 97175, bound to native high affinity kainate receptors and rat GluR5-GluR7 subunits, i.e. low affinity kainate binding sites, with much higher affinities than to AMPA receptors. All compounds potently blocked AMPA-induced cell death in vitro and, except LU 97175, AMPA-induced convulsions in vivo. In the kindling model, compounds with a high affinity for GluR7 (LU 97175) or compounds (LU 115455, LU 136541) which potently bind to AMPA receptors and low affinity kainate receptor subunits were potent anticonvulsants in the kindling model, whereas the AMPA

  3. Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance.

    Science.gov (United States)

    Wang, Zi-Long; Li, Ning; Wang, Pei; Tang, Hong-Hai; Han, Zheng-Lan; Song, Jing-Jing; Li, Xu-Hui; Yu, Hong-Ping; Zhang, Ting; Zhang, Run; Xu, Biao; Zhang, Meng-Na; Fang, Quan; Wang, Rui

    2016-09-01

    Mounting evidences indicate the functional interactions between neuropeptide FF (NPFF) and opioids, including the endogenous opioids. In the present work, EN-9, a chimeric peptide containing the functional domains of the endogenous opioid endomorphin-2 (EM-2) and NPFF, was synthesized and pharmacologically characterized. In vitro cAMP assay demonstrated that EN-9 was a multifunctional agonist of κ-opioid, NPFF1 and NPFF2 receptors. In the mouse tail-flick test, intracerebroventricularly (i.c.v.) administration of EN-9 produced significant antinociception with an ED50 value of 13.44 nmol, which lasted longer than that of EM-2. In addition, EN-9 induced potent antinociception after both intravenous (i.v.) and subcutaneous (s.c.) injection. Furthermore, the experiments using the antagonists of opioid and NPFF receptors indicated that the central antinociception of EN-9 was mainly mediated by κ-opioid receptor, independently on NPFF receptors. Notably, the central antinociception of EN-9 was not reduced over a period of 6 days repeated i.c.v. injection. Repeated i.c.v. administration of EN-9 with the NPFF1 and NPFF2 receptors antagonist RF9 resulted in a progressive loss of analgesic potency, consistent with the development of tolerance. Moreover, central administration of EN-9 induced the place conditioning aversion only at a high dose of 60 nmol, but not at low doses. At supraspinal level, only high dose of EN-9 (60 nmol, i.c.v.) inhibited gastrointestinal transit via NPFF receptors. Similarly, systemic administration of EN-9 also inhibited gastrointestinal transit at high doses (10 and 30 mg/kg, i.v.). Taken together, the multifunctional agonist of κ-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects.

  4. Characterizing brain anatomical connections using diffusion weighted MRI and graph theory.

    Science.gov (United States)

    Iturria-Medina, Y; Canales-Rodríguez, E J; Melie-García, L; Valdés-Hernández, P A; Martínez-Montes, E; Alemán-Gómez, Y; Sánchez-Bornot, J M

    2007-07-01

    A new methodology based on Diffusion Weighted Magnetic Resonance Imaging (DW-MRI) and Graph Theory is presented for characterizing the anatomical connections between brain gray matter areas. In a first step, brain voxels are modeled as nodes of a non-directed graph in which the weight of an arc linking two neighbor nodes is assumed to be proportional to the probability of being connected by nervous fibers. This probability is estimated by means of probabilistic tissue segmentation and intravoxel white matter orientational distribution function, obtained from anatomical MRI and DW-MRI, respectively. A new tractography algorithm for finding white matter routes is also introduced. This algorithm solves the most probable path problem between any two nodes, leading to the assessment of probabilistic brain anatomical connection maps. In a second step, for assessing anatomical connectivity between K gray matter structures, the previous graph is redefined as a K+1 partite graph by partitioning the initial nodes set in K non-overlapped gray matter subsets and one subset clustering the remaining nodes. Three different measures are proposed for quantifying anatomical connections between any pair of gray matter subsets: Anatomical Connection Strength (ACS), Anatomical Connection Density (ACD) and Anatomical Connection Probability (ACP). This methodology was applied to both artificial and actual human data. Results show that nervous fiber pathways between some regions of interest were reconstructed correctly. Additionally, mean connectivity maps of ACS, ACD and ACP between 71 gray matter structures for five healthy subjects are presented.

  5. Characterization and localization of arginine vasotocin receptors in the brain and kidney of an amphibian

    Energy Technology Data Exchange (ETDEWEB)

    Boyd, S.K.

    1987-01-01

    Because arginine vasotocin (AVT) activates male sexual behaviors in the rough-skinned newt (Taricha granulosa), quantitative autoradiography with radiolabeled arginine vasopressin (/sup 3/H-AVP) was used to localize and characterize putative AVT receptors in the brain of this amphibian. Binding of /sup 3/H-AVP to sites within the medial pallium was saturable, specific, reversible, of high affinity and low capacity. These binding sites appear to represent authentic central nervous system receptors for AVT. Furthermore, ligand specificity for the binding sites in this amphibian differs from that reported for AVP binding sites in rat brains. Dense concentrations of specific binding sites were located in the olfactory nerve as it entered the olfactory bulb within the medial pallium, dorsal pallium, and amygdala pars lateralis of the telencephalon, and in the tegmental region of the medulla. Concentrations of binding sites differed significantly among various brain regions. A comparison of male and female newts collected during the breeding season revealed no sexual dimorphism. These areas may represent site(s) of action where AVT elicits sexual behaviors in male T. granulosa.

  6. Characterization of catalytic efficiency parameters of brain cholinesterases in tropical fish.

    Science.gov (United States)

    de Assis, Caio Rodrigo Dias; Linhares, Amanda Guedes; Oliveira, Vagne Melo; França, Renata Cristina Penha; Santos, Juliana Ferreira; Marcuschi, Marina; Carvalho, Elba Verônica Matoso Maciel; Bezerra, Ranilson Souza; Carvalho, Luiz Bezerra

    2014-12-01

    Brain cholinesterases from four fish (Arapaima gigas, Colossoma macropomum, Rachycentron canadum and Oreochromis niloticus) were characterized using specific substrates and selective inhibitors. Parameters of catalytic efficiency such as activation energy (AE), k(cat) and k(cat)/k(m) as well as rate enhancements produced by these enzymes were estimated by a method using crude extracts described here. Despite the BChE-like activity, specific substrate kinetic analysis pointed to the existence of only acetylcholinesterase (AChE) in brain of the species studied. Selective inhibition suggests that C. macropomum brain AChE presents atypical activity regarding its behavior in the presence of selective inhibitors. AE data showed that the enzymes increased the rate of reactions up to 10(12) in relation to the uncatalyzed reactions. Zymograms showed the presence of AChE isoforms with molecular weights ranging from 202 to 299 kDa. Values of k(cat) and k(cat)/k(m) were similar to those found in the literature.

  7. Image characterization by fractal descriptors in variational mode decomposition domain: Application to brain magnetic resonance

    Science.gov (United States)

    Lahmiri, Salim

    2016-08-01

    The main purpose of this work is to explore the usefulness of fractal descriptors estimated in multi-resolution domains to characterize biomedical digital image texture. In this regard, three multi-resolution techniques are considered: the well-known discrete wavelet transform (DWT) and the empirical mode decomposition (EMD), and; the newly introduced; variational mode decomposition mode (VMD). The original image is decomposed by the DWT, EMD, and VMD into different scales. Then, Fourier spectrum based fractal descriptors is estimated at specific scales and directions to characterize the image. The support vector machine (SVM) was used to perform supervised classification. The empirical study was applied to the problem of distinguishing between normal and abnormal brain magnetic resonance images (MRI) affected with Alzheimer disease (AD). Our results demonstrate that fractal descriptors estimated in VMD domain outperform those estimated in DWT and EMD domains; and also those directly estimated from the original image.

  8. Stress-induced neuroinflammation: mechanisms and new pharmacological targets

    Directory of Open Access Journals (Sweden)

    C.D. Munhoz

    2008-12-01

    Full Text Available Stress is triggered by numerous unexpected environmental, social or pathological stimuli occurring during the life of animals, including humans, which determine changes in all of their systems. Although acute stress is essential for survival, chronic, long-lasting stress can be detrimental. In this review, we present data supporting the hypothesis that stress-related events are characterized by modifications of oxidative/nitrosative pathways in the brain in response to the activation of inflammatory mediators. Recent findings indicate a key role for nitric oxide (NO and an excess of pro-oxidants in various brain areas as responsible for both neuronal functional impairment and structural damage. Similarly, cyclooxygenase-2 (COX-2, another known source of oxidants, may account for stress-induced brain damage. Interestingly, some of the COX-2-derived mediators, such as the prostaglandin 15d-PGJ2 and its peroxisome proliferator-activated nuclear receptor PPARγ, are activated in the brain in response to stress, constituting a possible endogenous anti-inflammatory mechanism of defense against excessive inflammation. The stress-induced activation of both biochemical pathways depends on the activation of the N-methyl-D-aspartate (NMDA glutamate receptor and on the activation of the transcription factor nuclear factor kappa B (NFκB. In the case of inducible NO synthase (iNOS, release of the cytokine TNF-α also accounts for its expression. Different pharmacological strategies directed towards different sites in iNOS or COX-2 pathways have been shown to be neuroprotective in stress-induced brain damage: NMDA receptor blockers, inhibitors of TNF-α activation and release, inhibitors of NFκB, specific inhibitors of iNOS and COX-2 activities and PPARγ agonists. This article reviews recent contributions to this area addressing possible new pharmacological targets for the treatment of stress-induced neuropsychiatric disorders.

  9. Characterization of [125I]omega-conotoxin binding to brain N calcium channels and (-)[3H] desmethoxyverapamil binding to novel calcium channels in osteoblast-like osteosarcoma cells

    International Nuclear Information System (INIS)

    This dissertation provides molecular evidence for a diversity of Ca2+ channels in neuronal and non-neuronal tissues. First, I demonstrated specific, reversible, saturable binding sites for omega [125I]conotoxin GVIA (omega[125I]CTX) in rat brain and rabbit sympathetic ganglion. Omega [125I]CTX binding has a unique pharmacology, ion selectivity, and anatomical distribution in rat brain. Omega [125I]CTX binding was solubilized, retaining an appropriate pharmacology and ion selectivity. Omega[125I]CTX binding may be associated with a Ca2+ channel because the K/sub D/ of omega [125I]CTX is similar to the IC50 of inhibition of depolarization-induced 45Ca2+ flux into rat brain synaptosomes. Specific (-)[3H]desmethoxyverapamil ((-)[3H]DMV) binding sites were demonstrated on osteoblast-like osteosarcoma cell membranes

  10. Zebrafish brain lipid characterization and quantification by ¹H nuclear magnetic resonance spectroscopy and MALDI-TOF mass spectrometry.

    Science.gov (United States)

    van Amerongen, Yvonne F; Roy, Upasana; Spaink, Herman P; de Groot, Huub J M; Huster, Daniel; Schiller, Jürgen; Alia, A

    2014-06-01

    Lipids play an important role in many neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and Huntington's disease. Zebrafish models for these diseases have been recently developed. The detailed brain lipid composition of the adult zebrafish is not known, and therefore, the representativeness of these models cannot be properly evaluated. In this study, we characterized the total lipid composition of healthy adult zebrafish using (1)H nuclear magnetic resonance spectroscopy. A close resemblance of the zebrafish brain composition is shown in comparison to the human brain. Moreover, several lipids involved in the pathogenesis of neurodegenerative diseases (i.e., cholesterol, phosphatidylcholine, docosahexaenoic acid, and further, polyunsaturated fatty acids) are detected and quantified. These lipids might represent useful biomarkers in future research toward human therapies. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry coupled with high-performance thin-layer chromatography was used for further characterization of zebrafish brain lipids. Our results show that the lipid composition of the zebrafish brain is rather similar to the human brain and thus confirms that zebrafish represents a good model for studying various brain diseases.

  11. Characterization and pharmacological modulation of intestinal inflammation induced by ionizing radiation; Caracterisation et modulation pharmacologique de l'inflammation intestinale induite par les rayonnements ionisants

    Energy Technology Data Exchange (ETDEWEB)

    Gremy, O

    2006-12-15

    The use of radiation therapy to treat abdominal and pelvic malignancies inevitably involves exposure of healthy intestinal tissues which are very radiosensitive. As a result, most patients experience symptoms such as abdominal pain, nausea and diarrhea. Such symptoms are associated with acute damage to intestine mucosa including radio-induced inflammatory processes. With a rat model of colorectal fractionated radiation, we have shown a gradual development of a colonic inflammation during radiation planning, without evident tissue injury. This radio-induced inflammation is characterized not only by the sur expressions of pro-inflammatory cytokines and chemokines, a NF-kB activation, but also by a repression of anti-inflammatory cytokines and the nuclear receptors PPARa and RXRa, both involved in inflammation control. This early inflammation is associated with a discreet neutrophil recruitment and a macrophage accumulation. Macrophages are still abnormally numerous in tissue 27 weeks after the last day of irradiation. Inflammatory process is the most often related to a specific immune profile, either a type Th1 leading to a cellular immune response, or a type Th2 for humoral immunity. According to our studies, a unique abdominal radiation in the rat induces an ileum inflammation and an immune imbalance resulting in a Th2-type profile. Inhibiting this profile is important as its persistence promotes chronic inflammation, predisposition to bacterial infections and fibrosis which is the main delayed side-effect of radiotherapy. The treatment of rats with an immuno-modulator compound, the caffeic acid phenethyl ester (C.A.P.E.), have the potential to both reduce ileal mucosal inflammation and inhibit the radio-induced Th2 status. In order to search new therapeutic molecular target, we has been interested in the PPARg nuclear receptor involved in the maintenance of colon mucosal integrity. In our abdominal irradiation model, we have demonstrated that the prophylactic

  12. Pharmacological Treatment Effects on Eye Movement Control

    Science.gov (United States)

    Reilly, James L.; Lencer, Rebekka; Bishop, Jeffrey R.; Keedy, Sarah; Sweeney, John A.

    2008-01-01

    The increasing use of eye movement paradigms to assess the functional integrity of brain systems involved in sensorimotor and cognitive processing in clinical disorders requires greater attention to effects of pharmacological treatments on these systems. This is needed to better differentiate disease and medication effects in clinical samples, to…

  13. Characterizing brain mineral deposition in patients with Wilson disease using susceptibility-weighted imaging

    Directory of Open Access Journals (Sweden)

    Xiang-Xue Zhou

    2014-01-01

    Full Text Available Aims: The aim of this study was to evaluate the feasibility of characterizing the brain-mineral deposition in patients with Wilson disease (WD using susceptibility-weighted imaging (SWI. Materials and Methods: The study enrolled 30 WD patients and 20 age-matched healthy controls. Neurological symptoms were scored using the modified Young Scale. The hepatic function indices, serum and urinary copper content, and serum iron content were determined. All study objects received the magnetic resonance imaging (MRI and SWI test of the brain. The values of corrected phase (CP were calculated on SWI. The relationship between CP values and the clinical status were evaluated. Results: The serum iron content of WD patients was higher than the normal. The CP values of substantia nigra, caudate nucleus, and globus pallidus of WD were lower than the normal values, while the CP value of substantia nigra was the lowest. No correlations were determined between the CP values and the iron and copper parameters. There was negative correlation between the scores of dysarthria and the CP values of the globus pallidus. There was negative correlation between the scores of tremor and the CP values of caudate nucleus. Some regions, which had high signals on T2-weighted image, had low signals on SWI. Conclusions: There might be abnormal iron metabolism in patients with WD. The decreased CP values might reflect a deposition of both copper and iron. SWI may be more sensitive than the ordinary MRI. The mineral deposition may contribute to the neural symptoms.

  14. Conus venom peptide pharmacology.

    Science.gov (United States)

    Lewis, Richard J; Dutertre, Sébastien; Vetter, Irina; Christie, MacDonald J

    2012-04-01

    Conopeptides are a diverse group of recently evolved venom peptides used for prey capture and/or defense. Each species of cone snails produces in excess of 1000 conopeptides, with those pharmacologically characterized (≈ 0.1%) targeting a diverse range of membrane proteins typically with high potency and specificity. The majority of conopeptides inhibit voltage- or ligand-gated ion channels, providing valuable research tools for the dissection of the role played by specific ion channels in excitable cells. It is noteworthy that many of these targets are found to be expressed in pain pathways, with several conopeptides having entered the clinic as potential treatments for pain [e.g., pyroglutamate1-MrIA (Xen2174)] and one now marketed for intrathecal treatment of severe pain [ziconotide (Prialt)]. This review discusses the diversity, pharmacology, structure-activity relationships, and therapeutic potential of cone snail venom peptide families acting at voltage-gated ion channels (ω-, μ-, μO-, δ-, ι-, and κ-conotoxins), ligand-gated ion channels (α-conotoxins, σ-conotoxin, ikot-ikot, and conantokins), G-protein-coupled receptors (ρ-conopeptides, conopressins, and contulakins), and neurotransmitter transporters (χ-conopeptides), with expanded discussion on the clinical potential of sodium and calcium channel inhibitors and α-conotoxins. Expanding the discovery of new bioactives using proteomic/transcriptomic approaches combined with high-throughput platforms and better defining conopeptide structure-activity relationships using relevant membrane protein crystal structures are expected to grow the already significant impact conopeptides have had as both research probes and leads to new therapies. PMID:22407615

  15. Photodynamic characterization and optimization using multifunctional nanoparticles for brain cancer treatment

    Science.gov (United States)

    Herrmann, Kristen; Lee Koo, Yong-Eun; Orringer, Daniel A.; Sagher, Oren; Philbert, Martin; Kopelman, Raoul

    2013-03-01

    Photosensitizer-conjugated polyacrylamide nanoparticles were prepared for in vivo characterization of the minimally invasive and localized treatment of photodynamic therapy (PDT) on brain tumors. By incorporating a variety of nanoparticle matrixes, choosing methylene blue as a photosensitizer, and targeting the nanoparticle by the use of F3 peptide we have made nanoparticle-based PDT improvements to current PDT efficiency. Quantitative growth patterns were determined through visual observation of the tumorigenic response to various treatments by the use of an animal cranial window model. PDT treatments with methylene blue-polyacrylamide (MB-PAA) nanoparticles produced significant adjournment of tumor growth over control groups, clearly demonstrating the advantages of nanoparticle-based PDT agents for the eradication of local tumors, leading to the potential palliation of the advancing disease.

  16. Cloning of a serine proteinase inhibitor from bovine brain: expression in the brain and characterization of its target proteinases.

    Science.gov (United States)

    Nakaya, N; Nishibori, M; Kawabata, M; Saeki, K

    1996-12-01

    A cDNA encoding of the serine proteinase inhibitor (serpin), B-43, was cloned from the cDNA library of the bovine brain. It encoded 378 amino acids, and the MW of the protein was estimated to be 42.6 kDa, which is consistent with that of the native B-43 purified from the bovine brain. The homology search revealed that B-43 belongs to the ovalbumin branch of the serpin superfamily. Among them, B-43 was most homologous to human placental thrombin inhibitor (PI-6) and its murine counterpart, with the amino acid identity of 76% and 71%, respectively. Northern blot analysis showed that the size of the transcript was 1.4 kb, and that the expression of B-43 in the bovine brain varied depending on the brain regions, i.e. a lower level of expression was observed in the cerebral cortex and the hippocampus compared to the level of expression that was observed in the medulla oblongata. [35S]-labeled B-43 protein was synthesized in vitro by using a rabbit reticulocyte lysate system, which formed complexes with proteinases such as thrombin, trypsin, alpha-chymotrypsin, and 7S nerve growth factor (NGF), but not with urokinase or plasmin. These results, together with the immunohistochemical localization of B-43 in astrocytes and in some neurons which was observed in the previous study suggest that B-43 may be involved in the regulation of serine proteinases present in the brain or extravasated from the blood.

  17. Pharmacological activation of CB2 receptors counteracts the deleterious effect of ethanol on cell proliferation in the main neurogenic zones of the adult rat brain

    Science.gov (United States)

    Rivera, Patricia; Blanco, Eduardo; Bindila, Laura; Alen, Francisco; Vargas, Antonio; Rubio, Leticia; Pavón, Francisco J.; Serrano, Antonia; Lutz, Beat; Rodríguez de Fonseca, Fernando; Suárez, Juan

    2015-01-01

    Chronic alcohol exposure reduces endocannabinoid activity and disrupts adult neurogenesis in rodents, which results in structural and functional alterations. Cannabinoid receptor agonists promote adult neural progenitor cell (NPC) proliferation. We evaluated the protective effects of the selective CB1 receptor agonist ACEA, the selective CB2 receptor agonist JWH133 and the fatty-acid amide-hydrolase (FAAH) inhibitor URB597, which enhances endocannabinoid receptor activity, on NPC proliferation in rats with forced consumption of ethanol (10%) or sucrose liquid diets for 2 weeks. We performed immunohistochemical and stereological analyses of cells expressing the mitotic phosphorylation of histone-3 (phospho-H3+) and the replicating cell DNA marker 5-bromo-2'-deoxyuridine (BrdU+) in the main neurogenic zones of adult brain: subgranular zone of dentate gyrus (SGZ), subventricular zone of lateral ventricles (SVZ) and hypothalamus. Animals were allowed ad libitum ethanol intake (7.3 ± 1.1 g/kg/day) after a controlled isocaloric pair-feeding period of sucrose and alcoholic diets. Alcohol intake reduced the number of BrdU+ cells in SGZ, SVZ, and hypothalamus. The treatments (URB597, ACEA, JWH133) exerted a differential increase in alcohol consumption over time, but JWH133 specifically counteracted the deleterious effect of ethanol on NPC proliferation in the SVZ and SGZ, and ACEA reversed this effect in the SGZ only. JWH133 also induced an increased number of BrdU+ cells expressing neuron-specific β3-tubulin in the SVZ and SGZ. These results indicated that the specific activation of CB2 receptors rescued alcohol-induced impaired NPC proliferation, which is a potential clinical interest for the risk of neural damage in alcohol dependence. PMID:26483633

  18. Neurocomputational models of brain disorders

    NARCIS (Netherlands)

    Cutsuridis, Vassilis; Heida, Tjitske; Duch, Wlodek; Doya, Kenji

    2011-01-01

    Recent decades have witnessed dramatic accumulation of knowledge about the genetic, molecular, pharmacological, neurophysiological, anatomical, imaging and psychological characteristics of brain disorders. Despite these advances, however, experimental brain science has offered very little insight in

  19. Low-frequency noise characterization of near-IR VCSELs for functional brain imaging

    Science.gov (United States)

    Lee, Thomas T.; Lim, Paul G.; Harris, James S., Jr.; Shenoy, Krishna V.; Smith, Stephen J.

    2008-02-01

    Recent years have seen rising interest in optical system-on-a-chip sensors for biological applications. Vertical cavity surface emitting lasers (VCSELs) are a natural choice for array-based sensors requiring high power and low noise. However, much of the noise characterization of VCSELs has been performed in frequency ranges on the order of 10 8 to 10 10 Hz, whereas many physiological phenomena occur in frequency bands in the hertz to kilohertz range where 1/f and 1/f2 noise is dominant. In this work we characterize the relative intensity noise (RIN) of commercial VCSEL devices and evaluate their feasibility for use in an integrated semiconductor optical sensor for functional brain imaging using Intrinsic Optical Signals (IOS). Our results show RIN on the order of -196 to -174 dB/Hz at an offset of 10 Hz. This is well below the signal-to-background and dynamic range requirements of 6 dB and 86 dB, respectively, for this application.

  20. Pharmacological disruption of maladaptive memory.

    Science.gov (United States)

    Taylor, Jane R; Torregrossa, Mary M

    2015-01-01

    Many psychiatric disorders are characterized by intrusive, distracting, and disturbing memories that either perpetuate the illness or hinder successful treatment. For example, posttraumatic stress disorder (PTSD) involves such strong reemergence of memories associated with a traumatic event that the individual feels like the event is happening again. Furthermore, drug addiction is characterized by compulsive use and repeated relapse that is often driven by internal memories of drug use and/or by exposure to external stimuli that were associated with drug use. Therefore, identifying pharmacological methods to weaken the strength of maladaptive memories is a major goal of research efforts aimed at finding new treatments for these disorders. The primary mechanism by which memories could be pharmacologically disrupted or altered is through manipulation of memory reconsolidation. Reconsolidation occurs when an established memory is remembered or reactivated, reentering a labile state before again being consolidated into long-term memory storage. Memories are subject to disruption during this labile state. In this chapter we will discuss the preclinical and clinical studies identifying potential pharmacological methods for disrupting the integrity of maladaptive memory to treat mental illness. PMID:25977090

  1. HERMES: towards an integrated toolbox to characterize functional and effective brain connectivity.

    Science.gov (United States)

    Niso, Guiomar; Bruña, Ricardo; Pereda, Ernesto; Gutiérrez, Ricardo; Bajo, Ricardo; Maestú, Fernando; del-Pozo, Francisco

    2013-10-01

    The analysis of the interdependence between time series has become an important field of research in the last years, mainly as a result of advances in the characterization of dynamical systems from the signals they produce, the introduction of concepts such as generalized and phase synchronization and the application of information theory to time series analysis. In neurophysiology, different analytical tools stemming from these concepts have added to the 'traditional' set of linear methods, which includes the cross-correlation and the coherency function in the time and frequency domain, respectively, or more elaborated tools such as Granger Causality.This increase in the number of approaches to tackle the existence of functional (FC) or effective connectivity (EC) between two (or among many) neural networks, along with the mathematical complexity of the corresponding time series analysis tools, makes it desirable to arrange them into a unified-easy-to-use software package. The goal is to allow neuroscientists, neurophysiologists and researchers from related fields to easily access and make use of these analysis methods from a single integrated toolbox.Here we present HERMES ( http://hermes.ctb.upm.es ), a toolbox for the Matlab® environment (The Mathworks, Inc), which is designed to study functional and effective brain connectivity from neurophysiological data such as multivariate EEG and/or MEG records. It includes also visualization tools and statistical methods to address the problem of multiple comparisons. We believe that this toolbox will be very helpful to all the researchers working in the emerging field of brain connectivity analysis. PMID:23812847

  2. Pharmacology Information System Ready

    Science.gov (United States)

    Chemical and Engineering News, 1973

    1973-01-01

    Discusses the development and future of Prophet,'' a specialized information handling system for pharmacology research. It is designed to facilitate the acquisition and dissemination of knowledge about mechanisms of drug action, and it is hoped that it will aid in converting pharmacology research from an empirical to a predictive science. (JR)

  3. Curriculum Guidelines for Pharmacology.

    Science.gov (United States)

    Shaw, David H.; And Others

    1990-01-01

    Pharmacology embraces the physical and chemical properties of drugs; the preparation of pharmaceutical agents; the absorption, fate, and excretion of drugs; and the effects of drugs on living systems. These guidelines represent a consensus on what would constitute a minimally acceptable pharmacology course for predoctoral dental students. (MLW)

  4. Pharmacology of cannabinoids.

    Science.gov (United States)

    Grotenhermen, Franjo

    2004-01-01

    Dronabinol (Delta 9-tetrahydocannabinol, THC), the main source of the pharmacological effects caused by the use of cannabis, is an agonist to both the CB1 and the CB2 subtype of cannabinoid receptors. It is available on prescription in several countries. The non-psychotropic cannabidiol (CBD), some analogues of natural cannabinoids and their metabolites, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues including spleen, leukocytes; reproductive, urinary and gastrointestinal tracts; endocrine glands, arteries and heart. Five endogenous cannabinoids have been detected so far, of whom anandamide and 2-arachidonylglycerol are best characterized. There is evidence that besides the two cannabinoid receptor subtypes cloned so far additional cannabinoid receptor subtypes and vanilloid receptors are involved in the complex physiological functions of the cannabinoid system that include motor coordination, memory procession, control of appetite, pain modulation and neuroprotection. Strategies to modulate their activity include inhibition of re-uptake into cells and inhibition of their degradation to increase concentration and duration of action. Properties of cannabinoids that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects. PMID:15159677

  5. Physicochemical characterization and in vivo bioluminescence imaging of nanostructured lipid carriers for targeting the brain: apomorphine as a model drug

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Shu-Hui [Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan (China); Wen, Chih-Jen; Yen, Tzu-Chen [Animal Molecular Imaging Center, Chang Gung Memorial Hospital, Kweishan, Taoyuan 333, Taiwan (China); Al-Suwayeh, S A; Fang, Jia-You [Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh (Saudi Arabia); Chang, Hui-Wen, E-mail: fajy@mail.cgu.edu.tw [Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan 333, Taiwan (China)

    2010-10-08

    Nanostructured lipid carriers (NLCs) were prepared to investigate whether the duration of brain targeting and accumulation of drugs in the brain can be improved by intravenous delivery. NLCs were developed using cetyl palmitate as the lipid matrix, squalene as the cationic surfactant, and Pluronic F68, polysorbate 80 and polyethylene glycol as the interfacial additives. Solid lipid nanoparticles (SLNs) and lipid emulsions (LEs) were also prepared for comparison. An anti-Parkinson's drug, apomorphine, was used as the model drug. Nuclear magnetic resonance and differential scanning calorimetry showed possible interactions between the solid and liquid lipids in the inner core. The lipid nanoparticles with different compositions were characterized by mean size, zeta potential, apomorphine encapsulation and in vitro drug release. NLCs were 370-430 nm in size, which was between the sizes of the SLNs and LEs. A cationic surfactant was used to produce a positive surface charge of 42-50 mV. The base form of apomorphine was successfully entrapped by NLCs with an entrapment percentage of > 60%. The loading of apomorphine in nanoparticles resulted in a slower release behavior compared to the aqueous solution, with LEs showing the lowest release. In vivo real-time bioluminescence imaging of the rat brain revealed that NLCs could be targeted, through certain vessels, to selected brain regions. This effect was further confirmed by imaging the entire brain and brain slices. The results indicated that NLCs with moderate additives are a promising controlled-release and drug-targeting system.

  6. Physicochemical characterization and in vivo bioluminescence imaging of nanostructured lipid carriers for targeting the brain: apomorphine as a model drug

    Science.gov (United States)

    Hsu, Shu-Hui; Wen, Chih-Jen; Al-Suwayeh, S. A.; Chang, Hui-Wen; Yen, Tzu-Chen; Fang, Jia-You

    2010-10-01

    Nanostructured lipid carriers (NLCs) were prepared to investigate whether the duration of brain targeting and accumulation of drugs in the brain can be improved by intravenous delivery. NLCs were developed using cetyl palmitate as the lipid matrix, squalene as the cationic surfactant, and Pluronic F68, polysorbate 80 and polyethylene glycol as the interfacial additives. Solid lipid nanoparticles (SLNs) and lipid emulsions (LEs) were also prepared for comparison. An anti-Parkinson's drug, apomorphine, was used as the model drug. Nuclear magnetic resonance and differential scanning calorimetry showed possible interactions between the solid and liquid lipids in the inner core. The lipid nanoparticles with different compositions were characterized by mean size, zeta potential, apomorphine encapsulation and in vitro drug release. NLCs were 370-430 nm in size, which was between the sizes of the SLNs and LEs. A cationic surfactant was used to produce a positive surface charge of 42-50 mV. The base form of apomorphine was successfully entrapped by NLCs with an entrapment percentage of > 60%. The loading of apomorphine in nanoparticles resulted in a slower release behavior compared to the aqueous solution, with LEs showing the lowest release. In vivo real-time bioluminescence imaging of the rat brain revealed that NLCs could be targeted, through certain vessels, to selected brain regions. This effect was further confirmed by imaging the entire brain and brain slices. The results indicated that NLCs with moderate additives are a promising controlled-release and drug-targeting system.

  7. Physicochemical characterization and in vivo bioluminescence imaging of nanostructured lipid carriers for targeting the brain: apomorphine as a model drug

    International Nuclear Information System (INIS)

    Nanostructured lipid carriers (NLCs) were prepared to investigate whether the duration of brain targeting and accumulation of drugs in the brain can be improved by intravenous delivery. NLCs were developed using cetyl palmitate as the lipid matrix, squalene as the cationic surfactant, and Pluronic F68, polysorbate 80 and polyethylene glycol as the interfacial additives. Solid lipid nanoparticles (SLNs) and lipid emulsions (LEs) were also prepared for comparison. An anti-Parkinson's drug, apomorphine, was used as the model drug. Nuclear magnetic resonance and differential scanning calorimetry showed possible interactions between the solid and liquid lipids in the inner core. The lipid nanoparticles with different compositions were characterized by mean size, zeta potential, apomorphine encapsulation and in vitro drug release. NLCs were 370-430 nm in size, which was between the sizes of the SLNs and LEs. A cationic surfactant was used to produce a positive surface charge of 42-50 mV. The base form of apomorphine was successfully entrapped by NLCs with an entrapment percentage of > 60%. The loading of apomorphine in nanoparticles resulted in a slower release behavior compared to the aqueous solution, with LEs showing the lowest release. In vivo real-time bioluminescence imaging of the rat brain revealed that NLCs could be targeted, through certain vessels, to selected brain regions. This effect was further confirmed by imaging the entire brain and brain slices. The results indicated that NLCs with moderate additives are a promising controlled-release and drug-targeting system.

  8. On the mechanical characterization and modeling of polymer gel brain substitute under dynamic rotational loading.

    Science.gov (United States)

    Fontenier, B; Hault-Dubrulle, A; Drazetic, P; Fontaine, C; Naceur, H

    2016-10-01

    The use of highly sensitive soft materials has become increasingly apparent in the last few years in numerous industrial fields, due to their viscous and damping nature. Unfortunately these materials remain difficult to characterize using conventional techniques, mainly because of the very low internal forces supported by these materials especially under high strain-rates of deformation. The aim of this work is to investigate the dynamic response of a polymer gel brain analog material under specific rotational-impact experiments. The selected polymer gel commercially known as Sylgard 527 has been studied using a specific procedure for its experimental characterization and numerical modeling. At first an indentation experiment was conducted at several loading rates to study the strain rate sensitivity of the Sylgard 527 gel. During the unloading several relaxation tests were performed after indentation, to assess the viscous behavior of the material. A specific numerical procedure based on moving least square approximation and response surface method was then performed to determine adequate robust material parameters of the Sylgard 527 gel. A sensitivity analysis was assessed to confirm the robustness of the obtained material parameters. For the validation of the obtained material model, a second experiment was conducted using a dynamic rotational loading apparatus. It consists of a metallic cylindrical cup filled with the polymer gel and subjected to an eccentric transient rotational impact. Complete kinematics of the cup and the large strains induced in the Sylgard 527 gel, have been recorded at several patterns by means of optical measurement. The whole apparatus was modeled by the Finite Element Method using explicit dynamic time integration available within Ls-dyna(®) software. Comparison between the physical and the numerical models of the Sylgard 527 gel behavior under rotational choc shows excellent agreements.

  9. Activity Staining and Inhibition Characterization of Dipeptidylpeptidase-III Enzyme from Goat Brain

    Directory of Open Access Journals (Sweden)

    Pooja Attri

    2011-01-01

    Full Text Available Dipeptidylpeptidase-III (DPP-III from goat brain was purified and characterized using Arginyl-Arginyl-4-methoxy-β-naphthylamide (Arg-Arg-4mβNA substrate. This enzyme retained its activity in native 10% polyacrylamide gel when stained using Arg-Arg-4mβNA. The activity was significantly increased by 100 mM chloride. Studies for its inhibition with some peptides and chemical inhibitors revealed that Leu-Trp-Met-Arg-Phe-Ala was most potent inhibitor followed by Arg-Phe-Ala and Gly-Phe-Leu. All the studied chemical inhibitors caused 40–50% inhibition at 1 mM. Metal ions helped to regain activity of EDTA pretreated enzyme. ZnCl2 at 50 μM almost completely restored the enzyme activity. Further ZnCl2 and CoCl2 exerted protective effects on EDTA pretreated enzyme for its susceptibility to DTNB inhibition. Therefore, DPP-III is a metalloprotease with the involvement of cysteine residues either located at the catalytic site or involved in regulation.

  10. Electrochemical preparation and characterization of brain-like nanostructures of Y2O3

    Institute of Scientific and Technical Information of China (English)

    Mustafa Aghazadeh; Mojtaba Hosseinifard; Mohammad Hassan Peyrovi; Behrouz Sabour

    2013-01-01

    Nanostructured Y2O3 was successfully prepared via a two-step and template-free method.Firstly,yttrium hydroxide precursor was galvanostatically grown on the steel substrate from chloride bath by direct and pulse current deposition modes.Direct current deposition was carried out at the constant current density of 0.1 A/dm2 for 600 s.The pulse current was also performed at a typical on-time and off-time (ton=l s and ton=l s) with an average current density of 0.05 A/dm2 (Ia=0.05 A/dm2) for 600 s.The obtained hydroxide films were then scraped from the substrates and thermally converted into final oxide product via heat-treatment.Thermal behaviors and phase transformations during the heat treatment of the hydroxide powder samples were investigated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).The final oxide products were characterized by means of X-ray diffraction (XRD),Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM).The results showed that the well-crystallized Y2O3 with brain-and sphere-like morphology were achievable via pulse and direct deposition modes,respectively.It was concluded that pulse current cathodic electrodeposition offered a facile route for preparation of nanostructured Y2O3.

  11. Pharmacology and function of melatonin receptors

    Energy Technology Data Exchange (ETDEWEB)

    Dubocovich, M.L.

    1988-09-01

    The hormone melatonin is secreted primarily from the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone, through an action in the brain, appears to be involved in the regulation of various neural and endocrine processes that are cued by the daily change in photoperiod. This article reviews the pharmacological characteristics and function of melatonin receptors in the central nervous system, and the role of melatonin in mediating physiological functions in mammals. Melatonin and melatonin agonists, at picomolar concentrations, inhibit the release of dopamine from retina through activation of a site that is pharmacologically different from a serotonin receptor. These inhibitory effects are antagonized by the novel melatonin receptor antagonist luzindole (N-0774), which suggests that melatonin activates a presynaptic melatonin receptor. In chicken and rabbit retina, the pharmacological characteristics of the presynaptic melatonin receptor and the site labeled by 2-(125I)iodomelatonin are identical. It is proposed that 2-(125I)iodomelatonin binding sites (e.g., chicken brain) that possess the pharmacological characteristics of the retinal melatonin receptor site (order of affinities: 2-iodomelatonin greater than 6-chloromelatonin greater than or equal to melatonin greater than or equal to 6,7-di-chloro-2-methylmelatonin greater than 6-hydroxymelatonin greater than or equal to 6-methoxymelatonin greater than N-acetyltryptamine greater than or equal to luzindole greater than N-acetyl-5-hydroxytryptamine greater than 5-methoxytryptamine much greater than 5-hydroxytryptamine) be classified as ML-1 (melatonin 1). The 2-(125I)iodomelatonin binding site of hamster brain membranes possesses different binding and pharmacological characteristics from the retinal melatonin receptor site and should be classified as ML-2. 64 references.

  12. Robust estimation of fractal measures for characterizing the structural complexity of the human brain: optimization and reproducibility.

    Science.gov (United States)

    Goñi, Joaquín; Sporns, Olaf; Cheng, Hu; Aznárez-Sanado, Maite; Wang, Yang; Josa, Santiago; Arrondo, Gonzalo; Mathews, Vincent P; Hummer, Tom A; Kronenberger, William G; Avena-Koenigsberger, Andrea; Saykin, Andrew J; Pastor, María A

    2013-12-01

    High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter structures can be characterized to quantify aspects of their shape, volume and topological complexity. In particular, methods based on fractal analysis have been applied in neuroimaging studies to quantify the structural complexity of the brain in both healthy and impaired conditions. The usefulness of such measures for characterizing individual differences in brain structure critically depends on their within-subject reproducibility in order to allow the robust detection of between-subject differences. This study analyzes key analytic parameters of three fractal-based methods that rely on the box-counting algorithm with the aim to maximize within-subject reproducibility of the fractal characterizations of different brain objects, including the pial surface, the cortical ribbon volume, the white matter volume and the gray matter/white matter boundary. Two separate datasets originating from different imaging centers were analyzed, comprising 50 subjects with three and 24 subjects with four successive scanning sessions per subject, respectively. The reproducibility of fractal measures was statistically assessed by computing their intra-class correlations. Results reveal differences between different fractal estimators and allow the identification of several parameters that are critical for high reproducibility. Highest reproducibility with intra-class correlations in the range of 0.9-0.95 is achieved with the correlation dimension. Further analyses of the fractal dimensions of parcellated cortical and subcortical gray matter regions suggest robustly estimated and region-specific patterns of individual variability. These results are valuable for defining appropriate parameter configurations when studying changes in fractal descriptors of human brain structure, for instance in studies of neurological diseases that do not allow repeated measurements or for disease

  13. Autoradiographic characterization of (+-)-1-(2,5-dimethoxy-4-[125I] iodophenyl)-2-aminopropane ([125I]DOI) binding to 5-HT2 and 5-HT1c receptors in rat brain

    International Nuclear Information System (INIS)

    The 5-HT2 (serotonin) receptor has traditionally been labeled with antagonist radioligands such as [3H]ketanserin and [3H]spiperone, which label both agonist high-affinity (guanyl nucleotide-sensitive) and agonist low-affinity (guanyl nucleotide-insensitive) states of this receptor. The hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) is an agonist which labels the high-affinity guanyl nucleotide-sensitive state of brain 5-HT2 receptors selectively. In the present study, conditions for autoradiographic visualization of (+/-)-[125I]DOI-labeled 5-HT2 receptors were optimized and binding to slide-mounted sections was characterized with respect to pharmacology, guanyl nucleotide sensitivity and anatomical distribution. In slide-mounted rat brain sections (+/-)-[125I]DOI binding was saturable, of high affinity (KD approximately 4 nM) and displayed a pharmacologic profile typical of 5-HT2 receptors. Consistent with coupling of 5-HT2 receptors in the high-affinity state to a guanyl nucleotide regulatory protein, [125I]DOI binding was inhibited by guanyl nucleotides but not by adenosine triphosphate. Patterns of autoradiographic distribution of [125I]DOI binding to 5-HT2 receptors were similar to those seen with [3H]ketanserin- and [125I]-lysergic acid diethylamide-labeled 5-HT2 receptors. However, the density of 5-HT2 receptors labeled by the agonist [125I]DOI was markedly lower (30-50%) than that labeled by the antagonist [3H]ketanserin. High densities of [125I]DOI labeling were present in olfactory bulb, anterior regions of cerebral cortex (layer IV), claustrum, caudate putamen, globus pallidus, ventral pallidum, islands of Calleja, mammillary nuclei and inferior olive. Binding in hippocampus, thalamus and hypothalamus was generally sparse

  14. Who needs pharmacologic therapy?

    Directory of Open Access Journals (Sweden)

    Christopher Porterfield; Rohit Malhotra

    2014-06-01

    Full Text Available Treatment of atrial fibrillation has evolved significantly in the last ten years, with ablation becoming a far more common form of treatment for this most common of arrhythmias. However, while ablation has become more common, certain populations derive continued benefit from the use of pharmacologic therapy for treatment. We review the use of pharmacologic therapy and novel considerations for treatment of atrial fibrillation.

  15. Pharmacological Effects of Mangiferin

    Institute of Scientific and Technical Information of China (English)

    WEI Zhi-quan; DENG Jia-gang; YAN Li

    2011-01-01

    Mango leaves have been widely used in the clinical practice for thousands of years in traditional Chinese medicine.Mangiferin,an effective constituent in the mango leaves,has multiple pharmacological actions involved in some basic pathological processes,such as inflammation,oxidative injury,tumor growth,micro-organism infections,metabolic regulations,and immunological regulations.The pharmacological effects of mangiferin from some published data are reviewed in this article.

  16. The pharmacology of psilocybin.

    Science.gov (United States)

    Passie, Torsten; Seifert, Juergen; Schneider, Udo; Emrich, Hinderk M

    2002-10-01

    Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is the major psychoactive alkaloid of some species of mushrooms distributed worldwide. These mushrooms represent a growing problem regarding hallucinogenic drug abuse. Despite its experimental medical use in the 1960s, only very few pharmacological data about psilocybin were known until recently. Because of its still growing capacity for abuse and the widely dispersed data this review presents all the available pharmacological data about psilocybin.

