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Sample records for brain pharmacological characterization

  1. Pharmacological characterization and autoradiographic localization of substance P receptors in guinea pig brain

    International Nuclear Information System (INIS)

    Dam, T.V.; Quirion, R.

    1986-01-01

    [ 3 H]Substance P ([ 3 H]SP) was used to characterize substance P (SP) receptor binding sites in guinea pig brain using membrane preparations and in vitro receptor autoradiography. Curvilinear Scatchard analysis shows that [ 3 H]SP binds to a high affinity site (Kd = 0.5 nM) with a Bmax of 16.4 fmol/mg protein and a low affinity site (Kd = 29.6 nM) with a Bmax of 189.1 fmol/mg protein. Monovalent cations generally inhibit [ 3 H]SP binding while divalent cations substantially increased it. The ligand selectivity pattern is generally similar to the one observed in rat brain membrane preparation with SP being more potent than SP fragments and other tachykinins. However, the potency of various nucleotides is different with GMP-PNP greater than GDP greater than GTP. The autoradiographic distribution of [ 3 H]SP binding sites shows that high amounts of sites are present in the hippocampus, striatum, olfactory bulb, central nucleus of the amygdala, certain thalamic nuclei and superior colliculus. The cortex is moderately enriched in [ 3 H]SP binding sites while the substantia nigra contains only very low amounts of sites. Thus, the autoradiographic distribution of SP binding sites is fairly similar in both rat and guinea pig brain

  2. Pharmacological and immunochemical characterization of α2* nicotinic acetylcholine receptors (nAChRs) in mouse brain

    Science.gov (United States)

    Whiteaker, Paul; Wilking, Jennifer A; Brown, Robert WB; Brennan, Robert J; Collins, Allan C; Lindstrom, Jon M; Boulter, Jim

    2009-01-01

    Aim: α2 nAChR subunit mRNA expression in mice is most intense in the olfactory bulbs and interpeduncular nucleus. We aimed to investigate the properties of α2* nAChRs in these mouse brain regions. Methods: α2 nAChR subunit-null mutant mice were engineered. Pharmacological and immunoprecipitation studies were used to determine the composition of α2 subunit-containing (α2*) nAChRs in these two regions. Results: [125I]Epibatidine (200 pmol/L) autoradiography and saturation binding demonstrated that α2 deletion reduces nAChR expression in both olfactory bulbs and interpeduncular nucleus (by 4.8±1.7 and 92±26 fmol̇mg-1 protein, respectively). Pharmacological characterization using the β2-selective drug A85380 to inhibit [125I]epibatidine binding proved inconclusive, so immunoprecipitation methods were used to further characterize α2* nAChRs. Protocols were established to immunoprecipitate β2 and β4 nAChRs. Immunoprecipitation specificity was ascertained using tissue from β2- and β4-null mutant mice, and efficacy was good (>90% of β2* and >80% of β4* nAChRs were routinely recovered). Conclusion: Immunoprecipitation experiments indicated that interpeduncular nucleus α2* nAChRs predominantly contain β2 subunits, while those in olfactory bulbs contain mainly β4 subunits. In addition, the immunoprecipitation evidence indicated that both nuclei, but especially the interpeduncular nucleus, express nAChR complexes containing both β2 and β4 subunits. PMID:19498420

  3. Pharmacological characterization of the dopamine-sensitive adenylate cyclase in cockroach brain: evidence for a distinct dopamine receptor

    International Nuclear Information System (INIS)

    Orr, G.L.; Gole, J.W.D.; Notman, H.J.; Downer, R.G.H.

    1987-01-01

    Dopamine increases cyclic AMP production in crude membrane preparations of cockroach brain with plateaus in cyclic AMP production occurring between 1-10 μM and 10 mM. Maximal production of cyclic AMP is 2.25 fold greater than that of control values. Octopamine also increases cyclic AMP production with a Ka of 1.4 μM and maximal production 3.5 fold greater than that of control. 5-Hydroxytryptamine does not increase cyclic AMP production. The effects of octopamine and dopamine are fully additive. The vertebrate dopamine agonists ADTN and epinine stimulate the dopamine-sensitive adenylate cyclase (AC) with Ka values of 4.5 and 0.6 μM respectively and with maximal effectiveness 1.7 fold greater than that of control. The selective D 2 -dopamine agonist LY-171555 stimulates cyclic AMP production to a similar extent with a Ka of 50 μM. Other dopamine agonists have no stimulatory effects. With the exception of mianserin, 3 H-piflutixol is displaced from brain membranes by dopamine antagonists with an order of potency similar to that observed for the inhibition of dopamine-sensitive AC. The results indicate that the octopamine- and dopamine-sensitive AC in cockroach brain can be distinguished pharmacologically and the dopamine receptors coupled to AC have pharmacological characteristics distinct from vertebrate D 1 - and D 2 -dopamine receptors. 33 references, 3 figures, 2 tables

  4. Traumatic brain injury pharmacological treatment: recommendations

    Directory of Open Access Journals (Sweden)

    Renato Anghinah

    Full Text Available ABSTRACT This article presents the recommendations on the pharmacological treatment employed in traumatic brain injury (TBI at the outpatient clinic of the Cognitive Rehabilitation after TBI Service of the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil. A systematic assessment of the consensus reached in other countries, and of articles on TBI available in the PUBMED and LILACS medical databases, was carried out. We offer recommendations of pharmacological treatments in patients after TBI with different symptoms.

  5. 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.

  6. [{sup 11}C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats

    Energy Technology Data Exchange (ETDEWEB)

    Zessin, Joerg [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany)]. E-mail: j.zessin@fz-rossendorf.de; Deuther-Conrad, Winnie [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Kretzschmar, Marion [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Wuest, Frank [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Pawelke, Beate [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Brust, Peter [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Steinbach, Joerg [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Bergmann, Ralf [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany)

    2006-01-15

    N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (S Me-Adam, 1) is a highly potent and selective inhibitor of the serotonin transporter (SPERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [{sup 11}C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [{sup 11}C]S Me-Adam. The radiochemical yield was 27{+-}5%, and the specific radioactivity was 26-40 GBq/{mu}mol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SPERT, such as the thalamus/hypothalamus region (3.59{+-}0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74{+-}0.95 at 60 min postinjection. The [{sup 11}C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38{+-}11% of the control value. Furthermore, no metabolites of [{sup 11}C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [{sup 11}C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain.

  7. [11C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats

    International Nuclear Information System (INIS)

    Zessin, Joerg; Deuther-Conrad, Winnie; Kretzschmar, Marion; Wuest, Frank; Pawelke, Beate; Brust, Peter; Steinbach, Joerg; Bergmann, Ralf

    2006-01-01

    N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (S Me-Adam, 1) is a highly potent and selective inhibitor of the serotonin transporter (SPERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [ 11 C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [ 11 C]S Me-Adam. The radiochemical yield was 27±5%, and the specific radioactivity was 26-40 GBq/μmol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SPERT, such as the thalamus/hypothalamus region (3.59±0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74±0.95 at 60 min postinjection. The [ 11 C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38±11% of the control value. Furthermore, no metabolites of [ 11 C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [ 11 C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain

  8. [11C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats.

    Science.gov (United States)

    Zessin, Jörg; Deuther-Conrad, Winnie; Kretzschmar, Marion; Wüst, Frank; Pawelke, Beate; Brust, Peter; Steinbach, Jörg; Bergmann, Ralf

    2006-01-01

    N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (SMe-ADAM, 1) is a highly potent and selective inhibitor of the serotonin transporter (SERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [(11)C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [(11)C]SMe-ADAM. The radiochemical yield was 27 +/- 5%, and the specific radioactivity was 26-40 GBq/micromol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SERT, such as the thalamus/hypothalamus region (3.59 +/- 0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74 +/- 0.95 at 60 min postinjection. The [(11)C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38 +/- 11% of the control value. Furthermore, no metabolites of [(11)C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [(11)C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain.

  9. 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...... 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...

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

    DEFF Research Database (Denmark)

    Jin, Guang; Duggan, Michael; Imam, Ayesha

    2012-01-01

    [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....

  11. 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...

  12. Anatomical and pharmacological characterization of excitatory amino acid receptors

    International Nuclear Information System (INIS)

    Monaghan, D.T.

    1985-01-01

    The majority of the excitatory neurotransmission in the vertebrate Central Nervous System is thought to be mediated by acidic amino acid neurotransmitters. However, relatively little is known about the excitatory amino acid receptors and their distribution within the CNS. By analyzing radioligand binding to purified synaptic plasma membranes and to thin tissue sections processed for autoradiography, multiple distinct binding sites were found. These binding sites exhibited the pharmacological properties indicative of the excitatory amino acid receptors, which had been identified by electrophysiological techniques. Specifically, L-[ 3 H]-glutamate and D-[ 3 H]-amino-5-phosphonopentanoate appear to label N-methyl-D-aspartate receptors, L-[ 3 H]-glutamate and [ 3 H]-kainic acid appear to label kainic acid receptors, and L-[ 3 H]-glutamate and [ 3 H]-amino-3-hydroxy-5-methyl-4-isoxazolepropionate appear to label quisqualate receptors. Together, these results confirm the three receptor scheme proposed for excitatory amino acid neurotransmission. These results also show that these transmitter-receptor systems are differentially distributed in the brain, and that the total distribution is consistent with that found by other markers for excitatory amino acid-using neurons

  13. Pharmacologic Effects in vivo in Brain by Vector-Mediated Peptide Drug Delivery

    Science.gov (United States)

    Bickel, Ulrich; Yoshikawa, Takayoshi; Landaw, Elliot M.; Faull, Kym F.; Pardridge, William M.

    1993-04-01

    Pharmacologic effects in brain caused by systemic administration of neuropeptides are prevented by poor transport of the peptide through the brain vascular endothelium, which comprises the blood-brain barrier in vivo. In the present study, successful application of a chimeric peptide approach to enhance drug delivery through the blood-brain barrier for the purpose of achieving a central nervous system pharmacologic effect is described. The chimeric peptide was formed by linkage of a potent vasoactive intestinal peptide (VIP) analogue, which had been monobiotinylated, to a drug transport vector. The vector consisted of a covalent conjugate of avidin and the OX26 monoclonal antibody to the transferrin receptor. Owing to the high concentration of transferrin receptors on brain capillary endothelia, OX26 targets brain and undergoes receptor-mediated transcytosis through the blood-brain barrier. Systemic infusion of low doses (12 μg/kg) of the VIP chimeric peptide in rats resulted in an in vivo central nervous system pharmacologic effect: a 65% increase in cerebral blood flow. Biotinylated VIP analogue without the brain transport vector was ineffective.

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

    International Nuclear Information System (INIS)

    Mishra, Ashutosh; Veerasamy, Ravichandran; Jain, Prateek Kumar; Dixit, Vinod Kumar; Agrawal, Ram Kishor

    2008-01-01

    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 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)

  15. 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)

  16. Quantitative pharmacological analysis of 2-125I-iodomelatonin binding sites in discrete areas of the chicken brain

    International Nuclear Information System (INIS)

    Siuciak, J.A.; Krause, D.N.; Dubocovich, M.L.

    1991-01-01

    The authors have localized and characterized 2-125I-iodomelatonin binding sites in the chicken brain using in vitro quantitative autoradiography. Binding sites were widely distributed throughout the chicken brain, predominantly in regions associated with the visual system. The specific binding of 2-125I-iodomelatonin to discrete chicken brain areas was found to be saturable, reversible, and of high affinity. The specific binding of 2-125I-iodomelatonin (75 pm) was quantitated for 40 identifiable brain regions. Eight brain regions were chosen for binding characterization and pharmacological analysis: optic tectum, Edinger-Westphal nucleus, oculomotor nucleus, nucleus rotundus, ventral supraoptic decussation, ventrolateral geniculate nucleus, neostriatum, and ectostriatum. These regions showed no rostral-caudal gradient in 2-125I-iodomelatonin specific binding, and saturation analysis revealed a single class of high-affinity sites with KD values in the range of 33-48 pM and receptor site density (Bmax) ranging from 31 to 58 fmol/mg protein. Competition experiments carried out with various indoles revealed a similar order of pharmacological affinities in these areas: melatonin greater than 6-chloromelatonin greater than methoxyluzindole greater than N-acetylserotonin greater than luzindole much greater than 5-HT greater than 5-methoxytryptamine. The affinity constants determined by quantitative autoradiography for these compounds to compete for 2-125I-iodomelatonin binding in the optic tectum correlated well with the affinities in chicken brain membranes at 25 degrees C (r = 0.966; slope = 0.845; n = 7) and 0 degree C (r = 0.946; slope = 0.379; n = 7), chicken retinal membranes (r = 0.973; slope = 0.759; n = 7), and the potency or affinity of these compounds to affect the calcium-dependent release of 3H-dopamine from the rabbit retina (r = 0.902; slope = 0.506; n = 6)

  17. 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....

  18. Pharmacological management of traumatic brain injury and implications for speech language pathology.

    Science.gov (United States)

    Rivera, José O

    2014-08-01

    This article provides an overview of the pharmacological management of traumatic brain injury (TBI). A basic introduction to key pharmacokinetic and pharmacodynamic principles is used to guide the reader. The goals of the pharmacological management of TBI are explained starting with mild TBI. The main medications used for each medical condition are described with a primary emphasis of effects that may interfere with the role of speech-language pathology (SLP). Some medications may interfere with cognitive, motor, and neuromuscular functions, and others may cause ototoxicity. A basic overview of the pharmacological management of moderate to severe TBI is included because the SLP practitioner may encounter patients with TBI during the recovery phase. The importance of assessment of swallowing evaluations is discussed because the oral route of administration of medications is preferred once the patient is stable. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  19. Pharmacological characterization of VIP and PACAP receptors in the human meningeal and coronary artery

    DEFF Research Database (Denmark)

    Chan, Kayi Y; Baun, Michael; de Vries, René

    2011-01-01

    We pharmacologically characterized pituitary adenylate cyclase-activating polypeptides (PACAPs), vasoactive intestinal peptide (VIP) and the VPAC(1), VPAC(2) and PAC(1) receptors in human meningeal (for their role in migraine) and coronary (for potential side effects) arteries.......We pharmacologically characterized pituitary adenylate cyclase-activating polypeptides (PACAPs), vasoactive intestinal peptide (VIP) and the VPAC(1), VPAC(2) and PAC(1) receptors in human meningeal (for their role in migraine) and coronary (for potential side effects) arteries....