  17. Pharmacological characterization of homobaclofen on wild type and mutant GABA(B)1b receptors coexpressed with the GABA(B)2 receptor

    DEFF Research Database (Denmark)

    Jensen, Anders A.; Madsen, Bo E.; Krogsgaard-Larsen, P;

    2001-01-01

    Homobaclofen (5-amino-3-(4-chlorophenyl) pentanoic acid) is a homologue of the classical GABA(B) receptor agonist baclofen. In a recent study, the two enantiomers of this compound were tested in a GABA(B) receptor selective [3H]gamma-aminobutyric acid ([3H]GABA) binding assay using rat brain homo...

  18. Characterization of the pharmacology, signal transduction and internalization of the fluorescent PACAP ligand, fluor-PACAP, on NIH/3T3 cells expressing PAC1.

    Science.gov (United States)

    Germano, P M; Stalter, J; Le, S V; Wu, M; Yamaguchi, D J; Scott, D; Pisegna, J R

    2001-06-01

    Fluor-PACAP, a fluorescent derivative of PACAP-27, has been confirmed to share a high affinity for PAC1 receptors transfected into NIH/3T3 cells and to have comparable pharmacological characteristics to the unconjugated, native form. Through competitive binding with 125I-PACAP-27, the two ligands exhibited similar dose- dependent inhibition. Additional examination of the efficacy of activating adenylyl cyclase revealed that both ligands analogously stimulated the production of cyclic AMP. Furthermore, PAC1 internalization visualized by our Fluor-PACAP, is compareable to that performed with the radioligand, 125I-PACAP-27, with maximal internalization achieved within thirty minutes. Thus, Fluor-PACAP exhibits intracellular signaling abilities homologous to the native ligand.

  19. Non Pharmacological Cognitive Enhancers - Current Perspectives.

    Science.gov (United States)

    Sachdeva, Ankur; Kumar, Kuldip; Anand, Kuljeet Singh

    2015-07-01

    Cognition refers to the mental processes involved in thinking, knowing, remembering, judging, and problem solving. Cognitive dysfunctions are an integral part of neuropsychiatric disorders as well as in healthy ageing. Cognitive Enhancers are molecules that help improve aspects of cognition like memory, intelligence, motivation, attention and concentration. Recently, Non Pharmacological Cognitive Enhancers have gained popularity as effective and safe alternative to various established drugs. Many of these Non Pharmacological Cognitive Enhancers seem to be more efficacious compared to currently available Pharmacological Cognitive Enhancers. This review describes and summarizes evidence on various Non Pharmacological Cognitive Enhancers such as physical exercise, sleep, meditation and yoga, spirituality, nutrients, computer training, brain stimulation, and music. We also discuss their role in ageing and different neuro-psychiatric disorders, and current status of Cochrane database recommendations. We searched the Pubmed database for the articles and reviews having the terms 'non pharmacological and cognitive' in the title, published from 2000 till 2014. A total of 11 results displayed, out of which 10 were relevant to the review. These were selected and reviewed. Appropriate cross-references within the articles along with Cochrane reviews were also considered and studied. PMID:26393186

  20. Persistent impact of in utero irradiation on mouse brain structure and function characterized by MR imaging and behavioral analysis

    OpenAIRE

    Verreet, Tine; Rangarajan, Janaki Raman; Quintens, Roel; Verslegers, Mieke; Govaerts, Kristof; Lo, Adrian; Neefs, Mieke; Leysen, Liselotte; Baatout, Sarah; Maes, Frederik; Himmelreich, Uwe; D'Hooge, Rudi; Moons, Lieve; Mohammed A. Benotmane

    2016-01-01

    Verreet T., Rangarajan J.R., Quintens R., Verslegers M., Lo A.C., Govaerts K., Neefs M., Leysen L., Baatout S., Maes F., Himmelreich U., D'Hooge R., Moons L., Benotmane M.A., ''Persistent impact of in utero irradiation on mouse brain structure and function characterized by MR imaging and behavioral analysis'', Frontiers in behavioral neuroscience, vol. 10, article 83, May 2016.

  1. In Vitro Characterization of the Pharmacological Properties of the Anti-Cancer Chelator, Bp4eT, and Its Phase I Metabolites.

    Directory of Open Access Journals (Sweden)

    Eliška Potůčková

    Full Text Available Cancer cells have a high iron requirement and many experimental studies, as well as clinical trials, have demonstrated that iron chelators are potential anti-cancer agents. The ligand, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT, demonstrates both potent anti-neoplastic and anti-retroviral properties. In this study, Bp4eT and its recently identified amidrazone and semicarbazone metabolites were examined and compared with respect to their anti-proliferative activity towards cancer cells (HL-60 human promyelocytic leukemia, MCF-7 human breast adenocarcinoma, HCT116 human colon carcinoma and A549 human lung adenocarcinoma, non-cancerous cells (H9c2 neonatal rat-derived cardiomyoblasts and 3T3 mouse embryo fibroblasts and their interaction with intracellular iron pools. Bp4eT was demonstrated to be a highly potent and selective anti-neoplastic agent that induces S phase cell cycle arrest, mitochondrial depolarization and apoptosis in MCF-7 cells. Both semicarbazone and amidrazone metabolites showed at least a 300-fold decrease in cytotoxic activity than Bp4eT towards both cancer and normal cell lines. The metabolites also lost the ability to: (1 promote the redox cycling of iron; (2 bind and mobilize iron from labile intracellular pools; and (3 prevent 59Fe uptake from 59Fe-labeled transferrin by MCF-7 cells. Hence, this study demonstrates that the highly active ligand, Bp4eT, is metabolized to non-toxic and pharmacologically inactive analogs, which most likely contribute to its favorable pharmacological profile. These findings are important for the further development of this drug candidate and contribute to the understanding of the structure-activity relationships of these agents.

  2. In Vitro Characterization of the Pharmacological Properties of the Anti-Cancer Chelator, Bp4eT, and Its Phase I Metabolites.

    Science.gov (United States)

    Potůčková, Eliška; Roh, Jaroslav; Macháček, Miloslav; Sahni, Sumit; Stariat, Ján; Šesták, Vít; Jansová, Hana; Hašková, Pavlína; Jirkovská, Anna; Vávrová, Kateřina; Kovaříková, Petra; Kalinowski, Danuta S; Richardson, Des R; Šimůnek, Tomáš

    2015-01-01

    Cancer cells have a high iron requirement and many experimental studies, as well as clinical trials, have demonstrated that iron chelators are potential anti-cancer agents. The ligand, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), demonstrates both potent anti-neoplastic and anti-retroviral properties. In this study, Bp4eT and its recently identified amidrazone and semicarbazone metabolites were examined and compared with respect to their anti-proliferative activity towards cancer cells (HL-60 human promyelocytic leukemia, MCF-7 human breast adenocarcinoma, HCT116 human colon carcinoma and A549 human lung adenocarcinoma), non-cancerous cells (H9c2 neonatal rat-derived cardiomyoblasts and 3T3 mouse embryo fibroblasts) and their interaction with intracellular iron pools. Bp4eT was demonstrated to be a highly potent and selective anti-neoplastic agent that induces S phase cell cycle arrest, mitochondrial depolarization and apoptosis in MCF-7 cells. Both semicarbazone and amidrazone metabolites showed at least a 300-fold decrease in cytotoxic activity than Bp4eT towards both cancer and normal cell lines. The metabolites also lost the ability to: (1) promote the redox cycling of iron; (2) bind and mobilize iron from labile intracellular pools; and (3) prevent 59Fe uptake from 59Fe-labeled transferrin by MCF-7 cells. Hence, this study demonstrates that the highly active ligand, Bp4eT, is metabolized to non-toxic and pharmacologically inactive analogs, which most likely contribute to its favorable pharmacological profile. These findings are important for the further development of this drug candidate and contribute to the understanding of the structure-activity relationships of these agents. PMID:26460540

  3. Characterization of a novel brain barrier ex vivo insect-based P-glycoprotein screening model

    DEFF Research Database (Denmark)

    Andersson, O.; Badisco, L.; Hansen, A. H.;

    2014-01-01

    locust brains demonstrated differences in permeation of high and low permeability compounds. The vertebrate Pgp inhibitor verapamil did not affect the uptake of passively diffusing compounds but significantly increased the brain uptake of Pgp substrates in the ex vivo model. In addition, studies at 2°C...

  4. The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase.

    Science.gov (United States)

    Haile, Pamela A; Votta, Bartholomew J; Marquis, Robert W; Bury, Michael J; Mehlmann, John F; Singhaus, Robert; Charnley, Adam K; Lakdawala, Ami S; Convery, Máire A; Lipshutz, David B; Desai, Biva M; Swift, Barbara; Capriotti, Carol A; Berger, Scott B; Mahajan, Mukesh K; Reilly, Michael A; Rivera, Elizabeth J; Sun, Helen H; Nagilla, Rakesh; Beal, Allison M; Finger, Joshua N; Cook, Michael N; King, Bryan W; Ouellette, Michael T; Totoritis, Rachel D; Pierdomenico, Maria; Negroni, Anna; Stronati, Laura; Cucchiara, Salvatore; Ziółkowski, Bartłomiej; Vossenkämper, Anna; MacDonald, Thomas T; Gough, Peter J; Bertin, John; Casillas, Linda N

    2016-05-26

    RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments. We present, herein, the discovery and pharmacological characterization of GSK583, a next-generation RIP2 inhibitor possessing exquisite selectivity and potency. Having demonstrated the pharmacological precision of this tool compound, we report its use in elucidating the role of RIP2 kinase in a variety of in vitro, in vivo, and ex vivo experiments, further clarifying our understanding of the role of RIP2 in NOD1 and NOD2 mediated disease pathogenesis. PMID:27109867

  5. Characterizing self-reported sleep disturbance after mild traumatic brain injury.

    Science.gov (United States)

    Sullivan, Karen A; Edmed, Shannon L; Allan, Alicia C; Karlsson, Lina J E; Smith, Simon S

    2015-04-01

    Sleep disturbance after mild traumatic brain injury (mTBI) is commonly reported as debilitating and persistent. However, the nature of this disturbance is poorly understood. This study sought to characterize sleep after mTBI compared with a control group. A cross-sectional matched case control design was used. Thirty-three persons with recent mTBI (1-6 months ago) and 33 age, sex, and ethnicity matched controls completed established questionnaires of sleep quality, quantity, timing, and sleep-related daytime impairment. The mTBI participants were compared with an independent sample of close-matched controls (CMCs; n = 33) to allow partial internal replication. Compared with controls, persons with mTBI reported significantly greater sleep disturbance, more severe insomnia symptoms, a longer duration of wake after sleep onset, and greater sleep-related impairment (all medium to large effects, Cohen's d > 0.5). No differences were found in sleep quantity, timing, sleep onset latency, sleep efficiency, or daytime sleepiness. All findings except a measure of sleep timing (i.e., sleep midpoint) were replicated for CMCs. These results indicate a difference in the magnitude and nature of perceived sleep disturbance after mTBI compared with controls, where persons with mTBI report poorer sleep quality and greater sleep-related impairment. Sleep quantity and timing did not differ between the groups. These preliminary findings should guide the provision of clearer advice to patients about the aspects of their sleep that may change after mTBI and could inform treatment selection.

  6. Characterization of (/sup 3/H)paroxetine binding in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Marcusson, J.O.; Bergstroem, M.E.; Eriksson, K.; Ross, S.B.

    1988-06-01

    The binding of the 5-hydroxytryptamine (5-HT, serotonin) uptake inhibitor (3H)paroxetine to rat cortical homogenates has been characterized. The effect of tissue concentration was examined and, with 0.75 mg wet weight tissue/ml in a total volume of 1,600 microliter, the binding was optimized with an apparent dissociation constant (KD) of 0.03-0.05 nM. Competition experiments with 5-HT, citalopram, norzimeldine, and desipramine revealed a high (90%) proportion of displaceable binding that fitted a single-site binding model. Fluoxetine and imipramine revealed, in addition to a high-affinity (nanomolar) site, also a low-affinity (micromolar) site representing approximately 10% of the displaceable binding. The specificity of the (3H)paroxetine binding was emphasized by the fact that 5-HT was the only active neurotransmitter bound and that the serotonin S1 and S2 antagonist methysergide was without effect on the binding. Both 5-HT- and fluoxetine-sensitive (3H)paroxetine binding was completely abolished after protease treatment, suggesting that the binding site is of protein nature. Saturation studies with 5-HT (100 microM) sensitive (3H)paroxetine binding were also consistent with a single-site binding model, and the binding was competitively inhibited by 5-HT and imipramine. The number of binding sites (Bmax) for 5-HT-sensitive (3H)paroxetine and (3H)imipramine binding was the same, indicating that the radioligands bind to the same sites. Lesion experiments with p-chloroamphetamine resulted in a binding in frontal and parietal cortices becoming undetectable and a greater than 60% reduction in the striatum and hypothalamus, indicating a selective localization on 5-HT terminals. Together these findings suggest that (3H)paroxetine specifically and selectively labels the substrate recognition site for 5-HT uptake in rat brain.

  7. Pharmacological and clinical properties of curcumin

    Directory of Open Access Journals (Sweden)

    Huang S

    2011-06-01

    Full Text Available Christopher S Beevers¹, Shile Huang²¹Department of Pharmacology, Ross University School of Medicine, Picard-Portsmouth, Commonwealth of Dominica; ²Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USAAbstract: The polyphenol natural product curcumin has been the subject of numerous studies over the past decades, which have identified and characterized the compound's pharmacokinetic, pharmacodynamic, and clinical pharmacological properties. In in vitro and in vivo model systems, curcumin displays potent pharmacological effects, by targeting many critical cellular factors, through a diverse array of mechanisms of action. Despite this tremendous molecular versatility, however, the clinical application of curcumin remains limited due to poor pharmacokinetic characteristics in human beings. The current trend is to develop and utilize unique delivery systems, chemical derivatives, and chemical analogs to circumvent these pharmacological obstacles, in order to optimize the conditions for curcumin as a chemopreventive and chemotherapeutic agent in diseases such as cancer, diabetes, obesity, Alzheimer's disease, and inflammatory disorders. The present work seeks to review recent studies in the basic pharmacological principles and potential clinical applications of curcumin.Keywords: curcumin, pharmacological properties, signal transduction, cellular targets, cancer, inflammation

  8. Theta burst stimulation to characterize changes in brain plasticity following mild traumatic brain injury: a proof-of-principle study

    Science.gov (United States)

    Tremblay, Sara; Vernet, Marine; Bashir, Shahid; Pascual-Leone, Alvaro; Théoret, Hugo

    2016-01-01

    Purpose Recent studies investigating the acute effects of mild traumatic brain injury (mTBI) suggest the presence of unbalanced excitatory and inhibitory mechanisms within primary motor cortex (M1). Whether these abnormalities are associated with impaired synaptic plasticity remains unknown. Methods The effects of continuous theta burst stimulation (cTBS) on transcranial magnetic stimulation-induced motor evoked potentials (MEPs) were assessed on average two weeks and six weeks following mTBI in five individuals. Results The procedure was well-tolerated by all participants. Continuous TBS failed to induce a significant reduction of MEP amplitudes two weeks after the injury, but response to cTBS normalized six weeks following injury, as a majority of patients became asymptomatic. Conclusions These preliminary results suggest that cTBS can be used to assess M1 synaptic plasticity in the acute and sub-acute phases following mTBI and may provide insights into neurobiological substrates of symptoms and consequences of mTBI. PMID:25735241

  9. Radiation-Induced Alterations in Mouse Brain Development Characterized by Magnetic Resonance Imaging

    International Nuclear Information System (INIS)

    Purpose: The purpose of this study was to identify regions of altered development in the mouse brain after cranial irradiation using longitudinal magnetic resonance imaging (MRI). Methods and Materials: Female C57Bl/6 mice received a whole-brain radiation dose of 7 Gy at an infant-equivalent age of 2.5 weeks. MRI was performed before irradiation and at 3 time points following irradiation. Deformation-based morphometry was used to quantify volume and growth rate changes following irradiation. Results: Widespread developmental deficits were observed in both white and gray matter regions following irradiation. Most of the affected brain regions suffered an initial volume deficit followed by growth at a normal rate, remaining smaller in irradiated brains compared with controls at all time points examined. The one exception was the olfactory bulb, which in addition to an early volume deficit, grew at a slower rate thereafter, resulting in a progressive volume deficit relative to controls. Immunohistochemical assessment revealed demyelination in white matter and loss of neural progenitor cells in the subgranular zone of the dentate gyrus and subventricular zone. Conclusions: MRI can detect regional differences in neuroanatomy and brain growth after whole-brain irradiation in the developing mouse. Developmental deficits in neuroanatomy persist, or even progress, and may serve as useful markers of late effects in mouse models. The high-throughput evaluation of brain development enabled by these methods may allow testing of strategies to mitigate late effects after pediatric cranial irradiation.

  10. Radiation-Induced Alterations in Mouse Brain Development Characterized by Magnetic Resonance Imaging

    Energy Technology Data Exchange (ETDEWEB)

    Gazdzinski, Lisa M.; Cormier, Kyle [Mouse Imaging Centre, Hospital for Sick Children, Toronto (Canada); Lu, Fred G. [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto (Canada); Lerch, Jason P. [Mouse Imaging Centre, Hospital for Sick Children, Toronto (Canada); Department of Medical Biophysics, University of Toronto, Toronto (Canada); Wong, C. Shun [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto (Canada); Department of Medical Biophysics, University of Toronto, Toronto (Canada); Department of Radiation Oncology, University of Toronto, Toronto (Canada); Nieman, Brian J., E-mail: bjnieman@phenogenomics.ca [Mouse Imaging Centre, Hospital for Sick Children, Toronto (Canada); Department of Medical Biophysics, University of Toronto, Toronto (Canada)

    2012-12-01

    Purpose: The purpose of this study was to identify regions of altered development in the mouse brain after cranial irradiation using longitudinal magnetic resonance imaging (MRI). Methods and Materials: Female C57Bl/6 mice received a whole-brain radiation dose of 7 Gy at an infant-equivalent age of 2.5 weeks. MRI was performed before irradiation and at 3 time points following irradiation. Deformation-based morphometry was used to quantify volume and growth rate changes following irradiation. Results: Widespread developmental deficits were observed in both white and gray matter regions following irradiation. Most of the affected brain regions suffered an initial volume deficit followed by growth at a normal rate, remaining smaller in irradiated brains compared with controls at all time points examined. The one exception was the olfactory bulb, which in addition to an early volume deficit, grew at a slower rate thereafter, resulting in a progressive volume deficit relative to controls. Immunohistochemical assessment revealed demyelination in white matter and loss of neural progenitor cells in the subgranular zone of the dentate gyrus and subventricular zone. Conclusions: MRI can detect regional differences in neuroanatomy and brain growth after whole-brain irradiation in the developing mouse. Developmental deficits in neuroanatomy persist, or even progress, and may serve as useful markers of late effects in mouse models. The high-throughput evaluation of brain development enabled by these methods may allow testing of strategies to mitigate late effects after pediatric cranial irradiation.

  11. Pharmacological and nonpharmacological management of delirium in critically ill patients.

    Science.gov (United States)

    Hipp, Dustin M; Ely, E Wesley

    2012-01-01

    Delirium is a common yet under-diagnosed syndrome of acute brain dysfunction, which is characterized by inattention, fluctuating mental status, altered level of consciousness, or disorganized thinking. Although our recognition of risk factors for delirium has progressed, our understanding of the underlying pathophysiologic mechanisms remains limited. Improvements in monitoring and assessment for delirium (particularly in the intensive care setting) have resulted in validated and reliable tools such as arousal scales and bedside delirium monitoring instruments. Once delirium is recognized and the modifiable risk factors are addressed, the next step in management (if delirium persists) is often pharmacological intervention. The sedatives, analgesics, and hypnotics most often used in the intensive care unit (ICU) to achieve patient comfort are all too frequently deliriogenic, resulting in a longer duration of ICU and hospital stay, and increased costs. Therefore, identification of safe and efficacious agents to reduce the incidence, duration, and severity of ICU delirium is a hot topic in critical care. Recognizing that there are no medications approved by the Food and Drug Administration (FDA) for the prevention or treatment of delirium, we chose anti-psychotics and alpha-2 agonists as the general pharmacological focus of this article because both were subjects of relatively recent data and ongoing clinical trials. Emerging pharmacological strategies for addressing delirium must be combined with nonpharmacological approaches (such as daily spontaneous awakening trials and spontaneous breathing trials) and early mobility (combined with the increasingly popular approach called: Awakening and Breathing Coordination, Delirium Monitoring, Early Mobility, and Exercise [ABCDE] of critical care) to develop evidence-based approaches that will ensure safer and faster recovery of the sickest patients in our healthcare system. PMID:22270810

  12. Characterization of piRNAs across postnatal development in mouse brain

    KAUST Repository

    Ghosheh, Yanal

    2016-04-26

    PIWI-interacting RNAs (piRNAs) are responsible for maintaining the genome stability by silencing retrotransposons in germline tissues– where piRNAs were first discovered and thought to be restricted. Recently, novel functions were reported for piRNAs in germline and somatic cells. Using deep sequencing of small RNAs and CAGE of postnatal development of mouse brain, we identified piRNAs only in adult mouse brain. These piRNAs have similar sequence length as those of MILI-bound piRNAs. In addition, we predicted novel candidate regulators and putative targets of adult brain piRNAs.

  13. Characterization of TLX Expression in Neural Stem Cells and Progenitor Cells in Adult Brains

    OpenAIRE

    Shengxiu Li; Guoqiang Sun; Kiyohito Murai; Peng Ye; Yanhong Shi

    2012-01-01

    TLX has been shown to play an important role in regulating the self-renewal and proliferation of neural stem cells in adult brains. However, the cellular distribution of endogenous TLX protein in adult brains remains to be elucidated. In this study, we used immunostaining with a TLX-specific antibody to show that TLX is expressed in both neural stem cells and transit-amplifying neural progenitor cells in the subventricular zone (SVZ) of adult mouse brains. Then, using a double thymidine analo...

  14. Recognition and characterization of Erythropoietin binding-proteins in the brain of mice

    Science.gov (United States)

    Kowsari, Reza; Yazdian-Robati, Rezvan; Razavi, Bibi Marjan; Pourtaji, Atena; Ghorbani, Maryam; Moghadam-Omranipour, Hediye; Hosseinzadeh, Hossein; Lari, Parisa; Abnous, Khalil

    2016-01-01

    Objective(s): Erythropoietin (EPO), is a 34KDa glycoprotein hormone, which belongs to type 1 cytokine superfamily. EPO involves in erythrocyte maturation through inhibition of apoptosis in erythroid cells. Besides its main function, protective effects of EPO in heart and brain tissues have been reported. EPO has a critical role in development, growth, and homeostasis of brain. Furthermore EPO has great potential in the recovery of different brain diseases which are still under studying. In this research, EPO binding pattern to brain proteins in animal model was studied. Materials and Methods: EPO antibody was covalently crosslinked to protein A/G agarose. in order to interact between EPO and its target in brain, about 5µg EPO added to brain homogenates(500ul of 1 mg/ml) and incubate at 4ο C for 30 min. brain tissue lysate were added to agarose beads, After isolation of target proteins(EPO - protein) both one and two-dimensional gel electrophoresis were performed. Proteins were identified utilizing MALDI-TOF/TOF and MASCOT software. Results: This research showed that EPO could physically interact with eightproteins including Tubulin beta, Actin cytoplasmic 2, T-complex protein 1, TPR and ankyrin repeat-containing protein 1, Centromere-associated protein E, Kinesin-like protein KIF7, Growth arrest-specific protein 2 and Pleckstrin homology-like domain family B member 2. Conclusion: Since EPO is a promising therapeutic drug for the treatment of neurological diseases, identified proteins may help us to have a better understanding about the mechanism of protective effects of EPO in the brain. Our data needs to be validated by complementary bioassays. PMID:27803781

  15. Mitochondrial biogenesis: pharmacological approaches.

    Science.gov (United States)

    Valero, Teresa

    2014-01-01

    diseases do not have exclusively a mitochondrial origin but they might have an important mitochondrial component both on their onset and on their development. This is the case of type 2 diabetes or neurodegenerative diseases. Type 2 diabetes is characterized by a peripheral insulin resistance accompanied by an increased secretion of insulin as a compensatory system. Among the explanations about the origin of insulin resistance Mónica Zamora and Josep A. Villena (Department of Experimental and Health Sciences, Universitat Pompeu Fabra / Laboratory of Metabolism and Obesity, Universitat Autònoma de Barcelona, Spain) [5] consider the hypothesis that mitochondrial dysfunction, e.g. impaired (mitochondrial) oxidative capacity of the cell or tissue, is one of the main underlying causes of insulin resistance and type 2 diabetes. Although this hypothesis is not free of controversy due to the uncertainty on the sequence of events during type 2 diabetes onset, e.g. whether mitochondrial dysfunction is the cause or the consequence of insulin resistance, it has been widely observed that improving mitochondrial function also improves insulin sensitivity and prevents type 2 diabetes. Thus restoring oxidative capacity by increasing mitochondrial mass appears as a suitable strategy to treat insulin resistance. The effort made by researchers trying to understand the signaling pathways mediating mitochondrial biogenesis has uncovered new potential pharmacological targets and opens the perspectives for the design of suitable treatments for insulin resistance. In addition some of the current used strategies could be used to treat insulin resistance such as lifestyle interventions (caloric restriction and endurance exercise) and pharmacological interventions (thiazolidinediones and other PPAR agonists, resveratrol and other calorie restriction mimetics, AMPK activators, ERR activators). Mitochondrial biogenesis is of special importance in modern neurochemistry because of the broad spectrum

  16. Pharmacologic Therapies in Anticoagulation.

    Science.gov (United States)

    Ferreira, Joana Lima; Wipf, Joyce E

    2016-07-01

    Anticoagulants are beneficial for prevention and treatment of venous thromboembolism and stroke prevention in atrial fibrillation. The development of target-specific oral anticoagulants is changing the landscape of anticoagulation therapy and created growing interest on this subject. Understanding the pharmacology of different anticoagulants is the first step to adequately treat patients with best available therapy while avoiding serious bleeding complications. This article reviews the pharmacology of the main anticoagulant classes (vitamin K antagonists, direct oral anticoagulants, and heparins) and their clinical indications based on evidence-based data currently available in the literature. PMID:27235611

  17. Characterizing pharmacological ligands to study the long-chain fatty acid receptors GPR40/FFA1 and GPR120/FFA4.

    Science.gov (United States)

    Milligan, G; Alvarez-Curto, E; Watterson, K R; Ulven, T; Hudson, B D

    2015-07-01

    The free fatty acid receptors (FFA) 1 (previously designated GPR40) and FFA4 (previously GPR120) are two GPCRs activated by saturated and unsaturated longer-chain free fatty acids. With expression patterns and functions anticipated to directly or indirectly promote insulin secretion, provide homeostatic control of blood glucose and improve tissue insulin sensitivity, both receptors are being studied as potential therapeutic targets for the control of type 2 diabetes. Furthermore, genetic and systems biology studies in both humans and mouse models link FFA4 receptors to diabetes and obesity. Although activated by the same group of free fatty acids, FFA1 and FFA4 receptors are not closely related and, while the basis of recognition of fatty acids by FFA1 receptors is similar to that of the short-chain fatty acid receptors FFA2 and FFA3, the amino acid residues involved in endogenous ligand recognition by FFA4 receptors are more akin to those of the sphingosine 1 phosphate receptor S1P1 . Screening and subsequent medicinal chemistry programmes have developed a number of FFA1 receptor selective agonists that are effective in promoting insulin secretion in a glucose concentration-dependent manner, and in lowering blood glucose levels. However, the recent termination of Phase III clinical trials employing TAK-875/fasiglifam has caused a setback and raises important questions over the exact nature and mechanistic causes of the problems. Progress in the identification and development of highly FFA4 receptor-selective pharmacological tools has been less rapid and several issues remain to be clarified to fully validate this receptor as a therapeutic target. Despite this, the ongoing development of a range of novel ligands offers great opportunities to further unravel the contributions of these receptors. PMID:25131623

  18. SU-E-T-457: Design and Characterization of An Economical 192Ir Hemi-Brain Small Animal Irradiator

    Energy Technology Data Exchange (ETDEWEB)

    Grams, M; Wilson, Z; Sio, T; Beltran, C; Tryggestad, E; Gupta, S; Blackwell, C; McCollough, K; Sarkaria, J; Furutani, K [Mayo Clinic, Rochester, MN (United States)

    2014-06-01

    Purpose: To describe the design and dosimetric characterization of a simple and economical small animal irradiator. Methods: A high dose rate 192Ir brachytherapy source from a commercially available afterloader was used with a 1.3 centimeter thick tungsten collimator to provide sharp beam penumbra suitable for hemi-brain irradiation of mice. The unit is equipped with continuous gas anesthesia to allow robust animal immobilization. Dosimetric characterization of the device was performed with Gafchromic film. The penumbra from the small animal irradiator was compared under similar collimating conditions to the penumbra from 6 MV photons, 6 MeV electrons, and 20 MeV electrons from a linear accelerator as well as 300 kVp photons from an orthovoltage unit and Monte Carlo simulated 90 MeV protons. Results: The tungsten collimator provides a sharp penumbra suitable for hemi-brain irradiation, and dose rates on the order of 200 cGy/minute were achieved. The sharpness of the penumbra attainable with this device compares favorably to those measured experimentally for 6 MV photons, and 6 and 20 MeV electron beams from a linear accelerator. Additionally, the penumbra was comparable to those measured for a 300 kVp orthovoltage beam and a Monte Carlo simulated 90 MeV proton beam. Conclusions: The small animal irradiator described here can be built for under $1,000 and used in conjunction with any commercial brachytherapy afterloader to provide a convenient and cost-effective option for small animal irradiation experiments. The unit offers high dose rate delivery and sharp penumbra, which is ideal for hemi-brain irradiation of mice. With slight modifications to the design, irradiation of sites other than the brain could be accomplished easily. Due to its simplicity and low cost, the apparatus described is an attractive alternative for small animal irradiation experiments requiring a sharp penumbra.

  19. SU-E-T-457: Design and Characterization of An Economical 192Ir Hemi-Brain Small Animal Irradiator

    International Nuclear Information System (INIS)

    Purpose: To describe the design and dosimetric characterization of a simple and economical small animal irradiator. Methods: A high dose rate 192Ir brachytherapy source from a commercially available afterloader was used with a 1.3 centimeter thick tungsten collimator to provide sharp beam penumbra suitable for hemi-brain irradiation of mice. The unit is equipped with continuous gas anesthesia to allow robust animal immobilization. Dosimetric characterization of the device was performed with Gafchromic film. The penumbra from the small animal irradiator was compared under similar collimating conditions to the penumbra from 6 MV photons, 6 MeV electrons, and 20 MeV electrons from a linear accelerator as well as 300 kVp photons from an orthovoltage unit and Monte Carlo simulated 90 MeV protons. Results: The tungsten collimator provides a sharp penumbra suitable for hemi-brain irradiation, and dose rates on the order of 200 cGy/minute were achieved. The sharpness of the penumbra attainable with this device compares favorably to those measured experimentally for 6 MV photons, and 6 and 20 MeV electron beams from a linear accelerator. Additionally, the penumbra was comparable to those measured for a 300 kVp orthovoltage beam and a Monte Carlo simulated 90 MeV proton beam. Conclusions: The small animal irradiator described here can be built for under $1,000 and used in conjunction with any commercial brachytherapy afterloader to provide a convenient and cost-effective option for small animal irradiation experiments. The unit offers high dose rate delivery and sharp penumbra, which is ideal for hemi-brain irradiation of mice. With slight modifications to the design, irradiation of sites other than the brain could be accomplished easily. Due to its simplicity and low cost, the apparatus described is an attractive alternative for small animal irradiation experiments requiring a sharp penumbra

  20. Characterization of the melanoma brain metastatic niche in mice and humans

    International Nuclear Information System (INIS)

    Brain metastases occur in 15% of patients with melanoma and are associated with a dismal prognosis. Here, we investigate the architectural phenotype and stromal reaction of melanoma brain metastasis in mice and humans. A syngeneic, green fluorescence protein (GFP)-expressing murine B16-F1 melanoma clone was introduced via intracardiac injection, and was examined in vivo in comparison with human specimens. Immunofluorescence analyses of the brain metastases revealed that F4/80+ macrophages/microglia were most abundant at the tumor front, but rare in its core, where they were found only around blood vessels (P = 0.01). Similar pattern of infiltration was found in CD3+ T cells (P < 0.01). Infiltrating T cells were prominently CD4+ compared with CD8+ T cells (P < 0.001). Blood vessels (CD31+) were less abundant at the tumor front than in its center (12 ± 1 vs. 4 ± 0.6 vessels per high-power field [HPF], P < 0.001). In contrast, there were few vessels at the tumor front, but their diameter was significantly larger at the front (8236 μm2 vs. 4617 μm2 average cross-sectional area, P < 0.005). This is the first comparative analysis of melanoma brain metastases showing similar stromal reaction in murine models and human specimens. Our results validate the utility of this murine model of melanoma brain metastases for investigating the mechanism of the human disease

  1. Social Pharmacology: Expanding horizons

    Directory of Open Access Journals (Sweden)

    Rituparna Maiti

    2014-01-01

    Full Text Available In the current modern and global society, social changes are in constant evolution due to scientific progress (technology, culture, customs, and hygiene and produce the freedom in individuals to take decisions by themselves or with their doctors toward drug consumption. In the arena of marketed drug products which includes society, individual, administration, and pharmaceutical industry, the young discipline emerged is social pharmacology or sociopharmacology. This science arises from clinical pharmacology, and deals with different parameters, which are important in creating knowledge on marketed drugs. However, the scope of "social pharmacology" is not covered by the so-called "Phase IV" alone, but it is the science that handles the postmarketing knowledge of drugs. The social pharmacology studies the "life cycle" of any marketed pharmaceutical product in the social terrain, and evaluates the effects of the real environment under circumstances totally different in the drug development process. Therefore, there are far-reaching horizons, plural, and shared predictions among health professionals and other, for beneficial use of a drug, toward maximizing the benefits of therapy, while minimizing negative social consequences.

  2. Pharmacological management of sepsis

    Energy Technology Data Exchange (ETDEWEB)

    Fletcher, J.R.

    1985-01-01

    Systemic sepsis continues to be the most-difficult management problem in caring for the combat casualty. The complications of sepsis pervade all areas of injury to soldiers in the field, whether it is mechanical (missiles), thermal (burns), chemical, biological, or radiation injury. With the advent of tactical nuclear weapons, the problem of sepsis will be much higher in future wars than has previously been experienced through the world. The purpose of this chapter is a) to review the data suggesting pharmacological agents that may benefit the septic patient, and b) to emphasize the adjunctive therapies that should be explored in clinical trials. The pharmacological management of sepsis remains controversial. Most of the drugs utilized clinically treat the symptoms of the disease and are not necessarily directed at fundamental mechanisms that are known to be present in sepsis. A broad data base is emerging, indicating that NSAID should be used in human clinical trials. Prostaglandins are sensitive indicators of cellular injury and may be mediators for a number of vasoactive chemicals. Opiate antagonists and calcium channel blockers require more in-depth data; however, recent studies generate excitement for their potential use in the critically ill patient. Pharmacological effects of antibiotics, in concert with other drugs, suggest an entirely new approach to pharmacological treatment in sepsis. There is no doubt that new treatment modalities or adjunctive therapies must be utilized to alter the poor prognosis of severe sepsis that we have observed in the past 4 decades.

  3. Developmental paediatric anaesthetic pharmacology

    DEFF Research Database (Denmark)

    Hansen, Tom Giedsing

    2015-01-01

    Safe and effective drug therapy in neonates, infants and children require detailed knowledge about the ontogeny of drug disposition and action as well how these interact with genetics and co-morbidity of children. Recent advances in developmental pharmacology in children follow the increased...

  4. Molecular pharmacology of human NMDA receptors

    DEFF Research Database (Denmark)

    Hedegaard, Maiken; Hansen, Kasper Bø; Andersen, Karen Toftegaard;

    2012-01-01

    current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side......-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest...... that the binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human...

  5. PHARMACOLOGICAL IMPORTANCE OF CITRUS FRUITS

    OpenAIRE

    Amita Tomar *, Mridula Mall and Pragya Rai

    2013-01-01

    This paper reviews the pharmacological importance of citrus fruits. Citrus fruits are used for various pharmacological importance. According to literature the citrus fruit possess anti-cancer, antimicrobial, antioxidant, antiulcer, anti-inflammatory, and hypolipidemic and hepatoprotective properties.

  6. In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging.

    Science.gov (United States)

    Barrio, Jorge R; Small, Gary W; Wong, Koon-Pong; Huang, Sung-Cheng; Liu, Jie; Merrill, David A; Giza, Christopher C; Fitzsimmons, Robert P; Omalu, Bennet; Bailes, Julian; Kepe, Vladimir

    2015-04-21

    Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-β] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

  7. Characterization of the putative cholesterol transport protein metastatic lymph node 64 in the brain.

    Science.gov (United States)

    King, S R; Smith, A G A; Alpy, F; Tomasetto, C; Ginsberg, S D; Lamb, D J

    2006-01-01

    Intracellular management of cholesterol is a critical process in the brain. Deficits with cholesterol transport and storage are linked to neurodegenerative disorders such as Neimann-Pick disease type C and Alzheimer's disease. One protein putatively involved in cholesterol transport is metastatic lymph node 64 (MLN64). MLN64 localizes to late endosomes which are part of the cholesterol internalization pathway. However, a detailed pattern of MLN64 expression in the brain is unclear. Using immunocytochemical and immunoblot analyses, we demonstrated the presence of MLN64 in several tissue types and various regions within the brain. MLN64 immunostaining in the CNS was heterogeneous, indicating selective expression in discrete specific cell populations and regions. MLN64 immunoreactivity was detected in glia and neurons, which displayed intracellular labeling consistent with an endosomal localization. Although previous studies suggested that MLN64 may promote steroid production in the brain, MLN64 immunoreactivity did not colocalize with steroidogenic cells in the CNS. These results demonstrate that MLN64 is produced in the mouse and human CNS in a restricted pattern of expression, suggesting that MLN64 serves a cell-specific function in cholesterol transport.

  8. All or None Hypothesis: A Global-Default Mode that Characterizes the Brain and Mind

    Science.gov (United States)

    Diamond, Adele

    2009-01-01

    It is proposed that the mind and brain often work at a gross level and only with fine tuning or inhibition act in a more differentiated manner, even when one might think the domains being issued the global command should be distinct. This applies to disparate findings in cognitive science and neuroscience in both children and adults. Thus, it is…

  9. Mechanical Characterization of Brain Tissue in Compression at Dynamic Strain Rates

    CERN Document Server

    Rashid, Badar; Gilchrist, Michael; 10.1016/j.jmbbm.2012.01.022

    2013-01-01

    Traumatic brain injury (TBI) occurs when local mechanical load exceeds certain tolerance levels for brain tissue. Extensive research has been done previously for brain matter experiencing compression at quasistatic loading; however, limited data is available to model TBI under dynamic impact conditions. In this research, an experimental setup was developed to perform unconfined compression tests and stress relaxation tests at strain rates < 90/s. The brain tissue showed a stiffer response with increasing strain rates, showing that hyperelastic models are not adequate. Specifically, the compressive nominal stress at 30% strain was 8.83 +/- 1.94, 12.8 +/- 3.10 and 16.0 +/- 1.41 kPa (mean +/- SD) at strain rates of 30, 60 and 90/s, respectively. Relaxation tests were also conducted at 10%-50% strain with the average rise time of 10 ms, which can be used to derive time dependent parameters. Numerical simulations were performed using one-term Ogden model with initial shear modulus mu_0 = 6.06 +/- 1.44, 9.44 +/-...

  10. The Trees and the Forest: Characterization of complex brain networks with minimum spanning trees

    NARCIS (Netherlands)

    Stam, C.J.; Tewarie, P.; Van Dellen, E.; Van Straaten, E.C.W.; Hillebrand, A.; Van Mieghem, P.

    2014-01-01

    In recent years there has been a shift in focus from the study of local, mostly task-related activation to the exploration of the organization and functioning of large-scale structural and functional complex brain networks. Progress in the interdisciplinary field of modern network science has introd

  11. Molecular characterization of the porcine deleted in malignant brain tumors 1 gene (DMBT1)

    DEFF Research Database (Denmark)

    Haase, Bianca; Humphray, Sean J; Lyer, Stefan;

    2006-01-01

    The human gene deleted in malignant brain tumors 1 (DMBT1) is considered to play a role in tumorigenesis and pathogen defense. It encodes a protein with multiple scavenger receptor cysteine-rich (SRCR) domains, which are involved in recognition and binding of a broad spectrum of bacterial pathoge...

  12. A fatal case of Nocardia otitidiscaviarum pulmonary infection and brain abscess: taxonomic characterization by molecular techniques

    Directory of Open Access Journals (Sweden)

    Aranaz Carlos

    2009-04-01

    Full Text Available Abstract We report on a rare case of pulmonary Nocardiosis and brain abscess caused by Nocardia otitidiscaviarum in an elderly woman with chronic obstructive pulmonary disease. Taxonomic identification involved phenotypic testing, restriction fragment length polymorphism (RFLP, and complete 16S rRNA gene sequencing.

  13. Novel insect orcokinins: characterization and neuronal distribution in the brains of selected dicondylian insects.

    Science.gov (United States)

    Hofer, Sabine; Dircksen, Heinrich; Tollbäck, Petter; Homberg, Uwe

    2005-09-12

    Orcokinins are a family of myotropic neuropeptides identified in various decapod crustaceans and recently in a cockroach. Their presence in the crustacean nervous system and hemolymph suggests that they act as hormones and as locally acting neuromodulators. To provide further evidence for the existence of orcokinins in insects, we identified a novel orcokinin-related peptide in the locust Schistocerca gregaria and used an antiserum against Asn13-orcokinin for immunostaining in the brains of selected dicondylian insects, including a silverfish, three polyneopteran species (a cockroach and two locusts), and three endopterygote species (a moth, a bee, and a fly). As analyzed by MALDI-TOF spectrometry and nanoelectrospray Q-TOF, the locust orcokinin is a novel tetradecapeptide with striking sequence similarity to crustacean orcokinins. Orcokinin immunostaining was widespread and occurred in similar patterns in the brain of the silverfish and the polyneopteran species. Prominent immunostaining was detected in the optic lobe, especially in the medulla and in the accessory medulla, in local interneurons of the antennal lobe, and in extrinsic and intrinsic mushroom-body neurons. All parts of the central complex and many other areas of the brains were densely stained. In the silverfish, the cockroach, and the locusts, processes in the corpora cardiaca showed orcokinin immunoreactivity, suggesting that orcokinins also serve a hormonal role. In contrast to the case in polyneopteran species, immunostaining was completely lacking in the brains of the honeybee, fruitfly, and sphinx moth. This indicates that orcokinins either are modified considerably or may be completely absent in the brains of endopterygote insects. PMID:16041719

  14. Concise Asymmetric Synthesis and Pharmacological Characterization of All Stereoisomers of Glutamate Transporter Inhibitor TFB-TBOA and Synthesis of EAAT Photoaffinity Probes.

    Science.gov (United States)

    Leuenberger, Michele; Ritler, Andreas; Simonin, Alexandre; Hediger, Matthias A; Lochner, Martin

    2016-05-18

    Glutamate is the major excitatory neurotransmitter in the mammalian brain. Its rapid clearance after the release into the synaptic cleft is vital in order to avoid toxic effects and is ensured by several transmembrane transport proteins, so-called excitatory amino acid transporters (EAATs). Impairment of glutamate removal has been linked to several neurodegenerative diseases and EAATs have therefore received increased attention as therapeutic targets. O-Benzylated l-threo-β-hydroxyaspartate derivatives have been developed previously as highly potent inhibitors of EAATs with TFB-TBOA ((2S,3S)-2-amino-3-((3-(4-(trifluoromethyl)benzamido)benzyl)oxy)succinic acid) standing out as low-nanomolar inhibitor. We report the stereoselective synthesis of all four stereoisomers of TFB-TBOA in less than a fifth of synthetic steps than the published route. For the first time, the inhibitory activity and isoform selectivity of these TFB-TBOA enantio- and diastereomers were assessed on human glutamate transporters EAAT1-3. Furthermore, we synthesized potent photoaffinity probes based on TFB-TBOA using our novel synthetic strategy. PMID:26918289

  15. Pharmacological characterization and modeling of the binding sites of novel 1,3-bis(pyridinylethynyl)benzenes as metabotropic glutamate receptor 5-selective negative allosteric modulators

    DEFF Research Database (Denmark)

    Mølck, Christina; Harpsøe, Kasper; Gloriam, David E;

    2012-01-01

    Metabotropic glutamate receptor subtype 5 (mGluR5) is a potential drug target in neurological and psychiatric disorders, and subtype-selective allosteric modulators have attracted much attention as potential drug candidates. In this study, the binding sites of three novel 2-methyl-6-(phenylethynyl......)pyridine (MPEP)-derived negative allosteric modulators, 2-, 3-, and 4-BisPEB, have been characterized. 2-, 3-, and 4-BisPEB are 1,3-bis(pyridinylethynyl)-benzenes and differ only by the position of the nitrogen atoms in the pyridine rings. Despite their high structural similarity, 2-BisPEB [1,3-bis(pyridin-2...

  16. Mechanical characterization of brain tissue in compression at dynamic strain rates.

    Science.gov (United States)

    Rashid, Badar; Destrade, Michel; Gilchrist, Michael D

    2012-06-01

    Traumatic brain injury (TBI) occurs when local mechanical load exceeds certain tolerance levels for brain tissue. Extensive research has been done previously for brain matter experiencing compression at quasistatic loading; however, limited data is available to model TBI under dynamic impact conditions. In this research, an experimental setup was developed to perform unconfined compression tests and stress relaxation tests at strain rates ≤90/s. The brain tissue showed a stiffer response with increasing strain rates, showing that hyperelastic models are not adequate. Specifically, the compressive nominal stress at 30% strain was 8.83 ± 1.94, 12.8 ± 3.10 and 16.0 ± 1.41 kPa (mean ± SD) at strain rates of 30, 60 and 90/s, respectively. Relaxation tests were also conducted at 10%-50% strain with the average rise time of 10 ms, which can be used to derive time dependent parameters. Numerical simulations were performed using one-term Ogden model with initial shear modulus μ(o)=6.06±1.44, 9.44 ± 2.427 and 12.64 ± 1.227 kPa (mean ± SD) at strain rates of 30, 60 and 90/s, respectively. A separate set of bonded and lubricated tests were also performed under the same test conditions to estimate the friction coefficient μ, by adopting combined experimental-computational approach. The values of μ were 0.1 ± 0.03 and 0.15 ± 0.07 (mean ± SD) at 30 and 90/s strain rates, respectively, indicating that pure slip conditions cannot be achieved in unconfined compression tests even under fully lubricated test conditions. The material parameters obtained in this study will help to develop biofidelic human brain finite element models, which can subsequently be used to predict brain injuries under impact conditions. PMID:22520416

  17. 7.0-T magnetic resonance imaging characterization of acute blood-brain-barrier disruption achieved with intracranial irreversible electroporation.

    Directory of Open Access Journals (Sweden)

    Paulo A Garcia

    Full Text Available The blood-brain-barrier (BBB presents a significant obstacle to the delivery of systemically administered chemotherapeutics for the treatment of brain cancer. Irreversible electroporation (IRE is an emerging technology that uses pulsed electric fields for the non-thermal ablation of tumors. We hypothesized that there is a minimal electric field at which BBB disruption occurs surrounding an IRE-induced zone of ablation and that this transient response can be measured using gadolinium (Gd uptake as a surrogate marker for BBB disruption. The study was performed in a Good Laboratory Practices (GLP compliant facility and had Institutional Animal Care and Use Committee (IACUC approval. IRE ablations were performed in vivo in normal rat brain (n = 21 with 1-mm electrodes (0.45 mm diameter separated by an edge-to-edge distance of 4 mm. We used an ECM830 pulse generator to deliver ninety 50-μs pulse treatments (0, 200, 400, 600, 800, and 1000 V/cm at 1 Hz. The effects of applied electric fields and timing of Gd administration (-5, +5, +15, and +30 min was assessed by systematically characterizing IRE-induced regions of cell death and BBB disruption with 7.0-T magnetic resonance imaging (MRI and histopathologic evaluations. Statistical analysis on the effect of applied electric field and Gd timing was conducted via Fit of Least Squares with α = 0.05 and linear regression analysis. The focal nature of IRE treatment was confirmed with 3D MRI reconstructions with linear correlations between volume of ablation and electric field. Our results also demonstrated that IRE is an ablation technique that kills brain tissue in a focal manner depicted by MRI (n = 16 and transiently disrupts the BBB adjacent to the ablated area in a voltage-dependent manner as seen with Evan's Blue (n = 5 and Gd administration.

  18. Pharmacology and drug distribution

    Energy Technology Data Exchange (ETDEWEB)

    Morgan, L.R.; Weatherall, T.J.

    1979-08-01

    An overview of the pharmacology of drugs in the treatment of cancer is presented. The discussion begins with the simplest relationship of drugs and particles to one another then proceeds to demonstrate the interrelationship in a biologic system to produce a chemobiodynamic response. The basic principles of pharmacokinetics are reviewed and their correlation with investigational and standard drug therapies is discussed. Voids in the consideration of interactions between chemotherapy and radiotherapy are discussed.

  19. Synthesis characterization and biological evaluation of a novel mixed ligand 99mTc complex as potential brain imaging agent

    International Nuclear Information System (INIS)

    One approach in the design of neutral oxotechnetium complexes is based on the simultaneous substitution of a tridentate dianionic ligand and a monodentate monoanionic coligand on a [Tc(V)O]+3 precursor. Following this ''mixed ligand'' concept, a novel 99mTc complex with N,N-bis(2-mercaptoethyl)-N'N'-diethylethylenediamine as ligand and 1-octanethiol as coligand is prepared and evaluated as potential brain radiopharmaceutical. Preparation of the complex at tracer level was accomplished by using 99mTc-glucoheptonate as precursor. The substitution was optimized and a coligand/ligand ratio of 5 was selected. Under this conditions the labeling yield was over 80% and a major product (with radiochemical purity > 80%) was isolated by HPLC methods and used for biological evaluation. Chemical characterization at carrier level was developed using the corresponding rhenium complex as structural model. The Re complex was also prepared by substitution method and isolated as a crystalline product. The crystals were characterized by UV-vis and IR spectra and elemental analysis. Results were consistent with the expected ReOLC structure. X ray crystallographic study demonstrated that the complex adopts a distorted trigonal bipyramidal geometry. The basal plane is defined by the SS atoms of the ligand and the oxo group, while the N of the ligand and the S of the colligand occupy the two apical positions. All sulphur atoms underwent ionization leading to the formation of a neutral compound. 99Tc complex was also prepared. Although it was not isolated due to the small amount of reagents employed, the HPLC profile was identical to the one observed for the rhenium complex suggesting the same chemical structure. Biodistribution in mice demonstrated early brain uptake, fast blood clearance, excretion through hepatobiliary system and a brain/blood ratio that increased significantly with time. (author)

  20. Overview of safety pharmacology.

    Science.gov (United States)

    Goineau, Sonia; Lemaire, Martine; Froget, Guillaume

    2013-01-01

    Safety pharmacology entails the assessment of the potential risks of novel pharmaceuticals for human use. As detailed in the ICH S7A guidelines, safety pharmacology for drug discovery involves a core battery of studies on three vital systems: central nervous (CNS), cardiovascular (CV), and respiratory. Primary CNS studies are aimed at defining compound effects on general behavior, locomotion, neuromuscular coordination, seizure threshold, and vigilance. The primary CV test battery includes an evaluation of proarrhythmic risk using in vitro tests (hERG channel and Purkinje fiber assays) and in vivo measurements in conscious animals via telemetry. Comprehensive cardiac risk assessment also includes full hemodynamic evaluation in a large, anesthetized animal. Basic respiratory function can be examined in conscious animals using whole-body plethysmography. This allows for an assessment of whether the sensitivity to respiratory-depressant effects can be enhanced by exposure to increased CO2 . Other safety pharmacology topics detailed in this unit are the timing of such studies, ethical and animal welfare issues, and statistical evaluation. PMID:24510755

  1. Advanced shotgun lipidomics for characterization of altered lipid patterns in neurodegenerative diseases and brain injury

    Science.gov (United States)

    Wang, Miao; Han, Xianlin

    2016-01-01

    Summary Multi-dimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) is a powerful technology platform among current lipidomics practices due to its high efficiency, sensitivity, and reproducibility, as well as its broad coverage. This platform has been broadly used to determine the altered lipid profiles induced by diseases, injury, genetic manipulations, drug treatments, and aging, among others. Herein, we summarized the principles underlying this platform and presented a protocol for analysis of many of the lipid classes and subclasses covered by MDMS-SL directly from lipid extracts of brain samples. We believe that this protocol could aid the researchers in the field to determine the altered lipid patterns in neurodegenerative diseases and brain injury. PMID:26235081

  2. [{sup 11}C]d-threo-Methylphenidate, a new radiotracer for the dopamine transporter. Characterization in baboon and human brain

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Y.S.; Volkow, N.D.; Fowler, J.S. [Brookhaven National Laboratory, Upton, NY (United States)] [and others

    1995-05-01

    dl-threo Methylphenidate (MP, Ritalin) is a psychostimulant drug which binds to the dopamine transporter (DAT). We evaluated [{sup 11}C]d-threo-methylphenidate ([{sup 11}C]d-MP), the more active enantiomer, as a radiotracer for the DAT in baboons and human brain. Stereoselectivity, saturability and pharmacological specificity and reproducibility were examined. Stereoselectivity was examined in baboons by comparing [{sup 11C}]d-MP,[{sup 11}C]l-MP and [{sup 11}C]dl-MP. Unlabeled MP was used to assess the reversibility and saturability of the binding. GBR 12909,{beta}-(4-iodophenyl)tropane-2-carboxylic acid methyl ester ({beta}-CIT), tomoxetine and citalopram were used to assess the specificity of the binding. The ratios between the radioactivity in the striatum to that in cerebellum (ST/CB) were 3.3,2.2 and 1.1 for [{sup 11}C]d-MP,[{sup 11}C]dl-MP and [{sup 11}C]l-MP respectively. Most of the striatal binding of [{sup 11}C]d-threo-MP was displaced by injection of nonradioactive MP demonstrating reversibility. Pretreatment with MP (0.5 mg/kg), GBR12909 (1.5 mg/kg) or {beta}-CIT (0.3 mg/kg) reduced ST/CB by about 60% and the ratios of distribution volumes at the steady-state for the triatum to cerebellum (DV{sub st/}DV{sub cb}) by about 50%. Pretreatment with tomoxetine (3.0 mg/kg) or citalopram (2.0 mg/kg), inhibitors of the norepinephrine and serotonin transporter, had no effect. Studies of [{sup 11}C]d-MP in the human brain showed highest uptake in basal ganglia with a half clearance time of about 60 minutes. Repeated studies in 6 normal human subjects showed differences in DV{sub st/}DV{sub cb} between -7% and 8%. MP pretreatment decreased BG but no cortical or cerebellar binding and reduced Bmax/Kd by 91%.

  3. Characterization of multiciliated ependymal cells that emerge in the neurogenic niche of the aged zebrafish brain.

    Science.gov (United States)

    Ogino, Takashi; Sawada, Masato; Takase, Hiroshi; Nakai, Chiemi; Herranz-Pérez, Vicente; Cebrián-Silla, Arantxa; Kaneko, Naoko; García-Verdugo, José Manuel; Sawamoto, Kazunobu

    2016-10-15

    In mammals, ventricular walls of the developing brain maintain a neurogenic niche, in which radial glial cells act as neural stem cells (NSCs) and generate new neurons in the embryo. In the adult brain, the neurogenic niche is maintained in the ventricular-subventricular zone (V-SVZ) of the lateral wall of lateral ventricles and the hippocampal dentate gyrus. In the neonatal V-SVZ, radial glial cells transform into astrocytic postnatal NSCs and multiciliated ependymal cells. On the other hand, in zebrafish, radial glial cells continue to cover the surface of the adult telencephalic ventricle and maintain a higher neurogenic potential in the adult brain. However, the cell composition of the neurogenic niche of the aged zebrafish brain has not been investigated. Here we show that multiciliated ependymal cells emerge in the neurogenic niche of the aged zebrafish telencephalon. These multiciliated cells appear predominantly in the dorsal part of the ventral telencephalic ventricular zone, which also contains clusters of migrating new neurons. Scanning electron microscopy and live imaging analyses indicated that these multiple cilia beat coordinately and generate constant fluid flow within the ventral telencephalic ventricle. Analysis of the cell composition by transmission electron microscopy revealed that the neurogenic niche in the aged zebrafish contains different types of cells, with ultrastructures similar to those of ependymal cells, transit-amplifying cells, and migrating new neurons in postnatal mice. These data suggest that the transformation capacity of radial glial cells is conserved but that its timing is different between fish and mice. J. Comp. Neurol. 524:2982-2992, 2016. © 2016 Wiley Periodicals, Inc. PMID:26991819

  4. 3D perfused brain phantom for interstitial ultrasound thermal therapy and imaging: design, construction and characterization

    International Nuclear Information System (INIS)

    Thermal therapy has emerged as an independent modality of treating some tumors. In many clinics the hyperthermia, one of the thermal therapy modalities, has been used adjuvant to radio- or chemotherapy to substantially improve the clinical treatment outcomes. In this work, a methodology for building a realistic brain phantom for interstitial ultrasound low dose-rate thermal therapy of the brain is proposed. A 3D brain phantom made of the tissue mimicking material (TMM) had the acoustic and thermal properties in the 20–32 °C range, which is similar to that of a brain at 37 °C. The phantom had 10–11% by mass of bovine gelatin powder dissolved in ethylene glycol. The TMM sonicated at 1 MHz, 1.6 MHz and 2.5 MHz yielded the amplitude attenuation coefficients of 62  ±  1 dB m−1, 115  ±  4 dB m−1 and 175  ±  9 dB m−1, respectively. The density and acoustic speed determination at room temperature (∼24 °C) gave 1040  ±  40 kg m−3 and 1545  ±  44 m s−1, respectively. The average thermal conductivity was 0.532 W m−1 K−1. The T1 and T2 values of the TMM were 207  ±  4 and 36.2  ±  0.4 ms, respectively. We envisage the use of our phantom for treatment planning and for quality assurance in MRI based temperature determination. Our phantom preparation methodology may be readily extended to other thermal therapy technologies. (paper)

  5. Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases.

    Science.gov (United States)

    Thorsen, Frits; Fite, Brett; Mahakian, Lisa M; Seo, Jai W; Qin, Shengping; Harrison, Victoria; Johnson, Sarah; Ingham, Elizabeth; Caskey, Charles; Sundstrøm, Terje; Meade, Thomas J; Harter, Patrick N; Skaftnesmo, Kai Ove; Ferrara, Katherine W

    2013-12-28

    Our goal was to develop strategies to quantify the accumulation of model therapeutics in small brain metastases using multimodal imaging, in order to enhance the potential for successful treatment. Human melanoma cells were injected into the left cardiac ventricle of immunodeficient mice. Bioluminescent, MR and PET imaging were applied to evaluate the limits of detection and potential for contrast agent extravasation in small brain metastases. A pharmacokinetic model was applied to estimate vascular permeability. Bioluminescent imaging after injecting d-luciferin (molecular weight (MW) 320 D) suggested that tumor cell extravasation had already occurred at week 1, which was confirmed by histology. 7T T1w MRI at week 4 was able to detect non-leaky 100 μm sized lesions and leaky tumors with diameters down to 200 μm after contrast injection at week 5. PET imaging showed that (18)F-FLT (MW 244 Da) accumulated in the brain at week 4. Gadolinium-based MRI tracers (MW 559 Da and 2.066 kDa) extravasated after 5 weeks (tumor diameter 600 μm), and the lower MW agent cleared more rapidly from the tumor (mean apparent permeabilities 2.27 × 10(-5)cm/s versus 1.12 × 10(-5)cm/s). PET imaging further demonstrated tumor permeability to (64)Cu-BSA (MW 65.55 kDa) at week 6 (tumor diameter 700 μm). In conclusion, high field T1w MRI without contrast may improve the detection limit of small brain metastases, allowing for earlier diagnosis of patients, although the smallest lesions detected with T1w MRI were permeable only to d-luciferin and the amphipathic small molecule (18)F-FLT. Different-sized MR and PET contrast agents demonstrated the gradual increase in leakiness of the blood tumor barrier during metastatic progression, which could guide clinicians in choosing tailored treatment strategies.

  6. Evaluation and characterization of generalized anxiety and depression in patients with primary brain tumors

    OpenAIRE

    Arnold, Staci D.; Forman, Leslie M.; Brigidi, Bart D.; Carter, Karen E.; Schweitzer, Holly A.; Quinn, Heather E.; Guill, A. Bebe; Herndon, James E.; Raynor, Renee H.

    2008-01-01

    To determine clinical and sociodemographic factors that are associated with major neuropsychiatric illnesses among brain tumor patients, we administered a modified version of the Brief Patient Health Questionnaire and a demographic data form to 363 adult neuro-oncology patients. Responses were analyzed to assess for associations between demographic variables, clinical variables, and symptoms consistent with diagnoses of generalized anxiety disorder and/or depression. Multivariate logistic reg...

  7. Imaging of dopamine release induced by pharmacologic and nonpharmacologic stimulations

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Sang Soo; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    Technological advances in molecular imaging made it possible to image synaptic neurotransmitter concentration in living human brain. The dopaminergic system has been most intensively studied because of its importance in neurological as well as psychiatric disorders. This paper provides a brief overview of recent progress in imaging studies of dopamine release induced by pharmacologic and nonpharmacologic stimulations.

  8. Attitudes toward pharmacological cognitive enhancement-a review

    NARCIS (Netherlands)

    Schelle, K.J.; Faulmüller, N.S.; Caviola, L.; Hewstone, M.

    2014-01-01

    A primary means for the augmentation of cognitive brain functions is "pharmacological cognitive enhancement" (PCE). The term usually refers to the off-label use of medical substances to improve mental performance in healthy individuals. With the final aim to advance the normative debate taking place

  9. Synthesis and characterization of EADAM: a selective radioligand for mapping the brain serotonin transporters by positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Jarkas, Nachwa [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); McConathy, Jonathan [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Department of Psychiatry and Behavior Sciences, Emory University, Atlanta, GA 30322 (United States); Votaw, John R. [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Voll, Ronald J. [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Malveaux, Eugene [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Camp, Vernon M. [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Williams, Larry [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Goodman, Robin R. [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Kilts, Clinton D. [Department of Psychiatry and Behavior Sciences, Emory University, Atlanta, GA 30322 (United States); Goodman, Mark M. [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States) and Department of Psychiatry and Behavior Sciences, Emory University, Atlanta, GA 30322 (United States)]. E-mail: mgoodma@emory.edu

    2005-01-01

    [{sup 11}C]N,N-Dimethyl-2-(2'-amino-4'-ethylphenylthio)benzylamine ([{sup 11}C]EADAM) was synthesized in the development of a serotonin transporter (SERT) imaging ligand for positron emission tomography (PET). The methods of ligand synthesis, results of in vitro characterization, {sup 11}C labeling and in vivo micro-PET imaging studies of [{sup 11}C]EADAM in cynomolgus monkey brain are described. {sup 11}C was introduced into N,N-dimethyl-2-(2'-amino-4'-ethylphenylthio)benzylamine () by alkylation of N-methyl-2-(2'-amino-4'-ethylphenylthio)benzylamine () in 32% radiochemical yield (end of bombardment [EOB], decay-corrected from [{sup 11}C]methyl iodide). Competition binding assays in cells stably expressing the transfected human dopamine transporter (DAT), SERT and norepinephrine transporter (NET) labeled with [{sup 3}H]WIN 35428 or [{sup 125}I]RTI-55, [{sup 3}H]citalopram and [{sup 3}H]nisoxetine, respectively, indicated the following order of SERT affinity: ADAM>EADAM>>fluvoxamine. The affinity of EADAM for DAT and NET was 500- and >1000-fold lower, respectively, than for SERT. Micro-PET brain imaging studies in a cynomolgus monkey demonstrated high [{sup 11}C]EADAM uptake in the striatum, thalamus and brainstem. [{sup 11}C]EADAM uptake in these brain regions peaked in less than 60 min following administration of [{sup 11}C]EADAM. The tissue-to-cerebellum ratios of the striatum, thalamus and brainstem were 1.67, 1.71 and 1.63, respectively, at 120 min postinjection of [{sup 11}C]EADAM. Analysis of monkey arterial plasma samples using high-pressure liquid chromatography determined there was no detectable formation of lipophilic radiolabeled metabolites capable of entering the brain. In a displacement experiment with citalopram in a cynomolgus monkey, radioactivity in the striatum, thalamus and brainstem was displaced 20-60 min after administration of citalopram. In a blocking experiment with citalopram in a cynomolgus monkey

  10. Functional and pharmacological characterization of two different ASIC1a/2a heteromers reveals their sensitivity to the spider toxin PcTx1.

    Science.gov (United States)

    Joeres, Niko; Augustinowski, Katrin; Neuhof, Andreas; Assmann, Marc; Gründer, Stefan

    2016-01-01

    Acid Sensing Ion Channels (ASICs) detect extracellular proton signals and are involved in synaptic transmission and pain sensation. ASIC subunits assemble into homo- and heteromeric channels composed of three subunits. Single molecule imaging revealed that heteromers composed of ASIC1a and ASIC2a, which are widely expressed in the central nervous system, have a flexible 2:1/1:2 stoichiometry. It was hitherto not possible, however, to functionally differentiate these two heteromers. To have a homogenous population of ASIC1a/2a heteromers with either 2:1 or 1:2 stoichiometry, we covalently linked subunits in the desired configuration and characterized their functional properties in Xenopus oocytes. We show that the two heteromers have slightly different proton affinity, with an additional ASIC1a subunit increasing apparent affinity. Moreover, we found that zinc, which potentiates ASIC2a-containing ASICs but not homomeric ASIC1a, potentiates both heteromers. Finally, we show that PcTx1, which binds at subunit-subunit interfaces of homomeric ASIC1a, inhibits both heteromers suggesting that ASIC2a can also contribute to a PcTx1 binding site. Using this functional fingerprint, we show that rat cortical neurons predominantly express the ASIC1a/2a heteromer with a 2:1 stoichiometry. Collectively, our results reveal the contribution of individual subunits to the functional properties of ASIC1a/2a heteromers. PMID:27277303

  11. Characterization of 5-HT1D receptor binding sites in post-mortem human brain cortex.

    OpenAIRE

    Martial, J; de Montigny, C; Cecyre, D; Quirion, R

    1991-01-01

    The present study provides further evidence for the presence of serotonin1D (5-HT1D) receptors in post-mortem human brain. Receptor binding parameters in temporal cortex homogenates were assessed using [3H]5-HT in the presence of 100 nM 8-OH-DPAT, 1 microM propranolol and 1 microM mesulergine to prevent labelling of the 5-HT1A, 5-HT1B and 5-HT1C sites, respectively. Under these conditions, [3H]5-HT apparently bound to a class of high affinity (Kd = 5.0 +/- 1.0 nM) low capacity (Bmax = 96 +/- ...

  12. Isolation and Pharmacological Characterization of α-Elapitoxin-Ot1a, a Short-Chain Postsynaptic Neurotoxin from the Venom of the Western Desert Taipan, Oxyuranus temporalis

    Science.gov (United States)

    Barber, Carmel M.; Ahmad Rusmili, Muhamad Rusdi; Hodgson, Wayne C.

    2016-01-01

    Taipans (Oxyuranus spp.) are elapids with highly potent venoms containing presynaptic (β) and postsynaptic (α) neurotoxins. O. temporalis (Western Desert taipan), a newly discovered member of this genus, has been shown to possess venom which displays marked in vitro neurotoxicity. No components have been isolated from this venom. We describe the characterization of α-elapitoxin-Ot1a (α-EPTX-Ot1a; 6712 Da), a short-chain postsynaptic neurotoxin, which accounts for approximately 30% of O. temporalis venom. α-Elapitoxin-Ot1a (0.1–1 µM) produced concentration-dependent inhibition of indirect-twitches, and abolished contractile responses to exogenous acetylcholine and carbachol, in the chick biventer cervicis nerve-muscle preparation. The inhibition of indirect twitches by α-elapitoxin-Ot1a (1 µM) was not reversed by washing the tissue. Prior addition of taipan antivenom (10 U/mL) delayed the neurotoxic effects of α-elapitoxin-Ot1a (1 µM) and markedly attenuated the neurotoxic effects of α-elapitoxin-Ot1a (0.1 µM). α-Elapitoxin-Ot1a displayed pseudo-irreversible antagonism of concentration-response curves to carbachol with a pA2 value of 8.02 ± 0.05. De novo sequencing revealed the main sequence of the short-chain postsynaptic neurotoxin (i.e., α-elapitoxin-Ot1a) as well as three other isoforms found in O. temporalis venom. α-Elapitoxin-Ot1a shows high sequence similarity (i.e., >87%) with other taipan short-chain postsynaptic neurotoxins. PMID:26938558

  13. Isolation and Pharmacological Characterization of α-Elapitoxin-Ot1a, a Short-Chain Postsynaptic Neurotoxin from the Venom of the Western Desert Taipan, Oxyuranus temporalis

    Directory of Open Access Journals (Sweden)

    Carmel M. Barber

    2016-02-01

    Full Text Available Taipans (Oxyuranus spp. are elapids with highly potent venoms containing presynaptic (β and postsynaptic (α neurotoxins. O. temporalis (Western Desert taipan, a newly discovered member of this genus, has been shown to possess venom which displays marked in vitro neurotoxicity. No components have been isolated from this venom. We describe the characterization of α-elapitoxin-Ot1a (α-EPTX-Ot1a; 6712 Da, a short-chain postsynaptic neurotoxin, which accounts for approximately 30% of O. temporalis venom. α-Elapitoxin-Ot1a (0.1–1 µM produced concentration-dependent inhibition of indirect-twitches, and abolished contractile responses to exogenous acetylcholine and carbachol, in the chick biventer cervicis nerve-muscle preparation. The inhibition of indirect twitches by α-elapitoxin-Ot1a (1 µM was not reversed by washing the tissue. Prior addition of taipan antivenom (10 U/mL delayed the neurotoxic effects of α-elapitoxin-Ot1a (1 µM and markedly attenuated the neurotoxic effects of α-elapitoxin-Ot1a (0.1 µM. α-Elapitoxin-Ot1a displayed pseudo-irreversible antagonism of concentration-response curves to carbachol with a pA2 value of 8.02 ± 0.05. De novo sequencing revealed the main sequence of the short-chain postsynaptic neurotoxin (i.e., α-elapitoxin-Ot1a as well as three other isoforms found in O. temporalis venom. α-Elapitoxin-Ot1a shows high sequence similarity (i.e., >87% with other taipan short-chain postsynaptic neurotoxins.

  14. Pharmacological treatment of schizophrenia.

    Science.gov (United States)

    Leucht, S; Heres, S; Kissling, W; Davis, J M

    2013-05-01

    We present the pharmacological treatment of schizophrenia based on a simple algorithm that starts with the most important decisions starting from the choice of an antipsychotic drug for an acutely ill patient and ends with maintenance treatment. It represents experts opinions, a formal guideline development process was not followed. Concerning acute treatment we present recommendations for the choice of drug in acutely patients, the treatment of agitated patients, persistent depression, negative symptoms and treatment resistance. Concerning maintenance treatment with antipsychotics we discuss indication, choice of drug, continuous versus intermittent treatment, duration of relapse prevention and dose.

  15. Characterization of monoaminergic systems in brain regions of prematurely ageing mice.

    Science.gov (United States)

    De la Fuente, Monica; Hernanz, Angel; Medina, Sonia; Guayerbas, Noelia; Fernández, Beatriz; Viveros, Maria Paz

    2003-07-01

    We have previously shown that differences in life span among members of Swiss mouse populations appear to be related to their exploration of a T-maze, with a slow exploration ("slow mice") being linked to increased levels of emotionality/anxiety, an impaired immune function and a shorter life span. Thus, we proposed the slow mice as prematurely ageing mice (PAM). We have now compared the monoaminergic systems of the PAM and of the non-prematurely ageing mice (NPAM), in discrete brain regions. PAM had decreased noradrenaline (NA) levels in all the brain regions analysed, whereas the 3-methoxy-4-hydroxyphenyl glycol (MHPG)/NA ratios were not significantly modified. PAM also showed decreased serotonine (5-HT) levels in hypothalamus, striatum and midbrain, as well as increased 5-hydroxyindol-3-acetic acid (5-HIAA)/5-HT ratios in hypothalamus and hippocampus. The dopamine (DA) content was lower in PAM in most regions, whereas the 3,4-dihydroxyphenylacetic acid (DOPAC)/DA and homovanillic acid (HVA)/DA ratios were either increased or unchanged depending on the region analysed. In most cases, the differences between PAM and NPAM involved both sexes. One exception was the hypothalamus where the differences only affected the male mice. The neurochemical alterations found in PAM resemble some changes reported for aged animals and are related with their behavioural features.

  16. /sup 31/P NMR characterization of graded traumatic brain injury in rats

    Energy Technology Data Exchange (ETDEWEB)

    Vink, R.; McIntosh, T.K.; Yamakami, I.; Faden, A.I.

    1988-01-01

    Irreversible tissue injury following central nervous system trauma is believed to result from both mechanical disruption at the time of primary insult, and more delayed autodestructive processes. These delayed events are associated with various biochemical changes, including alterations in phosphate energy metabolism and intracellular pH. Using /sup 31/P NMR, we have monitored the changes in phosphorus energy metabolism and intracellular pH in a single hemisphere of the rat brain over an 8-h period following graded, traumatic, fluid percussion-induced brain injury. Following trauma the ratio of phosphocreatine to inorganic phosphate (PCr/Pi) declined in each injury group. This decline was transitory with low injury (1.0 +/- 0.5 atm), biphasic with moderate (2.1 +/- 0.4 atm) and high (3.9 +/- 0.9 atm) injury, and sustained following severe injury (5.9 +/- 0.7 atm). The initial PCr/Pi decline in the moderate and high injury groups was associated with intracellular acidosis; however, the second decline occurred in the absence of any pH changes. Alterations in ATP occurred only in severely injured animals and such changes were associated with marked acidosis and 100% mortality rate. After 4h, the posttraumatic PCr/Pi ratio correlated linearly with the severity of injury. We suggest that a reduced posttraumatic PCr/Pi ratio may be indicative of altered mitochondrial energy production and may predict a reduced capacity of the cell to recover from traumatic injury.

  17. Numerical Characterization of Intraoperative and Chronic Electrodes in Deep Brain Stimulation

    Directory of Open Access Journals (Sweden)

    Alessandra ePaffi

    2015-02-01

    Full Text Available Intraoperative electrode is used in the Deep Brain stimulation (DBS technique to pinpoint the brain target and to choose the best parameters for the stimulating signal. However, when the intraoperative electrode is replaced with the chronic one, the observed effects do not always coincide with predictions.To investigate the causes of such discrepancies, in this work, a 3D model of the basal ganglia has been considered and realistic models of both intraoperative and chronic electrodes have been developed and numerically solved.Results of simulations on the electric potential and the activating function along neuronal fibers show that the different geometries and sizes of the two electrodes do not change shapes and polarities of these functions, but only the amplitudes. A similar effect is caused by the presence of different tissue layers (edema or glial tissue in the peri-electrode space. On the contrary, a not accurate positioning of the chronic electrode with respect to the intraoperative one (electric centers not coincident may induce a complete different electric stimulation on some groups of fibers.

  18. Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization.

    Science.gov (United States)

    Shah, Brijesh M; Misra, Manju; Shishoo, Chamanlal J; Padh, Harish

    2015-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to irreversible loss of neurons, cognition and formation of abnormal protein aggregates. Rivastigmine, a reversible cholinesterase inhibitor used for the treatment of AD, undergoes extensive first-pass metabolism, thus limiting its absolute bioavailability to only 36% after 3-mg dose. Due to extreme aqueous solubility, rivastigmine shows poor penetration and lesser concentration in the brain thus requiring frequent oral dosing. This investigation was aimed to formulate microemulsion (ME) and mucoadhesive microemulsions (MMEs) of rivastigmine for nose to brain delivery and to compare percentage drug diffused for both systems using in-vitro and ex-vivo study. Rivastigmine-loaded ME and MMEs were prepared by titration method and characterized for drug content, globule size distribution, zeta potential, pH, viscosity and nasal ciliotoxicity study. Rivastigmine-loaded ME system containing 8% w/w Capmul MCM EP, 44% w/w Labrasol:Transcutol-P (1:1) and 48% w/w distilled water was formulated, whereas 0.3% w/w chitosan (CH) and cetyl trimethyl ammonium bromide (as mucoadhesive agents) were used to formulate MMEs, respectively. ME and MMEs formulations were transparent with drug content, globule size and zeta potential in the range of 98.59% to 99.43%, 53.8 nm to 55.4 nm and -2.73 mV to 6.52 mV, respectively. MME containing 0.3% w/w CH followed Higuchi model (r(2) = 0.9773) and showed highest diffusion coefficient. It was free from nasal ciliotoxicity and stable for three months. However, the potential of developed CH-based MME for nose to brain delivery of rivastigmine can only be established after in-vivo and biodistribution study.

  19. Imaging tools to study pharmacology: functional MRI on small rodents

    Directory of Open Access Journals (Sweden)

    Elisabeth eJonckers

    2015-10-01

    Full Text Available Functional Magnetic Resonance Imaging (fMRI is an excellent tool to study the effect of pharmacological modulations on brain function in a non-invasive and longitudinal manner. We introduce several blood oxygenation level dependent (BOLD fMRI techniques, including resting state (rsfMRI, stimulus-evoked (st-fMRI, and pharmacological MRI (phMRI. Respectively, these techniques permit the assessment of functional connectivity during rest as well as brain activation triggered by sensory stimulation and/or a pharmacological challenge. The first part of this review describes the physiological basis of BOLD fMRI and the hemodynamic response on which the MRI contrast is based. Specific emphasis goes to possible effects of anaesthesia and the animal’s physiological conditions on neural activity and the hemodynamic response. The second part of this review describes applications of the aforementioned techniques in pharmacologically-induced, as well as in traumatic and transgenic disease models and illustrates how multiple fMRI methods can be applied successfully to evaluate different aspects of a specific disorder. For example, fMRI techniques can be used to pinpoint the neural substrate of a disease beyond previously defined hypothesis-driven regions-of-interest (ROIs. In addition, fMRI techniques allow one to dissect how specific modifications (e.g. treatment, lesion etc. modulate the functioning of specific brain areas (st-fMRI, phMRI and how functional connectivity (rsfMRI between several brain regions is affected, both in acute and extended time frames. Furthermore, fMRI techniques can be used to assess/explore the efficacy of novel treatments in depth, both in fundamental research as well as in preclinical settings. In conclusion, by describing several exemplary studies, we aim to highlight the advantages of functional MRI in exploring the acute and long-term effects of pharmacological substances and/or pathology on brain functioning along with

  20. Sevoflurane-Sulfobutylether-β-Cyclodextrin Complex: Preparation, Characterization, Cellular Toxicity, Molecular Modeling and Blood-Brain Barrier Transport Studies

    Directory of Open Access Journals (Sweden)

    Sergey Shityakov

    2015-06-01

    Full Text Available The objective of the present investigation was to study the ability of sulfobutylether-β-cyclodextrin (SBEβCD to form an inclusion complex with sevoflurane (SEV, a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBEβCD complex was nontoxic to the primary brain microvascular endothelial (pEND cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol concerning calculated apparent permeability values (Papp. In addition, SEV binding affinity to SBEβCD was confirmed by a minimal Gibbs free energy of binding (ΔGbind value of −1.727 ± 0.042 kcal·mol−1 and an average binding constant (Kb of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity.

  1. Sevoflurane-Sulfobutylether-β-Cyclodextrin Complex: Preparation, Characterization, Cellular Toxicity, Molecular Modeling and Blood-Brain Barrier Transport Studies.

    Science.gov (United States)

    Shityakov, Sergey; Puskás, István; Pápai, Katalin; Salvador, Ellaine; Roewer, Norbert; Förster, Carola; Broscheit, Jens-Albert

    2015-01-01

    The objective of the present investigation was to study the ability of sulfobutylether-β-cyclodextrin (SBEβCD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBEβCD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (Papp). In addition, SEV binding affinity to SBEβCD was confirmed by a minimal Gibbs free energy of binding (ΔGbind) value of -1.727 ± 0.042 kcal·mol-1 and an average binding constant (Kb) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity. PMID:26046323

  2. Characterization of neural stem/progenitor cells expressing VEGF and its receptors in the subventricular zone of newborn piglet brain.

    Science.gov (United States)

    Ara, Jahan; Fekete, Saskia; Zhu, Anli; Frank, Melissa

    2010-09-01

    Neural stem/progenitor cell (NSP) biology and neurogenesis in adult central nervous system (CNS) are important both towards potential future therapeutic applications for CNS repair, and for the fundamental function of the CNS. In the present study, we report the characterization of NSP population from subventricular zone (SVZ) of neonatal piglet brain using in vivo and in vitro systems. We show that the nestin and vimentin-positive neural progenitor cells are present in the SVZ of the lateral ventricles of neonatal piglet brain. In vitro, piglet NSPs proliferated as neurospheres, expressed the typical protein of neural progenitors, nestin and a range of well-established neurodevelopmental markers. Upon dissociation and subculture, piglet NSPs differentiated into neurons and glial cells. Clonal analysis demonstrates that piglet NSPs are multipotent and retain the capacity to generate both glia and neurons. These cells expressed VEGF, VEGFR1, VEGFR2 and Neuropilin-1 and -2 mRNAs. Real time PCR revealed that SVZ NSPs from newborn piglet expressed total VEGF and all VEGF splice variants. These findings show that piglet NSPs may be helpful to more effectively design growth factor based strategies to enhance endogenous precursor cells for cell transplantation studies potentially leading to the application of this strategy in the nervous system disease and injury.

  3. Material characterization and computer model simulation of low density polyurethane foam used in a rodent traumatic brain injury model.

    Science.gov (United States)

    Zhang, Liying; Gurao, Manish; Yang, King H; King, Albert I

    2011-05-15

    Computer models of the head can be used to simulate the events associated with traumatic brain injury (TBI) and quantify biomechanical response within the brain. Marmarou's impact acceleration rodent model is a widely used experimental model of TBI mirroring axonal pathology in humans. The mechanical properties of the low density polyurethane (PU) foam, an essential piece of energy management used in Marmarou's impact device, has not been fully characterized. The foam used in Marmarou's device was tested at seven strain rates ranging from quasi-static to dynamic (0.014-42.86 s⁻¹) to quantify the stress-strain relationships in compression. Recovery rate of the foam after cyclic compression was also determined through the periods of recovery up to three weeks. The experimentally determined stress-strain curves were incorporated into a material model in an explicit Finite Element (FE) solver to validate the strain rate dependency of the FE foam model. Compression test results have shown that the foam used in the rodent impact acceleration model is strain rate dependent. The foam has been found to be reusable for multiple impacts. However the stress resistance of used foam is reduced to 70% of the new foam. The FU_CHANG_FOAM material model in an FE solver has been found to be adequate to simulate this rate sensitive foam.

  4. Synthesis, in vitro pharmacologic characterization, and preclinical evaluation of N-[2-(1'-piperidinyl)ethyl]-3-[125I]iodo-4-methoxybenzamide (P[125I]MBA) for imaging breast cancer.

    Science.gov (United States)

    John, C S; Bowen, W D; Fisher, S J; Lim, B B; Geyer, B C; Vilner, B J; Wahl, R L

    1999-05-01

    The goal of this study was to investigate the potential use of a radioiodinated benzamide, N-[2-(1'-piperidinyl)ethyl]-3-iodo[125I]-4-methoxybenzamide (P[125I]MBA), a sigma receptor binding radioligand for imaging breast cancer. The chemical and radiochemical syntheses of PIMBA are described. The pharmacological evaluation of PIMBA was carried out for sigma-1 and sigma-2 receptor sites. The in vivo pharmacokinetics of the radioiodinated benzamide were determined in rats and comparison of P[125I]MBA with Tc-99m sestamibi were made in a rat mammary tumor model. Sigma-1 affinity (Ki) for PIMBA in guinea pig brain membranes using [3H](+)pentazocine was found to be 11.82 +/- 0.68 nM, whereas sigma-2 affinity in rat liver using [3H]DTG (1,3-o-di-tolylguanidine) was 206 +/- 11 nM. Sites in guinea pig brain membranes labeled by P[125I]MBA showed high affinity for haloperidol, (+)-pentazocine, BD1008, and PIMBA (Ki = 4.87 +/- 1.49, 8.81 +/- 1.97, 0.057 +/- 0.005, 46.9 +/- 1.8 nM, respectively). Competition binding studies were carried out in human ductal breast carcinoma cells (T47D). A dose-dependent inhibition of specific binding was observed with several sigma ligands. Ki values for the inhibition of P[125I]MBA binding in T47D cells for haloperidol, N-[2-(1'-piperidinyl)]ethyl]4-iodobenzamide (IPAB), N-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), and PIMBA were found to be 1.30 +/- 0.07, 13 +/- 1.5, 5.19 +/- 2.3, 1.06 +/- 0.5 nM, respectively. The in vitro binding data in guinea pig brain membranes and breast cancer cells confirmed binding to sigma sites. The saturation binding of P[125I]MBA in T47D cells as studied by Scatchard analysis showed saturable binding, with a Kd = 94 +/- 7 nM and a Bmax = 2035 +/- 305 fmol/mg of proteins. Biodistribution studies in Sprague-Dawley rats showed a rapid clearance of P[125I]MBA from the normal organs. The potential of PIMBA in imaging breast cancer was evaluated in Lewis rats bearing syngeneic RMT breast cancers, a cancer that

  5. Localization and characterization of brain somatostatin receptors as studied with somatostatin-14 and somatostatin-28 receptor radioautography

    International Nuclear Information System (INIS)

    The localization and characterization of receptors for somatostatin-14 (S-14) and somatostatin-28 (S-28) were studied in the rat brain using the iodinated agonists [Tyr0,D-Trp8]S-14 and [Leu8,D-Trp22,Tyr25]S-28 as tracers. By radioautography, the distribution of receptors for both S-14 and S-28 appeared very similar with high levels of binding in the deep layers of the cortex, the cingulate cortex, the claustrum, the locus coeruleus and most structures of the limbic system. Generally, there was a correlation between the localization of somatostatin receptors and that of immunoreactive somatostatin, as evaluated by immunocytochemistry. However, in some areas, an inverse correlation between receptor and peptide concentrations was observed. (Auth.)

  6. [Pharmacological treatment of hyperinflation].

    Science.gov (United States)

    Devillier, P; Roche, N

    2009-06-01

    Introduction Lung hyperinflation leads to breathlessness, limitation in exercise capacity and tolerance, and impaired quality of life. Thus, it is important to target this key and characteristic feature of COPD. Current knowledge Available pharmacological approaches rely mainly on bronchodilators, in particular beta2 agonists and anticholinergic agents. These treatments act through the reduction of expiratory airflow limitation. However, changes in classical indices of airflow obstruction do not accurately predict effects on hyperinflation and symptoms. The decrease in operating lung volumes (as reflected by inspiratory capacity or functional residual capacity) at rest and during exercise is one of the mechanisms by which these treatments improve quality of life and maybe also decrease the impact of exacerbations. The effect of beta2 agonists on hyperinflation might be amplified by concurrent treatment with inhaled corticosteroids. Perspectives The effect of new treatments targeting airways inflammation on hyperinflation remains to be explored. Conclusions Measuring the reduction in the degree of lung hyperinflation allows a better understanding of the symptomatic effect of COPD pharmacological treatments.

  7. Molecular cloning and characterization of rat brain 2',3'-cyclic nucleotide 3'-phosphodiesterase isoform 2.

    Science.gov (United States)

    Gravel, M; DeAngelis, D; Braun, P E

    1994-06-15

    We have isolated a cDNA coding for the larger isoform of the rat brain 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP2), a protein associated with myelination in the central nervous system (CNS). The complete 420 amino acid sequence was deduced from the nucleotide sequence of the cDNA. Sequence comparisons show that rat CNP shares 96% homology with mouse, 84% with bovine, and 86% with human CNP. Errors in the published sequence of rat CNP1 have now been corrected. Comparisons with other proteins reveal several interesting conserved motifs, including two leucine repeat heptads, and two consensus motifs for phosphorylation in the N-terminal domain of CNP2. PMID:7932861

  8. Development of a Fluorescence Assay for the Characterization of Brevenal Binding to Rat Brain Synaptosomes

    OpenAIRE

    McCall, Jennifer R.; Goodman, Allan J.; Henry M. Jacocks; Thompson, Alysha M.; Baden, Daniel G.; Bourdelais, Andrea J.