  20. Overview of non-pharmacological intervention for dementia and principles of brain-activating rehabilitation.

    Science.gov (United States)

    Yamaguchi, Haruyasu; Maki, Yohko; Yamagami, Tetsuya

    2010-12-01

    Non-pharmacological interventions for dementia are likely to have an important role in delaying disease progression and functional decline. Research into non-pharmacological interventions has focused on the differentiation of each approach and a comparison of their effects. However, Cochrane Reviews on non-pharmacological interventions have noted the paucity of evidence regarding the effects of these interventions. The essence of non-pharmacological intervention is dependent of the patients, families, and therapists involved, with each situation inevitably being different. To obtain good results with non-pharmacological therapy, the core is not 'what' approach is taken but 'how' the therapists communicate with their patients. Here, we propose a new type of rehabilitation for dementia, namely brain-activating rehabilitation, that consists of five principles: (i) enjoyable and comfortable activities in an accepting atmosphere; (ii) activities associated with empathetic two-way communication between the therapist and patient, as well as between patients; (iii) therapists should praise patients to enhance motivation; (iv) therapists should try to offer each patient some social role that takes advantage of his/her remaining abilities; and (v) the activities should be based on errorless learning to ensure a pleasant atmosphere and to maintain a patient's dignity. The behavioral and cognitive status is not necessarily a reflection of pathological lesions in the brain; there is cognitive reserve for improvement. The aim of brain-activating rehabilitation is to enhance patients' motivation and maximize the use of their remaining function, recruiting a compensatory network, and preventing the disuse of brain function. The primary expected effect is that patients recover a desire for life, as well as their self-respect. Enhanced motivation can lead to improvements in cognitive function. Amelioration of the behavioral and psychological symptoms of dementia and improvements in

  1. The power of using functional fMRI on small rodents to study brain pharmacology and disease

    OpenAIRE

    Jonckers, Elisabeth; Shah, Disha; Hamaide, Julie; Verhoye, Marleen; Van der Linden, Annemie

    2015-01-01

    Abstract: 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 sen...

  2. Cockroach GABAB receptor subtypes: molecular characterization, pharmacological properties and tissue distribution.

    Science.gov (United States)

    Blankenburg, S; Balfanz, S; Hayashi, Y; Shigenobu, S; Miura, T; Baumann, O; Baumann, A; Blenau, W

    2015-01-01

    γ-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the central nervous system (CNS). Its effects are mediated by either ionotropic GABAA receptors or metabotropic GABAB receptors. GABAB receptors regulate, via Gi/o G-proteins, ion channels, and adenylyl cyclases. In humans, GABAB receptor subtypes are involved in the etiology of neurologic and psychiatric disorders. In arthropods, however, these members of the G-protein-coupled receptor family are only inadequately characterized. Interestingly, physiological data have revealed important functions of GABAB receptors in the American cockroach, Periplaneta americana. We have cloned cDNAs coding for putative GABAB receptor subtypes 1 and 2 of P. americana (PeaGB1 and PeaGB2). When both receptor proteins are co-expressed in mammalian cells, activation of the receptor heteromer with GABA leads to a dose-dependent decrease in cAMP production. The pharmacological profile differs from that of mammalian and Drosophila GABAB receptors. Western blot analyses with polyclonal antibodies have revealed the expression of PeaGB1 and PeaGB2 in the CNS of the American cockroach. In addition to the widespread distribution in the brain, PeaGB1 is expressed in salivary glands and male accessory glands. Notably, PeaGB1-like immunoreactivity has been detected in the GABAergic salivary neuron 2, suggesting that GABAB receptors act as autoreceptors in this neuron. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. 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.

  4. 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...... of neutral, fearful and angry faces. In three separate and counterbalanced sessions, participants received citalopram (CIT) to raise serotonin levels, underwent acute tryptophan depletion (ATD) to lower serotonin, or were studied without pharmacological challenge (Control). An analysis designed to identify...

  5. 2-[125I]iodomelatonin binding sites in hamster brain membranes: pharmacological characteristics and regional distribution

    International Nuclear Information System (INIS)

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

    1988-01-01

    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)

  6. [Non-pharmacological treatment of neurobehavioural disorders following severe traumatic brain injury. A commented literature review].

    Science.gov (United States)

    Fayol, P

    2003-03-01

    Neurobehavioural disorders are a major public health problem and a daily challenge for neurological rehabilitation. This review presents the state of art in the field of traumatic brain injury regarding non-pharmacological treatments of neurobehavioral disorders. Medline data base and main reference books going back for 15 years were searched. Prevention is based on information and counselling for a better coherence in the care and a better understanding of behaviour problems. Prevention of complications is based on adaptation of units and management (one-on-one care for example). Non-pharmacological treatment can be classified according to 3 approaches: (1) Behavioural approaches: with well-established procedures for each patient; (2) Holistic approaches: addressing both lesional and psychopathological as well as environmental features; (3) Psychotherapeutic approaches: either integrated to holistic programs, or adapted from classical psychotherapy, or systemic therapy. Practices trend to a convergence through a comprehensive approach: behaviour analysis and management of its neuropsychological, psychopathological and environmental components. Everybody will be able to pick out elements adaptable for his own practice.

  7. Molecular, pharmacological, and signaling properties of octopamine receptors from honeybee (Apis mellifera) brain.

    Science.gov (United States)

    Balfanz, Sabine; Jordan, Nadine; Langenstück, Teresa; Breuer, Johanna; Bergmeier, Vera; Baumann, Arnd

    2014-04-01

    G protein-coupled receptors are important regulators of cellular signaling processes. Within the large family of rhodopsin-like receptors, those binding to biogenic amines form a discrete subgroup. Activation of biogenic amine receptors leads to transient changes of intracellular Ca²⁺-([Ca²⁺](i)) or 3',5'-cyclic adenosine monophosphate ([cAMP](i)) concentrations. Both second messengers modulate cellular signaling processes and thereby contribute to long-lasting behavioral effects in an organism. In vivo pharmacology has helped to reveal the functional effects of different biogenic amines in honeybees. The phenolamine octopamine is an important modulator of behavior. Binding of octopamine to its receptors causes elevation of [Ca²⁺](i) or [cAMP](i). To date, only one honeybee octopamine receptor that induces Ca²⁺ signals has been molecularly and pharmacologically characterized. Here, we examined the pharmacological properties of four additional honeybee octopamine receptors. When heterologously expressed, all receptors induced cAMP production after binding to octopamine with EC₅₀(s) in the nanomolar range. Receptor activity was most efficiently blocked by mianserin, a substance with antidepressant activity in vertebrates. The rank order of inhibitory potency for potential receptor antagonists was very similar on all four honeybee receptors with mianserin > cyproheptadine > metoclopramide > chlorpromazine > phentolamine. The subroot of octopamine receptors activating adenylyl cyclases is the largest that has so far been characterized in arthropods, and it should now be possible to unravel the contribution of individual receptors to the physiology and behavior of honeybees. © 2013 International Society for Neurochemistry.

  8. Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology.

    Science.gov (United States)

    Layé, Sophie; Nadjar, Agnès; Joffre, Corinne; Bazinet, Richard P

    2018-01-01

    Classically, polyunsaturated fatty acids (PUFA) were largely thought to be relatively inert structural components of brain, largely important for the formation of cellular membranes. Over the past 10 years, a host of bioactive lipid mediators that are enzymatically derived from arachidonic acid, the main n-6 PUFA, and docosahexaenoic acid, the main n-3 PUFA in the brain, known to regulate peripheral immune function, have been detected in the brain and shown to regulate microglia activation. Recent advances have focused on how PUFA regulate the molecular signaling of microglia, especially in the context of neuroinflammation and behavior. Several active drugs regulate brain lipid signaling and provide proof of concept for targeting the brain. Because brain lipid metabolism relies on a complex integration of diet, peripheral metabolism, including the liver and blood, which supply the brain with PUFAs that can be altered by genetics, sex, and aging, there are many pathways that can be disrupted, leading to altered brain lipid homeostasis. Brain lipid signaling pathways are altered in neurologic disorders and may be viable targets for the development of novel therapeutics. In this study, we discuss in particular how n-3 PUFAs and their metabolites regulate microglia phenotype and function to exert their anti-inflammatory and proresolving activities in the brain. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  9. 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

    2016-09-05

    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. Copyright © 2016. Published by Elsevier B.V.

  10. Traumatic brain injury is associated with the development of deep vein thrombosis independent of pharmacological prophylaxis.

    Science.gov (United States)

    Reiff, Donald A; Haricharan, Ramanath N; Bullington, Nathan M; Griffin, Russell L; McGwin, Gerald; Rue, Loring W

    2009-05-01

    Deep venous thrombosis (DVT) is common among trauma patients. If left untreated it may result in lethal pulmonary thromboembolism. Previous studies have suggested that intracranial hemorrhage serves as an independent risk factor for the development of DVT. These studies were not able to exclude anticoagulation therapy as a confounding variable in their analysis. Our objective was to determine the association of traumatic brain injury (TBI) to the formation of DVT irrespective of the use of anticoagulation therapy. All patients admitted to an academic level I Trauma Center between 2000 and 2007 with blunt or penetrating injuries were selected for inclusion in this study. Patients who died or who were discharged within 24 hours of admission were excluded in the analysis. TBI was defined as any intraparenchymal hemorrhage or extra-axial intracranial bleeding identified on radiographic imaging or both. Anticoagulation therapy was defined as the uninterrupted use of either subcutaneous lovenox or heparin. Risk ratios and 95% confidence intervals compared the risk of DVT among patients with and without TBI according to the initiation of anticoagulation therapy (no therapy, 48 hours) adjusted for age, gender, race, injury severity, mechanism of injury, spinal injury, and lower extremity fracture. Irrespective of the time of initiation of pharmacologic prophylaxis, TBI is independently associated with the formation of DVT. A threefold to fourfold increased risk of DVT formation is consistent across all prophylaxis groups among patients with TBI. The incidence of DVT among injured patients with TBI is significantly higher than those patients without head injury independent of anticoagulation therapy. Rigorous surveillance to detect DVT among trauma patients with TBI should be undertaken and where appropriate alternate means for pulmonary thromboembolism prevention used.

  11. 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

    homogenate and in an assay of electrically induced contractions of guinea pig ileum. The results from the two tissues did, however, not correlate very well, and in order to further investigate these discrepancies, we have pharmacologically characterized these enantiomers on recombinant wild type and mutant...... rat GABA(B)1b receptors coexpressed with rat GABA(B)2 receptors. The results from this study correlate nicely with the binding data from rat brain. (R)-Homobaclofen was shown to act like (R)-baclofen albeit with 20-fold less potency, and (S)-homobaclofen was inactive on the receptor. The discrepancies...

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

    International Nuclear Information System (INIS)

    Oliveira, Karina Corleto

    2014-01-01

    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 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 in

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

    International Nuclear Information System (INIS)

    Ardati, A.; Goetschy, V.; Gottowick, J.; Henriot, S.; Deuschle, U.; Kilpatrick, G.J.; Valdenaire, O.

    1999-01-01

    Corticotropin releasing factor (CRF) receptors belong to the super-family of G protein-coupled receptors. These receptors are classified into two subtypes (CRF 1 and CRF 2 ). Both receptors are positively coupled to adenylyl cyclase but they have a distinct pharmacology and distribution in brain. Two isoforms belonging to the CRF 2 subtype receptors, CRF 2α and CRF 2β , 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 hCRF 2β receptor. We have used radioligand binding with [ 125 I]-tyr 0 -sauvagine and a gene expression assay in which the firefly luciferase gene expression is under the control of cAMP responsive elements. Association kinetics of [ 125 I]-tyr 0 -sauvagine binding to the hCRF 2β receptor were monophasic while dissociation kinetics were biphasic, in agreement with the kinetics results obtained with the hCRF 2α 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 hCRF 2α receptor. A non-hydrolysable GTP analog, Gpp(NH)p, reduced the high affinity binding of [ 125 I]-tyr 0 -sauvagine to both hCRF 2 receptor isoforms in a similar manner. The rank order of potency of CRF agonist peptides in competition experiments was identical for both hCRF 2 α-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 hCRF 2 receptor isoforms. Taken together, these results indicate that the pharmacological profiles of the CRF 2 splice variants are identical. This indicates that the region of the N-terminus that varies

  14. Pharmacologic inhibition of phospholipase C in the brain attenuates early memory formation in the honeybee (Apis mellifera L.

    Directory of Open Access Journals (Sweden)

    Shota Suenami

    2018-01-01

    Full Text Available Although the molecular mechanisms involved in learning and memory in insects have been studied intensively, the intracellular signaling mechanisms involved in early memory formation are not fully understood. We previously demonstrated that phospholipase C epsilon (PLCe, whose product is involved in calcium signaling, is almost selectively expressed in the mushroom bodies, a brain structure important for learning and memory in the honeybee. Here, we pharmacologically examined the role of phospholipase C (PLC in learning and memory in the honeybee. First, we identified four genes for PLC subtypes in the honeybee genome database. Quantitative reverse transcription-polymerase chain reaction revealed that, among these four genes, three, including PLCe, were expressed higher in the brain than in sensory organs in worker honeybees, suggesting their main roles in the brain. Edelfosine and neomycin, pan-PLC inhibitors, significantly decreased PLC activities in homogenates of the brain tissues. These drugs injected into the head of foragers significantly attenuated memory acquisition in comparison with the control groups, whereas memory retention was not affected. These findings suggest that PLC in the brain is involved in early memory formation in the honeybee. To our knowledge, this is the first report of a role for PLC in learning and memory in an insect.

  15. Characterizing brain oscillations in cognition and disease

    NARCIS (Netherlands)

    Jiang, H.

    2016-01-01

    It has been suggested that neuronal oscillations play a fundamental role for shaping the functional architecture of the working brain. This thesis investigates brain oscillations in rat, human healthy population and major depressive disorder (MDD) patients. A novel measurement termed

  16. In vitro and in vivo pharmacological characterization of a neuropeptide S tetrabranched derivative.

    Science.gov (United States)

    Ruzza, Chiara; Rizzi, Anna; Malfacini, Davide; Pulga, Alice; Pacifico, Salvatore; Salvadori, Severo; Trapella, Claudio; Reinscheid, Rainer K; Calo, Girolamo; Guerrini, Remo

    2015-02-01

    The peptide welding technology (PWT) is a novel chemical strategy that allows the synthesis of multibranched peptides with high yield, purity, and reproducibility. With this approach, a tetrabranched derivative of neuropeptide S (NPS) has been synthesized and pharmacologically characterized. The in vitro activity of PWT1-NPS has been studied in a calcium mobilization assay. In vivo, PWT1-NPS has been investigated in the locomotor activity (LA) and recovery of the righting reflex (RR) tests. In calcium mobilization studies, PWT1-NPS behaved as full agonist at the mouse NPS receptor (NPSR) being threefold more potent than NPS. The selective NPSR antagonists [ (t) Bu-D-Gly(5)]NPS and SHA 68 displayed similar potency values against NPS and PWT1-NPS. In vivo, both NPS (1-100 pmol, i.c.v.) and PWT1-NPS (0.1-100 pmol, i.c.v.) stimulated mouse LA, with PWT1-NPS showing higher potency than NPS. In the RR assay, NPS (100 pmol, i.c.v.) was able to reduce the percentage of mice losing the RR after diazepam administration and their sleep time 5 min after the i.c.v. injection, but it was totally inactive 2 h after the injection. On the contrary, PWT1-NPS (30 pmol, i.c.v.), injected 2 h before diazepam, displayed wake-promoting effects. This PWT1-NPS stimulant effect was no longer evident in mice lacking the NPSR receptor. The PWT1 technology can be successfully applied to the NPS sequence. PWT1-NPS displayed in vitro a pharmacological profile similar to NPS. In vivo PWT1-NPS mimicked NPS effects showing higher potency and long-lasting action.