    2014-01-01

    The marine dinoflagellate Karenia brevis produces a family of neurotoxins known as brevetoxins. Brevetoxins elicit their effects by binding to and activating voltage-sensitive sodium channels (VSSCs) in cell membranes. K. brevis also produces brevenal, a brevetoxin antagonist, which is able to inhibit and/or negate many of the detrimental effects of brevetoxins. Brevenal binding to VSSCs has yet to be fully characterized, in part due to the difficulty and expense of current techniques. In thi...

  9. [Pharmacological treatment of schizophrenia].

    Science.gov (United States)

    Thomas, Pierre

    2013-03-01

    Decades of practice in psychiatriy and hundreds of clinical trials have demonstrated the efficacy of antipsychotics on symptoms of schizophrenia. Recently, the knowledge acquired from non-interventional studies have supplemented the information needed in daily practice by raising the issue of efficiency by incorporating not only the effectiveness and safety of treatment but also its acceptability by the patient. Adherence to antipsychotic treatment has become the key issue of the prognosis. The pharmacological management of patients with an acute episode of schizophrenia requires rapid therapeutic decisions to treat a patient who is likely to be sometimes unhelpful and agitated. The choice of treatment will have a significant impact on the prevention of psychotic relapses, on the overall prognosis and on the quality of life of the patient. In many countries of the recommendations and treatment algorithms for the management of acute psychosis were distributed, considering factors specific to the patient and his environment, his mental characteristics and local care setting.

  10. Pharmacology of Quercus infectoria.

    Science.gov (United States)

    Dar, M S; Ikram, M; Fakouhi, T

    1976-12-01

    The galls of Quercus infectoria (Fagaceae), a commonly available plant in Iran, were studied pharmacologically. Two fractions were employed, a dried acetone-treated methanol extract dissolved in water (Fraction A) and a subfraction prepared by chloroform-methanol extraction (Fraction B). Fraction A was active as an analgesic in rats and significantly reduced blood sugar levels in rabbits. Fraction B had CNS depressant activity. Data obtained with a treadmill indicated a decreased activity ratio by Fraction B, suggesting a possible interference in motor coordination. It potentiated the barbiturate sleeping time significantly without changing the onset time or the loss of the righting reflex. In addition, Fraction B exhibited a moderate antitremorine activity by causing a delay in the onset and a decrease in the severity of tremorine-induced tremors. The local anesthetic action of Fraction B was evident due to the complete blockade of the isolated frog sciatic nerve conduction. PMID:1032663

  11. Pharmacology of antihypertensive drugs.

    Science.gov (United States)

    Pepper, G A

    1999-01-01

    The wide variety of first-line agents available for managing high blood pressure include diuretics, beta adrenergic receptor blockers, alpha adrenergic receptor blockers, angiotensin converting enzyme inhibitors, and calcium channel blockers. Supplemental agents used for second-line therapy and special indications, such as pregnancy and hypertensive emergencies, include angiotensin receptor blockers, central-acting agents, direct vasodilators, and adrenergic neuron inhibitors. Selection of agents for particular patients requires consideration of research-based evidence for positive long-term outcomes and of the unique patient profile of age, race, co-morbidities, and lifestyle. A thorough understanding of the pharmacology (mechanism, pharmacokinetics, adverse effects and drug interactions, clinical use) of antihypertensive agents is an essential foundation for nursing practice in women's health. PMID:10584919

  12. Brain abscess: Current management

    OpenAIRE

    Hernando Alvis-Miranda; Sandra Milena Castellar-Leones; Mohammed Awad Elzain; Luis Rafael Moscote-Salazar

    2013-01-01

    Brain abscess (BA) is defined as a focal infection within the brain parenchyma, which starts as a localized area of cerebritis, which is subsequently converted into a collection of pus within a well-vascularized capsule. BA must be differentiated from parameningeal infections, including epidural abscess and subdural empyema. The BA is a challenge for the neurosurgeon because it is needed good clinical, pharmacological, and surgical skills for providing good clinical outcomes and prognosis to ...

  13. Non-pharmacological intervention for memory decline

    Directory of Open Access Journals (Sweden)

    Maria eCotelli

    2012-03-01

    Full Text Available Non-pharmacological treatment of memory difficulties in healthy older adults, as well as those with brain damage and neurodegenerative disorders, has gained much attention in recent years (Ball et al., 2002, Willis et al., 2006, Acevedo and Loewenstein, 2007. The two main reasons that explain this growing interest in memory rehabilitation are the limited efficacy of current drug therapies and the plasticity of the human central nervous system (Cotelli et al., 2011c and the discovery that during aging, the connections in the brain are not fixed but retain the capacity to change with learning.Moreover, several studies have reported enhanced cognitive performance in patients with neurological disease, following non-invasive brain stimulation (i.e., repetitive transcranial magnetic stimulation (rTMS and transcranial direct current stimulation (tDCS to specific cortical areas. The present review provides an overview of memory rehabilitation in individuals with Mild Cognitive Impairment (MCI and in patients with Alzheimer’s Disease (AD with particular regard to cognitive rehabilitation interventions focused on memory and non-invasive brain stimulation. Reviewed data suggest that in patients with memory deficits, memory intervention therapy could lead to performance improvements in memory, nevertheless further studies need to be conducted in order to establish the real value of this approach.

  14. Characterization and distribution of [125I]epidepride binding to dopamine D2 receptors in basal ganglia and cortex of human brain

    International Nuclear Information System (INIS)

    The distribution and pharmacology of the binding of 125I-epidepride, a substituted benzamide with high affinity and selectivity for dopamine (DA) D2 receptors in rat brain is described in human brain. Saturation analysis of the binding of 125I-epidepride to membranes derived from striatum and regions of cortex demonstrated similar Kd values (34 and 28-33 pM, respectively) but differing maximum density of binding site values (152 and 3-8 fmol/mg of protein, respectively). The pharmacological profile of binding in cortex was also similar to striatum (epidepride greater than spiperone greater than butaclamol = flupenthixol greater than clozapine) except that an additional low-affinity site, blocked by the alpha-2 adrenergic antagonist idazoxan, was present in cortex. Quantification by autoradiography also demonstrated the greatest binding in the basal ganglia, with the striatum exhibiting greater binding than the pallidal complex or midbrain regions. For the pallidum, binding in the external segment was higher than the internal segment. Within the midbrain the binding of 125I-epidepride correlated well with the known distribution of DA-containing cell bodies, with the substantia nigra (pars compacta and pars lateralis) and ventral tegmental area (A10) higher than area A8 and central gray. Binding in frontal and parietal cortex was highest in the internal layers (layers V and VI). Temporal cortex showed a 2-fold higher density of binding than other cortical regions and a trilaminar pattern; binding was greater in the external (layers I and II) and internal layers than in the middle layers (III and IV). This pattern changed in the parahippocampal complex. Within the lateral occipitotemporal cortex, binding was densest in layers I to III and very low in layers IV to VI, but binding was almost nonexistent in the adjacent entorhinal cortex

  15. Characterization and distribution of (125I)epidepride binding to dopamine D2 receptors in basal ganglia and cortex of human brain

    Energy Technology Data Exchange (ETDEWEB)

    Joyce, J.N.; Janowsky, A.; Neve, K.A. (Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia (USA))

    1991-06-01

    The distribution and pharmacology of the binding of {sup 125}I-epidepride, a substituted benzamide with high affinity and selectivity for dopamine (DA) D2 receptors in rat brain is described in human brain. Saturation analysis of the binding of {sup 125}I-epidepride to membranes derived from striatum and regions of cortex demonstrated similar Kd values (34 and 28-33 pM, respectively) but differing maximum density of binding site values (152 and 3-8 fmol/mg of protein, respectively). The pharmacological profile of binding in cortex was also similar to striatum (epidepride greater than spiperone greater than butaclamol = flupenthixol greater than clozapine) except that an additional low-affinity site, blocked by the alpha-2 adrenergic antagonist idazoxan, was present in cortex. Quantification by autoradiography also demonstrated the greatest binding in the basal ganglia, with the striatum exhibiting greater binding than the pallidal complex or midbrain regions. For the pallidum, binding in the external segment was higher than the internal segment. Within the midbrain the binding of {sup 125}I-epidepride correlated well with the known distribution of DA-containing cell bodies, with the substantia nigra (pars compacta and pars lateralis) and ventral tegmental area (A10) higher than area A8 and central gray. Binding in frontal and parietal cortex was highest in the internal layers (layers V and VI). Temporal cortex showed a 2-fold higher density of binding than other cortical regions and a trilaminar pattern; binding was greater in the external (layers I and II) and internal layers than in the middle layers (III and IV). This pattern changed in the parahippocampal complex. Within the lateral occipitotemporal cortex, binding was densest in layers I to III and very low in layers IV to VI, but binding was almost nonexistent in the adjacent entorhinal cortex.

  16. PHARMACOLOGICAL IMPORTANCE OF CITRUS FRUITS

    Directory of Open Access Journals (Sweden)

    Amita Tomar *, Mridula Mall and Pragya Rai

    2013-01-01

    Full Text Available This paper reviews the pharmacological importance of citrus fruits. Citrus fruits are used for various pharmacological importance. According to literature the citrus fruit possess anti-cancer, antimicrobial, antioxidant, antiulcer, anti-inflammatory, and hypolipidemic and hepatoprotective properties.

  17. Characterization of GABA/sub A/ receptor-mediated 36chloride uptake in rat brain synaptoneurosomes

    International Nuclear Information System (INIS)

    γ-Aminobutyric acid (GABA) receptor-mediated 36chloride (36Cl-) uptake was measured in synaptoneurosomes from rat brain. GABA and GABA agonists stimulated 36Cl- uptake in a concentration-dependent manner with the following order of potency: Muscimol>GABA>piperidine-4-sulfonic acid (P4S)>4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP)=3-aminopropanesulfonic acid (3APS)>>taurine. Both P4S and 3APS behaved as partial agonists, while the GABA/sub B/ agonist, baclofen, was ineffective. The response to muscimol was inhibited by bicuculline and picrotoxin in a mixed competitive/non-competitive manner. Other inhibitors of GABA receptor-opened channels or non-neuronal anion channels such as penicillin, picrate, furosemide and disulfonic acid stilbenes also inhibited the response to muscimol. A regional variation in muscimol-stimulated 36Cl- uptake was observed; the largest responses were observed in the cerebral cortex, cerebellum and hippocampus, moderate responses were obtained in the striatum and hypothalamus and the smallest response was observed in the pons-medulla. GABA receptor-mediated 36Cl- uptake was also dependent on the anion present in the media. The muscinol response varied in media containing the following anions: Br->Cl-≥NO3->I-≥SCN->>C3H5OO-≥ClO4->F-, consistent with the relative anion permeability through GABA receptor-gated anion channels and the enhancement of convulsant binding to the GABA receptor-gated Cl- channel. 43 references, 4 figures, 3 tables

  18. Characterization of multiphoton photoacoustic spectroscopy for subsurface brain tissue diagnosis and imaging

    Science.gov (United States)

    Dahal, Sudhir; Cullum, Brian M.

    2016-04-01

    The development and demonstration of a multiphoton photoacoustic imaging technique capable of providing high spatial resolution chemical images of subsurface tissue components as deep as 1.4 cm below the tissue surface is described. By combining multiphoton excitation in the diagnostic window (650 to 1100 nm), with ultrasonic detection of nonradiative relaxation events, it is possible to rapidly reconstruct three-dimensional, chemical specific, images of samples underneath overlying structures as well as chemical species of the same material. Demonstration of this technique for subsurface tissue differentiation is shown, with the ability to distinguish between grade III astrocytoma tissue and adjacent healthy tissue in blind studies. By employing photoacoustic signal detection, the high nonradiative relaxation rates of most biological tissue components (>90%) and the minimal signal attenuation of the resulting ultrasound compensate for excitation efficiency losses associated with two-photon absorption. Furthermore, the two-photon absorption process results in a highly localized excitation volume (ca., 60 μm). Characterization of the probing depth, spatial resolution, and ability to image through overlying structures is also demonstrated in this paper using tissue phantoms with well-characterized optical scattering properties, mimicking those of tissues.

  19. Characterizing functional integrity: intraindividual brain signal variability predicts memory performance in patients with medial temporal lobe epilepsy.

    Science.gov (United States)

    Protzner, Andrea B; Kovacevic, Natasa; Cohn, Melanie; McAndrews, Mary Pat

    2013-06-01

    Computational modeling suggests that variability in brain signals provides important information regarding the system's capacity to adopt different network configurations that may promote optimal responding to stimuli. Although there is limited empirical work on this construct, a recent study indicates that age-related decreases in variability across the adult lifespan correlate with less efficient and less accurate performance. Here, we extend this construct to the assessment of cerebral integrity by comparing fMRI BOLD variability and fMRI BOLD amplitude in their ability to account for differences in functional capacity in patients with focal unilateral medial temporal dysfunction. We were specifically interested in whether either of these BOLD measures could identify a link between the affected medial temporal region and memory performance (as measured by a clinical test of verbal memory retention). Using partial least-squares analyses, we found that variability in a set of regions including the left hippocampus predicted verbal retention and, furthermore, this relationship was similar across a range of cognitive tasks measured during scanning (i.e., the same pattern was seen in fixation, autobiographical recall, and word generation). In contrast, signal amplitude in the hippocampus did not predict memory performance, even for a task that reliably activates the medial temporal lobes (i.e., autobiographical recall). These findings provide a powerful validation of the concept that variability in brain signals reflects functional integrity. Furthermore, this measure can be characterized as a robust biomarker in this clinical setting because it reveals the same pattern regardless of cognitive challenge or task engagement during scanning.

  20. Characterization of Artifacts produced by gel displacement on non-invasive Brain-Machine Interfaces during ambulation

    Directory of Open Access Journals (Sweden)

    Alvaro eCosta

    2016-02-01

    Full Text Available So far, Brain-Machine Interfaces (BMIs have been mainly used to study brain potentials during movement-free conditions. Recently, due to the emerging concern of improving rehabilitation therapies, these systems are also being used during gait experiments. Under this new condition, the evaluation of motion artifacts has become a critical point to assure the validity of the results obtained. Due to the high signal to noise ratio provided, the use of wet electrodes is a widely accepted technic to acquire electroencephalographic (EEG signals. To perform these recordings it is necessary to apply a conductive gel between the scalp and the electrodes. This work is focused on the study of gel displacements produced during ambulation and how they affect the amplitude of EEG signals. Data recorded during three ambulation conditions (gait training and one movement-free condition (BMI motor imagery task are compared to perform this study.Two phenomenons, manifested as unusual increases of the signals' amplitude, have been identified and characterized during this work. Results suggest that they are caused by abrupt changes on the conductivity between the electrode and the scalp due to gel displacement produced during ambulation and head movements. These artifacts significantly increase the Power Spectral Density (PSD of EEG recordings at all frequencies from 5 to 90 Hz, corresponding to the main bandwidth of electrocortical potentials. They should be taken into consideration before performing EEG recordings in order to asses the correct gel allocation and to avoid the use of electrodes on certain scalp areas depending on the experimental conditions.

  1. Characterization of the Community Structure of Large Scale Functional Brain Networks During Ketamine-Medetomidine Anesthetic Induction

    OpenAIRE

    Padovani, Eduardo C.

    2016-01-01

    One of the central questions in neuroscience is to understand the way communication is organized in the brain, trying to comprehend how cognitive capacities or physiological states of the organism are potentially related to brain activities involving interactions of several brain areas. One important characteristic of the functional brain networks is that they are modularly structured, being this modular architecture regarded to account for a series of properties and functional dynamics. In t...

  2. Synthesis of [11C-methyl]-(-)-OSU6162, its regional brain distribution and some pharmacological effects of (-)-OSU6162 on the dopaminergic system studied in the rhesus monkey by positron emission tomography

    International Nuclear Information System (INIS)

    The labelling of the presynaptic dopamine receptor antagonist (-)-OSU6162, ((S)-(-)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine) was performed by an alkylation with [11C]methyl iodide of the thio anion (-)-OSU1281, followed by a selective oxidation to the corresponding methyl sulfone, [11C-methyl]-(-)-OSU6162. The total radiochemical yield calculated from the produced [11C]carbon dioxide to final product was about 25% and the time of synthesis was in the range of 40 min from end of bombardment. The synthesis of the precursor, (-)-OSU1281, was performed from (-)-3PPP in a three-step synthesis. The regional brain distribution of (-)-OSU6162 radiolabelled with 11C was studied in rhesus monkeys by means of positron emission tomography, PET. [11C-Methyl]-(-)-OSU6162 was rapidly and uniformly distributed to gray matters of the brain, and no decrease of radioactivity uptake in the brain was seen after pretreatment with 1 to 3 mg/kg/h of (-)-OSU6162. The effect of doses of 1 to 3 mg/kg/h of (-)-OSU6162 on the dopamine binding was studied by PET using [11C-methyl]raclopride. Radioactivity in the striatum was significantly and dose-dependently decreased by (-)-OSU6162 (r = 0.88), supporting competition with dopamine for selective binding to dopamine receptors

  3. Characterization of opioid receptor types modulating acetylcholine release in septal regions of the rat brain.

    Science.gov (United States)

    Gazyakan, E; Hennegriff, M; Haaf, A; Landwehrmeyer, G B; Feuerstein, T J; Jackisch, R

    2000-07-01

    antibody-linked enzymatic staining procedure, whereas mRNAs for mu- or delta-opioid receptors were detected with radioactive probes. These experiments revealed that in the septal region mainly mu-opioid receptors were expressed by neurons positive for ChAT mRNA, whereas in the rat striatum the expression of delta-opioid receptors prevailed in those neurons. We conclude that in the septal area of the rat brain, in contrast to the rat striatum and hippocampus, both presynaptic mu- and delta-opioid receptors modulate the evoked release of ACh. Whether presynaptic mu- and delta-opioid receptors occur on the same or on different septal cells or axon terminals remains to be clarified. PMID:10935530

  4. Characterization of kappa 1 and kappa 2 opioid binding sites in frog (Rana esculenta) brain membrane preparation

    International Nuclear Information System (INIS)

    The distribution and properties of frog brain kappa-opioid receptor subtypes differ not only from those of the guinea pig brain, but also from that of the rat brain. In guinea pig cerebellum the kappa 1 is the dominant receptor subtype, frog brain contains mainly the kappa 2 subtype, and the distribution of the rat brain subtypes is intermediate between the two others. In competition experiments it has been established that ethylketocyclazocine and N-cyclopropylmethyl-norazidomorphine, which are nonselective kappa-ligands, have relatively high affinities to frog brain membranes. The kappa 2 ligands (Met5)enkephalin-Arg6-Phe7 and etorphine also show high affinities to the frog brain. Kappa 1 binding sites measured in the presence of 5 microM/D-Ala2-Leu5/enkephalin represent 25-30% of [3H]ethylketocyclazocine binding in frog brain membranes. The kappa 2 subtype in frog brain resembles more to the mu subtype than the delta subtype of opioid receptors, but it differs from the mu subtype in displaying low affinity toward beta-endorphin and /D-Ala2-(Me)Phe4-Gly5-ol/enkephalin (DAGO). From our data it is evident that the opioid receptor subtypes are already present in the amphibian brain but the differences among them are less pronounced than in mammalian brain

  5. In vivo imaging and characterization of [18F]DPA-714, a potential new TSPO ligand, in mouse brain and peripheral tissues using small-animal PET

    International Nuclear Information System (INIS)

    Introduction: The translocator protein 18 kDa (TSPO), a biochemical marker of neuroinflammation, is highly expressed in the brain activated microglia and it is also expressed by peripheral inflammatory cells and normal peripheral tissues. Thus, development of radioligands for the TSPO may contribute to further understanding the in vivo TSPO function in central and peripheral inflammatory processes and other pathologies. Here, we report the biodistribution, the specific binding and the radiometabolites of [18F]DPA-714, a promising fluorinated PET radiotracer, in normal mice using a microPET/CT scanner. Methods: The in vivo biodistribution and kinetics of [18F]DPA-714 were measured in mice brain and peripheral tissues. Specific binding to TSPO sites was assessed using pharmacological competitive studies by means of saturation experiments performed by i.v. injection of 1 mg/kg of unlabeled DPA-714 or 3 mg/kg of unlabeled PK11195. A region of interest analysis was performed to generate time-activity curves in the brain, heart, lung, kidney, spleen and liver. Metabolites assay was performed in the plasma and peripheral organs by radio-HPLC. Results: [18F]DPA-714 reached high concentration in lung, heart, kidney and spleen, tissues well known to be rich in TSPO sites. [18F]DPA-714 kinetics were faster in the lung and slower in the kidney. Pre-injection of unlabeled DPA-714 or PK11195 inhibited about 80% of [18F]DPA-714 uptake in the lung and heart (p < 0.0005). The percentage of inhibition in the kidney was lower and achieved at later times only with DPA-714 (p < 0.05) but not with PK11195. Sixty minutes after radiotracer injection only unmetabolized radioligand was found in the brain, lung, heart and spleen. Conclusion: These results suggest that [18F]DPA-714 is a suitable PET ligand for imaging in mice brain and peripheral tissues since it binds with high specificity TSPO binding sites and it is almost unchanged at 60 minutes after radiotracer injection in the brain

  6. Cannabinoid receptor localization in brain

    Energy Technology Data Exchange (ETDEWEB)

    Herkenham, M.; Lynn, A.B.; Little, M.D.; Johnson, M.R.; Melvin, L.S.; de Costa, B.R.; Rice, K.C. (National Institute of Mental Health, Bethesda, MD (USA))

    1990-03-01

    (3H)CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of (3H)CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.

  7. Characterization of rainbow trout gonad, brain and gill deep cDNA repertoires using a Roche 454-Titanium sequencing approach.

    Science.gov (United States)

    Le Cam, Aurélie; Bobe, Julien; Bouchez, Olivier; Cabau, Cédric; Kah, Olivier; Klopp, Christophe; Lareyre, Jean-Jacques; Le Guen, Isabelle; Lluch, Jérôme; Montfort, Jérôme; Moreews, Francois; Nicol, Barbara; Prunet, Patrick; Rescan, Pierre-Yves; Servili, Arianna; Guiguen, Yann

    2012-05-25

    Rainbow trout, Oncorhynchus mykiss, is an important aquaculture species worldwide and, in addition to being of commercial interest, it is also a research model organism of considerable scientific importance. Because of the lack of a whole genome sequence in that species, transcriptomic analyses of this species have often been hindered. Using next-generation sequencing (NGS) technologies, we sought to fill these informational gaps. Here, using Roche 454-Titanium technology, we provide new tissue-specific cDNA repertoires from several rainbow trout tissues. Non-normalized cDNA libraries were constructed from testis, ovary, brain and gill rainbow trout tissue samples, and these different libraries were sequenced in 10 separate half-runs of 454-Titanium. Overall, we produced a total of 3million quality sequences with an average size of 328bp, representing more than 1Gb of expressed sequence information. These sequences have been combined with all publicly available rainbow trout sequences, resulting in a total of 242,187 clusters of putative transcript groups and 22,373 singletons. To identify the predominantly expressed genes in different tissues of interest, we developed a Digital Differential Display (DDD) approach. This approach allowed us to characterize the genes that are predominantly expressed within each tissue of interest. Of these genes, some were already known to be tissue-specific, thereby validating our approach. Many others, however, were novel candidates, demonstrating the usefulness of our strategy and of such tissue-specific resources. This new sequence information, acquired using NGS 454-Titanium technology, deeply enriched our current knowledge of the expressed genes in rainbow trout through the identification of an increased number of tissue-specific sequences. This identification allowed a precise cDNA tissue repertoire to be characterized in several important rainbow trout tissues. The rainbow trout contig browser can be accessed at the following

  8. Teaching Pharmacology by Case Study.

    Science.gov (United States)

    Jordan, Sue

    1997-01-01

    Using pharmacology case studies with nursing students encourages theory-practice links and infuses real-life content. Cases provide rich qualitative data for evaluating curriculum. However, they are not a substitute for evidence-based practice. (SK)

  9. NASA 2010 Pharmacology Evidence Review

    Science.gov (United States)

    Steinberg, Susan

    2011-01-01

    In 2008, the Institute of Medicine reviewed NASA's Human Research Program Evidence in assessing the Pharmacology risk identified in NASA's Human Research Program Requirements Document (PRD). Since this review there was a major reorganization of the Pharmacology discipline within the HRP, as well as a re-evaluation of the Pharmacology evidence. This panel is being asked to review the latest version of the Pharmacology Evidence Report. Specifically, this panel will: (1) Appraise the descriptions of the human health-related risk in the HRP PRD. (2) Assess the relevance and comprehensiveness of the evidence in identifying potential threats to long-term space missions. (3) Assess the associated gaps in knowledge and identify additional areas for research as necessary.

  10. [Pharmacology of bone resorption inhibitor].

    Science.gov (United States)

    Menuki, Kunitaka; Sakai, Akinori

    2015-10-01

    Currently, bone resorption inhibitor is mainly used for osteoporosis. A number of these agents have been developed. These pharmacological action are various. Bisphosphonate inhibit functions of the osteoclasts by inducing apoptosis. On the one hand, RANK-ligand inhibitor and selective estrogen receptor modulator inhibit formation of osteoclasts. It is important to understand these pharmacological action for the selection of the appropriate medicine. PMID:26529923

  11. Pharmacological Effects of Rosa Damascena

    OpenAIRE

    Boskabady, Mohammad Hossein; Shafei, Mohammad Naser; Saberi, Zahra; Amini, Somayeh

    2011-01-01

    Rosa damascena mill L., known as Gole Mohammadi in is one of the most important species of Rosaceae family flowers. R. damascena is an ornamental plant and beside perfuming effect, several pharmacological properties including anti-HIV, antibacterial, antioxidant, antitussive, hypnotic, antidiabetic, and relaxant effect on tracheal chains have been reported for this plant. This article is a comprehensive review on pharmacological effects of R. damascena. Online literature searches were perform...

  12. Kindling: a pharmacological approach.

    Science.gov (United States)

    Wasterlain, C G; Morin, A M; Jonec, V

    1982-01-01

    Injection of a few nanomoles of the muscarinic agonists carbamylcholine, muscarine or (+)-acetyl-beta-methylcholine once a day into the rat amygdala was initially subconvulsive, but on repetition led to the progressive development of kindled epileptic seizures. This behaviour was stereospecific, was potentiated by the cholinesterase inhibitor physostigmine, and was blocked by the muscarinic antagonists atropine, QNB and scopolamine. The kindling potencies of cholinergic muscarinic agonists and antagonists paralleled their relative affinities for muscarinic receptors in vitro. No changes in muscarinic receptors, in cholinesterase or in choline acetyltransferase were observed in kindled brains after a stimulation-free period of at least 1 week. These data support the aggregate hypothesis of epileptogenesis and suggest that abnormal activity through a particular group of muscarinic synapses can be sufficient to generate an epileptic focus.

  13. Peripheral anti-inflammatory effects explain the ginsenosides paradox between poor brain distribution and anti-depression efficacy

    OpenAIRE

    Kang An; Hao Haiping; Zheng Xiao; Liang Yan; Xie Yuan; Xie Tong; Dai Chen; Zhao Qijin; Wu Xiaolan; Xie Lin; Wang Guangji

    2011-01-01

    Abstract Background The effectiveness of ginseng in preventing and treating various central nervous system (CNS) diseases has been widely confirmed. However, ginsenosides, the principal components of ginseng, are characterized by poor accessibility to the brain, and this pharmacokinetic-pharmacological paradox remains poorly explained. Anti-inflammatory approaches are becoming promising therapeutic strategies for depression and other CNS diseases; however, previous studies have focused largel...

  14. Recent Pharmacology Studies on the International Space Station

    Science.gov (United States)

    Wotring, Virginia

    2014-01-01

    The environment on the International Space Station (ISS) includes a variety of potential stressors including the absence of Earth's gravity, elevated exposure to radiation, confined living and working quarters, a heavy workload, and high public visibility. The effects of this extreme environment on pharmacokinetics, pharmacodynamics, and even on stored medication doses, are not yet understood. Dr. Wotring will discuss recent analyses of medication doses that experienced long duration storage on the ISS and a recent retrospective examination of medication use during long-duration spaceflights. She will also describe new pharmacology experiments that are scheduled for upcoming ISS missions. Dr. Virginia E. Wotring is a Senior Scientist in the Division of Space Life Sciences in the Universities Space Research Association, and Pharmacology Discipline Lead at NASA's Johnson Space Center, Human Heath and Countermeasures Division. She received her doctorate in Pharmacological and Physiological Science from Saint Louis University after earning a B.S. in Chemistry at Florida State University. She has published multiple studies on ligand gated ion channels in the brain and spinal cord. Her research experience includes drug mechanisms of action, drug receptor structure/function relationships and gene & protein expression. She joined USRA (and spaceflight research) in 2009. In 2012, her book reviewing pharmacology in spaceflight was published by Springer: Space Pharmacology, Space Development Series.

  15. Glutamate in peripheral organs: Biology and pharmacology.

    Science.gov (United States)

    Du, Jie; Li, Xiao-Hui; Li, Yuan-Jian

    2016-08-01

    Glutamate is a versatile molecule existing in both the central nervous system and peripheral organs. Previous studies have mainly focussed on the biological effect of glutamate in the brain. Recently, abundant evidence has demonstrated that glutamate also participates in the regulation of physiopathological functions in peripheral tissues, including the lung, kidney, liver, heart, stomach and immune system, where the glutamate/glutamate receptor/glutamate transporter system plays an important role in the pathogenesis of certain diseases, such as myocardial ischaemia/reperfusion injury and acute gastric mucosa injury. All these findings provide new insight into the biology and pharmacology of glutamate and suggest a potential therapeutic role of glutamate in non-neurological diseases. PMID:27164423

  16. [Pharmacological therapy of obesity].

    Science.gov (United States)

    Pagotto, Uberto; Vanuzzo, Diego; Vicennati, Valentina; Pasquali, Renato

    2008-04-01

    Obesity is reaching epidemic proportions worldwide and it is correlated with various comorbidities, among which the most relevant are diabetes mellitus, arterial hypertension, and cardiovascular diseases. Obesity management is a modern challenge because of the rapid evolution of unfavorable lifestyles and unfortunately there are no effective treatments applicable to the large majority of obese/overweight people. The current medical attitude is to treat the complications of obesity (e.g. dyslipidemia, hypertension, diabetes, and cardiovascular diseases). However, the potential of treating obesity is enormous, bearing in mind that a volitional weight loss of 10 kg is associated with important risk factor improvement: blood pressure -10 mmHg, total cholesterol -10%, LDL cholesterol -15%, triglycerides -30%, fasting glucose -50%, HDL cholesterol +8%. Drug treatment for obesity is an evolving branch of pharmacology, burdened by severe side effects and consequences of the early drugs, withdrawn from the market, and challenged by the lack of long-term data on the effect of medications on obesity-related morbidity and mortality, first of all cardiovascular diseases. In Europe three antiobesity drugs are currently licensed: sibutramine, orlistat, and rimonabant; important trials with clinical endpoints are ongoing for sibutramine and rimonabant. While waiting for their results, it is convenient to evaluate these drugs for their effects on body weight and cardiometabolic risk factors. Sibutramine is a centrally acting serotonin/noradrenaline reuptake inhibitor that mainly increases satiety. At the level of brown adipose tissue, sibutramine can also facilitate energy expenditure by increasing thermogenesis. The long-term studies (five) documented a mean differential weight reduction of 4.45 kg for sibutramine vs placebo. Considering the principal studies, attrition rate was 43%. This drug not only reduces body weight and waist circumference, but it decreases triglycerides and

  17. Quality management of pharmacology and safety pharmacology studies

    DEFF Research Database (Denmark)

    Spindler, Per; Seiler, Jürg P

    2002-01-01

    Pharmacology has traditionally been excluded from the mandatory application of good laboratory practice (GLP) principles. Consensus has been reached through the process of the International Conference on Harmonisation (ICH, Topic S7A) with regard to the definitions of the different types of pharm......Pharmacology has traditionally been excluded from the mandatory application of good laboratory practice (GLP) principles. Consensus has been reached through the process of the International Conference on Harmonisation (ICH, Topic S7A) with regard to the definitions of the different types...... of pharmacology studies (ICH S7A): primary pharmacodynamic, secondary pharmacodynamic and safety pharmacology studies, and guidance on the quality standards (expectations for GLP conformity) for these study types have been provided. Primary pharmacodynamic studies are the only study types that are fully exempt...... from GLP requirements. Secondary pharmacodynamic and safety pharmacology studies are expected to be conducted to GLP quality standards -- preferably to full, formal GLP compliance, when results are used for human safety assessment. At the present time, regulatory authorities will most likely...

  18. Oxytocin biotransformation in the rat limbic brain: Characterization of peptidase activities and significance in the formation of oxytocin fragments

    NARCIS (Netherlands)

    Burbach, J.P.H.; Kloet, E.R. de; Wied, D. de

    1980-01-01

    The enzymatic conversion of oxytocin by brain peptidases has been studied. Oxytocin was incubated with synaptosomal plasma membranes (SPM) isolated from the rat brain. Qualitative studies using a microdansylation technique revealed two types of oxytocin converting peptidases, e.g. aminopeptidase and

  19. Development of a Bifunctional Andrographolide-Based Chemical Probe for Pharmacological Study

    OpenAIRE

    Hsu, Ya-Hsin; Hsu, Yu-Ling; Liu, Sheng-Hung; Liao, Hsin-Chia; Lee, Po-Xuan; Lin, Chao-Hsiung; Lo, Lee-Chiang; Fu, Shu-ling

    2016-01-01

    Andrographolide (ANDRO) is a lactone diterpenoid compound present in the medicinal plant Andrographis paniculata which is clinically applied for multiple human diseases in Asia and Europe. The pharmacological activities of andrographolide have been widely demonstrated, including anti-inflammation, anti-cancer and hepatoprotection. However, the pharmacological mechanism of andrographolide remains unclear. Therefore, further characterization on the kinetics and molecular targets of andrographol...

  20. Behavioural pharmacology: 40+ years of progress, with a focus on glutamate receptors and cognition

    OpenAIRE

    Robbins, Trevor W.; Murphy, Emily R.

    2006-01-01

    Behavioural pharmacology is an interdisciplinary field at the intersection of several research areas that ultimately lead to the development of drugs for clinical use and build understanding of how brain functions enable cognition and behaviour. In this article, the development of behavioural pharmacology in the UK is briefly surveyed, and the current status and success of the field is highlighted by the progress in our understanding of learning and memory that has resulted from discoveries i...

  1. Characterization of Behavioral, Neuropathological, Brain Metabolic and Key Molecular Changes in zQ175 Knock-In Mouse Model of Huntington's Disease.

    Directory of Open Access Journals (Sweden)

    Qi Peng

    Full Text Available Huntington's disease (HD is caused by an expansion of the trinucleotide poly (CAG tract located in exon 1 of the huntingtin (Htt gene leading to progressive neurodegeneration in selected brain regions, and associated functional impairments in motor, cognitive, and psychiatric domains. Since the discovery of the gene mutation that causes the disease, mouse models have been developed by different strategies. Recently, a new model, the zQ175 knock-in (KI line, was developed in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. The behavioral phenotype was characterized across the independent laboratories and important features reminiscent of human HD are observed in zQ175 mice. In the current study, we characterized the zQ175 model housed in an academic laboratory under reversed dark-light cycle, including motor function, in vivo longitudinal structural MRI imaging for brain volume, MRS for striatal metabolites, neuropathology, as well as a panel of key disease marker proteins in the striatum at different ages. Our results suggest that homozygous zQ175 mice exhibited significant brain atrophy before the motor deficits and brain metabolite changes. Altered striatal medium spiny neuronal marker, postsynaptic marker protein and complement component C1qC also characterized zQ175 mice. Our results confirmed that the zQ175 KI model is valuable in understanding of HD-like pathophysiology and evaluation of potential therapeutics. Our data also provide suggestions to select appropriate outcome measurements in preclinical studies using the zQ175 mice.

  2. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Goldgaber, D.; Lerman, M.I.; McBride, O.W.; Saffiotti, U.; Gajdusek, D.C.

    1987-02-20

    Four clones were isolated from an adult human brain complementary DNA library with an oligonucleotide probe corresponding to the first 20 amino acids of the ..beta.. peptide of brain amyloid from Alzheimer's disease. The open reading frame of the sequenced clone coded for 97 amino acids, including the known amino acid sequence of this polypeptide. The 3.5-kilobase messenger RNA was detected in mammalian brains and human thymus. The gene is highly conserved in evolution and has been mapped to human chromosome 21.

  3. Tinnitus: Network pathophysiology-network pharmacology

    Directory of Open Access Journals (Sweden)

    Ana Belen eElgoyhen

    2012-01-01

    Full Text Available Tinnitus, the phantom perception of sound, is a prevalent disorder. One in 10 adults has clinically significant subjective tinnitus, and for 1 in 100, tinnitus severely affects their quality of life. Despite the significant unmet clinical need for a safe and effective drug targeting tinnitus relief, there is currently not a single FDA-approved drug on the market. The search for drugs that target tinnitus is hampered by the lack of a deep knowledge of the underlying neural substrates of this pathology. Recent studies are increasingly demonstrating that, as described for other central nervous system disorders, tinnitus is a pathology of brain networks. The application of graph theoretical analysis to brain networks has recently provided new information concerning their topology, their robustness and their vulnerability to attacks. Moreover, the philosophy behind drug design and pharmacotherapy in central nervous system pathologies is changing from that of magic bullets that target individual chemoreceptors or disease-causing genes into that of magic shotguns, promiscuous or dirty drugs that target disease-causing networks, also known as network pharmacology. In the present work we provide some insight into how this knowledge could be applied to tinnitus pathophysiology and pharmacotherapy.

  4. Nematode cholinergic pharmacology

    Energy Technology Data Exchange (ETDEWEB)

    Segerberg, M.A.

    1989-01-01

    Nematode acetylcholine (ACh) receptors were characterized using both biochemical and electrophysiological techniques, including: (1) receptor binding studies in crude homogenates of the free-living nematode Caenorhabditis elegans and the parasitic nematode Ascaris lumbricoides with the high-affinity probe ({sup 3}H)N-methylscopolamine (({sup 3}H)NMS) which binds to muscarinic receptors in many vertebrate and invertebrate tissues (2) measurement of depolarization and contraction induced by a variety of cholinergic agents, including N-methylscopolamine (NMS), in an innervated dorsal muscle strip preparation of Ascaris; (3) examination of the antagonistic actions of d-tubocurarine (dTC) and NMS at dorsal neuromuscular junction; (4) measurement of input resistance changes in Ascaris commissural motorneurons induced by ACh, dTC, NMS, pilocarpine and other cholinergic drugs.

  5. Clinical pharmacology of levosimendan.

    Science.gov (United States)

    Antila, Saila; Sundberg, Stig; Lehtonen, Lasse A

    2007-01-01

    Levosimendan has been developed for the treatment of decompensated heart failure and is used intravenously when patients with heart failure require immediate initiation of drug therapy. It increases cardiac contractility and induces vasodilatation. The pharmacokinetics of levosimendan are linear at the therapeutic dose range of 0.05-0.2 microg/kg/minute. The short half-life (about 1 hour) of the parent drug, levosimendan, enables fast onset of drug action, although the effects are long-lasting due to the active metabolite OR-1896, which has an elimination half-life of 70-80 hours in patients with heart failure (New York Heart Association functional class III-IV). Although levosimendan is administered intravenously, it is excreted into the small intestine and reduced by intestinal bacteria to an amino phenolpyridazinone metabolite (OR-1855). This metabolite is further metabolised by acetylation to N-acetylated conjugate (OR-1896). The circulating metabolites OR-1855 and OR-1896 are formed slowly, and their maximum concentrations are seen on average 2 days after stopping a 24-hour infusion. The haemodynamic effects after levosimendan seem to be similar between fast and slow acetylators despite the fact that the enzyme N-acetyltransferase-2, which is responsible for the metabolism of OR-1855 to OR-1896, is polymorphically distributed in the population. Levosimendan reduces peripheral vascular resistance and has direct contractility-enhancing effects on the failing left ventricle. It also improves indices of diastolic function and seems to improve the function of stunned myocardium. Despite an improvement in ventricular function, levosimendan does not increase myocardial oxygen uptake significantly. An increase in coronary blood flow and a reduction in coronary vascular resistance have been observed. Levosimendan reduces plasma brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels substantially, and a decrease in plasma endothelin-1 has been

  6. PHARMACOLOGICAL ACTIVITIES OF PROTOCATECHUIC ACID.

    Science.gov (United States)

    Khan, Abida Kalsoom; Rashid, Rehana; Fatima, Nighat; Mahmood, Sadaf; Mir, Sadullah; Khan, Sara; Jabeen, Nyla; Murtaza, Ghulam

    2015-01-01

    Protocatechuic acid (3,4-dihydroxybenzoic acid, PCA) is a simple phenolic acid. It is found in a large variety of edible plants and possesses various pharmacological activities. This article aims to review the modern trends in phytochemical isolation and extraction of PCA from plants and other natural resources. Moreover, this article also encompasses pharmacological and biological activities of PCA. It is well known to have anti-inflammatory, antioxidant, anti-hyperglycemia, antibacterial, anticancer, anti-ageing, anti-athro- genic, anti-tumoral, anti-asthma, antiulcer, antispasmodic and neurological properties. PMID:26647619

  7. MR imaging of the effects of methylphenidate on brain structure and function in Attention-Deficit/Hyperactivity Disorder

    NARCIS (Netherlands)

    Schweren, Lizanne J. S.; de Zeeuw, Patrick; Durston, Sarah

    2013-01-01

    Methylphenidate is the first-choice pharmacological intervention for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). The pharmacological and behavioral effects of methylphenidate are well described, but less is known about neurochemical brain changes induced by methylphenidate. Thi

  8. On the characterization of single-event related brain activity from functional Magnetic Resonance Imaging (fMRI) measurements

    KAUST Repository

    Khoram, Nafiseh

    2014-08-01

    We propose an efficient numerical technique for calibrating the mathematical model that describes the singleevent related brain response when fMRI measurements are given. This method employs a regularized Newton technique in conjunction with a Kalman filtering procedure. We have applied this method to estimate the biophysiological parameters of the Balloon model that describes the hemodynamic brain responses. Illustrative results obtained with both synthetic and real fMRI measurements are presented. © 2014 IEEE.

  9. Persistent Impact of In utero Irradiation on Mouse Brain Structure and Function Characterized by MR Imaging and Behavioral Analysis

    OpenAIRE

    Verreet, Tine; Rangarajan, Janaki Raman; QUINTENS, ROEL; Verslegers, Mieke; Lo, Adrian C; Govaerts, Kristof; Neefs, Mieke; Leysen, Liselotte; Baatout, Sarah; Maes, Frederik; Himmelreich, Uwe; D'Hooge, Rudi; Moons, Lieve; Benotmane, Mohammed A.

    2016-01-01

    Prenatal irradiation is known to perturb brain development. Epidemiological studies revealed that radiation exposure during weeks 8–15 of pregnancy was associated with an increased occurrence of mental disability and microcephaly. Such neurological deficits were reproduced in animal models, in which rodent behavioral testing is an often used tool to evaluate radiation-induced defective brain functionality. However, up to now, animal studies suggested a threshold dose of around 0.30 Gray (Gy) ...

  10. In-Vivo Characterization of Glassy Carbon Micro-Electrode Arrays for Neural Applications and Histological Analysis of the Brain Tissue

    Science.gov (United States)

    Vomero, Maria

    The aim of this work is to fabricate and characterize glassy carbon Microelectrode Arrays (MEAs) for sensing and stimulating neural activity, and conduct histological analysis of the brain tissue after the implant to determine long-term performance. Neural applications often require robust electrical and electrochemical response over a long period of time, and for those applications we propose to replace the commonly used noble metals like platinum, gold and iridium with glassy carbon. We submit that such material has the potential to improve the performances of traditional neural prostheses, thanks to better charge transfer capabilities and higher electrochemical stability. Great interest and attention is given in this work, in particular, to the investigation of tissue response after several weeks of implants in rodents' brain motor cortex and the associated materials degradation. As part of this work, a new set of devices for Electrocorticography (ECoG) has been designed and fabricated to improve durability and quality of the previous generation of devices, designed and manufactured by the same research group in 2014. In-vivo long-term impedance measurements and brain activity recordings were performed to test the functionality of the neural devices. In-vitro electrical characterization of the carbon electrodes, as well as the study of the adhesion mechanisms between glassy carbon and different substrates is also part of the research described in this book.

  11. Pharmacology Experiments on the Computer.

    Science.gov (United States)

    Keller, Daniel

    1990-01-01

    A computer program that replaces a set of pharmacology and physiology laboratory experiments on live animals or isolated organs is described and illustrated. Five experiments are simulated: dose-effect relationships on smooth muscle, blood pressure and catecholamines, neuromuscular signal transmission, acetylcholine and the circulation, and…

  12. Pharmacology of Marihuana (Cannabis sativa)

    Science.gov (United States)

    Maickel, Roger P.

    1973-01-01

    A detailed discussion of marihuana (Cannabis sativa) providing the modes of use, history, chemistry, and physiologic properties of the drug. Cites research results relating to the pharmacologic effects of marihuana. These effects are categorized into five areas: behavioral, cardiovascular-respiratory, central nervous system, toxicity-toxicology,…

  13. The pharmacological activities of (-)-anonaine.

    Science.gov (United States)

    Li, Hsing-Tan; Wu, Hui-Ming; Chen, Hsin-Liang; Liu, Chi-Ming; Chen, Chung-Yi

    2013-01-01

    Several species of Magnoliaceae and Annonaceae are used in Traditional Chinese Medicine. (-)-Anonaine, isolated from several species of Magnoliaceae and Annonaceae, presents antiplasmodial, antibacterial, antifungal, antioxidation, anticancer, antidepression, and vasorelaxant activity. This article provides an overview of the pharmacological functions of (-)-anonaine. PMID:23857128

  14. Pharmacologic Agents for Chronic Diarrhea

    OpenAIRE

    Lee, Kwang Jae

    2015-01-01

    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reductio...

  15. The Pharmacological Potential of Mushrooms

    Directory of Open Access Journals (Sweden)

    Ulrike Lindequist

    2005-01-01

    Full Text Available This review describes pharmacologically active compounds from mushrooms. Compounds and complex substances with antimicrobial, antiviral, antitumor, antiallergic, immunomodulating, anti-inflammatory, antiatherogenic, hypoglycemic, hepatoprotective and central activities are covered, focusing on the review of recent literature. The production of mushrooms or mushroom compounds is discussed briefly.

  16. Systems pharmacology of complex diseases

    OpenAIRE

    Hansen, Jens; Zhao, Shan; Iyengar, Ravi

    2011-01-01

    Systems pharmacology approaches can be used to identify and predict drug-induced adverse events. Disease-centered networks within the human interactome allow us to predict which drugs may produce a similar pathophysiology. Such predictions can be tested in animal models.

  17. Chemotaxonomy and pharmacology of Gentianaceae

    DEFF Research Database (Denmark)

    Jensen, Søren Rosendal; Schripsema, Jan

    2002-01-01

    the remaining six are members of the Gentianeae. Based on the above results, a tentative list of chemical characteristics for the tribes of the Gentianaceae is presented. Finally, some pharmacologically interesting properties of plant extracts or compounds from taxa within Gentianaceae are listed....

  18. Pharmacologic neuroimaging of the ontogeny of dopamine receptor function.

    Science.gov (United States)

    Chen, Y Iris; Choi, Ji-Kyung; Xu, Haibo; Ren, Jiaqian; Andersen, Susan L; Jenkins, Bruce G

    2010-07-01

    Characterization of the ontogeny of the cerebral dopaminergic system is crucial for gaining a greater understanding of normal brain development and its alterations in response to drugs of abuse or conditions such as attention-deficit hyperactivity disorder. Pharmacological MRI (phMRI) was used to determine the response to dopamine transporter (DAT) blockers cocaine and methylphenidate (MPH), the dopamine releaser D-amphetamine (AMPH), the selective D1 agonist dihydrexidine, and the D2/D3 agonist quinpirole in young (60 days old) rats. In adult rats, cocaine (0.5 mg/kg i.v.) or MPH (2 mg/kg) induced primarily positive cerebral blood volume (rCBV) changes in the dopaminergic circuitry, but negative rCBV changes in the young animals. Microdialysis measurements in the striatum showed that young rats have a smaller increase in extracellular dopamine in response to cocaine than adults. The young rats showed little rCBV response to the selective D1 agonist dihydrexidine in contrast to robust rCBV increases observed in the adults, whereas there was a similar negative rCBV response in the young and adult rats to the D2 agonist quinpirole. We also performed a meta-analysis of literature data on the development of D1 and D2 receptors and the DAT. These data suggest a predominance of D2-like over D1-like function between 20 and 30 days of age. These combined results suggested that the dopamine D1 receptor is functionally inhibited at young age. PMID:20523024

  19. Clinical pharmacology of homoharringtonine

    Energy Technology Data Exchange (ETDEWEB)

    Savaraj, N.; Lu, K.; Dimery, I.; Feun, L.G.; Burgess, M.; Keating, M.; Loo, T.L.

    1986-12-01

    Clinical pharmacokinetics of homoharringtonine (HHT) were studied in eight patients who received uniformly labeled HHT at 3-4 mg/m2 (150 mu Ci) by continuous 6-hour infusion. The drug and metabolites were quantified by radiochemical and high-performance liquid chromatographic techniques. Computerized nonlinear least-square regression and curve stripping were used to characterize HHT and total (/sup 3/H)HHT equivalent pharmacokinetics. Unchanged HHT in the plasma declined biphasically, with an alpha-half-life of 0.5 +/- 0.1 hours and a beta-half-life of 9.3 +/- 1.4 hours. The total clearance of HHT was 177.4 +/- 27.7 ml X hour-1 X kg-1, and the apparent volume of distribution, estimated from the area under the drug concentration versus time curve, was 2.4 +/- 0.4 L X kg-1. Correspondingly, the total (/sup 3/H)HHT equivalent disappeared from the plasma in a triphasic manner. Compared with the pharmacokinetic parameters of unchanged HHT, the terminal half-life of total /sup 3/H was 67.5 +/- 7.5 hours, 7.4 times longer; the total clearance was 30.9 +/- 3.1 ml X hour-1 X kg-1, 5.5 times slower; but the volume of distribution by area was 2.7 +/- 0.1 L X kg-1, nearly the same. The 72-hour cumulative urinary excretion of total tritium was 28.2% of the administered dose and only 38.3% of this resided in unchanged HHT. Thus, urinary excretion was not a major route of elimination of HHT. Moreover, HHT underwent extensive metabolism; one major and two minor unidentified products were detected in both plasma and urine.

  20. Does brain slices from pentylenetetrazole-kindled mice provide a more predictive screening model for antiepileptic drugs?

    DEFF Research Database (Denmark)

    Hansen, Suzanne L.; Sterjev, Zoran; Werngreen, Marie;

    2012-01-01

    The cortical wedge is a commonly applied model for in vitro screening of new antiepileptic drugs (AEDs) and has been extensively used in characterization of well-known AEDs. However, the predictive validity of this model as a screening model has been questioned as, e.g., carbamazepine has been...... reported to lack effect in this model. The neuroplastic changes induced in acute and chronic animal models of epilepsy are known to affect the pharmacological profile of AEDs in vivo. Hence, we investigated whether brain slices from pentylenetetrazole (PTZ)-kindled animals could provide a more predictive...... screening model for AEDs. To this end, we compared the in vitro and in vivo pharmacological profile of several selected AEDs (phenobarbital, phenytoin, tiagabine, fosphenytoin, valproate, and carbamazepine) along with citalopram using the PTZ-kindled model and brain slices from naïve, saline...

  1. Clinical pharmacology and vascular risk.

    Science.gov (United States)

    Silvestrelli, G; Corea, F; Micheli, S; Lanari, A

    2010-01-01

    Pharmacological treatment and several drugs of abuse have been associated with ischemic heart disease (IHD) and cerebrovascular diseases (CVD). However, there is a paucity of data on the independent risk of vascular disease (VD) associated with pharmacological treatment and no controlled trials demonstrating a reduction in risk with abstinence. Information about IHD and CVD-related drug abuse is mainly limited to epidemiological studies focused on urban populations. The potential link between some pharmacological treatments (estrogen, some oncologic drugs and some atypical antipsychotics) and cerebrovascular adverse events was analyzed, but disagreement about an association persists. Drugs of abuse, including cocaine, amphetamines and heroin, have been associated with an increased vascular risk. These drugs can cause abrupt changes in blood pressure, vasculitic-type changes, lead to embolization caused by infective endocarditis, and hemostatic and hematologic abnormalities that can result in increased blood viscosity and platelet aggregation. Long-term treatment strategies based on medication, psychological support, and outreach programs play an important role in treatment of drug dependency. In these last years public interest in risk factors for VD has been constantly increasing and the successful identification and management of pharmacological treatment and drug abuse can be challenging. One of the major public health issues for the future will be to focus more on new vascular risk factor recognition and management. The objective of this chapter is to review the relevance of IHD and CVD associated with various pharmacological treatments and drug abuse with focusing on ischemic disease. This chapter reports the clinical evidence of this association and analyzes the experimental role of new drugs as a growing risk factor of VD with the hypothetical new association. In conclusion, in this chapter great attention is paid to evaluating the scientific and real

  2. A pharmacological characterization of GABA, THIP and DS2 at binary α4β3 and β3δ receptors: GABA activates β3δ receptors via the β3(+)δ(-) interface.

    Science.gov (United States)

    Lee, H J; Absalom, N L; Hanrahan, J R; van Nieuwenhuijzen, P; Ahring, P K; Chebib, M

    2016-08-01

    There is growing evidence that GABA (γ-aminobutyric acid) can activate GABAA receptors (GABAARs) in the absence of an α subunit. In this study, we compared the pharmacology of homomeric and binary α4, β3 or δ subunits with ternary α4β3δ to identify subunit interfaces that contribute to the pharmacology of GABA, THIP, and DS2, and the antagonists, Zn(2+), gabazine and bicuculline. β3δ receptors form functional GABA-gated channels when expressed in Xenopus oocytes with a pharmacology that differs to homomeric β3, binary α4β3 and ternary α4β3δ receptors. GABA had similar potency at α4β3 and β3δ receptors (25µM and 26µM, respectively) but differed at α4β3δ receptors where GABA exhibited a biphasic concentration-response (EC50 (1)=12.6nM; EC50 (2)=6.3μM). THIP activated β3δ receptors (EC50=456μM) but was a more potent activator of α4β3 (EC50=27μM) and α4β3δ receptors (EC50 (1)=27.5nM; EC50 (2)=29.5μΜ), indicating that the α4 subunit significantly contribute to its potency. The δ-preferring modulator, DS2 had marginal or no effect at β3δ and α4β3 receptors, indicating a role for both the α4 and δ subunits for its potency. Gabazine inhibited GABA-elicited currents at β3δ receptors whereas bicuculline activated these receptors. Mutational analysis verified that GABA binds to the β3(+)δ(-) interface formed by the β3 and δ subunits. In conclusion, evaluating agents against binary GABAARs such as β3δ and α4β3 receptors enables identification of interfaces that may contribute to the pharmacology of the more complex ternary α4β3δ receptors. PMID:27181518

  3. Phytochemistry and pharmacology of berberis species.

    Science.gov (United States)

    Mokhber-Dezfuli, Najmeh; Saeidnia, Soodabeh; Gohari, Ahmad Reza; Kurepaz-Mahmoodabadi, Mahdieh

    2014-01-01

    The genus Berberis (Berberidaceae) includes about 500 species worldwide, some of which are widely cultivated in the north-eastern regions of Iran. This genus consists of spiny deciduous evergreen shrubs, characterized by yellow wood and flowers. The cultivation of seedless barberry in South Khorasan goes back to two hundred years ago. Medicinal properties for all parts of these plants have been reported, including: Antimicrobial, antiemetic, antipyretic, antioxidant, anti-inflammatory, anti-arrhythmic, sedative, anti-cholinergic, cholagogic, anti-leishmaniasis, and anti-malaria. The main compounds found in various species of Berberis, are berberine and berbamine. Phytochemical analysis of various species of this genus revealed the presence of alkaloids, tannins, phenolic compounds, sterols and triterpenes. Although there are some review articles on Berberis vulgaris (as the most applied species), there is no review on the phytochemical and pharmacological activities of other well-known species of the genus Berberis. For this reason, the present review mainly focused on the diverse secondary metabolites of various species of this genus and the considerable pharmacological and biological activities together with a concise story of the botany and cultivation. PMID:24600191

  4. Phytochemistry and Pharmacology of Berberis Species

    Directory of Open Access Journals (Sweden)

    Najmeh Mokhber-Dezfuli

    2014-01-01

    Full Text Available The genus Berberis (Berberidaceae includes about 500 species worldwide, some of which are widely cultivated in the north-eastern regions of Iran. This genus consists of spiny deciduous evergreen shrubs, characterized by yellow wood and flowers. The cultivation of seedless barberry in South Khorasan goes back to two hundred years ago. Medicinal properties for all parts of these plants have been reported, including: Antimicrobial, antiemetic, antipyretic, antioxidant, anti-inflammatory, anti-arrhythmic, sedative, anti-cholinergic, cholagogic, anti-leishmaniasis, and anti-malaria. The main compounds found in various species of Berberis, are berberine and berbamine. Phytochemical analysis of various species of this genus revealed the presence of alkaloids, tannins, phenolic compounds, sterols and triterpenes. Although there are some review articles on Berberis vulgaris (as the most applied species, there is no review on the phytochemical and pharmacological activities of other well-known species of the genus Berberis. For this reason, the present review mainly focused on the diverse secondary metabolites of various species of this genus and the considerable pharmacological and biological activities together with a concise story of the botany and cultivation.

  5. Pharmacological benefits of agomelatine and vanillin in experimental model of Huntington's disease.

    Science.gov (United States)

    Gupta, Surbhi; Sharma, Bhupesh

    2014-07-01

    Huntington's disease (HD), a devastating neurodegenerative disorder, is characterized by progressive motor dysfunction, emotional disturbances, dementia, weight loss, depression. Melatonin receptors are widely expressed in the central nervous system. Vanilloids are also valuable as pharmacological tools for investigating neurobiology. This study investigates the utility of agomelatine, a dual agonist of MT₁ and MT₂ melatonin receptor as well as vanillin, a selective agonist of TRPV₁ (vanilloid receptor) in 3-nitropropionic acid (3-NPA) induced experimental HD in rats. Locomotor activity (Actophotometer), motor coordination (Rota rod) and learning-memory (Morris water maze) were assessed. Brain striatum oxidative stress (lipid peroxidation-MDA, glutathione-GSH, superoxide dismutase-SOD and catalase-CAT), nitrosative stress (nitrite/nitrate) and mitochondrial enzyme complexes (I, II and IV) were also assessed. 3-NPA has induced weight loss, impaired locomotion, motor coordination as well as learning and memory. It has induced brain striatum oxidative as well as nitrosative stress, cholinergic dysfunction and impaired mitochondrial enzyme complexes (I, II and IV). Tetrabenazine (TBZ) was used as positive control. Treatment with agomelatine and vanillin and TBZ has significantly attenuated 3-NPA induced weight loss, impaired locomotion, motor coordination and learning-memory as well as biochemical impairments. Thus, agomelatine and vanillin exhibit protective effects against 3-NPA induced HD. It may be concluded that agomelatine and vanillin may provide benefits in HD.

  6. Persistent Impact of In utero Irradiation on Mouse Brain Structure and Function Characterized by MR Imaging and Behavioral Analysis.

    Science.gov (United States)

    Verreet, Tine; Rangarajan, Janaki Raman; Quintens, Roel; Verslegers, Mieke; Lo, Adrian C; Govaerts, Kristof; Neefs, Mieke; Leysen, Liselotte; Baatout, Sarah; Maes, Frederik; Himmelreich, Uwe; D'Hooge, Rudi; Moons, Lieve; Benotmane, Mohammed A

    2016-01-01

    Prenatal irradiation is known to perturb brain development. Epidemiological studies revealed that radiation exposure during weeks 8-15 of pregnancy was associated with an increased occurrence of mental disability and microcephaly. Such neurological deficits were reproduced in animal models, in which rodent behavioral testing is an often used tool to evaluate radiation-induced defective brain functionality. However, up to now, animal studies suggested a threshold dose of around 0.30 Gray (Gy) below which no behavioral alterations can be observed, while human studies hinted at late defects after exposure to doses as low as 0.10 Gy. Here, we acutely irradiated pregnant mice at embryonic day 11 with doses ranging from 0.10 to 1.00 Gy. A thorough investigation of the dose-response relationship of altered brain function and architecture following in utero irradiation was achieved using a behavioral test battery and volumetric 3D T2-weighted magnetic resonance imaging (MRI). We found dose-dependent changes in cage activity, social behavior, anxiety-related exploration, and spatio-cognitive performance. Although behavioral alterations in low-dose exposed animals were mild, we did unveil that both emotionality and higher cognitive abilities were affected in mice exposed to ≥0.10 Gy. Microcephaly was apparent from 0.33 Gy onwards and accompanied by deviations in regional brain volumes as compared to controls. Of note, total brain volume and the relative volume of the ventricles, frontal and posterior cerebral cortex, cerebellum, and striatum were most strongly correlated to altered behavioral parameters. Taken together, we present conclusive evidence for persistent low-dose effects after prenatal irradiation in mice and provide a better understanding of the correlation between their brain size and performance in behavioral tests. PMID:27199692

  7. Persistent Impact of In Utero Irradiation on Mouse Brain Structure and Function Characterized by MR Imaging and Behavioral Analysis

    Directory of Open Access Journals (Sweden)

    Tine eVerreet

    2016-05-01

    Full Text Available Prenatal irradiation is known to perturb brain development. Epidemiological studies revealed that radiation exposure during weeks 8 to 15 of pregnancy was associated with an increased occurrence of mental disability and microcephaly. Such neurological deficits were reproduced in animal models, in which rodent behavioral testing is an often used tool to evaluate radiation-induced defective brain functionality. However, up to now, animal studies suggested a threshold dose of around 0.30 Gray (Gy below which no behavioral alterations can be observed, while human studies hinted at late defects after exposure to doses as low as 0.10 Gy. Here, we acutely irradiated pregnant mice at embryonic day 11 with doses ranging from 0.10 to 1.00 Gy. A thorough investigation of the dose-response relationship of altered brain function and architecture following in utero irradiation was achieved using a behavioral test battery and volumetric 3D T2-weighted magnetic resonance imaging (MRI. We found dose-dependent changes in cage activity, social behavior, anxiety-related exploration and spatio-cognitive performance. Although behavioral alterations in low-dose exposed animals were mild, we did unveil that both emotionality and higher cognitive abilities were affected in mice exposed to ≥ 0.10 Gy. Microcephaly was apparent from 0.33 Gy onwards and accompanied by deviations in regional brain volumes as compared to controls. Of note, total brain volume and the relative volume of the ventricles, frontal and posterior cerebral cortex, cerebellum and striatum were most strongly correlated to altered behavioral parameters. Taken together, we present conclusive evidence for persistent low-dose effects after prenatal irradiation in mice and provide a better understanding of the correlation between their brain size and performance in behavioral tests.

  8. Persistent Impact of In utero Irradiation on Mouse Brain Structure and Function Characterized by MR Imaging and Behavioral Analysis

    Science.gov (United States)

    Verreet, Tine; Rangarajan, Janaki Raman; Quintens, Roel; Verslegers, Mieke; Lo, Adrian C.; Govaerts, Kristof; Neefs, Mieke; Leysen, Liselotte; Baatout, Sarah; Maes, Frederik; Himmelreich, Uwe; D'Hooge, Rudi; Moons, Lieve; Benotmane, Mohammed A.

    2016-01-01

    Prenatal irradiation is known to perturb brain development. Epidemiological studies revealed that radiation exposure during weeks 8–15 of pregnancy was associated with an increased occurrence of mental disability and microcephaly. Such neurological deficits were reproduced in animal models, in which rodent behavioral testing is an often used tool to evaluate radiation-induced defective brain functionality. However, up to now, animal studies suggested a threshold dose of around 0.30 Gray (Gy) below which no behavioral alterations can be observed, while human studies hinted at late defects after exposure to doses as low as 0.10 Gy. Here, we acutely irradiated pregnant mice at embryonic day 11 with doses ranging from 0.10 to 1.00 Gy. A thorough investigation of the dose-response relationship of altered brain function and architecture following in utero irradiation was achieved using a behavioral test battery and volumetric 3D T2-weighted magnetic resonance imaging (MRI). We found dose-dependent changes in cage activity, social behavior, anxiety-related exploration, and spatio-cognitive performance. Although behavioral alterations in low-dose exposed animals were mild, we did unveil that both emotionality and higher cognitive abilities were affected in mice exposed to ≥0.10 Gy. Microcephaly was apparent from 0.33 Gy onwards and accompanied by deviations in regional brain volumes as compared to controls. Of note, total brain volume and the relative volume of the ventricles, frontal and posterior cerebral cortex, cerebellum, and striatum were most strongly correlated to altered behavioral parameters. Taken together, we present conclusive evidence for persistent low-dose effects after prenatal irradiation in mice and provide a better understanding of the correlation between their brain size and performance in behavioral tests. PMID:27199692

  9. Pharmacology teaching and its reform in China

    Institute of Scientific and Technical Information of China (English)

    Wei-dong LI; Yuan ZHANG; Cai-li ZHANG; Xiu-mei ZHANG

    2004-01-01

    The general situation of pharmacology teaching in China was introduced and the educational reform in China in recent decade is summarized. The aim of the article is to provide those who are interested in teaching of pharmacology to be acquainted with the teaching of pharmacology, including the teaching of both principles and practice, in China.

  10. Applications of stable isotopes in clinical pharmacology

    NARCIS (Netherlands)

    Schellekens, Reinout C A; Stellaard, Frans; Woerdenbag, Herman J; Frijlink, Henderik W; Kosterink, Jos G W

    2011-01-01

    This review aims to present an overview of the application of stable isotope technology in clinical pharmacology. Three main categories of stable isotope technology can be distinguished in clinical pharmacology. Firstly, it is applied in the assessment of drug pharmacology to determine the pharmacok

  11. Radioimmunoassay in basic and clinical pharmacology

    Energy Technology Data Exchange (ETDEWEB)

    Patrono, C.; Peskar, B.A.

    1987-01-01

    The subject of the book is the development, validation and application of radioimmunoassay (RIA) techniques for the measurement of a variety of substances in animal and human body fluids. The book discusses methodological and conceptual issues related to the main classes of mediators of drug action and to drugs themselves, as assayed by this particular analytical technique. A number of introductory chapters provide basic information concerning production and characterization of antibodies, labeling techniques, statistical aspects and validation criteria, insight into problems related to the development and validation of RIA for the newly discovered mediator(s). In the following chapters, the emphasis is placed on the technical details relevant to each class of compounds and on specific aspects of their applications to basic and/or clinical pharmacological studies. New developments in this area, such as monoclonal antibodies and non-radioactive labeling techniques, are also covered.

  12. Characterization of β-endorphin-immunoreactivity in limbic brain structures of rats self-administering heroin or cocaine

    NARCIS (Netherlands)

    Sweep, C.G.J.; Ree, J.M. van; Wiegant, V.M.

    1988-01-01

    The effects of intravenous self-administration of 30 μg infusions of either heroin or cocaine, or saline on the concentrations of β-endorphin-immunoreactivity (βE-IR) in the anterior part of the rat brain limbic system were studied. Self-administration of heroin and cocaine for 5 daily sessions resu

  13. Identification and characterization of neuroblasts in the subventricular zone and rostral migratory stream of the adult human brain

    Institute of Scientific and Technical Information of China (English)

    Congmin Wang; Qiangqiang Zhang; Yue Zhang; Rui Chen; Hongjun Song; Zhengang Yang; Fang Liu; Ying-Ying Liu; Cai-Hong Zhao; Yan You; Lei Wang; Jingxiao Zhang; Bin Wei; Tong Ma

    2011-01-01

    It is of great interest to identify new neurons in the adult human brain,but the persistence of neurogenesis in the subventricular zone (SVZ) and the existence of the rostral migratory stream (RMS)-like pathway in the adult human forebrain remain highly controversial.In the present study,we have described the general configuration of the RMS in adult monkey,fetal human and adult human brains.We provide evidence that neuroblasts exist continuously in the anterior ventral SVZ and RMS of the adult human brain.The neuroblasts appear singly or in pairs without forming chains; they exhibit migratory morphologies and co-express the immature neuronal markers doublecortin,polysialylated neural cell adhesion molecule and βI-tubulin.Few of these neuroblasts appear to be actively proliferating in the anterior ventral SVZ but none in the RMS,indicating that neuroblasts distributed along the RMS are most likely derived from the ventral SVZ.Interestingly,no neuroblasts are found in the adult human olfactory bulb.Taken together,our data suggest that the SVZ maintains the ability to produce neuroblasts in the adult human brain.

  14. Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist.

    Science.gov (United States)

    Steiner, Michel A; Gatfield, John; Brisbare-Roch, Catherine; Dietrich, Hendrik; Treiber, Alexander; Jenck, Francois; Boss, Christoph

    2013-06-01

    Stress relief: Orexin neuropeptides regulate arousal and stress processing through orexin receptor type 1 (OXR-1) and 2 (OXR-2) signaling. A selective OXR-1 antagonist, represented by a phenylglycine-amide substituted tetrahydropapaverine derivative (ACT-335827), is described that is orally available, penetrates the brain, and decreases fear, compulsive behaviors and autonomic stress reactions in rats.

  15. Pharmacological effects of Sapindus mukorossi.

    Science.gov (United States)

    Upadhyay, Aparna; Singh, D K

    2012-01-01

    Sapindus mukorossi is an extremely valuable medicinal plant, distributed in tropical and sub-tropical regions of Asia. The aim of present review is to form a short compilation of the phytochemical composition and pharmacological properties of this multipurpose tree. The main phytoconstituents isolated and identified from different parts of this plant are triterpenoidal saponins of oleanane, dammarane and tirucullane type. The structure and chemical names of all the types of triterpenoidal saponins reported in Sapindus mukorossi are included in this review. Many research studies have been conducted to prove the plant's potential as being spermicidal, contraceptive, hepatoprotective, emetic, anti-inflammatory and anti-protozoal. The present review highlights some of the salient pharmacological uses of Sapindus mukorossi. PMID:22983291

  16. Pharmacological effects of Sapindus mukorossi

    Directory of Open Access Journals (Sweden)

    Aparna Upadhyay

    2012-10-01

    Full Text Available Sapindus mukorossi is an extremely valuable medicinal plant, distributed in tropical and sub-tropical regions of Asia. The aim of present review is to form a short compilation of the phytochemical composition and pharmacological properties of this multipurpose tree. The main phytoconstituents isolated and identified from different parts of this plant are triterpenoidal saponins of oleanane, dammarane and tirucullane type. The structure and chemical names of all the types of triterpenoidal saponins reported in Sapindus mukorossi are included in this review. Many research studies have been conducted to prove the plant's potential as being spermicidal, contraceptive, hepatoprotective, emetic, anti-inflammatory and anti-protozoal. The present review highlights some of the salient pharmacological uses of Sapindus mukorossi.

  17. Pharmacological potential of cerium oxidenanoparticles

    Science.gov (United States)

    Celardo, Ivana; Pedersen, Jens Z.; Traversa, Enrico; Ghibelli, Lina

    2011-04-01

    Nanotechnology promises a revolution in pharmacology to improve or create ex novo therapies. Cerium oxidenanoparticles (nanoceria), well-known as catalysts, possess an astonishing pharmacological potential due to their antioxidant properties, deriving from a fraction of Ce3+ ions present in CeO2. These defects, compensated by oxygen vacancies, are enriched at the surface and therefore in nanosized particles. Reactions involving redox cycles between the Ce3+ and Ce4+oxidation states allow nanoceria to react catalytically with superoxide and hydrogen peroxide, mimicking the behavior of two key antioxidant enzymes, superoxide dismutase and catalase, potentially abating all noxious intracellularreactive oxygen species (ROS) via a self-regenerating mechanism. Hence nanoceria, apparently well tolerated by the organism, might fight chronic inflammation and the pathologies associated with oxidative stress, which include cancer and neurodegeneration. Here we review the biological effects of nanoceria as they emerge from in vitro and in vivo studies, considering biocompatibility and the peculiar antioxidant mechanisms.

  18. 3D characterization of brain atrophy in Alzheimer's disease and mild cognitive impairment using tensor-based morphometry.

    Science.gov (United States)

    Hua, Xue; Leow, Alex D; Lee, Suh; Klunder, Andrea D; Toga, Arthur W; Lepore, Natasha; Chou, Yi-Yu; Brun, Caroline; Chiang, Ming-Chang; Barysheva, Marina; Jack, Clifford R; Bernstein, Matt A; Britson, Paula J; Ward, Chadwick P; Whitwell, Jennifer L; Borowski, Bret; Fleisher, Adam S; Fox, Nick C; Boyes, Richard G; Barnes, Josephine; Harvey, Danielle; Kornak, John; Schuff, Norbert; Boreta, Lauren; Alexander, Gene E; Weiner, Michael W; Thompson, Paul M

    2008-05-15

    Tensor-based morphometry (TBM) creates three-dimensional maps of disease-related differences in brain structure, based on nonlinearly registering brain MRI scans to a common image template. Using two different TBM designs (averaging individual differences versus aligning group average templates), we compared the anatomical distribution of brain atrophy in 40 patients with Alzheimer's disease (AD), 40 healthy elderly controls, and 40 individuals with amnestic mild cognitive impairment (aMCI), a condition conferring increased risk for AD. We created an unbiased geometrical average image template for each of the three groups, which were matched for sex and age (mean age: 76.1 years+/-7.7 SD). We warped each individual brain image (N=120) to the control group average template to create Jacobian maps, which show the local expansion or compression factor at each point in the image, reflecting individual volumetric differences. Statistical maps of group differences revealed widespread medial temporal and limbic atrophy in AD, with a lesser, more restricted distribution in MCI. Atrophy and CSF space expansion both correlated strongly with Mini-Mental State Exam (MMSE) scores and Clinical Dementia Rating (CDR). Using cumulative p-value plots, we investigated how detection sensitivity was influenced by the sample size, the choice of search region (whole brain, temporal lobe, hippocampus), the initial linear registration method (9- versus 12-parameter), and the type of TBM design. In the future, TBM may help to (1) identify factors that resist or accelerate the disease process, and (2) measure disease burden in treatment trials.

  19. Brain Basics

    Medline Plus

    Full Text Available ... News About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The Working Brain ... to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are ...

  20. Brain Basics

    Science.gov (United States)

    ... News About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The Working Brain ... to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are ...

  1. Brain Basics

    Medline Plus

    Full Text Available ... Brain Basics provides information on how the brain works, how mental illnesses are disorders of the brain, ... learning more about how the brain grows and works in healthy people, and how normal brain development ...

  2. Pharmacological effects of Sapindus mukorossi

    OpenAIRE

    Aparna Upadhyay; D K Singh

    2012-01-01

    Sapindus mukorossi is an extremely valuable medicinal plant, distributed in tropical and sub-tropical regions of Asia. The aim of present review is to form a short compilation of the phytochemical composition and pharmacological properties of this multipurpose tree. The main phytoconstituents isolated and identified from different parts of this plant are triterpenoidal saponins of oleanane, dammarane and tirucullane type. The structure and chemical names of all the types of triterpenoidal sap...

  3. [Pharmacologic treatment of Asperger syndrome].

    Science.gov (United States)

    Yamada, Satoru

    2007-03-01

    Asperger syndrome is associated with various dysfunctional and problematic behaviors, in addition to the core features of communication and social skills dysfunction that define these conditions. Although there is currently no pharmacologic cure for the core features of Asperger syndrome. This article discusses the various medications for the behavioral symptoms of Asperger syndrome, which include hyperactivity, aggression, tantrums, self-injury, depression, obsession and so on. Methylphenidate, SSRIs, atypical antipsychotics and mood stabilizer were introduced.

  4. Pharmacologic management of eating disorders.

    Science.gov (United States)

    Price, W A

    1988-05-01

    Treatment of eating disorders is difficult regardless of the methods employed. Pharmacologic management in anorexia nervosa and in bulimia nervosa is especially helpful when it is part of a multimodal treatment approach that includes individual, family and behavioral therapy. Care must be taken to guard against side effects, abuse and noncompliance in a group of patients that tends to be prone to all three. PMID:3284300

  5. The clinical pharmacology of ageing

    OpenAIRE

    Swift, C G

    2003-01-01

    The ageing of populations and individuals continues to be as vital, yet to some extent as neglected, a topic in pharmacology and therapeutics as was first realised about 30 years ago. In parallel with the realisation of the predicted demographic shifts in both the developed and developing world, there have since been major developments in the basic biological concepts of ageing, in the physiology of ageing, in the study of pathogenetic mechanisms underlying a variety of age-associated disorde...

  6. Identification, characterization, and purification of a 65,000 dalton protein in rat brain is photolabeled by nitro-containing benzodiazepines

    International Nuclear Information System (INIS)

    Benzodiazepines bind to two well-characterized classes of nanomolar-affinity binding sites, the central and the peripheral types. Although these sites appear to mediate many of the effects of these compounds, they cannot account for all of the biochemical and physiologic effects of the benzodiazepines. In this investigation, a protein that is photolabeled by NO2-containing benzodiazepines was identified and characterized in rat brain by performing photaffinity labeling experiments with [3H]-clonazepam and [3H]-flunitrazepam. These experiments demonstrate that this photolabeled protein has a molecular weight of 65,000 daltons. Photolabeling of the protein was saturable, inhibited in a stereoselective manner by benzodiazepine enantiomers, inhibited by therapeutically-relevant concentrations of many different NO2-containing benzodiazepines, and was not inhibited by more than 70 non-benzodiazepine compounds. The photolabeled protein is distinct from the central and peripheral sites on the basis of molecular weight, benzodiazepine inhibitory potencies, subcellular localization, and tissue distribution

  7. Synthesis and pharmacological characterization of a new PET ligand for the serotonin transporter: [{sup 11}C]5-bromo-2-[2-(dimethylaminomethylphenylsulfanyl)]phenylamine ([{sup 11}C]DAPA)

    Energy Technology Data Exchange (ETDEWEB)

    Huang Yiyun E-mail: hh285@columbia.edu; Hwang, D.-R.; Zhu Zhihong; Bae, S.-A.; Guo Ningning; Sudo, Yasuhiko; Kegeles, Lawrence S.; Laruelle, Marc

    2002-10-01

    A new PET radioligand for the serotonin transporter (SERT), [{sup 11}C]-5-bromo-2-[2-(dimethylaminomethylphenylsulfanyl)]phenylamine ([{sup 11}C]DAPA (10), was synthesized and evaluated in vivo in rats and baboons. [{sup 11}C]DAPA (10) was prepared from its monomethylamino precursor 8 by reaction with high specific activity [{sup 11}C]methyl iodide. Radiochemical yield was 24{+-}5% based on [{sup 11}C]methyl iodide at end of bombardment (EOB, n=10) and specific activity was 1553{+-}939 Ci/mmol at end of synthesis (EOS, n=10). Binding assays indicated that [{sup 11}C]DAPA displays high affinity (Ki 1.49{+-}0.28 nM for hSERT) and good selectivity for the SERT in vitro. Biodistribution studies in rats indicated that [{sup 11}C]DAPA enters into the brain readily and localizes in brain regions known to contain high concentrations of SERT, such as the thalamus, hypothalamus, frontal cortex and striatum. Moreover, such binding in SERT-rich regions of the brain are blocked by pretreatment with either the selective serotonin reuptake inhibitor (SSRI) citalopram and by the cold compound itself, demonstrating that [{sup 11}C]DAPA binding in the rat brain is saturable and specific to SERT. Imaging experiments in baboons indicated that [{sup 11}C]DAPA binding is consistent with the known distribution of SERT in the baboon brain, with highest levels of radioactivity detected in the midbrain and thalamus, intermediate levels in the hippocampus and striatum, and lower levels in the cortical regions. Pretreatment of the baboon with citalopram 10 min before radioactivity injection blocked the binding of [{sup 11}C]DAPA in all brain regions that contain SERT. Kinetic analysis revealed that, in all brain regions examined, [{sup 11}C]DAPA specific to nonspecific distribution volume ratios (V{sub 3}'') are higher than [{sup 11}C](+)-McN 5652 and similar to [{sup 11}C]DASB. In summary, [{sup 11}C]DAPA appears to be a promising radioligand suitable for the visualization of SERT

  8. Characterization of seven cocaine- and amphetamine-regulated transcripts (CARTs) differentially expressed in the brain and peripheral tissues of Solea senegalensis (Kaup).

    Science.gov (United States)

    Bonacic, Kruno; Martínez, Almudena; Martín-Robles, Águeda J; Muñoz-Cueto, José A; Morais, Sofia

    2015-12-01

    CART (cocaine- and amphetamine-regulated transcript) is a peptide with neurotransmitter and neuroendocrine functions with several key roles, both centrally and peripherally. In mammals there is a single gene that produces two alternatively spliced variants in rat and a single transcript in human but in teleosts multiple genes have been found. In the present study we report the existence of seven transcripts in Senegalese sole and characterize their sequences and phylogenetic relationships, as well as their expression patterns in the brain and peripheral tissues, and in response to feeding. Both cart2a and cart4 showed a ubiquitous expression in the brain, while cart1a, cart1b and cart3a were similarly expressed and had higher transcript levels in the mesencephalon, followed by the diencephalon. On the other hand, cart2b showed a main expression in the olfactory bulbs, and cart3b was predominantly expressed in the spinal cord. The expression profile in peripheral tissues differed substantially between cart's, even between more recently duplicated genes. Collectively, all the tissues examined, except the muscle, express at least one of the different cart's, although the highest transcript levels were found in the brain, gonads (ovary and testis) and, in some cases, eye and kidney. Concerning the feeding response, only brain cart1a, cart2a and cart4 showed a significant postprandial regulation, although future studies are necessary to assess potential confounding effects of stress imposed by the force feeding technique employed. Senegalese sole exhibits the highest number of cart genes reported to date in a vertebrate species. Their differential expression patterns and feeding regulation suggest that multiple cart genes, resulting from at least 3 rounds of whole genome duplication, have been retained in fish genomes through subfunctionalization, or possibly even through neofunctionalization. PMID:26320854

  9. The pharmacology of catecholamine involvement in the neural mechanisms of reward.

    Science.gov (United States)

    Wauquier, A

    1980-01-01

    The neurophysiological basis of motivation became a major research goal with the discovery of brain self-stimulation. Correlative anatomical and neurochemical mapping of self-stimulation sites led to the catecholamine theory of self-stimulation. The present review summarizes the pharmacological evidence pertinent to this theory and formulates conclusions on the functional role of catecholamine systems in behavior reinforced by electrical brain-stimulation.

  10. Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington's disease.

    Directory of Open Access Journals (Sweden)

    Taneli Heikkinen

    Full Text Available Huntington's disease (HD is an autosomal neurodegenerative disorder, characterized by severe behavioral, cognitive, and motor deficits. Since the discovery of the huntingtin gene (HTT mutation that causes the disease, several mouse lines have been developed using different gene constructs of Htt. Recently, a new model, the zQ175 knock-in (KI mouse, was developed (see description by Menalled et al, [1] in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. Here we confirm the behavioral phenotypes reported by Menalled et al [1], and extend the characterization to include brain volumetry, striatal metabolite concentration, and early neurophysiological changes. The overall reproducibility of the behavioral phenotype across the two independent laboratories demonstrates the utility of this new model. Further, important features reminiscent of human HD pathology are observed in zQ175 mice: compared to wild-type neurons, electrophysiological recordings from acute brain slices reveal that medium spiny neurons from zQ175 mice display a progressive hyperexcitability; glutamatergic transmission in the striatum is severely attenuated; decreased striatal and cortical volumes from 3 and 4 months of age in homo- and heterozygous mice, respectively, with whole brain volumes only decreased in homozygotes. MR spectroscopy reveals decreased concentrations of N-acetylaspartate and increased concentrations of glutamine, taurine and creatine + phosphocreatine in the striatum of 12-month old homozygotes, the latter also measured in 12-month-old heterozygotes. Motor, behavioral, and cognitive deficits in homozygotes occur concurrently with the structural and metabolic changes observed. In sum, the zQ175 KI model has robust behavioral, electrophysiological, and histopathological features that may be valuable in both furthering our understanding of HD-like pathophyisology and the evaluation of potential therapeutic

  11. Understanding brain networks and brain organization

    Science.gov (United States)

    Pessoa, Luiz

    2014-09-01

    What is the relationship between brain and behavior? The answer to this question necessitates characterizing the mapping between structure and function. The aim of this paper is to discuss broad issues surrounding the link between structure and function in the brain that will motivate a network perspective to understanding this question. However, as others in the past, I argue that a network perspective should supplant the common strategy of understanding the brain in terms of individual regions. Whereas this perspective is needed for a fuller characterization of the mind-brain, it should not be viewed as panacea. For one, the challenges posed by the many-to-many mapping between regions and functions is not dissolved by the network perspective. Although the problem is ameliorated, one should not anticipate a one-to-one mapping when the network approach is adopted. Furthermore, decomposition of the brain network in terms of meaningful clusters of regions, such as the ones generated by community-finding algorithms, does not by itself reveal "true" subnetworks. Given the hierarchical and multi-relational relationship between regions, multiple decompositions will offer different "slices" of a broader landscape of networks within the brain. Finally, I described how the function of brain regions can be characterized in a multidimensional manner via the idea of diversity profiles. The concept can also be used to describe the way different brain regions participate in networks.

  12. Working memory in attention deficit/hyperactivity disorder is characterized by a lack of specialization of brain function.

    Directory of Open Access Journals (Sweden)

    Catherine Fassbender

    Full Text Available Working memory impairments are frequent in Attention Deficit/Hyperactivity Disorder (ADHD and create problems along numerous functional dimensions. The present study utilized the Visual Serial Addition Task (VSAT and functional magnetic resonance imaging (fMRI to explore working memory processes in thirteen typically developing (TD control and thirteen children with ADHD, Combined type. Analysis of Variance (ANOVA was used to examine both main effects and interactions. Working memory-specific activity was found in TD children in the bilateral prefrontal cortex. In contrast the within-group map in ADHD did not reveal any working-memory specific regions. Main effects of condition suggested that the right middle frontal gyrus (BA6 and the right precuneus were engaged by both groups during working memory processing. Group differences were driven by significantly greater, non-working memory-specific, activation in the ADHD relative to TD group in the bilateral insula extending into basal ganglia and the medial prefrontal cortex. A region of interest analysis revealed a region in left middle frontal gyrus that was more active during working memory in TD controls. Thus, only the TD group appeared to display working memory-modulated brain activation. In conclusion, children with ADHD demonstrated reduced working memory task specific brain activation in comparison to their peers. These data suggest inefficiency in functional recruitment by individuals with ADHD represented by a poor match between task demands and appropriate levels of brain activity.

  13. SPECT imaging of dopamine receptors with [123I]epidepride: characterization of uptake in the human brain

    International Nuclear Information System (INIS)

    Summary. [123I]Epidepride is a new ligand for single photon emission computerized tomography (SPECT) that specifically labels D2-like dopamine receptors with very high affinity. Here, we report on the regional kinetic uptake of [123I]epidepride in the brain of 4 normal volunteers and 3 patients with choreatic movement disorders. In healthy subjects striatal activity peaked at 2.5 hours after injection of the tracer and decreased slowly thereafter. There were no significant differences between left and right brain hemispheres. Activity above background was also measurable in areas corresponding to the thalamus, temporal cortex and frontal cortex. The striatal to cerebellar ratio was about 14 after 2.5 hours and this ratio steadily increased with time. The striatal to cerebellar ratio was clearly reduced in all 3 patients with choreatic movement disorders (from about 14 in control subjects after 2.5 hours to about 7 in choreatic patients). [123I]Epidepride may be a useful SPECT ligand for studying D2 receptors in the living human brain because of its high target to background ratio, its high affinity and the possibility to investigate extrastriatal D2 receptors. (author)

  14. A structural biology perspective on NMDA receptor pharmacology and function.

    Science.gov (United States)

    Regan, Michael C; Romero-Hernandez, Annabel; Furukawa, Hiro

    2015-08-01

    N-methyld-aspartate receptors (NMDARs) belong to the large family of ionotropic glutamate receptors (iGluRs), which are critically involved in basic brain functions as well as multiple neurological diseases and disorders. The NMDARs are large heterotetrameric membrane protein complexes. The extensive extracellular domains recognize neurotransmitter ligands and allosteric compounds and translate the binding information to regulate activity of the transmembrane ion channel. Here, we review recent advances in the structural biology of NMDARs with a focus on pharmacology and function. Structural analysis of the isolated extracellular domains in combination with the intact heterotetrameric NMDAR structure provides important insights into how this sophisticated ligand-gated ion channel may function.