  17. Isolation and characterization of halophilic Bacillus sp. BS3 able to produce pharmacologically important biosurfactants.

    Science.gov (United States)

    Donio, M B S; Ronica, S F A; Viji, V Thanga; Velmurugan, S; Jenifer, J Adlin; Michaelbabu, M; Citarasu, T

    2013-11-01

    To characterize the pharmacological importance of biosurfactants isolated from halophilic Bacillus sp BS3. Halophilic Bacillus sp. BS3 was isolated from solar salt works, identified by 16S 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. The biosurfactant were characterized by TLC, FTIR and GC-MS analysis and identified as lipopeptide type. GC-MS analysis revealed that, the biosurfactant had various compounds including 13-Docosenamide, (Z); Mannosamine, 9- and N,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 (Pbiosurfactants, among the various concentrations of biosurfactants such as 0.000 25, 0.002 5, 0.025, 0.25 and 2.5 μg, the 0.25 μg concentration suppressed the cells significantly (P<0.05) to 24.8%. 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. Copyright © 2013 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

  18. Systems pharmacology and blood-brain barrier functionality in Parkinson's disease

    NARCIS (Netherlands)

    Ravenstijn, Paulien Gerarda Maria

    2009-01-01

    Parkinson’s disease is a progressive neurodegenerative disease, which is composed of many components, each caused by interplay of a number of genetic and nongenetic causes. As the blood-brain barrier (BBB) is a key player in the relationship between plasma and brain pharmacokinetics, the influences

  19. 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

  20. Treatment of developmental stress disorder: mind, body and brain - analysis and pharmacology coupled.

    Science.gov (United States)

    McFadden, Joseph

    2017-11-01

    The schism between psychiatry, psychology and analysis, while long present, has widened even more in the past half-century with the advances in psychopharmacology. With the advances in electronic brain imaging, particularly in developmental and post-traumatic stress disorders, there has emerged both an understanding of brain changes resulting from severe, chronic stress and an ability to target brain chemistry in ways that can relieve clinical symptomatology. The use of alpha-1 adrenergic brain receptor antagonists decreases many of the manifestations of PTSD. Additionally, this paper discusses the ways in which dreaming, thinking and the analytic process are facilitated with this concomitant treatment and hypervigilence and hyper-arousal states are signficiantly decreased. © 2017, The Society of Analytical Psychology.

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

    International Nuclear Information System (INIS)

    Calcagni, Maria Lucia; Giordano, Alessandro; Bruno, Isabella; Di Giuda, Daniela; De Rossi, Giuseppe; Troncone, Luigi; Parbonetti, Giovanni; Colicchio, Gabriella

    2002-01-01

    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 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 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 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 of seizures, to avoid pitfalls due

  2. 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

  3. Canine osteosarcoma cell lines contain stem-like cancer cells: biological and pharmacological characterization.

    Science.gov (United States)

    Gatti, Monica; Wurth, Roberto; Vito, Guendalina; Pattarozzi, Alessandra; Campanella, Chiara; Thellung, Stefano; Maniscalco, Lorella; De Maria, Raffaella; Villa, Valentina; Corsaro, Alessandro; Nizzari, Mario; Bajetto, Adriana; Ratto, Alessandra; Ferrari, Angelo; Barbieri, Federica; Florio, Tullio

    2016-05-01

    Cancer stem cells (CSCs) represent a small subpopulation of cells responsible for tumor formation and progression, drug resistance, tumor recurrence and metastasization. CSCs have been identified in many human tumors including osteosarcoma (OSA). CSC distinctive properties are the expression of stem cell markers, sustained growth, self-renewal and tumorigenicity. Here we report the isolation of stem-like cells from two canine OSA cultures, characterized by self-renewal, evaluated by sphere formation ability, differential marker expression, and in vitro proliferation when cultured in a medium containing EGF and bFGF. Current therapies for OSA increased survival time, but prognosis remains poor, due to the development of drug resistance and metastases. Chemotherapy shrinks the tumor mass but CSCs remain unaffected, leading to tumor recurrence. Metformin, a drug for type 2 diabetes, has been shown to possess antitumor properties affecting CSC survival in different human and animal cancers. Here we show that metformin has a significant antiproliferative effect on canine OSA stem-like cells, validating this in vitro model for further pre-clinical drug evaluations. In conclusion, our results demonstrate the feasibility of obtaining CSC-enriched cultures from primary canine OSA cells as a promising model for biological and pharmacological studies of canine and human OSAs.

  4. Community structure in networks of functional connectivity: resolving functional organization in the rat brain with pharmacological MRI.

    Science.gov (United States)

    Schwarz, Adam J; Gozzi, Alessandro; Bifone, Angelo

    2009-08-01

    In the study of functional connectivity, fMRI data can be represented mathematically as a network of nodes and links, where image voxels represent the nodes and the connections between them reflect a degree of correlation or similarity in their response. Here we show that, within this framework, functional imaging data can be partitioned into 'communities' of tightly interconnected voxels corresponding to maximum modularity within the overall network. We evaluated this approach systematically in application to networks constructed from pharmacological MRI (phMRI) of the rat brain in response to acute challenge with three different compounds with distinct mechanisms of action (d-amphetamine, fluoxetine, and nicotine) as well as vehicle (physiological saline). This approach resulted in bilaterally symmetric sub-networks corresponding to meaningful anatomical and functional connectivity pathways consistent with the purported mechanism of action of each drug. Interestingly, common features across all three networks revealed two groups of tightly coupled brain structures that responded as functional units independent of the specific neurotransmitter systems stimulated by the drug challenge, including a network involving the prefrontal cortex and sub-cortical regions extending from the striatum to the amygdala. This finding suggests that each of these networks includes general underlying features of the functional organization of the rat brain.

  5. Brain Imaging Studies on the Cognitive, Pharmacological and Neurobiological Effects of Cannabis in Humans: Evidence from Studies of Adult Users.

    Science.gov (United States)

    Weinstein, Aviv; Livny, Abigail; Weizman, Abraham

    2016-01-01

    Cannabis is the most widely used illicit drug worldwide. Regular cannabis use has been associated with a range of acute and chronic mental health problems, such as anxiety, depression, psychotic symptoms and neurocognitive impairments and their neural mechanisms need to be examined. This review summarizes and critically evaluates brain-imaging studies of cannabis in recreational and regular cannabis users between January 2000 and January 2016. The search has yielded eligible 103 structural and functional studies. Regular use of cannabis results in volumetric, gray matter and white matter structural changes in the brain, in particular in the hippocampus and the amygdala. Regular use of cannabis affects cognitive processes such as attention, memory, inhibitory control, decision-making, emotional processing, social cognition and their associated brain areas. There is evidence that regular cannabis use leads to altered neural function during attention and working memory and that recruitment of activity in additional brain regions can compensate for it. Similar to other drugs of abuse, cannabis cues activated areas in the reward pathway. Pharmacological studies showed a modest increase in human striatal dopamine transmission after administration of THC in healthy volunteers. Regular cannabis use resulted in reduced dopamine transporter occupancy and reduced dopamine synthesis but not in reduced striatal D2/D3 receptor occupancy compared with healthy control participants. Studies also showed different effects of Δ-9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on emotion, cognition and associated brain regions in healthy volunteers, whereby CBD protects against the psychoactive effects of THC. Brain imaging studies using selective high-affinity radioligands for the imaging of cannabinoid CB1 receptor availability in Positron Emission Tomography (PET) showed downregulation of CB1 in regular users of cannabis. In conclusion, regular use of the cannabinoids exerts

  6. 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

    BACKGROUND: We have previously shown that addition of valproic acid (VPA; a histone deacetylase inhibitor) to hetastarch (Hextend [HEX]) resuscitation significantly decreases lesion size in a swine model of traumatic brain injury (TBI) and hemorrhagic shock (HS). However, the precise mechanisms...... have not been well defined. As VPA is a transcriptional modulator, the aim of this study was to investigate its effect on brain gene expression profiles. METHODS: Swine were subjected to controlled TBI and HS (40% blood volume), kept in shock for 2 hours, and resuscitated with HEX or HEX + VPA (n = 5...... 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...

  7. Fractal characterization of brain lesions in CT images

    International Nuclear Information System (INIS)

    Jauhari, Rajnish K.; Trivedi, Rashmi; Munshi, Prabhat; Sahni, Kamal

    2005-01-01

    Fractal Dimension (FD) is a parameter used widely for classification, analysis, and pattern recognition of images. In this work we explore the quantification of CT (computed tomography) lesions of the brain by using fractal theory. Five brain lesions, which are portions of CT images of diseased brains, are used for the study. These lesions exhibit self-similarity over a chosen range of scales, and are broadly characterized by their fractal dimensions

  8. 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.

  9. Differential effects of cathinone compounds and MDMA on body temperature in the rat, and pharmacological characterization of mephedrone-induced hypothermia.

    Science.gov (United States)

    Shortall, S E; Green, A R; Swift, K M; Fone, K C F; King, M V

    2013-02-01

    Recreational users report that mephedrone has similar psychoactive effects to 3,4-methylenedioxymethamphetamine (MDMA). MDMA induces well-characterized changes in body temperature due to complex monoaminergic effects on central thermoregulation, peripheral blood flow and thermogenesis, but there are little preclinical data on the acute effects of mephedrone or other synthetic cathinones. The acute effects of cathinone, methcathinone and mephedrone on rectal and tail temperature were examined in individually housed rats, with MDMA included for comparison. Rats were killed 2 h post-injection and brain regions were collected for quantification of 5-HT, dopamine and major metabolites. Further studies examined the impact of selected α-adrenoceptor and dopamine receptor antagonists on mephedrone-induced changes in rectal temperature and plasma catecholamines. At normal room temperature, MDMA caused sustained decreases in rectal and tail temperature. Mephedrone caused a transient decrease in rectal temperature, which was enhanced by α(1) -adrenoceptor and dopamine D(1) receptor blockade, and a prolonged decrease in tail temperature. Cathinone and methcathinone caused sustained increases in rectal temperature. MDMA decreased 5-HT and/or 5-hydroxyindoleacetic acid (5-HIAA) content in several brain regions and reduced striatal homovanillic acid (HVA) levels, whereas cathinone and methcathinone increased striatal HVA and 5-HIAA. Cathinone elevated striatal and hypothalamic 5-HT. Mephedrone elevated plasma noradrenaline levels, an effect prevented by α-adrenoceptor and dopamine receptor antagonists. MDMA and cathinones have different effects on thermoregulation, and their acute effects on brain monoamines also differ. These findings suggest that the adverse effects of cathinones in humans cannot be extrapolated from previous observations on MDMA. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  10. Pharmacological Inhibition of O-GlcNAcase Enhances Autophagy in Brain through an mTOR-Independent Pathway.

    Science.gov (United States)

    Zhu, Yanping; Shan, Xiaoyang; Safarpour, Farzaneh; Erro Go, Nancy; Li, Nancy; Shan, Alice; Huang, Mina C; Deen, Matthew; Holicek, Viktor; Ashmus, Roger; Madden, Zarina; Gorski, Sharon; Silverman, Michael A; Vocadlo, David J

    2018-03-05

    The glycosylation of nucleocytoplasmic proteins with O-linked N-acetylglucosamine residues (O-GlcNAc) is conserved among metazoans and is particularly abundant within brain. O-GlcNAc is involved in diverse cellular processes ranging from the regulation of gene expression to stress response. Moreover, O-GlcNAc is implicated in various diseases including cancers, diabetes, cardiac dysfunction, and neurodegenerative diseases. Pharmacological inhibition of O-GlcNAcase (OGA), the sole enzyme that removes O-GlcNAc, reproducibly slows neurodegeneration in various Alzheimer's disease (AD) mouse models manifesting either tau or amyloid pathology. These data have stimulated interest in the possibility of using OGA-selective inhibitors as pharmaceuticals to alter the progression of AD. The mechanisms mediating the neuroprotective effects of OGA inhibitors, however, remain poorly understood. Here we show, using a range of methods in neuroblastoma N2a cells, in primary rat neurons, and in mouse brain, that selective OGA inhibitors stimulate autophagy through an mTOR-independent pathway without obvious toxicity. Additionally, OGA inhibition significantly decreased the levels of toxic protein species associated with AD pathogenesis in the JNPL3 tauopathy mouse model as well as the 3×Tg-AD mouse model. These results strongly suggest that OGA inhibitors act within brain through a mechanism involving enhancement of autophagy, which aids the brain in combatting the accumulation of toxic protein species. Our study supports OGA inhibition being a feasible therapeutic strategy for hindering the progression of AD and other neurodegenerative diseases. Moreover, these data suggest more targeted strategies to stimulate autophagy in an mTOR-independent manner may be found within the O-GlcNAc pathway. These findings should aid the advancement of OGA inhibitors within the clinic.

  11. Pharmacological interventions for agitation in patients with traumatic brain injury: protocol for a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    David R. Williamson

    2016-11-01

    Full Text Available Abstract Background Traumatic brain injury (TBI is a worldwide leading cause of mortality and disability. Among TBI complications, agitation is a frequent behavioural problem. Agitation causes potential harm to patients and caregivers, interferes with treatments, leads to unnecessary chemical and physical restraints, increases hospital length of stay, delays rehabilitation, and impedes functional independence. Pharmacological treatments are often considered for agitation management following TBI. Several types of agents have been proposed for the treatment of agitation. However, the benefit and safety of these agents in TBI patients as well as their differential effects and interactions are uncertain. In addition, animal studies and observational studies have suggested impaired cognitive function with the use of certain antipsychotics and benzodiazepines. Hence, a safe and effective treatment for agitation, which does not interfere with neurological recovery, remains to be identified. Methods/design With the help of Health Sciences librarian, we will design a search strategy in the following databases: PubMed, Ovid MEDLINE®, EMBASE, CINAHL, PsycINFO, Cochrane Library, Google Scholar, Directory of Open Access Journals, LILACS, Web of Science, and Prospero. A grey literature search will be performed using the resources suggested in CADTH’s Grey Matters. We will include all randomized controlled, quasi-experimental, and observational studies with control groups. The population of interest is all patients, including children and adults, who have suffered a TBI. We will include studies in which agitation, not further defined, was the presenting symptom or one of the presenting symptoms. We will also include studies where agitation was not the presenting symptom but was measured as an outcome variable and studies assessing the safety of these pharmacological interventions in TBI patients. We will include studies evaluating all pharmacological

  12. Pharmacological characterization of a β-adrenergic-like octopamine receptor in Plutella xylostella.

    Science.gov (United States)

    Huang, Qing-Ting; Ma, Hai-Hao; Deng, Xi-Le; Zhu, Hang; Liu, Jia; Zhou, Yong; Zhou, Xiao-Mao

    2018-04-25

    The β-adrenergic-like octopamine receptor (OA2B2) belongs to the class of G-protein coupled receptors. It regulates important physiological functions in insects, thus is potentially a good target for insecticides. In this study, the putative open reading frame sequence of the Pxoa2b2 gene in Plutella xylostella was cloned. Orthologous sequence alignment, phylogenetic tree analysis, and protein sequence analysis all showed that the cloned receptor belongs to the OA2B2 protein family. PxOA2B2 was transiently expressed in HEK-293 cells. It was found that PxOA2B2 could be activated by both octopamine and tyramine, resulting in increased intracellular cyclic AMP (cAMP) levels, whereas dopamine and serotonin were not effective in eliciting cAMP production. Further studies with series of PxOA2B2 agonists and antagonists showed that all four tested agonists (e.g., naphazoline, clonidine, 2-phenylethylamine, and amitraz) could activate the PxOA2B2 receptor, and two of tested antagonists (e.g., phentolamine and mianserin) had significant antagonistic effects. However, antagonist of yohimbine had no effects. Quantitative real-time polymerase chain reaction analysis showed that Pxoa2b2 gene was expressed in all developmental stages of P. xylostella and that the highest expression occurred in male adults. Further analysis with fourth-instar P. xylostella larvae showed that the Pxoa2b2 gene was mainly expressed in Malpighian tubule, epidermal, and head tissues. This study provides both a pharmacological characterization and the gene expression patterns of the OA2B2 in P. xylostella, facilitating further research for insecticides using PxOA2B2 as a target. © 2018 Wiley Periodicals, Inc.