  15. CT and MRI assessment and characterization using segmentation and 3D modeling techniques: applications to muscle, bone and brain

    Directory of Open Access Journals (Sweden)

    Paolo Gargiulo

    2014-03-01

    Full Text Available This paper reviews the novel use of CT and MRI data and image processing tools to segment and reconstruct tissue images in 3D to determine characteristics of muscle, bone and brain.This to study and simulate the structural changes occurring in healthy and pathological conditions as well as in response to clinical treatments. Here we report the application of this methodology to evaluate and quantify: 1. progression of atrophy in human muscle subsequent to permanent lower motor neuron (LMN denervation, 2. muscle recovery as induced by functional electrical stimulation (FES, 3. bone quality in patients undergoing total hip replacement and 4. to model the electrical activity of the brain. Study 1: CT data and segmentation techniques were used to quantify changes in muscle density and composition by associating the Hounsfield unit values of muscle, adipose and fibrous connective tissue with different colors. This method was employed to monitor patients who have permanent muscle LMN denervation in the lower extremities under two different conditions: permanent LMN denervated not electrically stimulated and stimulated. Study 2: CT data and segmentation techniques were employed, however, in this work we assessed bone and muscle conditions in the pre-operative CT scans of patients scheduled to undergo total hip replacement. In this work, the overall anatomical structure, the bone mineral density (BMD and compactness of quadriceps muscles and proximal femoral was computed to provide a more complete view for surgeons when deciding which implant technology to use. Further, a Finite element analysis provided a map of the strains around the proximal femur socket when solicited by typical stresses caused by an implant press fitting. Study 3 describes a method to model the electrical behavior of human brain using segmented MR images. The aim of the work is to use these models to predict the electrical activity of the human brain under normal and pathological

  16. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth

    OpenAIRE

    Harel, Sivan; Higgins, Claire A.; Cerise, Jane E.; Dai, Zhenpeng; Chen, James C.; Clynes, Raphael; Christiano, Angela M.

    2015-01-01

    Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)–signal transducer and activator of transc...

  17. Brain herniation

    Science.gov (United States)

    ... herniation; Uncal herniation; Subfalcine herniation; Tonsillar herniation; Herniation - brain ... Brain herniation occurs when something inside the skull produces pressure that moves brain tissues. This is most ...

  18. Brain abscess: Current management.

    Science.gov (United States)

    Alvis Miranda, Hernando; Castellar-Leones, Sandra Milena; Elzain, Mohammed Awad; Moscote-Salazar, Luis Rafael

    2013-08-01

    Brain abscess (BA) is defined as a focal infection within the brain parenchyma, which starts as a localized area of cerebritis, which is subsequently converted into a collection of pus within a well-vascularized capsule. BA must be differentiated from parameningeal infections, including epidural abscess and subdural empyema. The BA is a challenge for the neurosurgeon because it is needed good clinical, pharmacological, and surgical skills for providing good clinical outcomes and prognosis to BA patients. Considered an infrequent brain infection, BA could be a devastator entity that easily left the patient into dead. The aim of this work is to review the current concepts regarding epidemiology, pathophysiology, etiology, clinical presentation, diagnosis, and management of BA. PMID:24174804

  19. Brain abscess: Current management

    Directory of Open Access Journals (Sweden)

    Hernando Alvis-Miranda

    2013-01-01

    Full Text Available Brain abscess (BA is defined as a focal infection within the brain parenchyma, which starts as a localized area of cerebritis, which is subsequently converted into a collection of pus within a well-vascularized capsule. BA must be differentiated from parameningeal infections, including epidural abscess and subdural empyema. The BA is a challenge for the neurosurgeon because it is needed good clinical, pharmacological, and surgical skills for providing good clinical outcomes and prognosis to BA patients. Considered an infrequent brain infection, BA could be a devastator entity that easily left the patient into dead. The aim of this work is to review the current concepts regarding epidemiology, pathophysiology, etiology, clinical presentation, diagnosis, and management of BA.

  20. Pharmacological approach to acute pancreatitis

    DEFF Research Database (Denmark)

    Bang, U.C.; Semb, S.; Nøjgaard, Camilla;

    2008-01-01

    The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may...... be useful as prophylaxis against post endoscopic retrograde cholangiopancreatography pancreatitis (PEP). The protease inhibitor gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL...

  1. Non-pharmacological intervention for posterior cortical atrophy.

    Science.gov (United States)

    Weill-Chounlamountry, Agnès; Alves, Jorge; Pradat-Diehl, Pascale

    2016-08-16

    Posterior cortical atrophy (PCA) is a rare neurodegenerative condition characterized by progressive visual-perceptual deficits. Although the neurocognitive profile of PCA is a growing and relatively well-established field, non-pharmacological care remains understudied and to be widely established in clinical practice. In the present work we review the available literature on non-pharmacological approaches for PCA, such as cognitive rehabilitation including individual cognitive exercises and compensatory techniques to improve autonomy in daily life, and psycho-education aiming to inform people with PCA about the nature of their visual deficits and limits of cognitive rehabilitation. The reviewed studies represented a total of 7 patients. There is a scarcity of the number of studies, and mostly consisting of case studies. Results suggest non-pharmacological intervention to be a potentially beneficial approach for the partial compensation of deficits, improvement of daily functionality and improvement of quality of life. Clinical implications and future directions are also highlighted for the advancement of the field, in order to clarify the possible role of non-pharmacological interventions, and its extent, in PCA. PMID:27574605

  2. Pharmacological approach to acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Ulrich Christian Bang; Synne Semb; Camilla Nφjgaard; Flemming Bendtsen

    2008-01-01

    The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP)based on experimental animal models and clinical trials.Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may be useful as prophylaxis against Post Endoscopic retrograde cholangiopancreatography Pancreatitis (PEP). The protease inhibitor Gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL) is a nitrogen oxide (NO) donor, which relaxes the sphincter of Oddi.Studies show conflicting results when applied prior to ERCP and a large multicenter randomized study is warranted. Steroids administered as prophylaxis against PEP has been validated without effect in several randomized trials. The non-steroidal anti-inflammatory drugs (NSAID) indomethacin and diclofenac have in randomized studies showed potential as prophylaxis against PEP. Interleukin 10 (IL-10) is a cytokine with anti-inflammatory properties but two trials testing IL-10 as prophylaxis to PEP have returned conflicting results.Antibodies against tumor necrosis factor-alpha (TNF-α)have a potential as rescue therapy but no clinical trials are currently being conducted. The antibiotics betalactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis. Evidence based pharmacological treatment of AP is limited and studies on the effect of potent anti-inflammatory drugs are warranted.

  3. Characterization of Brain-Penetrant Pyrimidine-Containing Molecules with Differential Microtubule-Stabilizing Activities Developed as Potential Therapeutic Agents for Alzheimer's Disease and Related Tauopathies.

    Science.gov (United States)

    Kovalevich, Jane; Cornec, Anne-Sophie; Yao, Yuemang; James, Michael; Crowe, Alexander; Lee, Virginia M-Y; Trojanowski, John Q; Smith, Amos B; Ballatore, Carlo; Brunden, Kurt R

    2016-05-01

    The microtubule (MT)-stabilizing protein tau disengages from MTs and forms intracellular inclusions known as neurofibrillary tangles in Alzheimer's disease and related tauopathies. Reduced tau binding to MTs in tauopathies may contribute to neuronal dysfunction through decreased MT stabilization and disrupted axonal transport. Thus, the introduction of brain-penetrant MT-stabilizing compounds might normalize MT dynamics and axonal deficits in these disorders. We previously described a number of phenylpyrimidines and triazolopyrimidines (TPDs) that induce tubulin post-translational modifications indicative of MT stabilization. We now further characterize the biologic properties of these small molecules, and our results reveal that these compounds can be divided into two general classes based on the cellular response they evoke. One group composed of the phenylpyrimidines and several TPD examples showed a bell-shaped concentration-response effect on markers of MT stabilization in cellular assays. Moreover, these compounds induced proteasome-dependent degradation of α- and β-tubulin and caused altered MT morphology in both dividing cells and neuron cultures. In contrast, a second group comprising a subset of TPD molecules (TPD+) increased markers of stable MTs in a concentration-dependent manner in dividing cells and in neurons without affecting total tubulin levels or disrupting MT architecture. Moreover, an example TPD+ compound was shown to increase MTs in a neuron culture model with induced tau hyperphosphorylation and associated MT deficits. Several TPD+ compounds were shown to be both brain penetrant and orally bioavailable, and a TPD+ example increased MT stabilization in the mouse brain, making these compounds potential candidate therapeutics for neurodegenerative tauopathies such as Alzheimer's disease. PMID:26980057

  4. A Pharmacological Primer of Biased Agonism

    OpenAIRE

    Andresen1, Bradley T.

    2011-01-01

    Biased agonism is one of the fastest growing topics in G protein-coupled receptor pharmacology; moreover, biased agonists are used in the clinic today: carvedilol (Coreg®) is a biased agonist of beta-adrenergic receptors. However, there is a general lack of understanding of biased agonism when compared to traditional pharmacological terminology. Therefore, this review is designed to provide a basic introduction to classical pharmacology as well as G protein-coupled receptor signal transductio...

  5. Synthesis and characterization in monkey of [{sup 11}C]SP203 as a radioligand for imaging brain metabotropic glutamate 5 receptors

    Energy Technology Data Exchange (ETDEWEB)

    Simeon, Fabrice G.; Liow, Jeih-San; Zhang, Yi; Hong, Jinsoo; Gladding, Robert L.; Zoghbi, Sami S.; Innis, Robert B.; Pike, Victor W. [National Institutes of Health, Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD (United States)

    2012-12-15

    [{sup 18}F]SP203 (3-fluoro-5-(2-(2-([{sup 18}F]fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile) is an effective high-affinity and selective radioligand for imaging metabotropic 5 receptors (mGluR5) in human brain with PET. To provide a radioligand that may be used for more than one scanning session in the same subject in a single day, we set out to label SP203 with shorter-lived {sup 11}C (t{sub 1/2} = 20.4 min) and to characterize its behavior as a radioligand with PET in the monkey. Iodo and bromo precursors were obtained by cross-coupling 2-fluoromethyl-4-((trimethylsilyl)ethynyl)-1,3-thiazole with 3,5-diiodofluorobenzene and 3,5-dibromofluorobenzene, respectively. Treatment of either precursor with [{sup 11}C]cyanide ion rapidly gave [{sup 11}C]SP203, which was purified with high-performance liquid chromatography. PET was used to measure the uptake of radioactivity in brain regions after injecting [{sup 11}C]SP203 intravenously into rhesus monkeys at baseline and under conditions in which mGluR5 were blocked with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP). The emergence of radiometabolites in monkey blood in vitro and in vivo was assessed with radio-HPLC. The stability of [{sup 11}C]SP203 in human blood in vitro was also measured. The iodo precursor gave [{sup 11}C]SP203 in higher radiochemical yield (>98 %) than the bromo precursor (20-52 %). After intravenous administration of [{sup 11}C]SP203 into three rhesus monkeys, radioactivity peaked early in brain (average 12.5 min) with a regional distribution in rank order of expected mGluR5 density. Peak uptake was followed by a steady decline. No radioactivity accumulated in the skull. In monkeys pretreated with MTEP before [{sup 11}C]SP203 administration, radioactivity uptake in brain was again high but then declined more rapidly than in the baseline scan to a common low level. [{sup 11}C]SP203 was unstable in monkey blood in vitro and in vivo, and gave predominantly less lipophilic radiometabolites

  6. Non-pharmacological cognitive enhancement

    NARCIS (Netherlands)

    Dresler, M.; Sandberg, A.; Ohla, K.; Bublitz, C.; Trenado, C.; Mroczko-Wasowicz, A.; Kuhn, S.; Repantis, D.

    2013-01-01

    The term "cognitive enhancement" usually characterizes interventions in humans that aim to improve mental functioning beyond what is necessary to sustain or restore good health. While the current bioethical debate mainly concentrates on pharmaceuticals, according to the given characterization, cogni

  7. A new positron emission tomography imaging agent for the serotonin transporter: synthesis, pharmacological characterization, and kinetic analysis of [{sup 11}C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine ([{sup 11}C]AFM)

    Energy Technology Data Exchange (ETDEWEB)

    Huang Yiyun E-mail: hh285@columbia.edu; Hwang, D.-R.; Bae, Sung-A; Sudo, Yasuhiko; Guo Ningning; Zhu Zhihong; Narendran, Raj; Laruelle, Marc

    2004-07-01

    The synthesis, radiolabeling, and in vitro and in vivo evaluation of a new positron emission tomography (PET) radioligand for the serotonin transporter (SERT), [{sup 11}C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine ([{sup 11}C]AFM) is reported. AFM was prepared from 4-chloro-3-nitrobenzyl acetate and thiosalicylic acid in a five-step synthetic sequence. In binding studies in vitro with cloned human transporters, AFM displayed high binding affinity (Ki 1.04 nmol/L for hSERT) and good selectivity (Ki 664 nmol/L for hNET and >10,000 nmol/L for hDAT) for SERT. The radiolabled compound [{sup 11}C]AFM was prepared in 30-37 minutes from its monomethylamine precursor by reaction with high specific activity [{sup 11}C]iodomethane. Radiochemical yield was 12.3 {+-} 8.1% based on [{sup 11}C]iodomethane and specific activity was 1733 {+-} 428 Ci/mmol at end of synthesis (EOS, n = 14). Radiochemical and chemical purity of the final product was >97%. Biodistribution studies in rats indicated that [{sup 11}C]AFM entered the brain readily and localized in regions known to contain high concentrations of SERT, with high specific to nonspecific binding ratios. Furthermore, binding of [{sup 11}C]AFM in SERT-rich regions was blocked by the cold compound AFM and the selective serotonin reuptake inhibitor citalopram but not by the selective norepinephrine reuptake inhibitor nisoxetine or the selective dopamine reuptake inhibitor GBR 12935. At 30 minutes after injection, >95% of the brain activity corresponded to the parent compound, indicating the absence of radiolabeled metabolites in the rat brain. PET imaging experiments in baboons showed a brain distribution pattern of [{sup 11}C]AFM consistent with the regional concentrations of SERT, with the highest levels of radioactivity detected in the midbrain and thalamus, moderate levels in the hippocampus and striatum, and the low levels in the cortical regions. Pretreatment of the baboons with citalopram (4 and 6 mg

  8. Comparison of Fluid Attenuated Inversion Recovery Sequence with Spin Echo T2-Weighted MRI for Characterization of Brain Pathology

    CERN Document Server

    Sahu, Indra Dev; Shrestha, Shanta Lal; Ghimire, Ram Kumar

    2009-01-01

    Twenty cases of different brain pathology have been studied via MRI using an open resistive magnet with magnetic field strength of 0.2 Tesla. The relative signal intensity with respect to the repetition time (TR) at fixed echo time (TE) 0.117 sec. has been studied. It was found that the signal intensity saturates for most lesions beyond a certain TR~6 sec in the T2 - weighted image. The signal intensity differs with respect to the inversion time (TI) for fat and cerebrospinal fluid (CSF). It was found that the intensity is nulled for CSF at TI ~1.5 sec. and for Fat at TI~0.10 sec in the FLAIR imaging sequence. Thus the intensity of the lesions is qualitatively different for the two sequences. From the radiological diagnostic point of view, it was concluded that the FLAIR sequence is more useful for the detection of lesions compared to T2 sequences.

  9. Brain SPECT in children; Explorations scintigraphiques en neurologie et psychiatrie de l`enfant

    Energy Technology Data Exchange (ETDEWEB)

    Guyot, M. [Hopital Pellegrin, 33 - Bordeaux (France); Baulieu, J.L. [Hopital Bretonneau, 37 - Tours (France)

    1996-12-31

    Brain SPECT in child involves specific trends regarding the patient cooperation, irradiation, resolution and especially interpretation because of the rapid scintigraphic modifications related to the brain maturation. In a general nuclear medicine department, child brain SPECT represents about 2 % of the activity. The choice indications are the perfusion children: thallium and MIBI in brain tumours, pharmacological and neuropsychological interventions. In the future, brain dedicated detectors and new radiopharmaceuticals will promote the development of brain SPECT in children. (author). 18 refs.

  10. Pharmacological neuroprotection after perinatal asphyxia

    NARCIS (Netherlands)

    Fan, Xiyong; van Bel, Frank

    2010-01-01

    Recent progress has provided us with several promising neuroprotective compounds to reduce perinatal hypoxic-ischemic (HI) brain injury. In the early post HI phase, therapies can be concentrated on ion channel blockage (Xenon), anti-oxidation (allopurinol, 2-iminobiotin, and indomethacin), anti-infl

  11. Pharmacological challenges in chronic pancreatitis

    DEFF Research Database (Denmark)

    Olesen, Anne Estrup; Brokjaer, Anne; Fischer, Iben Wendelboe Deleuran;

    2014-01-01

    Drug absorption in patients with chronic pancreatitis might be affected by the pathophysiology of the disease. The exocrine pancreatic insufficiency is associated with changes in gastrointestinal intraluminal pH, motility disorder, bacterial overgrowth and changed pancreatic gland secretion....... Together these factors can result in malabsorption and may also affect the efficacy of pharmacological intervention. The lifestyle of chronic pancreatitis patients may also contribute to gastrointestinal changes. Many patients limit their food intake because of the pain caused by eating and in some cases...... food intake is more or less substituted with alcohol, tobacco and coffee. Alcohol and drug interaction are known to influence the pharmacokinetics by altering either drug absorption or by affecting liver metabolism. Since patients suffering from chronic pancreatitis experience severe pain, opioids...

  12. Toxicological evidence in forensic pharmacology.

    Science.gov (United States)

    Ferner, R E

    2012-01-01

    Laboratory evidence of the presence and concentration of a drug in a person who has come to harm is often helpful in forensic pharmacology, and may be crucial. However, its value depends on two critical interpretations by the expert. First, the expert must make a careful analysis of the relationship between the results as measured in the sample and the drug in the patient at the time that harm occurred. That is especially difficult with post-mortem samples. Secondly, the expert must syntheses the laboratory information with the available clinical history and clinical or pathological findings. Even in the most favourable circumstances, when the sample is correctly obtained, identified, and analyzed, it can be hard to say that beyond reasonable doubt a given concentration had a given effect.

  13. Pharmacological activities of Curcuma caesia

    Directory of Open Access Journals (Sweden)

    Satyendra Singh Baghel

    2013-01-01

    Full Text Available Curcuma caesia Roxb. is a perennial, erect rhizomatous herb with large leaves. Fresh rhizomes are aromatic with intense camphoraceous odour, cultivated for its rhizomes, which are used in traditional medicine. The plant is reported to contain camphor, ar-turmerone, (Z-ocimene, ar-curcumene, 1, 8-cineole, elemene, borneol, bornyl acetate and curcumene as the major constituents. The plant has been reported to have antifungal activity, anti-asthmatic, smooth muscle relaxant, antimicrobial activity, antioxidant activity, analgesic, locomotor depressant, anticonvulsant and muscle relaxant effects, anti-inflammatory properties. It is now considered as a valuable source of unique natural products for development of medicines against various diseases. This review gives a view mainly on the meditional uses, phytochemistry and pharmacological actions of the plant.

  14. Pharmacology of human experimental anxiety

    Directory of Open Access Journals (Sweden)

    F.G. Graeff

    2003-04-01

    Full Text Available This review covers the effect of drugs affecting anxiety using four psychological procedures for inducing experimental anxiety applied to healthy volunteers and patients with anxiety disorders. The first is aversive conditioning of the skin conductance responses to tones. The second is simulated public speaking, which consists of speaking in front of a video camera, with anxiety being measured with psychometric scales. The third is the Stroop Color-Word test, in which words naming colors are painted in the same or in a different shade, the incongruence generating a cognitive conflict. The last test is a human version of a thoroughly studied animal model of anxiety, fear-potentiated startle, in which the eye-blink reflex to a loud noise is recorded. The evidence reviewed led to the conclusion that the aversive conditioning and potentiated startle tests are based on classical conditioning of anticipatory anxiety. Their sensitivity to benzodiazepine anxiolytics suggests that these models generate an emotional state related to generalized anxiety disorder. On the other hand, the increase in anxiety determined by simulated public speaking is resistant to benzodiazepines and sensitive to drugs affecting serotonergic neurotransmission. This pharmacological profile, together with epidemiological evidence indicating its widespread prevalence, suggests that the emotional state generated by public speaking represents a species-specific response that may be related to social phobia and panic disorder. Because of scant pharmacological data, the status of the Stroop Color-Word test remains uncertain. In spite of ethical and economic constraints, human experimental anxiety constitutes a valuable tool for the study of the pathophysiology of anxiety disorders.

  15. Characterization of recombinant RI beta and evaluation of the presence of RI beta protein in rat brain and testicular extracts.

    Science.gov (United States)

    DeManno, D A; Jackiw, V; Brooks, E; Hunzicker-Dunn, M

    1994-07-21

    Based upon recent reports that the mRNA from the regulatory (R) RI beta subunit of cAMP-dependent protein kinase (PKA) was expressed in testicular extracts, we determined whether testicular extracts exhibited RI beta protein. To accomplish this goal, we initially determined the fundamental labeling and ionic characteristics of recombinant RI beta. Recombinant RI beta eluted from DEAE-cellulose with a salt concentration (of 0.075 M) equivalent to its elution position from soluble mouse brain extracts with catalytic subunit-free RI alpha. As predicted by its amino acid sequence homology to RI alpha, recombinant RI beta was not phosphorylated by PKA but was labeled specifically with 8-azido-adenosine 3':5'-[32P]monophosphate (8-N3[32P]cAMP). Additionally, RI antisera reacted equally with RI alpha (47 kDa) and recombinant RI beta (53 kDa). However, recombinant RI beta exhibited an unexpectedly basic pI of 6.65-6.85. By using a pH gradient for isoelectric focussing that allowed for clear focussing of 8-N3[32P]cAMP-labeled recombinant RI beta, 8-N3[32P]cAMP-labeled RI beta was readily detected by two-dimensional gel electrophoresis in rat brain particulate extracts and exhibited a pI equivalent to that of recombinant RI beta. The 53-kDa RI beta was undetectable either by its immunoreactivity or upon photoaffinity labeling with 8-N3[32P]cAMP by one or two-dimensional gel electrophoresis in soluble or particulate extracts of testes of 14-day-old, 45-day-old, or adult rats or in epididymal sperm. However, 8-N3[32P]cAMP-labeled RI beta was detected, albeit in very small levels, by two-dimensional electrophoresis upon separation of PKAs in testes of 14-day-old rats by DEAE-cellulose chromatography but was absent in equivalent extracts from adult rat testes. These results demonstrate that the unexpectedly basic pI of RI beta allows for its clear separation by two-dimensional electrophoresis from the RII proteins and therefore allows for its unambiguous identification. Further

  16. Genomic architecture of pharmacological efficacy and adverse events.

    Science.gov (United States)

    Chhibber, Aparna; Kroetz, Deanna L; Tantisira, Kelan G; McGeachie, Michael; Cheng, Cheng; Plenge, Robert; Stahl, Eli; Sadee, Wolfgang; Ritchie, Marylyn D; Pendergrass, Sarah A

    2014-12-01

    The pharmacokinetic and pharmacodynamic disciplines address pharmacological traits, including efficacy and adverse events. Pharmacogenomics studies have identified pervasive genetic effects on treatment outcomes, resulting in the development of genetic biomarkers for optimization of drug therapy. Pharmacogenomics-based tests are already being applied in clinical decision making. However, despite substantial progress in identifying the genetic etiology of pharmacological response, current biomarker panels still largely rely on single gene tests with a large portion of the genetic effects remaining to be discovered. Future research must account for the combined effects of multiple genetic variants, incorporate pathway-based approaches, explore gene-gene interactions and nonprotein coding functional genetic variants, extend studies across ancestral populations, and prioritize laboratory characterization of molecular mechanisms. Because genetic factors can play a key role in drug response, accurate biomarker tests capturing the main genetic factors determining treatment outcomes have substantial potential for improving individual clinical care. PMID:25521360

  17. Isolation and characterization of primary microglia from post-natal murine brain tissues: a comparison of two methods.

    Science.gov (United States)

    Jose, Shinsmon; Tan, Shi Wei; Tong, Chih Kong; Vidyadaran, Sharmili

    2015-12-01

    Microglia are resident macrophages of the central nervous system (CNS). Apart from playing vital roles as sentinel cells, they are crucial in physiological processes such as synaptic pruning during brain development. CNS disorders require an understanding of the contribution of each cellular compartment to the pathogenesis. Elucidating the role of microglia in disease development and progression in the intricate CNS environment is technically challenging and requires the establishment of reliable, reproducible techniques to isolate and culture microglia. A number of different protocols have been developed for isolation of neonatal microglia and here we compare two widely used methods, namely, mild trypsinization and EasySep® magnetic separation. EasySep® magnetic separation provided higher microglia yield, and flow cytometric evaluation of CD11b and F4/80 markers revealed that EasySep® separation method also produced significantly higher purity compared to mild trypsinization. Microglia isolated using EasySep® separation method were functional, as demonstrated by the generation of nitric oxide, IL-6, TNF-α, and MCP-1 in response to lipopolysaccharide stimulation. In summary, this study has revealed that magnetic separation is superior to mild trypsinization in terms of yield and purity of microglia.

  18. Molecular cloning and characterization of a novel sequence, vof-16, with enhanced expression in permanent ischemic rat brain.

    Science.gov (United States)

    Tohda, Michihisa; Watanabe, Hiroshi

    2004-08-01

    We reported previously that chronic hypoperfusion induced by permanent occlusion of the bilateral common carotid arteries (2VO) in rats caused progressive cognitive deficits and neuronal damage in the hippocampus and the white matter. These changes are similar to those observed in human dementia. Reverse transcription-polymerase chain reaction (RT-PCR) differential display was carried out to identify mRNAs encoding the intrinsic factors involved in permanent ischemia from the 2VO rat brain. Over 20 clones which showed different expression levels in 2VO and sham-operated rats were isolated. One of these, named vof-16, was markedly enhanced the expression by 2VO. The whole sequence of vof-16 mRNA was 2098 nt. The distribution of vof-16 transcripts was examined by RT-PCR and in situ hybridization. The results revealed that vof-16 was abundant in the hippocampus, the tenia tecta, the piriform cortex and the area around the aorta. The expression levels of vof-16 in 2VO and sham-operated rat hippocampus were determined by a quantitative PCR method. The expression was abundant in the hippocampus of rats with cognitive impairment induced by 2VO. In contrast, the expression levels of vof-16 were lower in the 2VO rats with no impairment and in sham-operated rats. These results suggest that the expression levels of vof-16 may be related to the cognitive impairment induced by chronic ischemia after 2VO. PMID:15305027

  19. Imaging and histological characterization of a human brain xenograft in pig: the first induced glioma model in a large animal.

    Science.gov (United States)

    Selek, Laurent; Seigneuret, Eric; Nugue, Guillaume; Wion, Didier; Nissou, Marie France; Salon, Caroline; Seurin, Marie José; Carozzo, Claude; Ponce, Frédérique; Roger, Thierry; Berger, François

    2014-01-15

    The prognosis of glioblastoma remains poor despite significant improvement in cytoreductive surgery, external irradiation and new approach of systemic treatment as antiangiogenic therapy. One of the issues is the low concentration in the infiltrated parenchyma of therapeutic agent administered intravenously mainly due to the blood-brain barrier. An intracerebral injection is advocated to overpass this barrier, this kind of administration need a low flow and continuous injection. The development of sophisticated implanted devices for convection-enhanced delivery is a mandatory step to have a controlled released of a therapeutic agent in glioblastoma treatment. Before testing such a device in a clinical trial a serious preclinical studies are required, in order to test it in realistic conditions we have develop the first induced high grade glioma model in a non-rodent animal: the pig. 21 pigs have been implanted in the parietal lobe with human glioblastoma cell lineage under a chemical immunosuppression by ciclosporine. A MRI follow up was then realized. 15 pigs have been implanted with U87MG, 14 have presented a macroscopic significant tumor, with radiological and anatomapathological characteristics of high grade glioma. 6 pigs were implanted with G6, stem-like cells tumors of glioblastoma, 1 pig develops a macroscopic tumor. This is the first reproducible glioma model in a large animal described, it open the way to preclinical studies to test implanted devices in anatomic realistic conditions, without the ethical issues of a primate use. PMID:24126047

  20. Is Spreading Depolarization Characterized by an Abrupt, Massive Release of Gibbs Free Energy from the Human Brain Cortex?

    Science.gov (United States)

    Dreier, Jens P.; Isele, Thomas; Reiffurth, Clemens; Offenhauser, Nikolas; Kirov, Sergei A.; Dahlem, Markus A.; Herreras, Oscar

    2012-01-01

    In the evolution of the cerebral cortex, the sophisticated organization in a steady state far away from thermodynamic equilibrium has produced the side effect of two fundamental pathological network events: ictal epileptic activity and spreading depolarization. Ictal epileptic activity describes the partial disruption, and spreading depolarization describes the near-complete disruption of the physiological double Gibbs–Donnan steady state. The occurrence of ictal epileptic activity in patients has been known for decades. Recently, unequivocal electrophysiological evidence has been found in patients that spreading depolarizations occur abundantly in stroke and brain trauma. The authors propose that the ion changes can be taken to estimate relative changes in Gibbs free energy from state to state. The calculations suggest that in transitions from the physiological state to ictal epileptic activity to spreading depolarization to death, the cortex releases Gibbs free energy in a stepwise fashion. Spreading depolarization thus appears as a twilight state close to death. Consistently, electrocorticographic recordings in the core of focal ischemia or after cardiac arrest display a smooth transition from the initial spreading depolarization component to the later ultraslow negative potential, which is assumed to reflect processes in cellular death. PMID:22829393

  1. Identification, characterization, and purification of a 65,000 dalton protein in rat brain is photolabeled by nitro-containing benzodiazepines

    Energy Technology Data Exchange (ETDEWEB)

    Bowling, A.C.

    1988-01-01

    Benzodiazepines bind to two well-characterized classes of nanomolar-affinity binding sites, the central and the peripheral types. Although these sites appear to mediate many of the effects of these compounds, they cannot account for all of the biochemical and physiologic effects of the benzodiazepines. In this investigation, a protein that is photolabeled by NO{sub 2}-containing benzodiazepines was identified and characterized in rat brain by performing photaffinity labeling experiments with ({sup 3}H)-clonazepam and ({sup 3}H)-flunitrazepam. These experiments demonstrate that this photolabeled protein has a molecular weight of 65,000 daltons. Photolabeling of the protein was saturable, inhibited in a stereoselective manner by benzodiazepine enantiomers, inhibited by therapeutically-relevant concentrations of many different NO{sub 2}-containing benzodiazepines, and was not inhibited by more than 70 non-benzodiazepine compounds. The photolabeled protein is distinct from the central and peripheral sites on the basis of molecular weight, benzodiazepine inhibitory potencies, subcellular localization, and tissue distribution.

  2. Complex Pharmacology of Free Fatty Acid Receptors

    DEFF Research Database (Denmark)

    Milligan, Graeme; Shimpukade, Bharat; Ulven, Trond;

    2016-01-01

    G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond...... pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or "free" fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets...... for the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential....

  3. Chemistry, Pharmacology and Health Benefits of Anthocyanins.

    Science.gov (United States)

    Smeriglio, Antonella; Barreca, Davide; Bellocco, Ersilia; Trombetta, Domenico

    2016-08-01

    Anthocyanins are naturally occurring molecules belonging to the flavonoid class characterized by the presence of chromophores. Apart from their well-known antioxidant activity, they show a wide variety of health-promoting properties for human health, ranging from cytoprotective, antimicrobial and antitumour activities to neuroprotective, anti-obesity and lipidomic potential, properties for which anthocyanins have been prescribed as medicines in several countries for thousands of years. Despite this, these phytochemicals have received less attention than other flavonoids, and there is still a gap in the literature, particularly regarding pharmacological and toxicological aspects. Moreover, epidemiological evidence suggests a direct correlation between anthocyanin intake and a lower incidence of chronic and degenerative diseases. In light of this, the aim of this review is to cover the current literature on anthocyanins, their biological in vitro and in vivo effects and their potential therapeutic applications, as well as their bioavailability and pharmacokinetics, all of which are essential to gain a better understanding of their biological effectiveness and potential toxicity. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27221033

  4. Pharmacological, neurochemical, and behavioral profile of JB-788, a new 5-HT1A agonist.

    Science.gov (United States)

    Picard, M; Morisset, S; Cloix, J F; Bizot, J C; Guerin, M; Beneteau, V; Guillaumet, G; Hevor, T K

    2010-09-01

    A novel pyridine derivative, 8-{4-[(6-methoxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-ylmethyl)-amino]-butyl}-8-aza-spiro[4.5]decane-7,9-dione hydrochloride, termed JB-788, was designed to selectively target 5-HT(1A) receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT(1A) receptor expressed in human embryonic kidney 293 (HEK-293) cells with a K(i) value of 0.8 nM. Its binding affinity is in the same range as that observed for the (+/-)8-OH-DPAT, a reference 5HT(1A) agonist compound. Notably, JB-788 only bound weakly to 5-HT(1B) or 5-HT(2A) receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, alpha(2), beta(1) and beta(2) adrenergic receptors, or dopaminergic D(1) receptors. JB-788 was found to display substantial binding affinity for dopaminergic D(2) receptors and, to a lesser extend to alpha(1) adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT(1A), thus acting as a potent 5-HT(1A) receptor agonist (E(max.) 75%, EC(50) 3.5 nM). JB-788 did not exhibit any D(2) receptor agonism but progressively inhibited the effects of quinpirole, a D(2) receptor agonist, in the cAMP accumulation test with a K(i) value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area

  5. The role of the endocannabinoid system in eating disorders: pharmacological implications.

    Science.gov (United States)

    Marco, Eva M; Romero-Zerbo, Silvana Y; Viveros, María-Paz; Bermudez-Silva, Francisco J

    2012-09-01

    The endocannabinoid (eCB) system is a widespread intercellular signalling mechanism that plays a critical role in body homoeostasis. It is located in key points involved in food intake and energy expenditure, coordinating all the players involved in energy balance. As such, it has come to be seen as an interesting target for the management of diseases characterized by an imbalanced energy homoeostasis, such as obesity and eating disorders. The aetiology of eating disorders and the molecular systems involved are still largely a mystery. Research has focused on brain circuits where the eCB system plays an important role, such as those related to feeding behaviour and the rewarding properties of food. Accordingly, recent findings have suggested a deregulation of the eCB system in eating disorders. At present, cannabinoid agonists are safe and effective tools in the management of diseases in which weight gain is needed, for example cachexia in AIDS patients. However, studies on the potential therapeutic validity of cannabinoids in eating disorders are scarce and inconclusive. Taken together, all these considerations warrant more preclinical and clinical investigations in the role of the eCB system in eating disorders. Eventually, they may provide novel pharmacological approaches for the treatment of these diseases.

  6. Characterization of GABA/sub A/ receptor-mediated /sup 36/chloride uptake in rat brain synaptoneurosomes

    Energy Technology Data Exchange (ETDEWEB)

    Luu, M.D.; Morrow, A.L.; Paul, S.M.; Schwartz, R.D.

    1987-09-07

    ..gamma..-Aminobutyric acid (GABA) receptor-mediated /sup 36/chloride (/sup 36/Cl/sup -/) uptake was measured in synaptoneurosomes from rat brain. GABA and GABA agonists stimulated /sup 36/Cl/sup -/ uptake in a concentration-dependent manner with the following order of potency: Muscimol>GABA>piperidine-4-sulfonic acid (P4S)>4,5,6,7-tetrahydroisoxazolo-(5,4-c)pyridin-3-ol (THIP)=3-aminopropanesulfonic acid (3APS)>>taurine. Both P4S and 3APS behaved as partial agonists, while the GABA/sub B/ agonist, baclofen, was ineffective. The response to muscimol was inhibited by bicuculline and picrotoxin in a mixed competitive/non-competitive manner. Other inhibitors of GABA receptor-opened channels or non-neuronal anion channels such as penicillin, picrate, furosemide and disulfonic acid stilbenes also inhibited the response to muscimol. A regional variation in muscimol-stimulated /sup 36/Cl/sup -/ uptake was observed; the largest responses were observed in the cerebral cortex, cerebellum and hippocampus, moderate responses were obtained in the striatum and hypothalamus and the smallest response was observed in the pons-medulla. GABA receptor-mediated /sup 36/Cl/sup -/ uptake was also dependent on the anion present in the media. The muscinol response varied in media containing the following anions: Br/sup -/>Cl/sup -/greater than or equal toNO/sub 3//sup -/>I/sup -/greater than or equal toSCN/sup -/>>C/sub 3/H/sub 5/OO/sup -/greater than or equal toClO/sub 4//sup -/>F/sup -/, consistent with the relative anion permeability through GABA receptor-gated anion channels and the enhancement of convulsant binding to the GABA receptor-gated Cl/sup -/ channel. 43 references, 4 figures, 3 tables.

  7. Pharmacology of sexually compulsive behavior.

    Science.gov (United States)

    Codispoti, Victoria L

    2008-12-01

    In a meta-analysis on controlled outcomes evaluations of 22,000 sex offenders, Losel and Schmucker found 80 comparisons between treatment and control groups. The recidivism rate averaged 19% in treated groups, and 27% in controls. Most other reviews reported a lower rate of sexual recidivism in treated sexual offenders. Of 2039 citations in this study (including literature in five languages), 60 studies held independent comparisons. Problematic issues included the control groups; various hormonal, surgical, cognitive behavioral, and psychotherapeutic treatments; and sample sizes. In the 80 studies compared after the year 2000, 32% were reported after 2000, 45% originated in the United States, 45% were reported in journals, and 36% were unpublished. Treatment characteristics showed a significant lack of pharmacologic treatment (7.5%), whereas use cognitive and classical behavioral therapy was 64%. In 68% of the studies, no information was available on the integrity of the treatment implementation; 36% of the treatment settings were outpatient only, 31% were prison settings, and 12% were mixed settings (prison, hospital, and outpatient). Integrating research interpretations is complicated by the heterogeneity of sex offenders, with only 56% being adult men and 17.5% adolescents. Offense types reported included 74% child molestation, 48% incest, and 30% exhibitionism. Pedophilia was not singled out. Follow-up periods varied from 12 months to greater than 84 months. The definition of recidivism ran the gamut from arrest (24%), conviction (30%), charges (19%), and no indication (16%). Results were difficult to interpret because of the methodological problems with this type of study. Overall, a positive outcome was noted with sex offender treatment. Cognitive-behavioral and hormonal treatment were the most promising. Voluntary treatment led to a slightly better outcome than mandatory participation. When accounting for a low base rate of sexual recidivism, the reduction

  8. Brain Fingerprinting

    Directory of Open Access Journals (Sweden)

    Ravi Kumar

    2012-12-01

    Full Text Available Brain Fingerprinting is a scientific technique to determine whether or not specific information is stored in an individual's brain by measuring a electrical brain wave response to Word, phrases, or picture that are presented on computer screen. Brain Fingerprinting is a controversial forensic science technique that uses electroencephalography (EEG to determine whether specific information is stored in a subject's brain.

  9. Brain Fingerprinting

    Directory of Open Access Journals (Sweden)

    ravi kumar

    2012-12-01

    Full Text Available Brain Fingerprinting is a scientific technique to determine whether or not specific information is stored in an individual's brain by measuring a electrical brain wave response to Word, phrases, or picture that are presented on computer screen. Brain Fingerprinting is a controversial forensic science technique that uses electroencephalograph y (EEG to determine whether specific information is stored in a subject's brain

  10. Brain Tumors

    Science.gov (United States)

    A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

  11. Biochemical and pharmacological studies of native and irradiated crotamine with gamma radiation of Co60

    International Nuclear Information System (INIS)

    Ionizing radiation can change the molecular structure and affect the biological properties of biomolecules. This has been employed to attenuate animal toxins. Crotamine is a strongly basic polypeptide from South American rattlesnake venom, composed of 42 amino acid residues. It induces skeletal muscle spasms, leading to a spastic paralysis of hind limbs in mice. The objective was to carry out biochemical and pharmacological studies of native and irradiated crotamine with Co. Crotamine was purified from Crotalus durissus terrificus venom by Sephadex G-100 gel filtration followed by ion exchange chromatography, using a Fast performance Liquid Chromatography (FPLC) system. It was irradiated at 2 mg/ml in 0.15 m NaCl with 2.0 kGy gamma radiation emitted by a Co source. Native and irradiated crotamine were evaluated by biochemical characterization, toxic activity (LD50), and biodistribution. The native and irradiated crotamine were labeled with 29.6 MBq of I using chloramine T method and separated in a Sephadex G-50 column. Male Swiss mice (35 @ 5 g) were injected IP with 0.1 mL (2.4x10 cpm/mouse) of I native crotamine or with 0.4 mL (1.3 x 10 cpm/mouse) of I irradiated crotamine. The animals were sacrificed by ether inhalation at 0.08, 0.25, 0.5,1, 2, 3, 4, 8, 12, and 24 hours. Blood, spleen, liver, kidneys, brain, lungs, heart, and skeletal muscle were collected in order to determine radioactivity content. The results showed that gamma radiation did not change protein concentration, electrophoretic profile, or protein primary structure, although differences could be seen by spectroscopic techniques. Gamma radiation reduced crotamine toxicity, but did not eliminate bioactivity. Biodistribution studies showed that native and irradiated crotamine have hepatic metabolism and renal elimination. Native and irradiated crotamine have an affinity to skeletal muscle and did not cross the blood-brain barrier. (author)

  12. Characterization of Aromatase Expression in the Adult Male and Female Mouse Brain. I. Coexistence with Oestrogen Receptors α and β, and Androgen Receptors

    OpenAIRE

    Davor Stanić; Sydney Dubois; Hui Kheng Chua; Bruce Tonge; Nicole Rinehart; Malcolm K Horne; Wah Chin Boon

    2014-01-01

    Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, in...

  13. Expression patterns of nicotinic subunits α2, α7, α8, and β1 affect the kinetics and pharmacology of ACh-induced currents in adult bee olfactory neuropiles.

    Science.gov (United States)

    Dupuis, Julien Pierre; Gauthier, Monique; Raymond-Delpech, Valérie

    2011-10-01

    Acetylcholine (ACh) is the main excitatory neurotransmitter of the insect brain, where nicotinic acetylcholine receptors (nAChRs) mediate fast cholinergic synaptic transmission. In the honeybee Apis mellifera, nAChRs are expressed in diverse structures including the primary olfactory centers of the brain, the antennal lobes (ALs) and the mushroom bodies (MBs), where they participate in olfactory information processing. To understand the nature and properties of the nAChRs involved in these processes, we performed a pharmacological and molecular characterization of nAChRs on cultured Kenyon cells of the MBs, using whole cell patch-clamp recordings combined with single-cell RT-PCR. In all cells, applications of ACh as well as nicotinic agonists such as nicotine and imidacloprid induced inward currents with fast desensitization. These currents were fully blocked by saturating doses of the antagonists α-bungarotoxin (α-BGT), dihydroxy-β-erythroidine (DHE), and methyllycaconitine (MLA) (MLA ≥ α-BGT ≥ DHE). Molecular analysis of ACh-responding cells revealed that of the 11 nicotinic receptor subunits encoded within the honeybee genome, α2, α8, and β1 subunits were expressed in adult Kenyon cells. Comparison with the expression pattern of adult AL cells revealed the supplementary presence of subunit α7, which could be responsible for the kinetic and pharmacological differences observed when comparing ACh-induced currents from AL and Kenyon cells. Together, our data demonstrate the existence of functional nAChRs on adult MB Kenyon cells that differ from nAChRs on AL cells in both their molecular composition and pharmacological properties, suggesting that changing receptor subsets could mediate different processing functions depending on the brain structure within the olfactory pathway. PMID:21734106

  14. Pharmacologic Agents for Chronic Diarrhea.

    Science.gov (United States)

    Lee, Kwang Jae

    2015-10-01

    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly.

  15. Prostaglandins: pharmacology and clinical application.

    Science.gov (United States)

    Karim, S M; Hillier, K

    1974-01-01

    Prostaglandin research has been 1 of the most stimulating features of biomedical investigation in the past decade. Interest developed at a time of expanding knowledge of hormonal and neurohormonal behavior and research work received a tremendous impetus in the early 1960s with the elucidation in Sweden of the chemical structures of prostaglandins, followed by the discovery of their biosynthetic pathways. The original findings of large amounts of prostaglandin in the male accessory genital glands and their secretions, and subsequent discovery in the menstrual and amniotic fluids linked these substances with human production. As a result of further investigation, clinical applications of prostaglandins for the induction of labor and termination of early unwanted pregnancies have been developed. Apart from the functions of the prostaglandins in the reproductive area, they have been shown to have a widespread distribution in the body and produce many different pharmacological effects. Prostaglandins are thought to be involved in the regulation of blood pressure and through their vascular effects have therapeutic potential in the treatment of hypertension and peripheral vascular disease. Through their bronchodilator effect, some prostaglandins may become useful in the treatment of asthma. PMID:4611742

  16. Pharmacologic Agents for Chronic Diarrhea.

    Science.gov (United States)

    Lee, Kwang Jae

    2015-10-01

    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly. PMID:26576135

  17. Safety Pharmacology Evaluation of Biopharmaceuticals.

    Science.gov (United States)

    Amouzadeh, Hamid R; Engwall, Michael J; Vargas, Hugo M

    2015-01-01

    Biotechnology-derived pharmaceuticals or biopharmaceuticals (BPs) are molecules such as monoclonal antibodies, soluble/decoy receptors, hormones, enzymes, cytokines, and growth factors that are produced in various biological expression systems and are used to diagnose, treat, or prevent various diseases. Safety pharmacology (SP) assessment of BPs has evolved since the approval of the first BP (recombinant human insulin) in 1982. This evolution is ongoing and is informed by various international harmonization guidelines. Based on these guidelines, the potential undesirable effect of every drug candidate (small molecule or BP) on the cardiovascular, central nervous, and respiratory systems, referred to as the "core battery," should be assessed prior to first-in-human administration. However, SP assessment of BPs poses unique challenges such as choice of test species and integration of SP parameters into repeat-dose toxicity studies. This chapter reviews the evolution of SP assessment of BPs using the approval packages of marketed BPs and discusses the past, current, and new and upcoming approach and methods that can be used to generate high-quality data for the assessment of SP of BPs.

  18. Brain Basics

    Medline Plus

    Full Text Available ... as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are the basic working unit of the brain ... specialized for the function of conducting messages. A neuron has three basic parts: Cell body which includes ...

  19. Brain surgery

    Science.gov (United States)

    Craniotomy; Surgery - brain; Neurosurgery; Craniectomy; Stereotactic craniotomy; Stereotactic brain biopsy; Endoscopic craniotomy ... cut depends on where the problem in the brain is located. The surgeon creates a hole in ...

  20. Brain Malformations

    Science.gov (United States)

    Most brain malformations begin long before a baby is born. Something damages the developing nervous system or causes it ... medicines, infections, or radiation during pregnancy interferes with brain development. Parts of the brain may be missing, ...

  1. Brain Basics

    Medline Plus

    Full Text Available ... Brain Basics provides information on how the brain works, how mental illnesses are disorders of the brain, ... others live with symptoms of mental illness every day. They can be moderate, or serious and cause ...

  2. Brain Basics

    Medline Plus

    Full Text Available ... The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are the basic working unit of the ... distant nerve cells (via axons) to form brain circuits. These circuits control specific body functions such as ...

  3. Brain Basics

    Medline Plus

    Full Text Available ... Basics will introduce you to some of this science, such as: How the brain develops How genes and the environment affect the brain The basic structure of the brain How different parts of ...

  4. Brain Basics

    Medline Plus

    Full Text Available ... science, such as: How the brain develops How genes and the environment affect the brain The basic ... that with brain development in people mental disorders. Genes and environmental cues both help to direct this ...

  5. Advances in Studies on Pharmacological Functions of Ligustilide and their Mechanisms

    Institute of Scientific and Technical Information of China (English)

    YANG Jin-ying; CHEN Hu-hu; WU Jiang; GONG Su-xiao; CHEN Chang-qing; ZHANG Tie-jun; WANG Min-jie

    2012-01-01

    The article reviewed the research progress of ligustilide in recent years and elaborated its pharmacological functions and mechanisms in detail,especially in ischemic brain injury.Its mechanism includes reducing cerebral infarct volumes and improving neurobehavioral deficits,anti-oxidant and anti-apoptosis,antithrombotic activity,calcium channel blockers function,and effect on erythropoietin.Other pharmacological effects of ligustilide including inhibiting vascular smooth muscle cell proliferation,anti-inflammatory and analgesic effects,effects on LPS-induced endotoxic shock,inhibiting constriction effect,suppression of the central nervous system,and ameliorating the memory impairment induced by scopolamine and so on,are also introduced.Ligustilide has potential pharmacological value,which provides a reference for its further research and development.

  6. Occurrence of two somatostatin variants in the frog brain: characterization of the cDNAs, distribution of the mRNAs, and receptor-binding affinities of the peptides.

    OpenAIRE

    Tostivint, H; Lihrmann, I; Bucharles, C; Vieau, D; Coulouarn, Y; A. Fournier; Conlon, J M; Vaudry, H.

    1996-01-01

    In tetrapods, only one gene encoding a somatostatin precursor has been identified so far. The present study reports the characterization of the cDNA clones that encode two distinct somatostatin precursors in the brain of the frog Rana ridibunda. The cDNAs were isolated by using degenerate oligonucleotides based on the sequence of the central region of somatostatin to screen a frog brain cDNA library. One of the cDNAs encodes a 115-amino acid protein (prepro-somatostatin-14; PSS1) that exhibit...

  7. Pharmacologic treatment of migraine. Comparison of guidelines.

    NARCIS (Netherlands)

    Schuurmans, A.; Weel, C. van

    2005-01-01

    OBJECTIVE: To compare guidelines (not the primary studies) for pharmacologic treatment of migraine as to methods of guideline development; recommendations, particularly on triptans; and quality of supporting evidence (with emphasis on comparative studies of triptans versus ergot alkaloids and nonste

  8. Pharmacology profiling of chemicals and proteins

    DEFF Research Database (Denmark)

    Kringelum, Jens Vindahl

    of pharmaceuticals, a process referred to as pharmacology profiling. Pharmacology profiling of chemical and protein based pharmaceuticals has been proven valuable in a number studies [2], however missing values in the drug-protein interaction matrix limits the profile for novel or less studied compounds....... This limitation complicates adverse effect assessment in the early drug-development phase, thus contributing to drugattrition. Prediction models offer the possibility to close these gaps and provide more complete pharmacology profiles, however improvements in performances are required for these tools to serve...... as an alternative to experimentally obtained measurements. Here I present several different tools that aid pharmacology profiling of the two main classes of pharmaceuticals; chemicals (small molecules) and proteins (biopharmaceuticals). Biopharmaceuticals have the inherent risks of eliciting an immune response due...

  9. Anti-aging pharmacology: Promises and pitfalls.

    Science.gov (United States)

    Vaiserman, Alexander M; Lushchak, Oleh V; Koliada, Alexander K

    2016-11-01

    Life expectancy has grown dramatically in modern times. This increase, however, is not accompanied by the same increase in healthspan. Efforts to extend healthspan through pharmacological agents targeting aging-related pathological changes are now in the spotlight of geroscience, the main idea of which is that delaying of aging is far more effective than preventing the particular chronic disorders. Currently, anti-aging pharmacology is a rapidly developing discipline. It is a preventive field of health care, as opposed to conventional medicine which focuses on treating symptoms rather than root causes of illness. A number of pharmacological agents targeting basic aging pathways (i.e., calorie restriction mimetics, autophagy inducers, senolytics etc.) are now under investigation. This review summarizes the literature related to advances, perspectives and challenges in the field of anti-aging pharmacology.

  10. CASSIA TORA: A PHYTO-PHARMACOLOGICAL OVERVIEW

    OpenAIRE

    Das Chandan; Dash Sujit; Sahoo Durga Charan; Mohanty Arnabaditya; Rout Dolley

    2011-01-01

    Cassia tora, a popular Indian medicinal plant, has long been used in Ayurvedic system of medicine. The plant has been found to possess diverse number of pharmacological activities. The present paper gives an account of updated information on its phytochemical and pharmacological activities. The review reveals that wide range of phytochemical constituents have been isolated from the plant and it possess important activities like laxative, skin diseases, ringworm, eye diseases, liver complaint,...

  11. Methods in pharmacology: measurement of cardiac output

    OpenAIRE

    Geerts, Bart F; Aarts, Leon P; Jansen, Jos R.

    2011-01-01

    Many methods of cardiac output measurement have been developed, but the number of methods useful for human pharmacological studies is limited. The ‘holy grail’ for the measurement of cardiac output would be a method that is accurate, precise, operator independent, fast responding, non-invasive, continuous, easy to use, cheap and safe. This method does not exist today. In this review on cardiac output methods used in pharmacology, the Fick principle, indicator dilution techniques, arterial pul...

  12. Punishment, Pharmacological Treatment, and Early Release

    DEFF Research Database (Denmark)

    Ryberg, Jesper

    2013-01-01

    Recent studies have shown that pharmacological treatment may have an impact on aggressive and impulsive behavior. Assuming that these results are correct, would it be morally acceptable to instigate violent criminals to accept pharmacological rehabilitation by offering this treatment in return fo...... relates to the acceptability of the fact that those criminals who accepted the treatment would be exempted from the punishment they rightly deserved. It is argued that none of these reasons succeeds in rejecting this sort of offer....

  13. Methodological innovations expand the safety pharmacology horizon.

    Science.gov (United States)

    Pugsley, M K; Curtis, M J

    2012-09-01

    Almost uniquely in pharmacology, drug safety assessment is driven by the need for elaboration and validation of methods for detecting drug actions. This is the 9th consecutive year that the Journal of Pharmacological and Toxicological Methods (JPTM) has published themed issues arising from the annual meeting of the Safety Pharmacology Society (SPS). The SPS is now past its 10th year as a distinct (from pharmacology to toxicology) discipline that integrates safety pharmacologists from industry with those in academia and the various global regulatory authorities. The themes of the 2011 meeting were (i) the bridging of safety assessment of a new chemical entity (NCE) between all the parties involved, (ii) applied technologies and (iii) translation. This issue of JPTM reflects these themes. The content is informed by the regulatory guidance documents (S7A and S7B) that apply prior to first in human (FIH) studies, which emphasize the importance of seeking model validation. The manuscripts encompass a broad spectrum of safety pharmacology topics including application of state-of-the-art techniques for study conduct and data processing and evaluation. This includes some exciting novel integrated core battery study designs, refinements in hemodynamic assessment, arrhythmia analysis algorithms, and additionally an overview of safety immunopharmacology, and a brief survey discussing similarities and differences in business models that pharmaceutical companies employ in safety pharmacology, together with SPS recommendations on 'best practice' for the conduct of a non-clinical cardiovascular assessment of a NCE. PMID:22617368

  14. Exploring Hallucinogen Pharmacology and Psychedelic Medicine with Zebrafish Models.

    Science.gov (United States)

    Kyzar, Evan J; Kalueff, Allan V

    2016-10-01

    After decades of sociopolitical obstacles, the field of psychiatry is experiencing a revived interest in the use of hallucinogenic agents to treat brain disorders. Along with the use of ketamine for depression, recent pilot studies have highlighted the efficacy of classic serotonergic hallucinogens, such as lysergic acid diethylamide and psilocybin, in treating addiction, post-traumatic stress disorder, and anxiety. However, many basic pharmacological and toxicological questions remain unanswered with regard to these compounds. In this study, we discuss psychedelic medicine as well as the behavioral and toxicological effects of hallucinogenic drugs in zebrafish. We emphasize this aquatic organism as a model ideally suited to assess both the potential toxic and therapeutic effects of major known classes of hallucinogenic compounds. In addition, novel drugs with hallucinogenic properties can be efficiently screened using zebrafish models. Well-designed preclinical studies utilizing zebrafish can contribute to the reemerging treatment paradigm of psychedelic medicine, leading to new avenues of clinical exploration for psychiatric disorders.

  15. Pharmacological properties of homomeric and heteromeric GluR1o and GluR3o receptors

    DEFF Research Database (Denmark)

    Nielsen, B S; Banke, T G; Schousboe, A;

    1998-01-01

    .1+/-2.9. The pharmacological profiles of these receptors resembled that of native rat brain AMPA receptors: AMPA analogues > L-glutamate > quinoxaline-2,3-diones > kainate. In the Xenopus oocyte expression system we had previously shown that the agonist (R,S)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionate (ACPA...

  16. Brain Basics

    Medline Plus

    Full Text Available ... Welcome. Brain Basics provides information on how the brain works, how mental illnesses are disorders of the brain, ... highly developed area at the front of the brain that, in humans, plays a role in executive functions such as ...

  17. Brain Basics

    Medline Plus

    Full Text Available ... Research Modern research tools and techniques are giving scientists a more detailed understanding of the brain than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of the brain's structure, studies ...

  18. The pharmacology of topical analgesics.

    Science.gov (United States)

    Barkin, Robert L

    2013-07-01

    Pain management of patients continues to pose challenges to clinicians. Given the multiple dimensions of pain--whether acute or chronic, mild, moderate, or severe, nociceptive or neuropathic--a multimodal approach may be needed. Fortunately, clinicians have an array of nonpharmacologic and pharmacologic treatment choices; however, each modality must be chosen carefully, because some often used oral agents are associated with safety and tolerability issues that restrict their use in certain patients. In particular, orally administered nonsteroidal antiinflammatory drugs, opioids, antidepressants, and anticonvulsants are known to cause systemic adverse effects in some patients. To address this problem, a number of topical therapies in various therapeutic classes have been developed to reduce systemic exposure and minimize the risks of patients developing adverse events. For example, topical nonsteroidal anti-inflammatory drug formulations produce a site-specific effect (ie, cyclo-oxygenase inhibition) while decreasing the systemic exposure that may lead to undesired effects in patients. Similarly, derivatives of acetylsalicylic acid (ie, salicylates) are used in topical analgesic formulations that do not significantly enter the patient's systemic circulation. Salicylates, along with capsaicin, menthol, and camphor, compose the counterirritant class of topical analgesics, which produce analgesia by activating and then desensitizing epidermal nociceptors. Additionally, patches and creams that contain the local anesthetic lidocaine, alone or co-formulated with other local anesthetics, are also used to manage patients with select acute and chronic pain states. Perhaps the most common topical analgesic modality is the cautious application of cutaneous cold and heat. Such treatments may decrease pain not by reaching the target tissue through systemic distribution, but by acting more directly on the affected tissue. Despite the tolerability benefits associated with avoiding

  19. Cytokines and brain excitability

    OpenAIRE

    Galic, Michael A.; Riazi, Kiarash; Pittman, Quentin J.

    2011-01-01

    Cytokines are molecules secreted by peripheral immune cells, microglia, astrocytes and neurons in the central nervous system. Peripheral or central inflammation is characterized by an upregulation of cytokines and their receptors in the brain. Emerging evidence indicates that pro-inflammatory cytokines modulate brain excitability. Findings from both the clinical literature and from in vivo and in vitro laboratory studies suggest that cytokines can increase seizure susceptibility and may be in...

  20. Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU).

    Science.gov (United States)

    Harding, Cary O; Winn, Shelley R; Gibson, K Michael; Arning, Erland; Bottiglieri, Teodoro; Grompe, Markus

    2014-09-01

    Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU. PMID:24487571

  1. Drug targeting to the brain.

    Science.gov (United States)

    Pardridge, William M

    2007-09-01

    The goal of brain drug targeting technology is the delivery of therapeutics across the blood-brain barrier (BBB), including the human BBB. This is accomplished by re-engineering pharmaceuticals to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium. Certain endogenous peptides, such as insulin or transferrin, undergo receptor-mediated transport (RMT) across the BBB in vivo. In addition, peptidomimetic monoclonal antibodies (MAb) may also cross the BBB via RMT on the endogenous transporters. The MAb may be used as a molecular Trojan horse to ferry across the BBB large molecule pharmaceuticals, including recombinant proteins, antibodies, RNA interference drugs, or non-viral gene medicines. Fusion proteins of the molecular Trojan horse and either neurotrophins or single chain Fv antibodies have been genetically engineered. The fusion proteins retain bi-functional properties, and both bind the BBB receptor, to trigger transport into brain, and bind the cognate receptor inside brain to induce the pharmacologic effect. Trojan horse liposome technology enables the brain targeting of non-viral plasmid DNA. Molecular Trojan horses may be formulated with fusion protein technology, avidin-biotin technology, or Trojan horse liposomes to target to brain virtually any large molecule pharmaceutical. PMID:17554607

  2. SECONDARY BRAIN INJURY

    Directory of Open Access Journals (Sweden)

    Ida Ayu Basmatika

    2013-03-01

    Full Text Available Secondary brain injury is a condision that occurs at some times after the primary impact and can be largely prevented and treated. Most brain injury ends with deadly consequences which is caused by secondary damage to the brain. Traumatic brain injured still represents the leading cause of morbidity and mortality in individuals under the age of 45 years in the world. The classification of secondary brain injured is divided into extracranial and intracranial causes. The cause of extracranial such as hipoxia, hypotensi, hyponatremia, hypertermia, hypoglycemia or hyperglycemia. The cause of intracranial such as extradural, subdural, intraserebral, intraventrikular, dan subarachnoid hemorrhage. Beside that secondary injury can also be caused by edema and infection. Post-traumatic cerebral injured is characterized by direct tissue damage, impaired regulation of cerebral blood flow (cerebral blood flow / CBF, and disruption of metabolism. Manifestations of secondary brain injured include increased intracranial pressure, ischemic brain damage, cerebral hypoxia and hypercarbi, as well as disruption of cerebral autoregulation. The first priority is to stabilize the patient's cervical spine injury, relieve and maintain airway, ensure adequate ventilation (breathing, and making venous access for fluid resuscitation pathways (circulation and assessing the level of awareness and disability. This steps is crucial in patients with head injured to prevent hypoxia and hypotension, which is the main cause of secondary brain injury.

  3. Pharmacological Treatments in Pathological Gambling

    DEFF Research Database (Denmark)

    Grant, Jon E; Odlaug, Brian Lawrence; Schreiber, Liana R N

    2012-01-01

    AIMS: Pathological gambling (PG) is a relatively common and often disabling psychiatric condition characterized by intrusive urges to engage in deleterious gambling behavior. Although common and financially devastating to individuals and families, there currently exist no formally approved...... pharmacotherapeutic interventions for this disorder. This review seeks to examine the history of medication treatments for PG. METHODS: A systematic review of the 18 double-blind, placebo-controlled pharmacotherapy studies conducted for the treatment of pathological gambling was conducted. Study outcome and the mean...

  4. Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid

    DEFF Research Database (Denmark)

    Frydenvang, Karla Andrea; Pickering, Darryl S; Greenwood, Jeremy R;

    2010-01-01

    We describe an improved synthesis and detailed pharmacological characterization of the conformationally restricted analogue of the naturally occurring nonselective glutamate receptor agonist ibotenic acid (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA, 5) at A...

  5. Tetrazolyl isoxazole amino acids as ionotropic glutamate receptor antagonists: synthesis, modelling and molecular pharmacology

    DEFF Research Database (Denmark)

    Frølund, Bente; Greenwood, Jeremy R; Holm, Mai Marie;

    2005-01-01

    and 1b were pharmacologically characterized in receptor binding assays, and electrophysiologically on homomeric AMPA receptors (GluR1-4), homomeric (GluR5 and GluR6) and heteromeric (GluR6/KA2) kainic acid receptors, using two-electrode voltage-clamped Xenopus laevis oocytes expressing these receptors...

  6. Characterization of the Roman lines/strains of rats as a genetic model of psychiatric disorders: a behavioral and brain dialysis study

    OpenAIRE

    Piludu, Maria Antonietta

    2016-01-01

    State of the art Depressive disorders are fairly prevalent in the general population, with a higher rate in women compared to men, are disabling, since they can significantly impair psychosocial functioning, and are typically associated with high mortality due mainly to the high rate of suicides but also to the negative impact that depression has on the course of co-occurring illnesses. In addition, pharmacological and psychological antidepressant therapies in use have a limited efficacy and/...

  7. Gabapentin in the management of dysautonomia following severe traumatic brain injury: a case series

    DEFF Research Database (Denmark)

    Baguley, Ian J; Heriseanu, Roxana E; Gurka, Joseph A;

    2007-01-01

    The pharmacological management of dysautonomia, otherwise known as autonomic storms, following acute neurological insults, is problematic and remains poorly researched. This paper presents six subjects with dysautonomia following extremely severe traumatic brain injury where gabapentin controlled...

  8. Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist.

    Science.gov (United States)

    Zhang, Minli; Zhou, Diansong; Wang, Yi; Maier, Donna L; Widzowski, Daniel V; Sobotka-Briner, Cynthia D; Brockel, Becky J; Potts, William M; Shenvi, Ashok B; Bernstein, Peter R; Pierson, M Edward

    2011-11-01

    The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT(1B) receptor (K(i), 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC(50) values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients. PMID:21825000

  9. Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist.

    Science.gov (United States)

    Zhang, Minli; Zhou, Diansong; Wang, Yi; Maier, Donna L; Widzowski, Daniel V; Sobotka-Briner, Cynthia D; Brockel, Becky J; Potts, William M; Shenvi, Ashok B; Bernstein, Peter R; Pierson, M Edward

    2011-11-01

    The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT(1B) receptor (K(i), 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC(50) values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients.

  10. Conotoxins: Structure, Therapeutic Potential and Pharmacological Applications.

    Science.gov (United States)

    Mir, Rafia; Karim, Sajjad; Kamal, Mohammad Amjad; Wilson, Cornelia M; Mirza, Zeenat

    2016-01-01

    Cone snails, also known as marine gastropods, from Conus genus produce in their venom a diverse range of small pharmacologically active structured peptides called conotoxins. The cone snail venoms are widely unexplored arsenal of toxins with therapeutic and pharmacological potential, making them a treasure trove of ligands and peptidic drug leads. Conotoxins are small disulfide bonded peptides, which act as remarkable selective inhibitors and modulators of ion channels (calcium, sodium, potassium), nicotinic acetylcholine receptors, noradrenaline transporters, N-methyl-D-aspartate receptors, and neurotensin receptors. They are highly potent and specific against several neuronal targets making them valuable as research tools, drug leads and even therapeutics. In this review, we discuss their gene superfamily classification, nomenclature, post-translational modification, structural framework, pharmacology and medical applications of the active conopeptides. We aim to give an overview of their structure and therapeutic potential. Understanding these aspects of conopeptides will help in designing more specific peptidic analogues. PMID:26601961

  11. Towards a genealogy of pharmacological practice.

    Science.gov (United States)

    Camargo, Ricardo; Ried, Nicolás

    2016-03-01

    Following Foucault's work on disciplinary power and biopolitics, this article maps an initial cartography of the research areas to be traced by a genealogy of pharmacological practice. Pharmacology, as a practical activity, refers to the creation, production and sale of drugs/medication. This work identifies five lines of research that, although often disconnected from each other, may be observed in the specialized literature: (1) pharmaceuticalization; (2) regulation of the pharmaceutical industry; (3) the political-economic structure of the pharmaceutical industry; (4) consumption/consumerism of medications; (5) and bio-knowledge. The article suggests that a systematic analysis of these areas leads one to consider pharmacological practice a sui generis apparatus of power, which reaches beyond the purely disciplinary and biopolitical levels to encompass molecular configurations, thereby giving rise not only to new types of government over life, but also to new struggles for life, extending from molecular to population-wide levels. PMID:25956710

  12. Pharmacological action and mechanisms of ginkgolide B

    Institute of Scientific and Technical Information of China (English)

    XIA Shi-hai; FANG Dian-chun

    2007-01-01

    Objective To review the recent research progress in pharmacological actions and mechanisms of ginkgolide B.Data sources Information included in this article was identified by searching of PUBMED (1987-2006) online resources using the key terms "ginkgolide B", "platelet activating factor", and "pharmacological".Study selection Mainly original milestone articles and critical reviews written by major pioneer investigators of the field were selected.Results The key issues related to the pharmacological actions and mechanisms of ginkgolide B were summarized. The ginkgolide B possesses a number of beneficial effects such as anti-inflammatory, anti-allergic, antioxidant, and neuroprotective effects. Meantime, their mechaniams were discussed.Conclusions The Ginkgolide B is the most potent antagonist of platelet activating factor (PAF) and exhibits therapeutic action in a variety of diseases mainly by the PAF receptor.

  13. Pharmacology and toxicology of diphenyl diselenide in several biological models

    Directory of Open Access Journals (Sweden)

    R.M. Rosa

    2007-10-01

    Full Text Available The pharmacology of synthetic organoselenium compounds indicates that they can be used as antioxidants, enzyme inhibitors, neuroprotectors, anti-tumor and anti-infectious agents, and immunomodulators. In this review, we focus on the effects of diphenyl diselenide (DPDS in various biological model organisms. DPDS possesses antioxidant activity, confirmed in several in vitro and in vivo systems, and thus has a protective effect against hepatic, renal and gastric injuries, in addition to its neuroprotective activity. The activity of the compound on the central nervous system has been studied since DPDS has lipophilic characteristics, increasing adenylyl cyclase activity and inhibiting glutamate and MK-801 binding to rat synaptic membranes. Systemic administration facilitates the formation of long-term object recognition memory in mice and has a protective effect against brain ischemia and on reserpine-induced orofacial dyskinesia in rats. On the other hand, DPDS may be toxic, mainly because of its interaction with thiol groups. In the yeast Saccharomyces cerevisiae, the molecule acts as a pro-oxidant by depleting free glutathione. Administration to mice during cadmium intoxication has the opposite effect, reducing oxidative stress in various tissues. DPDS is a potent inhibitor of d-aminolevulinate dehydratase and chronic exposure to high doses of this compound has central effects on mouse brain, as well as liver and renal toxicity. Genotoxicity of this compound has been assessed in bacteria, haploid and diploid yeast and in a tumor cell line.

  14. Pharmacological evaluation of bee venom and melittin

    OpenAIRE

    Camila G. Dantas; Tássia L.G.M. Nunes; Tâmara L.G.M. Nunes; Ailma O. da Paixão; Francisco P. Reis; Waldecy de L. Júnior; Juliana C. Cardoso; Kátia P. Gramacho; Gomes, Margarete Z

    2014-01-01

    The objective of this study was to identify the pharmacological effects of bee venom and its major component, melittin, on the nervous system of mice. For the pharmacological analysis, mice were treated once with saline, 0.1 or 1.2 mg/kg of bee venom and 0.1 mg/kg of melittin, subcutaneously, 30 min before being submitted to behavioral tests: locomotor activity and grooming (open-field), catalepsy, anxiety (elevated plus-maze), depression (forced swimming test) and apomorphine-induced stereot...

  15. CASSIA TORA: A PHYTO-PHARMACOLOGICAL OVERVIEW

    Directory of Open Access Journals (Sweden)

    Das Chandan

    2011-04-01

    Full Text Available Cassia tora, a popular Indian medicinal plant, has long been used in Ayurvedic system of medicine. The plant has been found to possess diverse number of pharmacological activities. The present paper gives an account of updated information on its phytochemical and pharmacological activities. The review reveals that wide range of phytochemical constituents have been isolated from the plant and it possess important activities like laxative, skin diseases, ringworm, eye diseases, liver complaint, dysentery and anthelmentic. Various other activities like antioxidant, hypoglycemic, hypolipidemic, antinociceptive, antiplasmodial, antifungal & antimicrobial, hyperlipemia & hypotensive have also been reported. These reports are very encouraging and indicate that herb should be studied more extensively for its therapeutic benefits.

  16. PHYTO-PHARMACOLOGICAL REVIEW OF ARGYREIA NERVOSA

    Directory of Open Access Journals (Sweden)

    A. Krishnaveni

    2011-02-01

    Full Text Available Herbal medicines are the significant and reliable sources for treating various diseases. Argyreia nervosa is traditionally used in wound healing, syphilius,diuretics,rheumatic affections, leucohorrhoea.,cerebral disorders, ulcers, as anti-tumour and to prevent contraception.Phytoconstituents such as flavanoids, steroids, ergoline alkaloids and triterpenoids were identified. Pharmacological studies proved its anticonvulsant, immunomodulatory, hypotensive, anti- inflammatory and nootropic effect.The present form of article highlights the phytochemical and pharmacological studies including traditional practice of Argyreia nervosa have been carried out so far.

  17. Quantum biology and quantum pharmacology: proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Loewdin, P.O.; Oehrn, N.Y.; Sabin, J.R.; Zerner, M.C.

    1986-01-01

    The 25th Sanibel Symposia, which included the 12th meeting of the Symposium on Quantum Biology and Quantum Pharmacology, was held at the University of Florida Whitney Laboratory at Marineland on the Atlantic Coast of Florida, March 14-23, 1985. The three days (March 14-16) devoted to Quantum Biology and Quantum Pharmacology saw the presentation of more than 50 papers by the 90 participants representing about 20 different nations. These ''Proceedings'' comprise the contributions in both the invited talks and the poster sessions.

  18. Brain Basics

    Medline Plus

    Full Text Available ... all. She was happily married and successful in business. Then, after a serious setback at work, she ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses ...

  19. Brain Basics

    Medline Plus

    Full Text Available ... the anatomy, physiology, and chemistry of the nervous system. When the brain cannot effectively coordinate the billions ... basic working unit of the brain and nervous system. These cells are highly specialized for the function ...

  20. Brain Basics

    Medline Plus

    Full Text Available ... the brain cannot effectively coordinate the billions of cells in the body, the results can affect many ... unit of the brain and nervous system. These cells are highly specialized for the function of conducting ...

  1. Brain Basics

    Medline Plus

    Full Text Available ... Trials — Participants Statistics Help for Mental Illnesses Outreach Research Priorities Funding Labs at NIMH News About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The ...

  2. Brain Basics

    Medline Plus

    Full Text Available ... brain may play a role in disorders like schizophrenia or attention deficit hyperactivity disorder (ADHD) . Glutamate —the ... mental disorders, including autism , obsessive compulsive disorder (OCD) , schizophrenia , and depression . Brain Regions Just as many neurons ...

  3. Brain Basics

    Medline Plus

    Full Text Available ... body, the results can affect many aspects of life. Scientists are continually learning more about how the brain grows and works in healthy people, and how normal brain development and function ...

  4. Brain Basics

    Medline Plus

    Full Text Available ... Brain Basics will introduce you to some of this science, such as: How the brain develops How ... cell, and responds to signals from the environment; this all helps the cell maintain its balance with ...

  5. Brain Basics

    Medline Plus

    Full Text Available ... How the brain develops How genes and the environment affect the brain The basic structure of the ... inside contents of the cell from its surrounding environment and controls what enters and leaves the cell, ...

  6. Brain Basics

    Medline Plus

    Full Text Available ... affect many aspects of life. Scientists are continually learning more about how the brain grows and works ... early brain development. It may also assist in learning and memory. Problems in making or using glutamate ...

  7. Brain Basics

    Medline Plus

    Full Text Available ... have been linked to many mental disorders, including autism , obsessive compulsive disorder (OCD) , schizophrenia , and depression . Brain ... studies show that brain growth in children with autism appears to peak early. And as they grow ...

  8. Brain Basics

    Medline Plus

    Full Text Available ... may help improve treatments for anxiety disorders like phobias or post-traumatic stress disorder (PTSD) . Prefrontal cortex ( ... brain's structure, studies show that brain growth in children with autism appears to peak early. And as ...

  9. Brain Basics

    Medline Plus

    Full Text Available ... body, the results can affect many aspects of life. Scientists are continually learning more about how the brain grows and works in healthy people, and how normal brain development ...

  10. Brain Basics

    Medline Plus

    Full Text Available ... medications could reduce the amount of trial and error and frustration that many people with depression experience ... early brain development, and may also assist in learning and memory. hippocampus —A portion of the brain ...

  11. Brain Diseases

    Science.gov (United States)

    The brain is the control center of the body. It controls thoughts, memory, speech, and movement. It regulates the function of many organs. When the brain is healthy, it works quickly and automatically. However, ...

  12. Brain Basics

    Medline Plus

    Full Text Available ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses ... depression experience when starting treatment. Gene Studies Advanced technologies are also making it faster, easier, and more ...

  13. Brain Basics

    Medline Plus

    Full Text Available ... mainly involved in controlling movement and aiding the flow of information to the front of the brain, ... the neuron will fire. This enhances the electrical flow among brain cells required for normal function and ...

  14. Brain Basics

    Medline Plus

    Full Text Available ... works in healthy people, and how normal brain development and function can go awry, leading to mental ... and are working to compare that with brain development in people mental disorders. Genes and environmental cues ...

  15. Brain Basics

    Medline Plus

    Full Text Available ... and epigenetic changes can be passed on to future generations. Further understanding of genes and epigenetics may ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses ...

  16. Brain Basics

    Medline Plus

    Full Text Available ... neurons, the most highly specialized cells of all, conduct messages. Every cell in our bodies contains a ... brain's structure, studies show that brain growth in children with autism appears to peak early. And as ...

  17. Brain Basics

    Medline Plus

    Full Text Available ... can be related to changes in the anatomy, physiology, and chemistry of the nervous system. When the ... healthy people, and how normal brain development and function can go awry, leading to mental illnesses. Brain ...

  18. Brain Basics

    Medline Plus

    Full Text Available ... Real Life Brain Basics in Real Life—How Depression affects the Brain Meet Sarah Sarah is a ... blues" from time to time. In contrast, major depression is a serious disorder that lasts for weeks. ...

  19. Pharmacological characterization of KUR-1246, a selective uterine relaxant.

    Science.gov (United States)

    Kobayashi, M; Takeda, K; Murata, S; Kojima, M; Akahane, M; Inoue, Y; Kitamura, K; Kawarabayashi, T

    2001-05-01

    The aim of the present study was to evaluate the efficacy and beta 2-adrenoceptor (AR) selectivity of KUR-1246, a new uterine relaxant. Inhibition of spontaneous or drug-induced uterine contractions by KUR-1246 was evaluated in pregnant rats and rabbits by an organ bath method or by a balloon method. The selectivity of KUR-1246 was assessed simultaneously in organs isolated from late-pregnant rats. The affinity of KUR-1246 for human beta 1-, beta 2-, and beta 3-ARs was determined using two radioligands. KUR-1246 suppressed both spontaneous and drug-induced contractions in isolated uteri, the rank order of potency being isoproterenol > KUR-1246 > terbutaline > ritodrine. ICI-118551 (selective beta 2-AR antagonist) competitively antagonized the KUR-1246-induced inhibition of spontaneous uterine contractions, but CGP-20712A (selective beta 1-AR antagonist) and SR-58894A (selective beta 3-AR antagonist) did not. All beta-AR agonists tested produced significant inhibition of spontaneous uterine contractions in vivo: ED(30) value for KUR-1246 was 0.13 microg/kg/min, a potency about 6 times and 400 times greater than that of terbutaline and ritodrine, respectively. In contrast, the positive chronotropic effect was minimal in KUR-1246-treated rats. KUR-1246 displaced radioligand binding to beta 1-, beta 2-, and beta 3-ARs, the pK(i) values being 5.75 +/- 0.03, 7.59 +/- 0.08, and 4.75 +/- 0.03 for beta 1-, beta 2-, and beta 3-ARs, respectively. For the selectivity of KUR-1246 for human beta 2-AR, we obtained values of 39.2 ([IC(50) for beta 1-AR]/[IC(50) for beta 2-AR]) and 198.2 ([IC(50) for beta 3-AR]/[IC(50) for beta 2-AR]), indicating an apparently higher affinity for human beta 2-AR than for other beta-AR subtypes. The present study clearly demonstrated that KUR-1246 is a more selective beta 2-AR agonist than the drugs presently used for relaxing uterine muscle.

  20. PHARMACOLOGICAL CHARACTERIZATION OF TERPENIC SECONDARY METABOLITES ISOLATED FROM SALVIA SPECIES

    OpenAIRE

    Bonito, Maria Carmela

    2009-01-01

    Recently most interest has been focused on active compounds extracted from natural sources. This is due to the fact that many of these natural products in plants of medicinal value can offer new sources of drugs. The genus Salvia from the Lamiaceae family has numerous different species - about 900 species- which are extensively distributed in various regions of the world. Many Salvia species are well-studied and widely used in traditional medicine. Plants belonging to the genus Salvia are ...

  1. Secondary metabolites from natural sources: chemical and pharmacological characterization

    OpenAIRE

    Festa, Carmen

    2010-01-01

    Natural products have long been a source of bioactive metabolites utilized for the treatment of human disease. In spite the impressive progress of new competing methodologies, as for example, combinatorial chemistry and high-throughput screening or genetic engineering, natural products remain a valuable source of bioactive compounds with therapeutic potential. In recent years, the marine environment has been seen as a vast resource for the discovery of structurally unique bioactive secon...

  2. Brain Basics

    Medline Plus

    Full Text Available ... pituitary-adrenal (HPA) axis. Brain Basics in Real Life Brain Basics in Real Life—How Depression affects the Brain Meet Sarah Sarah ... having trouble coping with the stresses in her life. She began to think of suicide because she ...

  3. Brain Basics

    Medline Plus

    Full Text Available ... Life Brain Basics in Real Life—How Depression affects the Brain Meet Sarah Sarah is a middle-aged woman ... new memories. hypothalmic-pituitary-adrenal (HPA) axis —A brain-body ... stress. impulse —An electrical communication signal sent between neurons ...

  4. Brain Aneurysm

    Science.gov (United States)

    A brain aneurysm is an abnormal bulge or "ballooning" in the wall of an artery in the brain. They are sometimes called berry aneurysms because they ... often the size of a small berry. Most brain aneurysms produce no symptoms until they become large, ...

  5. Alternative Radioligands for Investigating the Molecular Pharmacology of Melatonin Receptors.

    Science.gov (United States)

    Legros, Céline; Brasseur, Chantal; Delagrange, Philippe; Ducrot, Pierre; Nosjean, Olivier; Boutin, Jean A

    2016-03-01

    Melatonin exerts a variety of physiologic activities that are mainly relayed through the melatonin receptors MT1 and MT2 Low expressions of these receptors in tissues have led to widespread experimental use of the agonist 2-[(125)I]-iodomelatonin as a substitute for melatonin. We describe three iodinated ligands: 2-(2-[(2-iodo-4,5-dimethoxyphenyl)methyl]-4,5-dimethoxy phenyl) (DIV880) and (2-iodo-N-2-[5-methoxy-2-(naphthalen-1-yl)-1H-pyrrolo[3,2-b]pyridine-3-yl])acetamide (S70254), which are specific ligands at MT2 receptors, and N-[2-(5-methoxy-1H-indol-3-yl)ethyl]iodoacetamide (SD6), an analog of 2-[(125)I]-iodomelatonin with slightly different characteristics. Here, we further characterized these new ligands with regards to their molecular pharmacology. We performed binding experiments, saturation assays, association/dissociation rate measurements, and autoradiography using sheep and rat tissues and recombinant cell lines. Our results showed that [(125)I]-S70254 is receptor, and can be used with both cells and tissue. This radioligand can be used in autoradiography. Similarly, DIV880, a partial agonist [43% of melatonin on guanosine 5'-3-O-(thio)triphosphate binding assay], selective for MT2, can be used as a tool to selectively describe the pharmacology of this receptor in tissue samples. The molecular pharmacology of both human melatonin receptors MT1 and MT2, using a series of 24 ligands at these receptors and the new radioligands, did not lead to noticeable variations in the profiles. For the first time, we described radiolabeled tools that are specific for one of the melatonin receptors (MT2). These tools are amenable to binding experiments and to autoradiography using sheep or rat tissues. These specific tools will permit better understanding of the role and implication in physiopathologic processes of the melatonin receptors. PMID:26759496

  6. Physician attitudes towards pharmacological cognitive enhancement: safety concerns are paramount.

    Directory of Open Access Journals (Sweden)

    Opeyemi C Banjo

    Full Text Available The ethical dimensions of pharmacological cognitive enhancement have been widely discussed in academic circles and the popular media, but missing from the conversation have been the perspectives of physicians - key decision makers in the adoption of new technologies into medical practice. We queried primary care physicians in major urban centers in Canada and the United States with the aim of understanding their attitudes towards cognitive enhancement. Our primary hypothesis was that physicians would be more comfortable prescribing cognitive enhancers to older patients than to young adults. Physicians were presented with a hypothetical pharmaceutical cognitive enhancer that had been approved by the regulatory authorities for use in healthy adults, and was characterized as being safe, effective, and without significant adverse side effects. Respondents overwhelmingly reported increasing comfort with prescribing cognitive enhancers as the patient age increased from 25 to 65. When asked about their comfort with prescribing extant drugs that might be considered enhancements (sildenafil, modafinil, and methylphenidate or our hypothetical cognitive enhancer to a normal, healthy 40 year old, physicians were more comfortable prescribing sildenafil than any of the other three agents. When queried as to the reasons they answered as they did, the most prominent concerns physicians expressed were issues of safety that were not offset by the benefit afforded the individual, even in the face of explicit safety claims. Moreover, many physicians indicated that they viewed safety claims with considerable skepticism. It has become routine for safety to be raised and summarily dismissed as an issue in the debate over pharmacological cognitive enhancement; the observation that physicians were so skeptical in the face of explicit safety claims suggests that such a conclusion may be premature. Thus, physician attitudes suggest that greater weight be placed upon the

  7. 阿片受体类型和功能及其在猪脑中的个体发育特点%Classification and Functions of Opioid Receptors and Their Ontogenic Characterization in Pig Brain

    Institute of Scientific and Technical Information of China (English)

    李定健

    2016-01-01

    The research progress on classification of opioid receptors and introduced functions of four main types of receptors were summarized. In animal brains, changes in the opioid receptor number and their afifnity to opioid ligands can affect opioidergic control of brain functions or central nervous control of endocrine system. In order to provide the references for changes of opioid receptors in pig brain, the ontogenic characterization of opioid receptors in pig brains was elaborated.%总结阿片受体类型的研究进展,介绍4种主要类型受体的功能。动物脑中阿片受体的数量以及它们与阿片配体亲和力的改变能够对脑功能的阿片控制或内分泌系统的中枢神经控制产生影响。为明确猪脑中阿片受体的变化,阐述了阿片受体在猪脑中的个体发育特点。

  8. In vitro characterization of pralidoxime transport and acetylcholinesterase reactivation across MDCK cells and stem cell-derived human brain microvascular endothelial cells (BC1-hBMECs)

    OpenAIRE

    Gallagher, Erin; Minn, IL; Chambers, Janice E.; Searson, Peter C.

    2016-01-01

    Background Current therapies for organophosphate poisoning involve administration of oximes, such as pralidoxime (2-PAM), that reactivate the enzyme acetylcholinesterase. Studies in animal models have shown a low concentration in the brain following systemic injection. Methods To assess 2-PAM transport, we studied transwell permeability in three Madin-Darby canine kidney (MDCKII) cell lines and stem cell-derived human brain microvascular endothelial cells (BC1-hBMECs). To determine whether 2-...

  9. The Pharmacological Activities of (−-Anonaine

    Directory of Open Access Journals (Sweden)

    Chung-Yi Chen

    2013-07-01

    Full Text Available Several species of Magnoliaceae and Annonaceae are used in Traditional Chinese Medicine. (−-Anonaine, isolated from several species of Magnoliaceae and Annonaceae, presents antiplasmodial, antibacterial, antifungal, antioxidation, anticancer, antidepression, and vasorelaxant activity. This article provides an overview of the pharmacological functions of (−-anonaine.

  10. Systems Pharmacology in Small Molecular Drug Discovery

    Directory of Open Access Journals (Sweden)

    Wei Zhou

    2016-02-01

    Full Text Available Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity, target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

  11. Pharmacological Interventions for Students with ADD.

    Science.gov (United States)

    Austin, Vance L.