  13. Pharmacological and biochemical properties of the benzodiazepine-GABA receptor in codfish brain in comparison with mammalian brain

    International Nuclear Information System (INIS)

    Deng, L.

    1989-01-01

    The GABA receptor of codfish brain is encoded by an ancestral gene of the mammalian GABA receptor based on phylogenetic studies. The mammalian GABA receptor consists of at least two subunits (β and α) which could be photoaffinity labeled by the GABA agonist [ 3 H]muscimol (57 kDa) and the benzodiazepine (BZ) agonist [ 3 H]flunitrazepam (52 kDa), respectively. In contrast, electrophoresis of codfish GABA receptor photoaffinity labeled by the same ligands showed a single radioactive peak on sodium dodecyl surface polyarcylamide gel, giving rise to a relative molecular weight of 56-57 kDa equivalent to the β subunit of 57 kDa in mammals. The homogeneity of purified receptor using benzodiazepine (Ro 7-1986/1) affinity chromatography was further verified by two-dimensional gel electrophoresis based on isoelectric point and molecular weight, in addition to a single band on a silver stained gel and specific activity. The receptor density and affinity constant for [ 3 H]muscimol and [ 3 H]flunitrazepam are comparable to those in bovine, rate, and human brain

  14. Molecules of various pharmacologically-relevant sizes can cross the ultrasound-induced blood-brain barrier opening in vivo.

    Science.gov (United States)

    Choi, James J; Wang, Shougang; Tung, Yao-Sheng; Morrison, Barclay; Konofagou, Elisa E

    2010-01-01

    Focused ultrasound (FUS) is hereby shown to noninvasively and selectively deliver compounds at pharmacologically relevant molecular weights through the opened blood-brain barrier (BBB). A complete examination on the size of the FUS-induced BBB opening, the spatial distribution of the delivered agents and its dependence on the agent's molecular weight were imaged and quantified using fluorescence microscopy. BBB opening in mice (n=13) was achieved in vivo after systemic administration of microbubbles and subsequent application of pulsed FUS (frequency: 1.525MHz, peak-rarefactional pressure in situ: 570 kPa) to the left murine hippocampus through the intact skin and skull. BBB-impermeant, fluorescent-tagged dextrans at three distinct molecular weights spanning over several orders of magnitude were systemically administered and acted as model therapeutic compounds. First, dextrans of 3 and 70 kDa were delivered trans-BBB while 2000 kDa dextran was not. Second, compared with 70 kDa dextran, a higher concentration of 3 kDa dextran was delivered through the opened BBB. Third, the 3 and 70 kDa dextrans were both diffusely distributed throughout the targeted brain region. However, high concentrations of 70 kDa dextran appeared more punctated throughout the targeted region. In conclusion, FUS combined with microbubbles opened the BBB sufficiently to allow passage of compounds of at least 70 kDa, but not greater than 2000 kDa into the brain parenchyma. This noninvasive and localized BBB opening technique could, thus, provide a unique means for the delivery of compounds of several magnitudes of kDa that include agents with shown therapeutic promise in vitro but whose in vivo translation has been hampered by their associated BBB impermeability. (E-mail: ek2191@columbia.edu).

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

    International Nuclear Information System (INIS)

    Gremy, O.

    2006-12-01

    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

  16. 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.

  17. Pharmacological manipulation of serotonin receptors during brain embryogenesis favours stress resiliency in female rats

    Directory of Open Access Journals (Sweden)

    Gianluca Lavanco

    2018-02-01

    Full Text Available Manipulations of the serotonin transmission during early development induce long-lasting changes in the serotonergic circuitry throughout the brain. However, little is known on the developmental consequences in the female progeny. Therefore, this study aimed at exploring the behavioural effects of pre- and postnatal stimulation of the serotonergic system by 5-methoxytryptamine in adolescent female rats on behavioural reactivity and anxiety- like phenotype. Our results show that perinatal 5- methoxythyptamine decreased total distance travelled and rearing frequency in the novel enviroment, and increased the preference for the centre of the arena in the open field test. Moreover, perinatal 5-methoxytryptamine increased the percentages of entries and time spent on the open arms of the elevated plus maze, with respect to perinatally vehicle-exposed rats. Thus, perinatal stimulation of serotonin receptors does not impair the functional response to the emotional challenges in female rats, favouring the occurrence of a stress-resilient phenotype.

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

    Directory of Open Access Journals (Sweden)

    Atsuo Tahara

    2016-03-01

    Full Text Available 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.

  19. 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...

  20. Novel methodology to characterize electromagnetic exposure of the brain

    Energy Technology Data Exchange (ETDEWEB)

    Crespo-Valero, Pedro [Schmid and Partner Engineering AG, Zeughausstr. 43, 8004, Zuerich (Switzerland); Christopoulou, Maria; Nikita, Konstantina S [Biomedical Simulations and Imaging Laboratory, School of Electrical and Computer Engineering, National Technical University of Athens, 9 Iroon Polytechniou Str., 157 80 Athens (Greece); Zefferer, Marcel; Christ, Andreas; Kuster, Niels [Foundation for Research on Information Technologies in Society (IT' IS), Zeughausstr. 43, 8004 Zuerich (Switzerland); Achermann, Peter, E-mail: crespo@speag.com [Institute of Pharmacology and Toxicology, University of Zuerich, Winterthurerstrasse 190, 8057, Zurich (Switzerland)

    2011-01-21

    Due to the greatly non-uniform field distribution induced in brain tissues by radio frequency electromagnetic sources, the exposure of anatomical and functional regions of the brain may be a key issue in interpreting laboratory findings and epidemiological studies concerning endpoints related to the central nervous system. This paper introduces the Talairach atlas in characterization of the electromagnetic exposure of the brain. A hierarchical labeling scheme is mapped onto high-resolution human models. This procedure is fully automatic and allows identification of over a thousand different sites all over the brain. The electromagnetic absorption can then be extracted and interpreted in every region or combination of regions in the brain, depending on the characterization goals. The application examples show how this methodology enhances the dosimetry assessment of the brain based on results obtained by either finite difference time domain simulations or measurements delivered by test compliance dosimetry systems. Applications include, among others, the detailed dosimetric analysis of the exposure of the brain during cell phone use, improved design of exposure setups for human studies or medical diagnostic and therapeutic devices using electromagnetic fields or ultrasound.

  1. Novel methodology to characterize electromagnetic exposure of the brain

    International Nuclear Information System (INIS)

    Crespo-Valero, Pedro; Christopoulou, Maria; Nikita, Konstantina S; Zefferer, Marcel; Christ, Andreas; Kuster, Niels; Achermann, Peter

    2011-01-01

    Due to the greatly non-uniform field distribution induced in brain tissues by radio frequency electromagnetic sources, the exposure of anatomical and functional regions of the brain may be a key issue in interpreting laboratory findings and epidemiological studies concerning endpoints related to the central nervous system. This paper introduces the Talairach atlas in characterization of the electromagnetic exposure of the brain. A hierarchical labeling scheme is mapped onto high-resolution human models. This procedure is fully automatic and allows identification of over a thousand different sites all over the brain. The electromagnetic absorption can then be extracted and interpreted in every region or combination of regions in the brain, depending on the characterization goals. The application examples show how this methodology enhances the dosimetry assessment of the brain based on results obtained by either finite difference time domain simulations or measurements delivered by test compliance dosimetry systems. Applications include, among others, the detailed dosimetric analysis of the exposure of the brain during cell phone use, improved design of exposure setups for human studies or medical diagnostic and therapeutic devices using electromagnetic fields or ultrasound.

  2. Cognitive Function and Brain Atrophy Predict Non-pharmacological Efficacy in Dementia: The Mihama-Kiho Scan Project2

    Directory of Open Access Journals (Sweden)

    Ken-ichi Tabei

    2018-04-01

    Full Text Available We aimed to determine whether neuropsychological deficits and brain atrophy could predict the efficacy of non-pharmacological interventions. Forty-six participants with mild-to-moderate dementia were monitored for 6 months; 25 underwent an intervention involving physical exercise with music, and 21 performed cognitive stimulation tasks. Participants were categorized into improvement (IMP and no-IMP subgroups. In the exercise-with-music group, the no-IMP subgroup performed worse than the IMP subgroup on the Rivermead Behavioural Memory Test at baseline. In the cognitive-stimulation group, the no-IMP subgroup performed worse than the IMP subgroup on Raven’s Colored Progressive Matrices and the cognitive functional independence measure at baseline. In the no-IMP subgroup, voxel-based morphometric analysis at baseline revealed more extensive gray matter loss in the anterior cingulate gyrus and left middle frontal gyrus in the exercise-with-music and cognitive-stimulation groups, respectively. Participants with mild-to-moderate dementia with cognitive decline and extensive cortical atrophy are less likely to show improved cognitive function after non-pharmaceutical therapy.

  3. Cognitive Function and Brain Atrophy Predict Non-pharmacological Efficacy in Dementia: The Mihama-Kiho Scan Project2.

    Science.gov (United States)

    Tabei, Ken-Ichi; Satoh, Masayuki; Ogawa, Jun-Ichi; Tokita, Tomoko; Nakaguchi, Noriko; Nakao, Koji; Kida, Hirotaka; Tomimoto, Hidekazu

    2018-01-01

    We aimed to determine whether neuropsychological deficits and brain atrophy could predict the efficacy of non-pharmacological interventions. Forty-six participants with mild-to-moderate dementia were monitored for 6 months; 25 underwent an intervention involving physical exercise with music, and 21 performed cognitive stimulation tasks. Participants were categorized into improvement (IMP) and no-IMP subgroups. In the exercise-with-music group, the no-IMP subgroup performed worse than the IMP subgroup on the Rivermead Behavioural Memory Test at baseline. In the cognitive-stimulation group, the no-IMP subgroup performed worse than the IMP subgroup on Raven's Colored Progressive Matrices and the cognitive functional independence measure at baseline. In the no-IMP subgroup, voxel-based morphometric analysis at baseline revealed more extensive gray matter loss in the anterior cingulate gyrus and left middle frontal gyrus in the exercise-with-music and cognitive-stimulation groups, respectively. Participants with mild-to-moderate dementia with cognitive decline and extensive cortical atrophy are less likely to show improved cognitive function after non-pharmaceutical therapy.

  4. Molecular and pharmacological characterization of serotonin 5-HT2α and 5-HT7 receptors in the salivary glands of the blowfly Calliphora vicina.

    Science.gov (United States)

    Röser, Claudia; Jordan, Nadine; Balfanz, Sabine; Baumann, Arnd; Walz, Bernd; Baumann, Otto; Blenau, Wolfgang

    2012-01-01

    Secretion in blowfly (Calliphora vicina) salivary glands is stimulated by the biogenic amine serotonin (5-hydroxytryptamine, 5-HT), which activates both inositol 1,4,5-trisphosphate (InsP(3))/Ca(2+) and cyclic adenosine 3',5'-monophosphate (cAMP) signalling pathways in the secretory cells. In order to characterize the signal-inducing 5-HT receptors, we cloned two cDNAs (Cv5-ht2α, Cv5-ht7) that share high similarity with mammalian 5-HT(2) and 5-HT(7) receptor genes, respectively. RT-PCR demonstrated that both receptors are expressed in the salivary glands and brain. Stimulation of Cv5-ht2α-transfected mammalian cells with 5-HT elevates cytosolic [Ca(2+)] in a dose-dependent manner (EC(50) = 24 nM). In Cv5-ht7-transfected cells, 5-HT produces a dose-dependent increase in [cAMP](i) (EC(50) = 4 nM). We studied the pharmacological profile for both receptors. Substances that appear to act as specific ligands of either Cv5-HT(2α) or Cv5-HT(7) in the heterologous expression system were also tested in intact blowfly salivary gland preparations. We observed that 5-methoxytryptamine (100 nM) activates only the Cv5-HT(2α) receptor, 5-carboxamidotryptamine (300 nM) activates only the Cv5-HT(7) receptor, and clozapine (1 µM) antagonizes the effects of 5-HT via Cv5-HT(7) in blowfly salivary glands, providing means for the selective activation of each of the two 5-HT receptor subtypes. This study represents the first comprehensive molecular and pharmacological characterization of two 5-HT receptors in the blowfly and permits the analysis of the physiological role of these receptors, even when co-expressed in cells, and of the modes of interaction between the Ca(2+)- and cAMP-signalling cascades.

  5. Molecular and pharmacological characterization of serotonin 5-HT2α and 5-HT7 receptors in the salivary glands of the blowfly Calliphora vicina.

    Directory of Open Access Journals (Sweden)

    Claudia Röser

    Full Text Available Secretion in blowfly (Calliphora vicina salivary glands is stimulated by the biogenic amine serotonin (5-hydroxytryptamine, 5-HT, which activates both inositol 1,4,5-trisphosphate (InsP(3/Ca(2+ and cyclic adenosine 3',5'-monophosphate (cAMP signalling pathways in the secretory cells. In order to characterize the signal-inducing 5-HT receptors, we cloned two cDNAs (Cv5-ht2α, Cv5-ht7 that share high similarity with mammalian 5-HT(2 and 5-HT(7 receptor genes, respectively. RT-PCR demonstrated that both receptors are expressed in the salivary glands and brain. Stimulation of Cv5-ht2α-transfected mammalian cells with 5-HT elevates cytosolic [Ca(2+] in a dose-dependent manner (EC(50 = 24 nM. In Cv5-ht7-transfected cells, 5-HT produces a dose-dependent increase in [cAMP](i (EC(50 = 4 nM. We studied the pharmacological profile for both receptors. Substances that appear to act as specific ligands of either Cv5-HT(2α or Cv5-HT(7 in the heterologous expression system were also tested in intact blowfly salivary gland preparations. We observed that 5-methoxytryptamine (100 nM activates only the Cv5-HT(2α receptor, 5-carboxamidotryptamine (300 nM activates only the Cv5-HT(7 receptor, and clozapine (1 µM antagonizes the effects of 5-HT via Cv5-HT(7 in blowfly salivary glands, providing means for the selective activation of each of the two 5-HT receptor subtypes. This study represents the first comprehensive molecular and pharmacological characterization of two 5-HT receptors in the blowfly and permits the analysis of the physiological role of these receptors, even when co-expressed in cells, and of the modes of interaction between the Ca(2+- and cAMP-signalling cascades.