    2003-01-01

    A review of the research on pharmacological interventions for students with attention deficit disorder finds that psychostimulants such as methylphenidate (Ritalin) are effective in improving focus and impulse control, but should be used in conjunction with psychosocial and behavioral interventions. Comprehensive medical screenings and guidelines…

  12. Non Pharmacological Cognitive Enhancers – Current Perspectives

    OpenAIRE

    Sachdeva, Ankur; Kumar, Kuldip; Anand, Kuljeet Singh

    2015-01-01

    Cognition refers to the mental processes involved in thinking, knowing, remembering, judging, and problem solving. Cognitive dysfunctions are an integral part of neuropsychiatric disorders as well as in healthy ageing. Cognitive Enhancers are molecules that help improve aspects of cognition like memory, intelligence, motivation, attention and concentration. Recently, Non Pharmacological Cognitive Enhancers have gained popularity as effective and safe alternative to various established drugs. ...

  13. Mitochondria: pharmacological manipulation of cell death

    OpenAIRE

    Bouchier-Hayes, Lisa; Lartigue, Lydia; Newmeyer, Donald D.

    2005-01-01

    Cell death by apoptosis or necrosis is often important in the etiology and treatment of disease. Since mitochondria play important roles in cell death pathways, these organelles are potentially prime targets for therapeutic intervention. Here we discuss the mechanisms through which mitochondria participate in the cell death process and also survey some of the pharmacological approaches that target mitochondria in various ways.

  14. KALANCHOE PINNATA: PHYTOCHEMICAL AND PHARMACOLOGICAL PROFILE

    OpenAIRE

    Seema V. Pattewar

    2012-01-01

    The main objective of this review is to provide advance information for the drug discovery research from the divine herb Kalanchoe pinnata, which contains a wide range of active compounds, including alkaloids, triterpenes, glycosides, flavonoids, steroids, bufadienolides, lipids and organic acids. The pharmacological studies are reviewed and discussed, focussing on activities as immunomodulator, CNS depressant, analgesic, antimicrobial, antiinflammatory, antiallergic, antianaphylactic, antile...

  15. Plant cannabinoids: a neglected pharmacological treasure trove

    OpenAIRE

    Mechoulam, Raphael

    2005-01-01

    Most of the cannabinoids in Cannabis sativa L. have not been fully evaluated for their pharmacological activity. A publication in this issue presents evidence that a plant cannabinoid, Δ9-tetrahydrocannabivarin is a potent antagonist of anandamide, a major endogenous cannabinoid. It seems possible that many of the non-psychoactive constituents of this plant will be of biological interest.

  16. PHYTO-PHARMACOLOGICAL REVIEW OF ARGYREIA NERVOSA

    OpenAIRE

    Krishnaveni, A; T. Sant Rani

    2011-01-01

    Herbal medicines are the significant and reliable sources for treating various diseases. Argyreia nervosa is traditionally used in wound healing, syphilius,diuretics,rheumatic affections, leucohorrhoea.,cerebral disorders, ulcers, as anti-tumour and to prevent contraception.Phytoconstituents such as flavanoids, steroids, ergoline alkaloids and triterpenoids were identified. Pharmacological studies proved its anticonvulsant, immunomodulatory, hypotensive, anti- inflammatory and no...

  17. Myocardial ATP catabolism and its pharmacological prevention

    NARCIS (Netherlands)

    T. Huizer (Tom)

    1991-01-01

    textabstractThis thesis deals with high-energy phosphate metabolism during myocardial ischemia. describes the effects of some pharmacological interventions on the energy metabolism of ischemic myocardium. The chapters of this thesis are based on 11 published papers, added as appendices.

  18. Clinical pharmacology of novel anticancer drug formulations

    NARCIS (Netherlands)

    Stuurman, F.E.

    2013-01-01

    Studies outlined in this thesis describe the impact of drug formulations on pharmacology of anticancer drugs. It consists of four parts and starts with a review describing the mechanisms of low oral bioavailability of anti-cancer drugs and strategies for improvement of the bioavailability. The major

  19. Molecular Pharmacology of CXCR4 inhibition

    DEFF Research Database (Denmark)

    Steen, Anne; Rosenkilde, Mette Marie

    2012-01-01

    pharmacology of well-known CXCR4 antagonists in order to augment the potency and affinity and to increase the specificity of future CXCR4-targeting compounds. In this chapter, binding modes of CXCR4 antagonists that have been shown to mobilize stem cells are discussed. In addition, comparisons between results...

  20. Pharmacological interventions for phantom limb pain

    Institute of Scientific and Technical Information of China (English)

    FANG Jun; LIAN Yan-hong; XIE Kang-jie; CAI Shu-nü

    2013-01-01

    Objective To review the mechanisms and current clinical application of pharmacological interventions for phantom limb pain.Data sources Both Chinese and English language literatures were searched using MEDLINE (1982-2011),Pubmed (1982-2011) and the Index of Chinese Language Literature (1982-2011).Study selection Data from published articles about pharmacological management of phantom limb pain in recent domestic and foreign literature were selected.Data extraction Data were mainly extracted from 96 articles which are listed in the reference section of this review.Results By reviewing the mechanisms and current clinical application of pharmacological interventions for phantom limb pain,including anticonvulsants,antidepressants,local anaesthetics,N-methyl-D-aspartate receptor antagonists,non-steroidal anti-inflammatory drugs,tramadol,opioids,calcitonin,capsaicin,beta-adrenergic blockers,clonidine,muscle relaxants,and emerging drugs,we examined the efficacy and safety of these medications,outlined the limitations and future directions.Conclusions Although there is lack of evidence-based consensus guidelines for the pharmacological management of phantom limb pain,we recommend tricyclic antidepressants,gabapentin,tramadol,opioids,local anaesthetics and N-methyl-D-aspartate receptor antagonists as the rational options for the treatment of phantom limb pain.

  1. The role of pharmacology in pediatric oncology

    Energy Technology Data Exchange (ETDEWEB)

    Poplack, D.G.; Massimo, L.; Cornaglia-Ferraris, P

    1987-01-01

    This book contains 25 chapters. Some of the Titles are: Genetic reasons for pharmacologic treatment failure: gene amplification; New approaches to overcome drug resistance; An overview of adverse late effects of cancer chemotherapy in children; the development of 9-substituted purines as immunomodulators; and High dose cisplatinum: a phase II study.

  2. Systems Pharmacology in Small Molecular Drug Discovery

    Science.gov (United States)

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-01-01

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level. PMID:26901192

  3. Radioreceptor assay: theory and applications to pharmacology

    Energy Technology Data Exchange (ETDEWEB)

    Perret, G. (U.E.R. de Medecine, Sante et Biologie Humaine, 93 - Bobigny (France)); Simon, P. (Faculte de Medecine Pitie-Salpetriere, 75 - Paris (France))

    The aim of the first part of this work is to present the theory of the radioreceptor assay and to compare it to the other techniques of radioanalysis (radioimmunoassay, competitive protein binding assays). The technology of the radioreceptor assay is then presented and its components (preparation of the receptors, radioligand, incubation medium) are described. The analytical characteristics of the radioreceptor assay (specificity, sensitivity, reproductibility, accuracy) and the pharmacological significance of the results are discussed. The second part is devoted to the description of the radioreceptor assays of some pharmacological classes (neuroleptics, tricyclic antidepressants, benzodiazepines, ..beta..-blockers, anticholinergic drugs) and to their use in therapeutic drug monitoring. In conclusion, by their nature, radioreceptor assays are highly sensitive, reliable, precise, accurate and simple to perform. Their chief disadvantage relates to specificity, since any substance having an appreciable affinity to the receptor site will displace the specifically bound radioligand. Paradoxically in some cases, this lack of specificity may be advantageous in that it allows for the detection of not only the apparent compound but of active metabolites and endogenous receptor agonists as well and in that radioreceptors assays can be devised for a whole pharmacological class and not only for one drug as it is the case for classical physico-chemical techniques. For all these reasons future of radioreceptor assay in pharmacology appears promising.

  4. Investigational pharmacology for low back pain

    Directory of Open Access Journals (Sweden)

    Avinash K Bhandary

    2010-09-01

    Full Text Available Avinash K Bhandary1 , Gary P Chimes2, Gerard A Malanga3 1Department of Physical Medicine and Rehabilitation, 2Department of Physical Medicine and Rehabilitation, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 3New Jersey Sports Medicine Institute; Overlook Hospital; Mountainside Hospital; Rehabilitation Medicine and Electrodiagnosis, St Michael’s Medical Center; Horizon Healthcare Worker’s Compensation Services, Blue Cross and Blue Shield Worker’s Compensation, Summit, NJ, USAStudy design: Review and reinterpretation of existing literature.Objective: This review article summarizes the anatomy and pathogenesis of disease processes that contribute to low back pain, and discusses key issues in existing therapies for chronic low back pain. The article also explains the scientific rationale for investigational pharmacology and highlights emerging compounds in late development.Results/conclusion: While the diverse and complex nature of chronic low back pain continues to challenge clinicians, a growing understanding of chronic low back pain on a cellular level has refined our approach to managing chronic low back pain with pharmacology. Many emerging therapies with improved safety profiles are currently in the research pipeline and will contribute to a multimodal therapeutic algorithm in the near future. With the heterogeneity of the patient population suffering from chronic low back pain, the clinical challenge will be accurately stratifying the optimal pharmacologic approach for each patient.Keywords: low back pain, investigational, pharmacology, drugs

  5. The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments

    Science.gov (United States)

    Farzaei, Mohammad H; Bahramsoltani, Roodabeh; Abdollahi, Mohammad; Rahimi, Roja

    2016-01-01

    Irritable bowel syndrome (IBS) is the most common disorder referred to gastroenterologists and is characterized by altered bowel habits, abdominal pain, and bloating. Visceral hypersensitivity (VH) is a multifactorial process that may occur within the peripheral or central nervous systems and plays a principal role in the etiology of IBS symptoms. The pharmacological studies on selective drugs based on targeting specific ligands can provide novel therapies for modulation of persistent visceral hyperalgesia. The current paper reviews the cellular and molecular mechanisms underlying therapeutic targeting for providing future drugs to protect or treat visceroperception and pain sensitization in IBS patients. There are a wide range of mediators and receptors participating in visceral pain perception amongst which substances targeting afferent receptors are attractive sources of novel drugs. Novel therapeutic targets for the management of VH include compounds which alter gut-brain pathways and local neuroimmune pathways. Molecular mediators and receptors participating in pain perception and visceroperception include histamine-1 receptors, serotonin (5-hydrodytryptamine) receptors, transient receptor potential vanilloid type I, tachykinins ligands, opioid receptors, voltage-gated channels, tyrosine receptor kinase receptors, protease-activated receptors, adrenergic system ligands, cannabinoid receptors, sex hormones, and glutamate receptors which are discussed in the current review. Moreover, several plant-derived natural compounds with potential to alleviate VH in IBS have been highlighted. VH has an important role in the pathology and severity of complications in IBS. Therefore, managing VH can remarkably modulate the symptoms of IBS. More preclinical and clinical investigations are needed to provide efficacious and targeted medicines for the management of VH. PMID:27431236

  6. Pharmacologic treatment of anorexia nervosa: where do we go from here?

    Science.gov (United States)

    Attia, Evelyn; Schroeder, Laura

    2005-01-01

    Anorexia nervosa (AN) is a serious mental disorder, characterized by severely low weight and cognitive distortions about body shape and weight. AN is generally associated with a range of psychological symptoms, including depression, anxiety, obsessions, and rituals. The current study summarized findings from randomized controlled trials (RCT) using pharmacologic treatments in patients with AN. We conducted a review of literature using Medline. Several classes of pharmacologic agents have been studied in small samples of patients with acute AN without finding clear benefit to eating, weight, body shape concerns, or associated psychopathology. Studies have been limited by small sample sizes, as well as by research design with most studies adding medication to comprehensive hospital-based treatment programs. Future directions for pharmacologic treatment research in AN should include outpatient trials, rigorous study of atypical antipsychotic medication, and assessment of medication effect for relapse prevention in weight-restored patients.

  7. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use.

    Science.gov (United States)

    Taylor, Charles P; Traynelis, Stephen F; Siffert, Joao; Pope, Laura E; Matsumoto, Rae R

    2016-08-01

    Dextromethorphan (DM) has been used for more than 50years as an over-the-counter antitussive. Studies have revealed a complex pharmacology of DM with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential. DM is rapidly metabolized to dextrorphan, which has hampered the exploration of DM therapy separate from its metabolites. Coadministration of DM with a low dose of quinidine inhibits DM metabolism, yields greater bioavailability and enables more specific testing of the therapeutic properties of DM apart from its metabolites. The development of the drug combination DM hydrobromide and quinidine sulfate (DM/Q), with subsequent approval by the US Food and Drug Administration for pseudobulbar affect, led to renewed interest in understanding DM pharmacology. This review summarizes the interactions of DM with brain receptors and transporters and also considers its metabolic and pharmacokinetic properties. To assess the potential clinical relevance of these interactions, we provide an analysis comparing DM activity from in vitro functional assays with the estimated free drug DM concentrations in the brain following oral DM/Q administration. The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α3β4 subunits, and cause agonist activity at sigma-1 receptors. PMID:27139517

  8. [Pharmacological update in attention deficit hyperactivity disorder: models of intervention and new drugs].

    Science.gov (United States)

    Mulas, Fernando; Gandía, Rubén; Roca, Patricia; Etchepareborda, Máximo C; Abad, Luis

    2012-05-21

    INTRODUCTION. Attention deficit hyperactivity disorder (ADHD) is the most frequent neurodevelopmental problem in childhood, with significant repercussions that continue into adulthood. This means that an appropriate therapeutic intervention is vital to improve its prognosis. AIMS. To identify the ideal pharmacological options according to the characteristics of the patient and to report on the new drugs. DEVELOPMENT. The work analyses how therapeutic interventions can be conditioned by the anatomical substrate of the brain, the biochemical bases, genetics, neurophysiological examinations, neuropsychological studies and the clinical symptoms and subtypes. A significant amount of importance is granted to neuropsychological studies, especially those dealing with the executive functions, including evaluation of attention, impulse control, and interference and cognitive flexibility. Taking into consideration the signal-to-noise characteristics can be useful when it comes to choosing the drug. CONCLUSIONS. The development of the pharmacological therapeutic options in ADHD opens up expectations concerning applicability and greater specificity in daily practice to fit the characteristics of each patient. Psychoeducation must always be included and a thorough study of each particular child is recommended. This should involve analysing the neuropsychological features of his or her brain function in order to be able to reflect on the ideal pharmacological option that allows more favourable progress.

  9. Effects of Menthol on Nicotine Pharmacokinetic, Pharmacology and Dependence in Mice.

    Directory of Open Access Journals (Sweden)

    Shakir D Alsharari

    Full Text Available Although menthol, a common flavoring additive to cigarettes, has been found to impact the addictive properties of nicotine cigarettes in smokers little is known about its pharmacological and molecular actions in the brain. Studies were undertaken to examine whether the systemic administration of menthol would modulate nicotine pharmacokinetics, acute pharmacological effects (antinociception and hypothermia and withdrawal in male ICR mice. In addition, we examined changes in the brain levels of nicotinic receptors of rodents exposed to nicotine and menthol. Administration of i.p. menthol significantly decreased nicotine's clearance (2-fold decrease and increased its AUC compared to i.p. vehicle treatment. In addition, menthol pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (2.5 mg/kg, s.c. for periods up to 180 min post-nicotine administration. Repeated administration of menthol with nicotine increased the intensity of mecamylamine-precipitated withdrawal signs in mice exposed chronically to nicotine. The potentiation of withdrawal intensity by menthol was accompanied by a significant increase in nicotine plasma levels in these mice. Western blot analyses of α4 and β2 nAChR subunit expression suggests that chronic menthol impacts the levels and distribution of these nicotinic subunits in various brain regions. In particular, co-administration of menthol and nicotine appears to promote significant increase in β2 and α4 nAChR subunit expression in the hippocampus, prefrontal cortex and striatum of mice. Surprisingly, chronic injections of menthol alone to mice caused an upregulation of β2 and α4 nAChR subunit levels in these brain regions. Because the addition of menthol to tobacco products has been suggested to augment their addictive potential, the current findings reveal several new pharmacological molecular adaptations that may contribute to its unique addictive profile.

  10. Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery

    Directory of Open Access Journals (Sweden)

    Md. Mirazul Islam

    2015-01-01

    Full Text Available The blood-brain barrier (BBB is a dynamic and highly selective permeable interface between central nervous system (CNS and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery.

  11. Cyclooxygenase inhibitors: From pharmacology to clinical read-outs.

    Science.gov (United States)

    Patrignani, Paola; Patrono, Carlo

    2015-04-01

    Acetylsalicylic acid (aspirin) is a prototypic cyclooxygenase (COX) inhibitor. It was synthesized serendipitously from a natural compound, i.e., salicylic acid, with known analgesic activity. This chemical modification, obtained for the first time in an industrial environment in 1897, endowed aspirin with the unique capacity of acetylating and inactivating permanently COX-isozymes. Traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) were developed to mimic the pharmacological effects of aspirin, using aspirin-sensitive experimental models of pain and inflammation as the template for screening new chemical entities. Among the tNSAIDs, some were endowed with moderate COX- selectivity (e.g., diclofenac), but no studies of sufficient size and duration were performed to show any clinically relevant difference between different members of the class. Similarly, no serious attempts were made to unravel the mechanisms involved in the shared therapeutic and toxic effects of tNSAIDs until the discovery of COX-2. This led to characterizing their main therapeutic effects as being COX-2-dependent and their gastrointestinal (GI) toxicity as being COX-1-dependent, and provided a rationale for developing a new class of selective COX-2 inhibitors, the coxibs. This review will discuss the clinical pharmacology of tNSAIDs and coxibs, and the clinical read-outs of COX-isozyme inhibition. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance." PMID:25263946

  12. Pharmacological management of anticholinergic delirium - theory, evidence and practice.

    Science.gov (United States)

    Dawson, Andrew H; Buckley, Nicholas A

    2016-03-01

    The spectrum of anticholinergic delirium is a common complication following drug overdose. Patients with severe toxicity can have significant distress and behavioural problems that often require pharmacological management. Cholinesterase inhibitors, such as physostigmine, are effective but widespread use has been limited by concerns about safety, optimal dosing and variable supply. Case series support efficacy in reversal of anticholinergic delirium. However doses vary widely and higher doses commonly lead to cholinergic toxicity. Seizures are reported in up to 2.5% of patients and occasional cardiotoxic effects are also recorded. This article reviews the serendipitous path whereby physostigmine evolved into the preferred anticholinesterase antidote largely without any research to indicate the optimal dosing strategy. Adverse events observed in case series should be considered in the context of pharmacokinetic/pharmacodynamic studies of physostigmine which suggest a much longer latency before the maximal increase in brain acetylcholine than had been previously assumed. This would favour protocols that use lower doses and longer re-dosing intervals. We propose based on the evidence reviewed that the use of cholinesterase inhibitors should be considered in anticholinergic delirium that has not responded to non-pharmacological delirium management. The optimal risk/benefit would be with a titrated dose of 0.5 to 1 mg physostigmine (0.01-0.02 mg kg(-1) in children) with a minimum delay of 10-15 min before re-dosing. Slower onset and longer acting agents such as rivastigmine would also be logical but more research is needed to guide the appropriate dose in this setting.

  13. The pharmacologic and clinical effects of medical cannabis.

    Science.gov (United States)

    Borgelt, Laura M; Franson, Kari L; Nussbaum, Abraham M; Wang, George S

    2013-02-01

    Cannabis, or marijuana, has been used for medicinal purposes for many years. Several types of cannabinoid medicines are available in the United States and Canada. Dronabinol (schedule III), nabilone (schedule II), and nabiximols (not U.S. Food and Drug Administration approved) are cannabis-derived pharmaceuticals. Medical cannabis or medical marijuana, a leafy plant cultivated for the production of its leaves and flowering tops, is a schedule I drug, but patients obtain it through cannabis dispensaries and statewide programs. The effect that cannabinoid compounds have on the cannabinoid receptors (CB(1) and CB(2) ) found in the brain can create varying pharmacologic responses based on formulation and patient characteristics. The cannabinoid Δ(9) -tetrahydrocannabinol has been determined to have the primary psychoactive effects; the effects of several other key cannabinoid compounds have yet to be fully elucidated. Dronabinol and nabilone are indicated for the treatment of nausea and vomiting associated with cancer chemotherapy and of anorexia associated with weight loss in patients with acquired immune deficiency syndrome. However, pain and muscle spasms are the most common reasons that medical cannabis is being recommended. Studies of medical cannabis show significant improvement in various types of pain and muscle spasticity. Reported adverse effects are typically not serious, with the most common being dizziness. Safety concerns regarding cannabis include the increased risk of developing schizophrenia with adolescent use, impairments in memory and cognition, accidental pediatric ingestions, and lack of safety packaging for medical cannabis formulations. This article will describe the pharmacology of cannabis, effects of various dosage formulations, therapeutics benefits and risks of cannabis for pain and muscle spasm, and safety concerns of medical cannabis use.

  14. Increasing pharmacological knowledge about human neurological and psychiatric disorders through functional neuroimaging and its application in drug discovery.

    Science.gov (United States)

    Nathan, Pradeep J; Phan, K Luan; Harmer, Catherine J; Mehta, Mitul A; Bullmore, Edward T

    2014-02-01

    Functional imaging methods such as fMRI have been widely used to gain greater understanding of brain circuitry abnormalities in CNS disorders and their underlying neurochemical basis. Findings suggest that: (1) drugs with known clinical efficacy have consistent effects on disease relevant brain circuitry, (2) brain activation changes at baseline or early drug effects on brain activity can predict long-term efficacy; and (3) fMRI together with pharmacological challenges could serve as experimental models of disease phenotypes and be used for screening novel drugs. Together, these observations suggest that drug related modulation of disease relevant brain circuitry may serve as a promising biomarker/method for use in drug discovery to demonstrate target engagement, differential efficacy, dose-response relationships, and prediction of clinically relevant changes.

  15. Increased expression of aquaporin-4 in human traumatic brain injury and brain tumors

    Institute of Scientific and Technical Information of China (English)

    HU Hua; YAO Hong-tian; ZHANG Wei-ping; ZHANG LEI; DING Wei; ZHANG Shi-hong; CHEN Zhong; WEI Er-qing

    2005-01-01

    Objective: To characterize the expression of aquaporin-4 (AQP4), one of the aquaporins (AQPs), in human brain specimens from patients with traumatic brain injury or brain tumors. Methods: Nineteen human brain specimens were obtained from the patients with traumatic brain injury, brain tumors, benign meningioma or early stage hemorrhagic stroke. MRI or CT imaging was used to assess brain edema. Hematoxylin and eosin staining were used to evaluate cell damage. Immunohistochemistry was used to detect the AQP4 expression. Results: AQP4 expression was increased from 15h to at least 8 d after injury. AQP4immunoreactivity was strong around astrocytomas, ganglioglioma and metastatic adenocarcinoma. However, AQP4 immunoreactivity was only found in the centers of astrocytomas and ganglioglioma, but not in metastatic adenocarcinoma derived from lung.Conclusion: AQP4 expression increases in human brains after traumatic brain injury, within brain-derived tumors, and around brain tumors.

  16. Characterization of 4-[18F]-ADAM as an imaging agent for SERT in non-human primate brain using PET: a dynamic study

    International Nuclear Information System (INIS)

    Introduction: Serotonin transporter (SERT) has been associated with many psychiatric diseases. This study investigated the biodistribution of a serotonin transporter imaging agent, N,N-dimethyl-2-(2-amino-4-18F-fluorophenylthio)benzylamine (4-[18F]-ADAM), in nonhuman primate brain using positron emission tomography (PET). Methods: Six and four Macaca cyclopis monkeys were used to determine the transit time (i.e., time necessary to reach biodistribution equilibrium) and the reproducibility of 4-[18F]-ADAM biodistribution in the brain, respectively. The sensitivity and specificity of 4-[18F]-ADAM binding to SERT were evaluated in one monkey challenged with different doses of fluoxetine and one monkey treated with 3,4-methylendioxymethamphetamine (MDMA). Dynamic PET imaging was performed for 3 h after 4-[18F]-ADAM intravenous bolus injection. The specific uptake ratios (SURs) in the midbrain (MB), thalamus (TH), striatum (ST) and frontal cortex (FC) were calculated. Results: The distribution of 4-[18F]-ADAM reached equilibrium 120–150 min after injection. The mean SURs were 2.49±0.13 in MB, 1.59±0.17 in TH, 1.35±0.06 in ST and 0.34±0.03 in FC, and the minimum variability was shown 120–150 min after 4-[18F]-ADAM injection. Using SURs and intraclass coefficient of correlation, the test/retest variability was under 8% and above 0.8, respectively, in SERT-rich areas. Challenge with fluoxetin (0.75–2 mg) dose-dependently inhibited the SURs in various brain regions. 4-[18F]-ADAM binding was markedly reduced in the brain of an MDMA-treated monkey compared to that in brains of normal controls. Conclusion: 4-[18F]-ADAM appears to be a highly selective radioligand for imaging SERT in monkey brain.

  17. Brain glycogen

    DEFF Research Database (Denmark)

    Obel, Linea Lykke Frimodt; Müller, Margit S; Walls, Anne B;

    2012-01-01

    Glycogen is a complex glucose polymer found in a variety of tissues, including brain, where it is localized primarily in astrocytes. The small quantity found in brain compared to e.g., liver has led to the understanding that brain glycogen is merely used during hypoglycemia or ischemia....... In this review evidence is brought forward highlighting what has been an emerging understanding in brain energy metabolism: that glycogen is more than just a convenient way to store energy for use in emergencies-it is a highly dynamic molecule with versatile implications in brain function, i.e., synaptic...... activity and memory formation. In line with the great spatiotemporal complexity of the brain and thereof derived focus on the basis for ensuring the availability of the right amount of energy at the right time and place, we here encourage a closer look into the molecular and subcellular mechanisms...

  18. Genetic and Pharmacologic Models for Type 1 Diabetes.

    Science.gov (United States)

    Leiter, Edward H; Schile, Andrew

    2013-03-01

    Type 1 diabetes (T1D) is characterized by a partial or total insufficiency of insulin. The premiere animal model of autoimmune T cell-mediated T1D is the NOD mouse. A dominant negative mutation in the mouse insulin 2 gene (Ins2(Akita) ) produces a severe insulin deficiency syndrome without autoimmune involvement, as do a variety of transgenes overexpressed in beta cells. Pharmacologically-induced T1D (without autoimmunity) elicted by alloxan or streptozotocin at high doses can generate hyperglycemia in almost any strain of mouse by direct toxicity. Multiple low doses of streptozotocin combine direct beta cell toxicity with local inflammation to elicit T1D in a male sex-specific fashion. A summary of protocols relevant to the management of these different mouse models will be covered in this overview.

  19. [Indications and future perspectives in the pharmacological treatment of hypercortisolism].

    Science.gov (United States)

    Stigliano, Antonio; Toscano, Vincenzo

    2016-03-01

    The hypercortisolism is a rare endocrine disease characterized by an autonomous steroid secretion or excessive adrenal stimulation by ACTH. the Surgical removal of the lesion directly responsible hypercortisolism represents the treatment of choice. When neurosurgery for pituitary adenoma is contraindicated, radiotherapy is candidate as the second line of therapy. Currently, the recent advances in medical therapy provide a viable alternative to surgery and radiotherapy, when these are not feasible or followed by relapses (present in more than one third of cases) of the underlying disease. Recently, also in Italy, are available pharmacological agents with central activity (pasireotide) specifically indicated for treating Cushing's disease together with peripherally acting drugs (metyrapone and ketoconazole) that are used in a broader spectrum of hypercortisolemic clinical pictures. In addition, drugs active in the inhibition of steroidogenesis provide a valid support to the patient's surgical preparation allowing the reduction or normalization of plasma cortisol levels. PMID:27030224

  20. Pharmacological diversity among drugs that inhibit bone resorption.

    Science.gov (United States)

    Russell, R Graham G

    2015-06-01

    Drugs that inhibit bone resorption ('anti-resorptives') continue to dominate the therapy of bone diseases characterized by enhanced bone destruction, including Paget's disease, osteoporosis and cancers. The historic use of oestrogens for osteoporosis led on to SERMs (Selective Estrogen Receptor Modulators, e.g. raloxifene and bazedoxifene). Currently the mainstay of treatment worldwide is still with bisphosphonates, as used clinically for over 40 years. The more recently introduced anti-RANK-ligand antibody, denosumab, is also very effective in reducing vertebral, non-vertebral and hip fractures. Odanacatib is the only cathepsin K inhibitor likely to be registered for clinical use. The pharmacological basis for the action of each of these drug classes is different, enabling choices to be made to ensure their optimal use in clinical practice. PMID:26048735

  1. Characterization of an Invertebrate-Type Dopamine Receptor of the American Cockroach, Periplaneta americana

    Directory of Open Access Journals (Sweden)

    Britta Troppmann

    2014-01-01

    Full Text Available We have isolated a cDNA coding for a putative invertebrate-type dopamine receptor (Peadop2 from P. americana brain by using a PCR-based strategy. The mRNA is present in samples from brain and salivary glands. We analyzed the distribution of the PeaDOP2 receptor protein with specific affinity-purified polyclonal antibodies. On Western blots, PeaDOP2 was detected in protein samples from brain, subesophageal ganglion, thoracic ganglia, and salivary glands. In immunocytochemical experiments, we detected PeaDOP2 in neurons with their somata being located at the anterior edge of the medulla bilaterally innervating the optic lobes and projecting to the ventro-lateral protocerebrum. In order to determine the functional and pharmacological properties of the cloned receptor, we generated a cell line constitutively expressing PeaDOP2. Activation of PeaDOP2-expressing cells with dopamine induced an increase in intracellular cAMP. In contrast, a C-terminally truncated splice variant of this receptor did not exhibit any functional property by itself. The molecular and pharmacological characterization of the first dopamine receptor from P. americana provides the basis for forthcoming studies focusing on the significance of the dopaminergic system in cockroach behavior and physiology.

  2. Non-pharmacological factors in drug abuse.

    Science.gov (United States)

    Hartnoll, R.

    1990-01-01

    This paper examines the relevance of laboratory models of drug abuse to drug taking in human societies, and discusses their significance relative to other explanatory frameworks. It argues that self-administration models are poor predictors of the prevalence of drug taking, and offer an inadequate basis for both explanation and intervention. Non-pharmacological factors that may be of greater importance derive from social perspectives (notably economic and market factors, socio-economic conditions, and cultural and subcultural processes) and psychological approaches (individual, social learning, cognitive and developmental). It is concluded that drug abuse should be understood within the same framework of explanation as other human behaviour and sentiment, having major cultural, social and cognitive dimensions as well as the strictly behavioural and pharmacological.

  3. Review of Rhubarbs: Chemistry and Pharmacology

    Institute of Scientific and Technical Information of China (English)

    ZHENG; Qing-xia; WU; Hai-feng; GUO; Jian; NAN; Hai-jiang; CHEN; Shi-lin; YANG; Jun-shan; XU; Xu-dong

    2013-01-01

    Rhubarb is a perennial herb belonging to the genus Rheum L. (Polygonaceae). Rhei Radix et Rhizoma (rhubarb roots and rhizomes) is one of the most popular Chinese materia medica and has been widely used for strong laxative function. About 200 compounds with six different types of skeletons (anthraquinone, anthrone, stilbene, flavonoids, acylglucoside, and pyrone) have so far been isolated from eighteen species of the genus Rheum L. These constituents showed extensive pharmacological activities including cathartic, diuretic, anticancer, hepatoprotective, anti-inflammatory, and analgesic effects, as well as toxicological effects. Chemical fingerprint, LC-MS, and other analytical techniques have been used for the quality control of rhubarb. This comprehensive review summarizes the researches into the isolation, pharmacological activities, and phytochemical analysis reported since investigations began in the late 1940s. In addition, pharmacokinetic studies and clinical application of rhubarb are also discussed in present paper.

  4. Pharmacological evaluation of bee venom and melittin

    Directory of Open Access Journals (Sweden)

    Camila G. Dantas

    2014-01-01

    Full Text Available The objective of this study was to identify the pharmacological effects of bee venom and its major component, melittin, on the nervous system of mice. For the pharmacological analysis, mice were treated once with saline, 0.1 or 1.2 mg/kg of bee venom and 0.1 mg/kg of melittin, subcutaneously, 30 min before being submitted to behavioral tests: locomotor activity and grooming (open-field, catalepsy, anxiety (elevated plus-maze, depression (forced swimming test and apomorphine-induced stereotypy. Haloperidol, imipramine and diazepam were administered alone (positive control or as a pre-treatment (haloperidol.The bee venom reduced motor activity and promoted cataleptic effect, in a similar manner to haloperidol.These effects were decreased by the pretreatment with haloperidol. Both melittin and bee venom decreased the apomorphine-induced stereotypies. The data indicated the antipsychotic activity of bee venom and melittin in a murine model.

  5. Common mullein, pharmacological and chemical aspects

    Directory of Open Access Journals (Sweden)

    Muhammad Riaz

    2013-12-01

    Full Text Available Verbascum thapsus L. [Khardhag or Common mullein], a member of the family Scrophulariaceae, is a famous herb that is found all over Europe, in temperate Asia, in North America and is well-reputed due to its medicinal properties. This medicinal herb contains various chemical constituents like saponins, iridoid and phenylethanoid glycosides, flavonoids, vitamin C and minerals. It is famous in various communities worldwide for the treatment of various disorders of both humans and animals aliments. A number of pharmacological activities such as anti-inflammatory, antioxidant, anticancer, antimicrobial, antiviral, antihepatotoxic and anti-hyperlipidemic activity have been ascribed to this plant. The plant is used to treat tuberculosis also, earache and bronchitis. In the present paper botanical and ethnomedicinal description, pharmacological profile and phytochemistry of this herb is being discussed.

  6. Review of Rhubarbs: Chemistry and Pharmacology

    Institute of Scientific and Technical Information of China (English)

    ZHENG Qing-xia; WU Hai-feng; GUO Jian; NAN Hai-jiang; CHEN Shi-lin; YANG Jun-shan; XU Xu-dong

    2013-01-01

    Rhubarb is a perennial herb belonging to the genus Rheum L.(Polygonaceae).Rhei Radix et Rhizoma (rhubarbroots and rhizomes) is one of the most popular Chinese materia medica and has been widely used for strong laxative function.About 200 compounds with six different types of skeletons (anthraquinone,anthrone,stilbene,flavonoids,acylglucoside,and pyrone) have so far been isolated from eighteen species of the genus Rheum L These constituents showed extensive pharmacological activities including cathartic,diuretic,anticancer,hepatoprotective,anti-inflammatory,and analgesic effects,as well as toxicological effects.Chemical fingerprint,LC-MS,and other analytical techniques have been used for the quality control of rhubarb.This comprehensive review summarizes the researches into the isolation,pharmacological activities,and phytochemical analysis reported since investigations began in the late 1940s.In addition,pharmacokinetic studies and clinical application of rhubarb are also discussed in present paper.

  7. Pharmacology exercise for undergraduate: MLNMC model

    Directory of Open Access Journals (Sweden)

    Rakesh C. Chaurasia

    2013-08-01

    Full Text Available Pharmacology is the backbone of clinical discipline of medical science. In the computer era of advancement, paraclinical teachings become more technical and clinical oriented. Regarding to undergraduate practical’s the animal experimentation and dispensing pharmacy are only exercises. But these are matter of critics due to their non-utility in future. Student’s apathy and non-interest are hidden factor to perform such boring experiments. Meanwhile the old-dated exercises have no potential to tone-up adequate clinical skills in future study instead of wastage of time and money. Killing of innocent animals is crucial and should be socially discouraged. Thus Pharmacology practical are matter of debate in current scenario. Being attachment with past sentiment of traditional dispensing pharmacy and animal experimentations, they are difficult to delete completely. The present article highlights some of our efforts in undergraduate exercises. [Int J Basic Clin Pharmacol 2013; 2(4.000: 495-497

  8. Angioedema: Clinical Presentations and Pharmacological Management.

    Science.gov (United States)

    Collins-Yoder, Angela Smith

    2016-01-01

    Angioedema (AE) is a unique clinical presentation of an unchecked release of bradykinin. The origin of this clinical presentation can be either genetic or acquired. The outcome within the patient is subcutaneous swelling of the lower layers of the epidermis. Symptoms are most often localized to the upper airway or the gastrointestinal tract. A typical course resolves in 5 to 7 days, but in some patients, the clinical manifestations exist up to 6 weeks. Hereditary AE is rare and genetically linked, and typically, the patient has episodes for many years before diagnosis. Episodes of acquired AE may be drug induced, triggered by a specific allergen, or idiopathic. Angioedema can elicit the need for critical care interventions, for advanced airway management, or unnecessary abdominal surgery. The treatment for these patients is evolving as new pharmacological agents are developed. This article addresses subtypes of AE, triggers, pharmacology, and information for interdisciplinary team planning of individualized case management. PMID:27258954

  9. Clinical pharmacology considerations in biologics development

    Institute of Scientific and Technical Information of China (English)

    Liang ZHAO; Tian-hua REN; Diane D WANG

    2012-01-01

    Biologics,including monoclonal antibodies (mAbs) and other therapeutic proteins such as cytokines and growth hormones,have unique characteristics compared to small molecules.This paper starts from an overview of the pharmacokinetics (PK) of biologics from a mechanistic perspective,the determination of a starting dose for first-in-human(FIH) studies,and dosing regimen optimisation for phase Ⅱ/Ⅲ clinical trials.Subsequently,typical clinical pharmacology issues along the corresponding pathways for biologics development are summarised,including drug-drug interactions,QTc prolongation,immunogenicity,and studies in specific populations.The relationships between the molecular structure of biologics,their pharmacokinetic and pharmacodynamic characteristics,and the corresponding clinical pharmacology strategies are summarised and depicted in a schematic diagram.

  10. Pills or push-ups? Effectiveness and public perception of pharmacological and non-pharmacological cognitive enhancement.

    OpenAIRE

    Caviola, L.; Faber, NS

    2015-01-01

    We review work on the effectiveness of different forms of cognitive enhancement, both pharmacological and non-pharmacological. We consider caffeine, methylphenidate, and modafinil for pharmacological cognitive enhancement (PCE) and computer training, physical exercise, and sleep for non-pharmacological cognitive enhancement (NPCE). We find that all of the techniques described can produce significant beneficial effects on cognitive performance. However, effect sizes are moderate, and consisten...

  11. Pills or Push-Ups? Effectiveness and Public Perception of Pharmacological and Non-Pharmacological Cognitive Enhancement

    OpenAIRE

    Caviola, Lucius; Nadira S. Faber

    2015-01-01

    We review work on the effectiveness of different forms of cognitive enhancement, both pharmacological and non-pharmacological. We consider caffeine, methylphenidate, and modafinil for pharmacological cognitive enhancement (PCE) and computer training, physical exercise, and sleep for non-pharmacological cognitive enhancement (NPCE). We find that all of the techniques described can produce significant beneficial effects on cognitive performance. However, effect sizes are moderate, and consisten...

  12. Pills or push-ups? Effectiveness and public perception of pharmacological and non-pharmacological cognitive enhancement

    OpenAIRE

    Lucius eCaviola; Nadira S. Faber

    2015-01-01

    We review work on the effectiveness of different forms of cognitive enhancement, both pharmacological and non-pharmacological. We consider caffeine, methylphenidate, and modafinil for pharmacological cognitive enhancement (PCE) and computer training, physical exercise, and sleep for non-pharmacological cognitive enhancement (NPCE). We find that all of the techniques described can produce significant beneficial effects on cognitive performance. However, effect sizes are moderate, and consisten...

  13. Chemical and Pharmacological Researches on Hyoscyamus niger

    Institute of Scientific and Technical Information of China (English)

    LI Jun; SHI Ji; YU Xin-wen; SUN Jing-kuan; MEN Qi-ming; KANG Ting-guo

    2011-01-01

    The reports on chemical constituents of Hyoscyamus niger were summarized. The compounds include alkaloids, saponins, lignans, coumarinolignans, flavonoids, and some other nonalkaloidal compounds. TLC, HPLC, and GC were used for the qualitative and quantitative analyses of some chemical constituents in H. niger. Modern pharmacological experiments showed that H. niger had the analgesic, anti-inflammatory, antipyretic, anticonvulsant, spasmolytic, antidiarrhoeal, antisecretory, bronchodilatory, urinary bladder relaxant, hypotensive, cardiosuppressant, vasodilator, antitumor, and feeding deterrent properties. In addition, the toxicities of this medicinal plant were also described.

  14. Chemistry and Pharmacology of Citrus sinensis

    OpenAIRE

    Juan Manuel J. Favela-Hernández; Omar González-Santiago; Mónica A. Ramírez-Cabrera; Patricia C. Esquivel-Ferriño; María del Rayo Camacho-Corona

    2016-01-01

    Presently the search for new drugs from natural resources is of growing interest to the pharmaceutical industry. Natural products have been the source of new drugs since ancient times. Plants are a good source of secondary metabolites which have been found to have beneficial properties. The present study is a review of the chemistry and pharmacology of Citrus sinensis. This review reveals the therapeutic potential of C. sinensis as a source of natural compounds with important activities that ...

  15. Natural Products and Ion Channel Pharmacology

    OpenAIRE

    Teichert, Russell W.; Olivera, Baldomero M.

    2010-01-01

    An accelerated rate of natural-product discovery is critical for the future of ion channel pharmacology. For the full potential of natural products to be realized, an interdisciplinary initiative is required that combines chemical ecology and ion channel physiology. A prime source of future drug leads targeted to ion channels is the vast assortment of compounds that mediate biotic interactions in the marine environment. Many animals have evolved a chemical strategy to change the behavior of t...

  16. Cocaine and "pharmacological kindling" in the rat.

    Science.gov (United States)

    Stripling, J S

    1983-11-01

    The concept of "pharmacological kindling" has been used to explain the behavioral sensitization to cocaine produced by repeated administration of subconvulsive doses. This idea was tested by the repeated administration of cocaine to rats followed by electrical kindling of the olfactory bulb (a site at which cocaine has prominent electrophysiologic effects). No significant effect of cocaine on kindling was found. The relationship of this finding to studies using other drugs is discussed.

  17. The genus chenopodium: Phytochemistry, ethnopharmacology and pharmacology

    OpenAIRE

    Zlatina Kokanova-Nedialkova, , , , , and; Paraskev T Nedialkov; Stefan D. Nikolov

    2009-01-01

    The review includes 154 references on the genus Chenopodium covered up to December 2008 and has been compiled using references mainly from Chemical Abstracts and Pubmed. This article briefly reviews the phytochemistry, ethnopharmacology and pharmacology of Chenopodium genus. Three hundred seventy nine compounds isolated from different species are reported. Fenolics, flavonoids, saponins, ecdysteroids and triterpenoids were the major classes of phytoconstituents of this genus. The detailed dis...

  18. An agenda for UK clinical pharmacology

    OpenAIRE

    Coleman, Jamie J.; McDowell, Sarah E

    2012-01-01

    The internet and the World Wide Web have changed the ways that we function. As technologies grow and adapt, there is a huge potential for the internet to affect drug research and development, as well as many other aspects of clinical pharmacology. We review some of the areas of interest to date and discuss some of the potential areas in which internet-based technology can be exploited.

  19. The GPCR Heterotetramer: Challenging Classical Pharmacology

    OpenAIRE

    Ferré, Sergi

    2015-01-01

    Two concepts are gaining increasing acceptance in GPCR pharmacology: (1) pre-coupling of GPCRs with their preferred signaling molecules, and (2) GPCR oligomerization. This is begging the introduction of new models, such as GPCR oligomer-containing signaling complexes with GPCR homodimers as functional building blocks. The model favors the formation of GPCR heterotetramers, heteromers of homodimers coupled to their cognate G-protein. The GPCR heterotetramer offers the optimal frame for a canon...

  20. Pharmacology of benzodiazepine receptors: an update.

    OpenAIRE

    Sieghart, W.

    1994-01-01

    Benzodiazepine receptors are allosteric modulatory sites on GABAA receptors. GABAA receptors are probably composed of five protein subunits, at least some of which belong to different subunit classes. So far six alpha-, four beta-, three gamma-, and delta- and two rho = p subunits of GABAA receptors have been identified. A large number of different subunit combinations, each of which will result in a GABAA receptor with distinct electrophysiological and pharmacological properties, are therefo...