  6. Brain Pharmacokinetics and the Pharmacological Effects on Striatal Neurotransmitter Levels of Pueraria lobata Isoflavonoids in Rat

    Directory of Open Access Journals (Sweden)

    Bingxin Xiao

    2017-09-01

    Full Text Available Isoflavonoids are putatively active components of Pueraria lobata and has been demonstrated prominent neuro-protection effect against cerebrovascular disorders, hypertension or Parkinson's disease (PD. However, the molecular basis for the beneficial effect of Pueraria lobata on nervous systems has not been well revealed. The present study aims to assess striatum exposure to main active isoflavonoids and changes of striatal extracellular neurotransmitters levels in rat brain after intravenous administration of Pueraria lobata isoflavonoids extracts (PLF, to further elucidate its' substantial bases for neuro activities. Fifteen rats were divided into 3 groups (five rats in each group to receive a dose of PLF at 80 or 160 mg/kg or normal saline (vehicle, respectively. An LC-MS/MS method was employed to determine the concentrations of five main isoflavonoids and multiple neurotransmitters in microdialysate from striatal extracellular fluid (ECF of the rats. The exposed quantities of puerarin (PU, 3′-methoxypuerarin (MPU, daidzein-8-C-apiosyl-(1-6-glucoside (DAC, and 3′-hydroxypuerarin (HPU in striatum were dose-dependent. The content of daidzein (DAZ was too low to be detected in all dialysate samples through the experiment. Optimal dose PLF (80 mg/kg promoted DA metabolism and inhibited 5-HT metabolism. No obvious change in the level of GLu was determined. The concentration of GABA presented a temporary decline firstly and then a gradual uptrend followed by a further downtrend. Higher dose (160 mg/kg PLF could enhance the metabolism of both DA and 5-HT, and lower the extracellular level of GLu, without changing GABA concentrations, which might result in alleviation on excitatory toxicity under conditions, such as ischemia. The results infer that different dose of PLF should be chosen to achieve appropriate neurochemical modulation effects under conditions, such as hypertension or ischemia/stroke. These findings may significantly contribute to a

  7. Dm5-HT2B: Pharmacological Characterization of the Fifth Serotonin Receptor Subtype of Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Wolfgang Blenau

    2017-05-01

    Full Text Available Serotonin (5-hydroxytryptamine, 5-HT is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects and deuterostomes (e.g., mammals. In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster, a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT1A, Dm5-HT1B, and Dm5-HT7 couple to cAMP signaling cascades, the Dm5-HT2A receptor leads to Ca2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT2B receptor. Knowledge about this receptor’s pharmacological properties is very limited. This is quite surprising because Dm5-HT2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT2B’s pharmacology, we evaluated the receptor’s response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT2B signaling in vitro and in vivo.

  8. Dm5-HT2B: Pharmacological Characterization of the Fifth Serotonin Receptor Subtype of Drosophila melanogaster.

    Science.gov (United States)

    Blenau, Wolfgang; Daniel, Stöppler; Balfanz, Sabine; Thamm, Markus; Baumann, Arnd

    2017-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects) and deuterostomes (e.g., mammals). In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster , a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT 1A , Dm5-HT 1B , and Dm5-HT 7 couple to cAMP signaling cascades, the Dm5-HT 2A receptor leads to Ca 2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT 2B receptor. Knowledge about this receptor's pharmacological properties is very limited. This is quite surprising because Dm5-HT 2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT 2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT 2B 's pharmacology, we evaluated the receptor's response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT 2B signaling in vitro and in vivo .

  9. The pharmacology of neuroplasticity induced by non-invasive brain stimulation: building models for the clinical use of CNS active drugs

    Science.gov (United States)

    Nitsche, Michael A; Müller-Dahlhaus, Florian; Paulus, Walter; Ziemann, Ulf

    2012-01-01

    The term neuroplasticity encompasses structural and functional modifications of neuronal connectivity. Abnormal neuroplasticity is involved in various neuropsychiatric diseases, such as dystonia, epilepsy, migraine, Alzheimer's disease, fronto-temporal degeneration, schizophrenia, and post cerebral stroke. Drugs affecting neuroplasticity are increasingly used as therapeutics in these conditions. Neuroplasticity was first discovered and explored in animal experimentation. However, non-invasive brain stimulation (NIBS) has enabled researchers recently to induce and study similar processes in the intact human brain. Plasticity induced by NIBS can be modulated by pharmacological interventions, targeting ion channels, or neurotransmitters. Importantly, abnormalities of plasticity as studied by NIBS are directly related to clinical symptoms in neuropsychiatric diseases. Therefore, a core theme of this review is the hypothesis that NIBS-induced plasticity can explore and potentially predict the therapeutic efficacy of CNS-acting drugs in neuropsychiatric diseases. We will (a) review the basics of neuroplasticity, as explored in animal experimentation, and relate these to our knowledge about neuroplasticity induced in humans by NIBS techniques. We will then (b) discuss pharmacological modulation of plasticity in animals and humans. Finally, we will (c) review abnormalities of plasticity in neuropsychiatric diseases, and discuss how the combination of NIBS with pharmacological intervention may improve our understanding of the pathophysiology of abnormal plasticity in these diseases and their purposeful pharmacological treatment. PMID:22869014

  10. Pharmacotherapy of Traumatic Brain Injury: State of the Science and the Road Forward: Report of the Department of Defense Neurotrauma Pharmacology Workgroup

    Science.gov (United States)

    Kochanek, Patrick M.; Bergold, Peter; Kenney, Kimbra; Marx, Christine E.; Grimes, Col. Jamie B.; Loh, LTC Yince; Adam, LTC Gina E.; Oskvig, Devon; Curley, Kenneth C.; Salzer, Col. Wanda

    2014-01-01

    Abstract Despite substantial investments by government, philanthropic, and commercial sources over the past several decades, traumatic brain injury (TBI) remains an unmet medical need and a major source of disability and mortality in both developed and developing societies. The U.S. Department of Defense neurotrauma research portfolio contains more than 500 research projects funded at more than $700 million and is aimed at developing interventions that mitigate the effects of trauma to the nervous system and lead to improved quality of life outcomes. A key area of this portfolio focuses on the need for effective pharmacological approaches for treating patients with TBI and its associated symptoms. The Neurotrauma Pharmacology Workgroup was established by the U.S. Army Medical Research and Materiel Command (USAMRMC) with the overarching goal of providing a strategic research plan for developing pharmacological treatments that improve clinical outcomes after TBI. To inform this plan, the Workgroup (a) assessed the current state of the science and ongoing research and (b) identified research gaps to inform future development of research priorities for the neurotrauma research portfolio. The Workgroup identified the six most critical research priority areas in the field of pharmacological treatment for persons with TBI. The priority areas represent parallel efforts needed to advance clinical care; each requires independent effort and sufficient investment. These priority areas will help the USAMRMC and other funding agencies strategically guide their research portfolios to ensure the development of effective pharmacological approaches for treating patients with TBI. PMID:23968241

  11. The Characterization of Brain Behavior Relationships via Cognitive Neuroinformatic Approaches

    Science.gov (United States)

    Kalar, Donald James, II

    2009-01-01

    The scope, breadth, and volume of data characterizing our current understanding of how the brain functions is growing at an increasingly rapid pace. What is more, theories are becoming increasing complex and nuanced, integrating knowledge from multiple previously independent sources of scientific inquiry. The research described within this…

  12. Chemical engineering and structural and pharmacological characterization of the α-scorpion toxin OD1.

    Science.gov (United States)

    Durek, Thomas; Vetter, Irina; Wang, Ching-I Anderson; Motin, Leonid; Knapp, Oliver; Adams, David J; Lewis, Richard J; Alewood, Paul F

    2013-01-01

    Scorpion α-toxins are invaluable pharmacological tools for studying voltage-gated sodium channels, but few structure-function studies have been undertaken due to their challenging synthesis. To address this deficiency, we report a chemical engineering strategy based upon native chemical ligation. The chemical synthesis of α-toxin OD1 was achieved by chemical ligation of three unprotected peptide segments. A high resolution X-ray structure (1.8 Å) of synthetic OD1 showed the typical βαββ α-toxin fold and revealed important conformational differences in the pharmacophore region when compared with other α-toxin structures. Pharmacological analysis of synthetic OD1 revealed potent α-toxin activity (inhibition of fast inactivation) at Nav1.7, as well as Nav1.4 and Nav1.6. In addition, OD1 also produced potent β-toxin activity at Nav1.4 and Nav1.6 (shift of channel activation in the hyperpolarizing direction), indicating that OD1 might interact at more than one site with Nav1.4 and Nav1.6. Investigation of nine OD1 mutants revealed that three residues in the reverse turn contributed significantly to selectivity, with the triple OD1 mutant (D9K, D10P, K11H) being 40-fold more selective for Nav1.7 over Nav1.6, while OD1 K11V was 5-fold more selective for Nav1.6 than Nav1.7. This switch in selectivity highlights the importance of the reverse turn for engineering α-toxins with altered selectivity at Nav subtypes.

  13. Human CRF{sub 2} {alpha} and {beta} splice variants: pharmacological characterization using radioligand binding and a luciferase gene expression assay

    Energy Technology Data Exchange (ETDEWEB)

    Ardati, A. [Rhone-Poulenc Rorer, Cardiovascular Biology, NW4, 500 Arcola Road, Collegeville, PA (United States); Goetschy, V.; Gottowick, J.; Henriot, S.; Deuschle, U.; Kilpatrick, G.J. [Central Nervous System, Pharma Division, F. Hoffmann-La Roche AG, CH-4070 Basel (Switzerland); Valdenaire, O. [Cardiovascular Research, Pharma Division, F. Hoffmann-La Roche AG, CH-4070 Basel (Switzerland)

    1999-03-14

    Corticotropin releasing factor (CRF) receptors belong to the super-family of G protein-coupled receptors. These receptors are classified into two subtypes (CRF{sub 1} and CRF{sub 2}). Both receptors are positively coupled to adenylyl cyclase but they have a distinct pharmacology and distribution in brain. Two isoforms belonging to the CRF{sub 2} subtype receptors, CRF{sub 2{alpha}} and CRF{sub 2{beta}}, 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 hCRF{sub 2{beta}} receptor. We have used radioligand binding with [{sup 125}I]-tyr{sup 0}-sauvagine and a gene expression assay in which the firefly luciferase gene expression is under the control of cAMP responsive elements. Association kinetics of [{sup 125}I]-tyr{sup 0}-sauvagine binding to the hCRF{sub 2{beta}} receptor were monophasic while dissociation kinetics were biphasic, in agreement with the kinetics results obtained with the hCRF{sub 2{alpha}} 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 hCRF{sub 2{alpha}} receptor. A non-hydrolysable GTP analog, Gpp(NH)p, reduced the high affinity binding of [{sup 125}I]-tyr{sup 0}-sauvagine to both hCRF{sub 2} receptor isoforms in a similar manner. The rank order of potency of CRF agonist peptides in competition experiments was identical for both hCRF{sub 2}{alpha}-helical CRF{sub (9-41)}oCRF). Similarly, agonist potency was similar for the two isoforms when studied using the luciferase gene reporter system. The peptide antagonist {alpha}-helical CRF{sub (9-41)} exhibited a non-competitive antagonism of urocortin-stimulated luciferase expression with both hCRF{sub 2} receptor isoforms. Taken together, these results indicate that the

  14. Pharmacological targeting of secondary brain damage following ischemic or hemorrhagic stroke, traumatic brain injury, and bacterial meningitis - a systematic review and meta-analysis.

    Science.gov (United States)

    Beez, Thomas; Steiger, Hans-Jakob; Etminan, Nima

    2017-12-07

    The effectiveness of pharmacological strategies exclusively targeting secondary brain damage (SBD) following ischemic stroke, aneurysmal subarachnoid hemorrhage, aSAH, intracerebral hemorrhage (ICH), traumatic brain injury (TBI) and bacterial meningitis is unclear. This meta-analysis studied the effect of SBD targeted treatment on clinical outcome across the pathological entities. Randomized, controlled, double-blinded trials on aforementioned entities with 'death' as endpoint were identified. Effect sizes were analyzed and expressed as pooled risk ratio (RR) estimates with 95% confidence intervals (CI). 123 studies fulfilled the criteria, with data on 66,561 patients. In the pooled analysis, there was a minor reduction of mortality for aSAH [RR 0.93 (95% CI:0.85-1.02)], ICH [RR 0.92 (95% CI:0.82-1.03)] and bacterial meningitis [RR 0.86 (95% CI:0.68-1.09)]. No reduction of mortality was found for ischemic stroke [RR 1.05 (95% CI:1.00-1.11)] and TBI [RR 1.03 (95% CI:0.93-1.15)]. Additional analysis of "poor outcome" as endpoint gave similar results. Subgroup analysis with respect to effector mechanisms showed a tendency towards a reduced mortality for the effector mechanism category "oxidative metabolism/stress" for aSAH with a risk ratio of 0.86 [95% CI: 0.73-1.00]. Regarding specific medications, a statistically significant reduction of mortality and poor outcome was confirmed only for nimodipine for aSAH and dexamethasone for bacterial meningitis. Our results show that only a few selected SBD directed medications are likely to reduce the rate of death and poor outcome following aSAH, and bacterial meningitis, while no convincing evidence could be found for the usefulness of SBD directed medications in ischemic stroke, ICH and TBI. However, a subtle effect on good or excellent outcome might remain undetected. These results should lead to a new perspective of secondary reactions following cerebral injury. These processes should not be seen as suicide mechanisms

  15. Pharmacological characterization and chemical fractionation of a liposterolic extract of saw palmetto (Serenoa repens): effects on rat prostate contractility.

    Science.gov (United States)

    Chua, Thiam; Eise, Nicole T; Simpson, Jamie S; Ventura, Sabatino

    2014-03-14

    Saw palmetto (Serenoa repens) was first used medicinally by native American Indians to treat urological disorders. Nowadays, saw palmetto extracts are widely used in Europe and North America to treat the urinary symptoms associated with benign prostatic hyperplasia even though its mechanisms of action are poorly understood. This study aimed to characterize the bioactive constituents of a lipid extract of saw palmetto that are able to affect contractility of the rat prostate gland. The mechanism of action will also be investigated. A commercially available lipid extract of saw palmetto was subjected to fractionation using normal phase column chromatography. Composition of fractions was assessed by proton nuclear magnetic resonance spectroscopy ((1)H NMR) and mass spectrometry (MS). Contractile activities of these fractions were evaluated pharmacologically using isolated preparations of rat prostate gland and compared to the activity of the crude extract. Saw palmetto extract inhibited contractions of the rat prostate gland which were consistent with smooth muscle relaxant activity. Only the ethyl acetate fraction resulting from chromatography inhibited contractions of isolated rat prostates similarly to the inhibition produced by the crude lipid extract. Comparison with authentic samples and analysis of NMR data revealed that this bioactivity was due to the fatty acid components present in the ethyl acetate fraction. Bioassay using various pharmacological tools identified multiple contractile mechanisms which were affected by the bioactive constituents. A fatty acid component of saw palmetto extract causes inhibition of prostatic smooth muscle contractions via a non-specific mechanism. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  16. Isolation and pharmacological characterization of fatty acids from saw palmetto extract.

    Science.gov (United States)

    Abe, Masayuki; Ito, Yoshihiko; Suzuki, Asahi; Onoue, Satomi; Noguchi, Hiroshi; Yamada, Shizuo

    2009-04-01

    Saw palmetto extract (SPE) has been widely used for the treatment of lower urinary-tract symptoms secondary to benign prostatic hyperplasia. The mechanisms of pharmacological effects of SPE include the inhibition of 5alpha-reductase, anti-androgenic effects, anti-proliferative effects, and anti-inflammatory effects. Previously, we showed that SPE bound actively to alpha(1)-adrenergic, muscarinic and 1,4-dihydropyridine calcium channel (1,4-DHP) receptors in the prostate and bladder of rats, whereas its active constituents have not been fully clarified. The present investigation is aimed to identify the main active components contained in hexane and diethyl ether extracts of SPE with the use of column chromatography and preparative HPLC. Based on the binding activity with alpha(1)-adrenergic, muscarinic, and 1,4-DHP receptors, both isolated oleic and lauric acids were deduced to be active components. Authentic samples of oleic and lauric acids also exhibited similar binding activities to these receptors as the fatty acids isolated from SPE, consistent with our findings. In addition, oleic and lauric acids inhibited 5alpha-reductase, possibly leading to therapeutic effects against benign prostatic hyperplasia and related lower urinary-tract symptoms.

  17. Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28.

    Science.gov (United States)

    Hulshof, Janneke W; Vischer, Henry F; Verheij, Mark H P; Fratantoni, Silvina A; Smit, Martine J; de Esch, Iwan J P; Leurs, Rob

    2006-11-01

    G-protein coupled receptors encoded by viruses represent an unexplored class of potential drug targets. In this study, we describe the synthesis and pharmacological characterization of the first class of inverse agonists acting on the HCMV-encoded receptor US28. It is shown that replacement of the 4-hydroxy group of lead compound 1 with a methylamine group results in a significant 6-fold increase in affinity. Interestingly, increasing the rigidity of the spacer by the introduction of a double bond also leads to a significant increase in binding affinity compared to 1. These novel inverse agonists serve as valuable tools to elucidate the role of constitutive signaling in the pathogenesis of viral infection and may have therapeutic potential as leads for new antiviral drugs.

  18. Synthesis and pharmacological characterization of a novel nitric oxide-releasing diclofenac derivative containing a benzofuroxan moiety.

    Science.gov (United States)

    de Carvalho, Paulo Sérgio; Maróstica, Marta; Gambero, Alessandra; Pedrazzoli, José

    2010-06-01

    1-oxy-benzo[1,2,5]oxadiazol-5-ylmethyl [2-(2,6-dichloro-phenylamino)-phenyl]-acetate, a new diclofenac derivative bearing a benzofuroxan heterocyclic moiety in its structure, was prepared by the reaction of sodium diclofenac and 5-bromomethyl-benzo[1,2,5]oxadiazole 1-oxide. Pharmacological characterization of this modified diclofenac maintained the anti-inflammatory activity similar to its parent compound assayed in vitro and in vivo. The ulcerogenic properties of native diclofenac were not observed with this modified compound, despite the inhibition of prostaglandin E2 gastric content. The better gastric tolerability seems to be related to nitric oxide release ability. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

  19. Pharmacological characterization of BR-A-657, a highly potent nonpeptide angiotensin II receptor antagonist.

    Science.gov (United States)

    Chi, Yong Ha; Lee, Joo Han; Kim, Je Hak; Tan, Hyun Kwang; Kim, Sang Lin; Lee, Jae Yeol; Rim, Hong-Kun; Paik, Soo Heui; Lee, Kyung-Tae

    2013-01-01

    The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new nonpeptide AT1-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [(125)I][Sar(1)-Ile(8)]angiotensin II (Ang II) from its specific binding sites to AT1 subtype receptors in membrane fractions of HEK-293 cells with an IC50 of 0.16 nM. In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (pD'2: 9.15) with a significant reduction in the maximum. In conscious rats, BR-A-657 (0.01, 0.1, 1 mg/kg; intravenously (i.v.)) dose-dependently antagonized Ang II-induced pressor responses. In addition, BR-A-657 dose-dependently decreased mean arterial pressure in furosemide-treated rats and renal hypertensive rats. Moreover, BR-A-657 given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats.

  20. Pharmacological characterization of the diuretic effect of Hibiscus sabdariffa Linn (Malvaceae) extract.

    Science.gov (United States)

    Alarcón-Alonso, Javier; Zamilpa, Alejandro; Aguilar, Francisco Alarcón; Herrera-Ruiz, Maribel; Tortoriello, Jaime; Jimenez-Ferrer, Enrique

    2012-02-15

    Hibiscus sabdariffa L. (Malvaceae) populary known in Mexico as "Jamaica", "flor de Jamaica", has widely used in Mexican Traditional Medicine as antihypertensive and diuretic, although the latter activity has been reported the present work show evidence about the diuretic, natriuretic and potassium-sparing effects. To evaluate the diuretic activity of Hibiscus sabdariffa aqueous extract on in vivo and in situ models. The Hibiscus sabdariffa aqueous extract was administrated in increasing doses and evaluated the diuresis produced and disposal of electrolytes. Moreover, in isolated kidney was determined the renal filtration rate with plant extract, furosemide and amiloride. The yield of Hibiscus sabdariffa aqueous extraction was 28.3% and the chemical standardization from 1 g of extract was: 56.5 mg delphinidin-3-O-sambubioside, 20.8 mg/g cyanidin-3-O-sambubioside, 3.2 mg/g quercetin, 2.1 mg/g rutin and 2.7 mg/g chlorogenic acid. The diuretic and natriuretic effect of Hibiscus sabdariffa aqueous extract showed a dose-dependent behavior. The pharmacological constants of natriuretic effect was ED50=86 mg/kg and Emax=0.9 mEq/100 g/5 h. In the model of kidney in situ was observed that renal filtration increased 48% with the aqueous extract of Hibiscus sabdariffa and an additive effect when was perfuse with furosemide. The compound presents in Hibiscus sabdariffa as quercetin had effect on the vascular endothelium causing oxide nitric release, increasing renal vasorelaxation by increasing kidney filtration. Therefore, the diuretic effect of Hibiscus sabdariffa may be mediated by nitric oxide release. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  1. Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor.

    Science.gov (United States)

    Armour, S L; Foord, S; Kenakin, T; Chen, W J

    1999-12-01

    Receptor-activity-modifying proteins (RAMPs) are a family of single transmembrane domain proteins shown to be important for the transport and ligand specificity of the calcitonin gene-related peptide (CGRP) receptor. In this report, we describe the analysis of pharmacological properties of the human calcitonin receptor (hCTR) coexpressed with different RAMPs with the use of the Xenopus laevis melanophore expression system. We show that coexpression of RAMP3 with human calcitonin receptor changed the relative potency of hCTR to human calcitonin (hCAL) and rat amylin. RAMP1 and RAMP2, in contrast, had little effect on the change of hCTR potency to hCAL or rat amylin. When coexpressed with RAMP3, hCTR reversed the relative potency by a 3.5-fold loss in sensitivity to hCAL and a 19-fold increase in sensitivity to rat amylin. AC66, an inverse agonist, produced apparent simple competitive antagonism of hCAL and rat amylin, as indicated by linear Schild regressions. The potency of AC66 was changed in the blockade of rat amylin but not hCAL responses with RAMP3 coexpression. The mean pK(B) for AC66 to hCAL was 9.4 +/- 0.3 without RAMP3 and 9.45 +/- 0.07 with RAMP3. For the antagonism of AC66 to rat amylin, the pK(B) was 9.25 +/- 0.15 without RAMP3 and 8.2 +/- 0.35 with RAMP3. The finding suggests that RAMP3 might modify the active states of calcitonin receptor in such a way as to create a new receptor phenotype that is "amylin-like." Irrespective of the physiological association of the new receptor species, the finding that a coexpressed membrane protein can completely change agonist and antagonist affinities for a receptor raises implications for screening in recombinant receptor systems.

  2. Pharmacological characterization of canine melancortin-4 receptor and its natural variant V213F.

    Science.gov (United States)

    Yan, J; Tao, Y-X

    2011-08-01

    Dogs have become one of the most important companion animals in modern society. However, it is estimated that 20% to 40% of owned dogs are obese, suggesting that obesity has become one of the most important canine health problem. In addition, obesity in dogs also leads to type II diabetes. Because the melanocortin-4 receptor (MC4R) has been shown to be essential in maintaining energy homeostasis in several different species, including rodents and humans, we initiated studies toward elucidating the roles of MC4R in obesity pathogenesis in dogs. Canine MC4R has been cloned, and a missense variant V213F was identified. We designed primers and successfully cloned canine MC4R and generated the variant V213F by site-directed mutagenesis. The objective of this study was to investigate the pharmacological properties of canine MC4R and its natural variant V213F. We measured ligand binding and signaling properties with the use of both natural and synthetic ligands. Human MC4R was also included in the experiments for comparison. Both wild-type canine MC4R and its natural variant V213F functioned normally in terms of binding and signaling. Of the ligands we used, [Nle(4), D-Phe(7)]-α-melanocyte-stimulating hormone is the most potent ligand. We conclude that the cloned canine MC4R is a functional receptor, and the natural variant V213F does not have any functional defect and therefore is not likely to cause obesity in dogs. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. 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. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Anti-inflammatory agents of the carbamoylmethyl ester class: synthesis, characterization, and pharmacological evaluation

    Directory of Open Access Journals (Sweden)

    Sadek B

    2013-03-01

    Full Text Available Bassem Sadek,1 Amar Mansuor Hamruoni,2 Abdu Adem1 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, 2Department of Pharmaceutical Sciences, College of Pharmacy, Al Ain University of Science and Technology, Al-Ain, United Arab Emirates Abstract: In this study, target compounds 5–12 were synthesized via acid amine coupling of ibuprofen and naproxen with methyl ester derivatives of amino acids, namely, l-proline, sarcosine, l-tyrosine, and l-glutamic acid. When tested for anti-inflammatory activity using the acute carrageenan-induced hind paw method in rats, compounds 5–12 showed significantly greater anti-inflammatory activity, in the range of 40.64%–87.82%, compared with a placebo control group (P < 0.001. Among the newly synthesized compounds 5–12, naproxen derivatives 9–12 with anti-inflammatory activity ranging between 66.99% and 87.82% showed significantly higher (P < 0.05 potency than ibuprofen derivatives 5–8 with inhibition in the range of 22.03%–52.91% and control groups of ibuprofen (76.34% or naproxen (75.59%, P < 0.05. Moreover, derivatives 9–12 derived from naproxen, in particular compounds 9 and 10 which achieved 83.91% and 87.82% inhibition of inflammation, respectively, showed significantly (P < 0.05 higher potency than naproxen derivatives 11 and 12. Notably, among naproxen derivatives 9–12, the gastric ulcerogenicity for 9 (ulcer index 11.73 and 10 (ulcer index 12.30 was found to be significantly lower (P < 0.05 than that of the active ibuprofen and naproxen control groups with ulcer indices of 22.87 and 24.13, respectively. On the other hand, naproxen derivatives 9–11 showed significant inhibition (P < 0.05 of prostaglandin E2 synthesis when compared with the active control group receiving indomethacin, suggesting a correlation between the observed low ulcerogenicity and effect on prostaglandin E2 synthesis for compounds 9 and 10. However

  5. Crystal habit, characterization and pharmacological activity of various crystal forms of arteether

    Directory of Open Access Journals (Sweden)

    Renu Chadha

    2011-08-01

    Full Text Available The aim of this study was to investigate and characterize different crystal forms of arteether, a rapidly acting, highly potent antimalarial drug for the treatment of acute Plasmodium falciparum malaria. Six different crystal forms were prepared utilizing various polar and non-polar solvents. Scanning electron microscopy (SEM revealed differences in the surface characteristics of the six forms from those of a commercial sample. Differential scanning calorimetry (DSC revealed the absence of a desolvation endotherm indicating that the forms were neither hydrates nor solvates. Powder X-ray diffraction (PXRD patterns of the forms showed much weaker major peaks than in the commercial sample indicating them to be less crystalline. Solubility and dissolution studies showed that the most amorphous form was the most soluble and possessed the highest antimalarial activity.

  6. Pharmacological characterization of NMDA-like receptors in the single-celled organism Paramecium primaurelia.

    Science.gov (United States)

    Ramoino, Paola; Candiani, Simona; Pittaluga, Anna Maria; Usai, Cesare; Gallus, Lorenzo; Ferrando, Sara; Milanese, Marco; Faimali, Marco; Bonanno, Giambattista

    2014-02-01

    Paramecium primaurelia is a unicellular eukaryote that moves in freshwater by ciliary beating and responds to environmental stimuli by altering motile behaviour. The movements of the cilia are controlled by the electrical changes of the cell membrane: when the intraciliary Ca(2+) concentration associated with plasma membrane depolarization increases, the ciliary beating reverses its direction, and consequently the swimming direction changes. The ciliary reversal duration is correlated with the amount of Ca(2+) influx. Here, we evaluated the effects due to the activation or blockade of N-methyl-d-aspartic acid (NMDA) receptors on swimming behaviour in Paramecium. Paramecia normally swim forward, drawing almost linear tracks. We observed that the simultaneous administration of NMDA and glycine induced a partial ciliary reversal (PaCR) leading to a continuous spiral-like swim. Furthermore, the duration of continuous ciliary reversal (CCR), triggered by high external KCl concentrations, was longer in NMDA+glycine-treated cells. NMDA action required the presence of Ca(2+), as the normal forward swimming was restored when the ion was omitted from the extracellular milieu. The PaCR and the enhancement of CCR duration significantly decreased when the antagonists of the glutamate site D-AP5 or CGS19755, the NMDA channel blocker MK-801 or the glycine site antagonist DCKA was added. The action of NMDA+glycine was also abolished by Zn(2+) or ifenprodil, the GluN2A and the GluN2B NMDA-containing subunit blockers, respectively. Searches of the Paramecium genome database currently available indicate that the NMDA-like receptor with ligand-binding characteristics of an NMDA receptor-like complex, purified from rat brain synaptic membranes and found in some metazoan genomes, is also present in Paramecium. These results provide evidence that functional NMDA receptors similar to those typical of mammalian neuronal cells are present in the single-celled organism Paramecium and thus

  7. On characterizing population commonalities and subject variations in brain networks.

    Science.gov (United States)

    Ghanbari, Yasser; Bloy, Luke; Tunc, Birkan; Shankar, Varsha; Roberts, Timothy P L; Edgar, J Christopher; Schultz, Robert T; Verma, Ragini

    2017-05-01

    Brain networks based on resting state connectivity as well as inter-regional anatomical pathways obtained using diffusion imaging have provided insight into pathology and development. Such work has underscored the need for methods that can extract sub-networks that can accurately capture the connectivity patterns of the underlying population while simultaneously describing the variation of sub-networks at the subject level. We have designed a multi-layer graph clustering method that extracts clusters of nodes, called 'network hubs', which display higher levels of connectivity within the cluster than to the rest of the brain. The method determines an atlas of network hubs that describes the population, as well as weights that characterize subject-wise variation in terms of within- and between-hub connectivity. This lowers the dimensionality of brain networks, thereby providing a representation amenable to statistical analyses. The applicability of the proposed technique is demonstrated by extracting an atlas of network hubs for a population of typically developing controls (TDCs) as well as children with autism spectrum disorder (ASD), and using the structural and functional networks of a population to determine the subject-level variation of these hubs and their inter-connectivity. These hubs are then used to compare ASD and TDCs. Our method is generalizable to any population whose connectivity (structural or functional) can be captured via non-negative network graphs. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Pharmacological characterization of memoquin, a multi-target compound for the treatment of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Valeria Capurro

    Full Text Available Alzheimer's disease (AD is characterized by progressive loss of cognitive function, dementia and altered behavior. Over 30 million people worldwide suffer from AD and available therapies are still palliative rather than curative. Recently, Memoquin (MQ, a quinone-bearing polyamine compound, has emerged as a promising anti-AD lead candidate, mainly thanks to its multi-target profile. MQ acts as an acetylcholinesterase and β-secretase-1 inhibitor, and also possesses anti-amyloid and anti-oxidant properties. Despite this potential interest, in vivo behavioral studies with MQ have been limited. Here, we report on in vivo studies with MQ (acute and sub-chronic treatments; 7-15 mg/kg per os carried out using two different mouse models: i scopolamine- and ii beta-amyloid peptide- (Aβ- induced amnesia. Several aspects related to memory were examined using the T-maze, the Morris water maze, the novel object recognition, and the passive avoidance tasks. At the dose of 15 mg/kg, MQ was able to rescue all tested aspects of cognitive impairment including spatial, episodic, aversive, short and long-term memory in both scopolamine- and Aβ-induced amnesia models. Furthermore, when tested in primary cortical neurons, MQ was able to fully prevent the Aβ-induced neurotoxicity mediated by oxidative stress. The results support the effectiveness of MQ as a cognitive enhancer, and highlight the value of a multi-target strategy to address the complex nature of cognitive dysfunction in AD.

  9. Pharmacological characterization of memoquin, a multi-target compound for the treatment of Alzheimer's disease.

    Science.gov (United States)

    Capurro, Valeria; Busquet, Perrine; Lopes, Joao Pedro; Bertorelli, Rosalia; Tarozzo, Glauco; Bolognesi, Maria Laura; Piomelli, Daniele; Reggiani, Angelo; Cavalli, Andrea

    2013-01-01

    Alzheimer's disease (AD) is characterized by progressive loss of cognitive function, dementia and altered behavior. Over 30 million people worldwide suffer from AD and available therapies are still palliative rather than curative. Recently, Memoquin (MQ), a quinone-bearing polyamine compound, has emerged as a promising anti-AD lead candidate, mainly thanks to its multi-target profile. MQ acts as an acetylcholinesterase and β-secretase-1 inhibitor, and also possesses anti-amyloid and anti-oxidant properties. Despite this potential interest, in vivo behavioral studies with MQ have been limited. Here, we report on in vivo studies with MQ (acute and sub-chronic treatments; 7-15 mg/kg per os) carried out using two different mouse models: i) scopolamine- and ii) beta-amyloid peptide- (Aβ-) induced amnesia. Several aspects related to memory were examined using the T-maze, the Morris water maze, the novel object recognition, and the passive avoidance tasks. At the dose of 15 mg/kg, MQ was able to rescue all tested aspects of cognitive impairment including spatial, episodic, aversive, short and long-term memory in both scopolamine- and Aβ-induced amnesia models. Furthermore, when tested in primary cortical neurons, MQ was able to fully prevent the Aβ-induced neurotoxicity mediated by oxidative stress. The results support the effectiveness of MQ as a cognitive enhancer, and highlight the value of a multi-target strategy to address the complex nature of cognitive dysfunction in AD.

  10. All-Optical Electrophysiology for Disease Modeling and Pharmacological Characterization of Neurons.

    Science.gov (United States)

    Werley, Christopher A; Brookings, Ted; Upadhyay, Hansini; Williams, Luis A; McManus, Owen B; Dempsey, Graham T

    2017-09-11

    A key challenge for establishing a phenotypic screen for neuronal excitability is measurement of membrane potential changes with high throughput and accuracy. Most approaches for probing excitability rely on low-throughput, invasive methods or lack cell-specific information. These limitations stimulated the development of novel strategies for characterizing the electrical properties of cultured neurons. Among these was the development of optogenetic technologies (Optopatch) that allow for stimulation and recording of membrane voltage signals from cultured neurons with single-cell sensitivity and millisecond temporal resolution. Neuronal activity is elicited using blue light activation of the channelrhodopsin variant 'CheRiff'. Action potentials and synaptic signals are measured with 'QuasAr', a rapid and sensitive voltage-indicating protein with near-infrared fluorescence that scales proportionately with transmembrane potential. This integrated technology of optical stimulation and recording of electrical signals enables investigation of neuronal electrical function with unprecedented scale and precision. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

  11. Pharmacologic modulation of cerebral metabolic derangement and excitotoxicity in a porcine model of traumatic brain injury and hemorrhagic shock

    DEFF Research Database (Denmark)

    Hwabejire, John O; Jin, Guang; Imam, Ayesha M

    2013-01-01

    Cerebral metabolic derangement and excitotoxicity play critical roles in the evolution of traumatic brain injury (TBI). We have shown previously that treatment with large doses of valproic acid (VPA) decreases the size of brain lesion. The goal of this experiment was to determine whether...

  12. An improved human anxiety process biomarker: characterization of frequency band, personality and pharmacology

    Science.gov (United States)

    Shadli, S M; Glue, P; McIntosh, J; McNaughton, N

    2015-01-01

    Anxiety disorders are among the most common mental illness in the western world with a major impact on disability. But their diagnosis has lacked objective biomarkers. We previously demonstrated a human anxiety process biomarker, goal-conflict-specific electroencephalography (EEG) rhythmicity (GCSR) in the stop-signal task (SST). Here we have developed and characterized an improved test appropriate for clinical group testing. We modified the SST to produce balanced numbers of trials in clearly separated stop-signal delay groups. As previously, right frontal (F8) GCSR was extracted as the difference in EEG log Fourier power between matching stop and go trials (that is, stop-signal-specific power) of a quadratic contrast of the three delay values (that is, power when stopping and going are in balanced conflict compared with the average of when stopping or going is greater). Separate experiments assessed drug sensitivity (n=34) and personality relations (n=59). GCSR in this new SST was reduced by three chemically distinct anxiolytic drugs (administered double-blind): buspirone (10 mg), triazolam (0.25 mg) and pregabalin (75 mg); had a frequency range (4–12 Hz) consistent with rodent model data; and positively correlated significantly with neuroticism and nonsignificantly with trait anxiety scores. GCSR, measured in our new form of the SST, should be suitable as a biomarker for one specific anxiety process in the testing of clinical groups and novel drugs and in the development of measures suitable for individual diagnosis. PMID:26670284

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

    International Nuclear Information System (INIS)

    Takao, T.; Tracey, D.E.; Mitchell, W.M.; De Souza, E.B.

    1990-01-01

    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

  14. 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

  15. Physiological and pharmacological characterization of transmembrane acid extruders in cultured human umbilical artery smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Gunng-Shinng Chen

    2015-01-01

    Full Text Available Background: Intracellular pH (pH i is a pivotal factor for cellular functions and homeostasis. Apart from passive intracellular buffering capacity, active transmembrane transporters responsible for kinetic changes of pH i impacts. Acid extrusion transporters such as Na + /H + exchanger (NHE and Na + /HCO3− cotransporter (NBC have been found to be activated when cells are in an acidic condition in different cell types. However, such far, the pH i regulators have not been characterized in human umbilical artery smooth muscle cells (HUASMCs. Materials and Methods: We, therefore, investigated the mechanism of pH i recovery from intracellular acidosis, induced by NH 4 Cl-prepulse, using pH-sensitive fluorescence dye: 2′,7′-bis(2-carboxethyl-5(6-carboxy-fluorescein in HUASMCs. Cultured HUASMCs were derived from the segments of the human umbilical artery that were obtained from women undergoing children delivery. Results: The resting pH i is 7.23 ± 0.03 when cells in HEPES (nominally HCO 3− -free buffered solution. The resting pH i is higher as 7.27 ± 0.03 when cells in CO 2 /HCO3− -buffered solution. In HEPES-buffered solution, a pH i recovery following induced intracellular acidosis could be inhibited completely by 30 μM HOE 694 (a specific NHE inhibitor or by removing [Na +]o . In 5% CO2/HCO3− -buffered solution, 30 μM HOE 694 slowed the pH i recovery from the induced intracellular acidosis only. On the contrary, HOE 694 adding together with 0.2 mM 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid (a specific NBC inhibitor or removal of [Na +]o entirely blocked the acid extrusion. By using Western blot technique, we demonstrated that four different isoforms of NBC, that is, SLC4A8 (NBCBE, SLC4A7 (NBCn1, SLC4A5 (NBCe2 and SLC4A4 (NBCe1, co-exist in the HUASMCs. Conclusions: We demonstrate, for the 1 st time, that apart from the housekeeping NHE1, another Na + couple HCO3− -transporter, that is, NBC, functionally coexists to

  16. Biophysical and Pharmacological Characterization of Nav1.9 Voltage Dependent Sodium Channels Stably Expressed in HEK-293 Cells.

    Directory of Open Access Journals (Sweden)

    Zhixin Lin

    Full Text Available The voltage dependent sodium channel Nav1.9, is expressed preferentially in peripheral sensory neurons and has been linked to human genetic pain disorders, which makes it target of interest for the development of new pain therapeutics. However, characterization of Nav1.9 pharmacology has been limited due in part to the historical difficulty of functionally expressing recombinant channels. Here we report the successful generation and characterization of human, mouse and rat Nav1.9 stably expressed in human HEK-293 cells. These cells exhibit slowly activating and inactivating inward sodium channel currents that have characteristics of native Nav1.9. Optimal functional expression was achieved by coexpression of Nav1.9 with β1/β2 subunits. While recombinantly expressed Nav1.9 was found to be sensitive to sodium channel inhibitors TC-N 1752 and tetracaine, potency was up to 100-fold less than reported for other Nav channel subtypes despite evidence to support an interaction with the canonical local anesthetic (LA binding region on Domain 4 S6. Nav1.9 Domain 2 S6 pore domain contains a unique lysine residue (K799 which is predicted to be spatially near the local anesthetic interaction site. Mutation of this residue to the consensus asparagine (K799N resulted in an increase in potency for tetracaine, but a decrease for TC-N 1752, suggesting that this residue can influence interaction of inhibitors with the Nav1.9 pore. In summary, we have shown that stable functional expression of Nav1.9 in the widely used HEK-293 cells is possible, which opens up opportunities to better understand channel properties and may potentially aid identification of novel Nav1.9 based pharmacotherapies.

  17. [Establishment pharmacological research platform for "Concurrent treatment of the brain and heart" and its application on dissecting mechanism of Danhong injection].

    Science.gov (United States)

    Zhao, Xiao-Ping; Yu, Yun-Ru; Li, Xue; Shao, Qing; Wang, Yi-Min; Zhao, Tao; Zhao, Chao; Zhao, Bu-Chang; Wang, Yue-Fei; Wang, Yi

    2017-12-01

    The Concurrent treatment of the brain and heart (CTBH) theory is proposed based on traditional Chinese medical theory and clinical practice. In this study, a framework for the pharmacological research platform was established to investigate the principles of concurrent treatment of the brain and heart. The platform for CTBH includes several key techniques for network modeling, discovery of active substances, dissecting mechanism of action and investigation of pharmacokinetic property of TCM. Taking network modeling of CTBH as an example, using database search, literature mining, network construction and module analysis, the that network modules closely associated with the pathological progress of cardiovascular and cerebrovascular diseases were identified, while further functional enrichment analysis of these modules indicated that the key biological processes included oxidative stress, metabolism and inflammation. GSK3B, NOTCH1, CDK4 were identified as key nodes in these network modules. The above-mentioned platform was applied to construct component-biomolecules network of Danhong injection for the identification of common targets and pathways. Among them, GSK3B had the highest correlation with the composition of Danhong injection in the network, and the biological function of whose cluster was related to cell oxidative stress. Based upon results of network analysis, validation experiments suggested that Danhong injection significantly improved the survival rate of oxidative injured myocardial cells and nerve cells, and the protective effect was related to the increase of phosphorylated GSK3β protein expression. Moreover, extracts of Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos exerted the synergisticcytoprotective effect. The results indicated that the mechanism of treatment of cardiovascular and cerebrovascular diseases of Danhong injection could be studied through network modeling and other methods. In summary, the proposed pharmacological

  18. 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.

  19. Pharmaceutical design and pharmacological characterization of Tc99m [99mTc] labelled somatostatin and gastrin analogues

    International Nuclear Information System (INIS)

    Guggenberg, E. von

    2004-10-01

    The development of regulatory peptide analogues radiolabelled with 99m Tc is of great interest for nuclear medicine applications, as 99m Tc shows very favourable imaging characteristics, such as low radiation burden to the patient, optimal image quality in SPECT, one-day-acquisition-protocol, availability on demand and cost effectiveness. In this work the principles of pharmaceutical design and preclinical pharmacological characterization of regulatory peptide analogues labelled with 99m Tc with possible application in tumour diagnosis are described. [ 99m Tc-EDDA-HYNIC0,Tyr3]octreotide ( 99m Tc-EDDA-HYNIC-TOC) is a promising new radiopharmaceutical with the potential to replace [ 111 In-DTPA0]octreotide in receptor scintigraphy of somatostatin receptor-positive tumours. Radiolabelling at high labelling yields and high specific activities could be obtained applying a coligand exchange labelling approach from tricine for EDDA under optimized conditions of pH, EDDA and stannous ion concentration. The resulting complex was characterized via HPLC, receptor binding and LC-MS. For the development of a freeze-dried kit formulation with long shelf-life, high stability of the final preparation and retained biological activity, the addition of bulking agent, the pH of the freeze-drying solution and the content of stannous chloride were of major importance. Different methods of radiochemical purity testing were evaluated to guarantee high quality of the preparation in a clinical setting, forming the basis for a further clinical evaluation of this promising new radiopharmaceutical. Radiolabelling of [D-Glu1]minigastrin (MG) with 99m Tc was studied applying two different labelling approaches. HYNIC-MG could be labelled using tricine and EDDA as coligands; and (Nalpha-His)Ac-MG was used as tridentate ligand for the 99m Tc carbonyl core. Stability experiments by HPLC analysis in PBS, serum, histidine- and cysteine-solutions as well as rat liver and kidney homogenates, receptor

  20. Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer's disease.

    Science.gov (United States)

    Huang, Xiao-Tian; Qian, Zhong-Ming; He, Xuan; Gong, Qi; Wu, Ka-Chun; Jiang, Li-Rong; Lu, Li-Na; Zhu, Zhou-Jing; Zhang, Hai-Yan; Yung, Wing-Ho; Ke, Ya

    2014-05-01

    Huperzine A (HupA), a natural inhibitor of acetylcholinesterase derived from a plant, is a licensed anti-Alzheimer's disease (AD) drug in China and a nutraceutical in the United States. In addition to acting as an acetylcholinesterase inhibitor, HupA possesses neuroprotective properties. However, the relevant mechanism is unknown. Here, we showed that the neuroprotective effect of HupA was derived from a novel action on brain iron regulation. HupA treatment reduced insoluble and soluble beta amyloid levels, ameliorated amyloid plaques formation, and hyperphosphorylated tau in the cortex and hippocampus of APPswe/PS1dE9 transgenic AD mice. Also, HupA decreased beta amyloid oligomers and amyloid precursor protein levels, and increased A Disintegrin And Metalloprotease Domain 10 (ADAM10) expression in these treated AD mice. However, these beneficial effects of HupA were largely abolished by feeding the animals with a high iron diet. In parallel, we found that HupA decreased iron content in the brain and demonstrated that HupA also has a role to reduce the expression of transferrin-receptor 1 as well as the transferrin-bound iron uptake in cultured neurons. The findings implied that reducing iron in the brain is a novel mechanism of HupA in the treatment of Alzheimer's disease. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. 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

    2014-10-03

    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. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Gamma-aminobutyric acid esters. 1. Synthesis, brain uptake, and pharmacological studies of aliphatic and steroid esters of gamma-aminobutyric acid

    International Nuclear Information System (INIS)

    Shashoua, V.E.; Jacob, J.N.; Ridge, R.; Campbell, A.; Baldessarini, R.J.

    1984-01-01

    Labeled and unlabeled aliphatic and steroid esters of gamma-amino[U- 14 C]butyric acid (GABA) were synthesized and tested for their capacity to penetrate the blood-brain barrier and for evidence of central neuropharmacological activity in rodents. The uptake of the labeled 9,12,15-octadecatrienyl (linolenyl), 3-cholesteryl, 1-butyl, and the 9-fluoro-11 beta,17-dihydroxy-16 alpha-methyl-3,20-dioxopregna -1,4-dien-21-yl (dexamethasone) esters of GABA into mouse brain increased 2-, 25-, 74-, and 81-fold over GABA, respectively. The cholesteryl ester of GABA depressed the general motor activity of mice and rats in a dose-dependent manner, whereas the 1-butyl, linolenyl, and dexamethasone esters were inactive by this test. Studies of the rates of hydrolysis, GABA receptor binding capacity, and octanol/water partition coefficients indicated that pharmacological activity of the esters after entry into the central nervous system (CNS) was dependent on their capacity to release GABA by enzymatic hydrolysis and their lipid solubility

  3. Characterization and localization of 3H-arginine8-vasopressin binding to rat kidney and brain tissue

    International Nuclear Information System (INIS)

    Dorsa, D.M.; Majumdar, L.A.; Petracca, F.M.; Baskin, D.G.; Cornett, L.E.

    1983-01-01

    Anatomic, behavioral and pharmacologic evidence suggests that arginine8-vasopressin (AVP) serves as a CNS neurotransmitter or neuromodulator. AVP binding to membrane and tissue slice preparations from brain and kidney was characterized, and the anatomical distribution of these binding sites was examined. Conditions for the binding assay were optimized using kidney medullary tissue. Binding of 3 H-AVP (S.A. . 30-51 Ci/mmol, NEN) to brain and kidney membranes and tissue slices was saturable, temperature dependent, linearly related to protein concentration (or number of tissue slices), reversible, and specific since the ability of cold AVP to displace 3 H-AVP from binding was greater than oxytocin and other related peptide fragments. Autoradiographic localization of 3 H-AVP binding was restricted to kidney medullary tissue. In brain tissue, 3 H-AVP binding was found to occur in concentrated foci. Brainstem areas such as the nucleus tractus solitarius (NTS) showed a high density of AVP binding sites. Since local injections of AVP into the NTS have been shown to influence blood pressure, the present study presents the first anatomical evidence for the presence of AVP specific binding sites which might mediate this effect

  4. In vitro pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107.

    Science.gov (United States)

    Malysz, John; Anderson, David J; Grønlien, Jens H; Ji, Jianguo; Bunnelle, William H; Håkerud, Monika; Thorin-Hagene, Kirten; Ween, Hilde; Helfrich, Rosalind; Hu, Min; Gubbins, Earl; Gopalakrishnan, Sujatha; Puttfarcken, Pamela S; Briggs, Clark A; Li, Jinhe; Meyer, Michael D; Dyhring, Tino; Ahring, Philip K; Nielsen, Elsebet Ø; Peters, Dan; Timmermann, Daniel B; Gopalakrishnan, Murali

    2010-09-01

    cortical cultures against glutamate-induced toxicity. In summary, ABT-107 is a selective high affinity alpha7 nAChR agonist suitable for characterizing the roles of this subtype in pharmacological studies.

  5. 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. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Anesthetic pharmacology

    National Research Council Canada - National Science Library

    Evers, Alex S; Maze, M; Kharasch, Evan D

    2011-01-01

    ...: Section 1 introduces the principles of drug action, Section 2 presents the molecular, cellular and integrated physiology of the target organ/functional system and Section 3 reviews the pharmacology...

  7. Characterizing Motif Dynamics of Electric Brain Activity Using Symbolic Analysis

    Directory of Open Access Journals (Sweden)

    Massimiliano Zanin

    2014-10-01

    Full Text Available Motifs are small recurring circuits of interactions which constitute the backbone of networked systems. Characterizing motif dynamics is therefore key to understanding the functioning of such systems. Here we propose a method to define and quantify the temporal variability and time scales of electroencephalogram (EEG motifs of resting brain activity. Given a triplet of EEG sensors, links between them are calculated by means of linear correlation; each pattern of links (i.e., each motif is then associated to a symbol, and its appearance frequency is analyzed by means of Shannon entropy. Our results show that each motif becomes observable with different coupling thresholds and evolves at its own time scale, with fronto-temporal sensors emerging at high thresholds and changing at fast time scales, and parietal ones at low thresholds and changing at slower rates. Finally, while motif dynamics differed across individuals, for each subject, it showed robustness across experimental conditions, indicating that it could represent an individual dynamical signature.

  8. 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

    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...... (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...

  9. Reduced ethanol consumption by alcohol-preferring (P) rats following pharmacological silencing and deep brain stimulation of the nucleus accumbens shell.

    Science.gov (United States)

    Wilden, Jessica A; Qing, Kurt Y; Hauser, Sheketha R; McBride, William J; Irazoqui, Pedro P; Rodd, Zachary A

    2014-04-01

    There is increasing interest in deep brain stimulation (DBS) for the treatment of addiction. Initial testing must be conducted in animals, and the alcohol-preferring (P) rat meets the criteria for an animal model of alcoholism. This study is composed of 2 experiments designed to examine the effects of 1) pharmacological inactivation and 2) DBS of the nucleus accumbens shell (AcbSh) on the consumption of alcohol by P rats. In the first experiment, the effects of reversible inactivation of the AcbSh were investigated by administering intracranial injections of γ-aminobutyric acid (GABA) agonists. Bilateral microinjections of drug were administered to the AcbSh in P rats (8-10 rats/group), after which the animals were placed in operant chambers containing 2 levers--one used to administer water and the other to administer 15% EtOH--to examine the acquisition and maintenance of oral EtOH self-administration. In the second experiment, a DBS electrode was placed in each P rat's left AcbSh. The animals then received 100 or 200 μA (3-4 rats/group) of DBS to examine the effect on daily consumption of oral EtOH in a free-access paradigm. In the first experiment, pharmacological silencing of the AcbSh with GABA agonists did not decrease the acquisition of EtOH drinking behavior but did reduce EtOH consumption by 55% in chronically drinking rats. Similarly, in the second experiment, 200 μA of DBS consistently reduced EtOH intake by 47% in chronically drinking rats. The amount of EtOH consumption returned to baseline levels following termination of therapy in both experiments. Pharmacological silencing and DBS of the AcbSh reduced EtOH intake after chronic EtOH use had been established in rodents. The AcbSh is a neuroanatomical substrate for the reinforcing effects of alcohol and may be a target for surgical intervention in cases of alcoholism.

  10. CNS-syndrome. Characterization of rat brain intermediate filaments

    International Nuclear Information System (INIS)

    Nedzvetskij, V.S.; Busygina, S.G.; Berezin, V.A.; Dvoretskij, A.I.

    1990-01-01

    A study was made of the effect of ionizing radiation on the content and polypeptide composition of filamentous and soluble glial fibrillary acidic protein (GFAP) in different regions of rat brain. Ionizing radiation was shown to decrease considerably the level of soluble GFAP in cerebral cortex, cerebellum, middle brain and hippocampus. Polypeptide composition of soluble GFAP detected by the immonublot-method was found to be changed considerably in different brain areas of irradiated animals

  11. Non-pharmacological interventions for perceptual disorders following stroke and other adult-acquired, non-progressive brain injury.

    Science.gov (United States)

    Bowen, Audrey; Knapp, Peter; Gillespie, David; Nicolson, Donald J; Vail, Andy

    2011-04-13

    Stroke and other adult-acquired brain injury may impair perception leading to distress and increased dependence on others. Perceptual rehabilitation includes functional training, sensory stimulation, strategy training and task repetition. To examine the evidence for improvement in activities of daily living (ADL) six months post randomisation for active intervention versus placebo or no treatment. We searched the trials registers of the Cochrane Stroke Group and the Cochrane Infectious Diseases Group (May 2009) but not the Injuries Group, the Cochrane Central Register of Controlled Trials (The Cochrane Library 2009, Issue 3), MEDLINE (1950 to August 2009), EMBASE (1980 to August 2009), CINAHL (1982 to August 2009), PsycINFO (1974 to August 2009), REHABDATA and PsycBITE (May to June 2009). We also searched trials and research registers, handsearched journals, searched reference lists and contacted authors. Randomised controlled trials of adult stroke or acquired brain injury. Our definition of perception excluded visual field deficits, neglect/inattention and apraxia. One review author assessed titles, abstracts and keywords for eligibility. At least two review authors independently extracted data. We requested unclear or missing information from corresponding authors. We included six single-site trials in rehabilitation settings, involving 338 participants. Four trials included people with only stroke. All studies provided sensory stimulation, sometimes with another intervention. Sensory stimulation typically involved practising tasks that required visuo-perceptual processing with occupational therapist assistance. Repetition was never used and only one study included functional training. No trials provided data on longer term improvement in ADL scores. Only three trials provided any data suitable for analysis. Two of these trials compared active to placebo intervention. There was no evidence of a difference in ADL scores at the scheduled end of intervention: mean

  12. 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.

  13. Biochemical and Pharmacological Characterizations of ESI-09 Based EPAC Inhibitors: Defining the ESI-09 “Therapeutic Window”

    OpenAIRE

    Yingmin Zhu; Haijun Chen; Stephen Boulton; Fang Mei; Na Ye; Giuseppe Melacini; Jia Zhou; Xiaodong Cheng

    2015-01-01

    The cAMP signaling cascade is one of the most frequently targeted pathways for the development of pharmaceutics. A plethora of recent genetic and pharmacological studies suggest that exchange proteins directly activated by cAMP (EPACs) are implicated in multiple pathologies. Selective EPAC inhibitors have been recently developed. One specific inhibitor, ESI-09, has been shown to block EPAC activity and functions, as well as to recapitulate genetic phenotypes of EPAC knockout mice when applied...

  14. Characterization of Cancer Stem Cells in Patients with Brain ...

    African Journals Online (AJOL)

    Background: Gliomas, in general, and astrocytomas, in particular, represent the most frequent primary brain tumors. Nowadays, it is increasingly believed that gliomas may arise from cancer stem cells, which share several characteristics with normal neural stem cells. Brain tumor stem cells have been found to express a ...

  15. 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.

  16. 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.

  17. 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

  18. 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 i...... for Cygb and involvement in sleep-wake cycling for Cygb and Ngb....

  19. 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

  20. Immunochemical characterization of the brain glutamate binding protein

    International Nuclear Information System (INIS)

    Roy, S.

    1986-01-01

    A glutamate binding protein (GBP) was purified from bovine and rat brain to near homogeneity. Polyclonal antibodies were raised against this protein. An enzyme-linked-immunosorbent-assay was used to quantify and determine the specificity of the antibody response. The antibodies were shown to strongly react with bovine brain GBP and the analogous protein from rat brain. The antibodies did not show any crossreactivity with the glutamate metabolizing enzymes, glutamate dehydrogenase, glutamine synthetase and glutamyl transpeptidase, however it crossreacted moderately with glutamate decarboxylase. The antibodies were also used to define the possible physiologic activity of GBP in synaptic membranes. The antibodies were shown: (i) to inhibit the excitatory amino-acid stimulation of thiocyanate (SCN)flux, (ii) had no effect on transport of L-Glutamic acid across the synaptic membrane, and (iii) had no effect on the depolarization-induced release of L-glutamate. When the anti-GBP antibodies were used to localize and quantify the GBP distribution in various subcellular fractions and in brain tissue samples, it was found that the hippocampus had the highest immunoreactivity followed by the cerebral cortex, cerebellar cortex and caudate-putamen. The distribution of immunoreactivity in the subcellular fraction were as follows: synaptic membranes > crude mitochondrial fraction > homogenate > myelin. In conclusion these studies suggest that: (a) the rat brain GBP and the bovine brain GBP are immunologically homologous protein, (b) there are no structural similarities between the GBP and the glutamate metabolizing enzymes with the exception of glutamate decarboxylase and (c) the subcellular and regional distribution of the GBP immunoreactivity followed a similar pattern as observed for L-[ 3 H]-binding

  1. Characterization of [3H] oxymorphone binding sites in mouse brain

    DEFF Research Database (Denmark)

    Yoo, Ji Hoon; Borsodi, Anna; Tóth, Géza

    2017-01-01

    Oxymorphone, one of oxycodone's metabolic products, is a potent opioid receptor agonist which is thought to contribute to the analgesic effect of its parent compound and may have high potential abuse liability. Nonetheless, the in vivo pharmacological binding profile of this drug is still unclear....... This study uses mice lacking mu (MOP), kappa (KOP) or delta (DOP) opioid receptors as well as mice lacking all three opioid receptors to provide full characterisation of oxymorphone binding sites in the brain. Saturation binding studies using [3H]oxymorphone revealed high affinity binding sites in mouse......]Oxymorphone binding was completely abolished across the majority of the brain regions in mice lacking MOP as well as in mice lacking all three opioid receptors. DOP and KOP knockout mice retained [3H]oxymorphone binding sites suggesting oxymorphone may not target DOP or KOP. These results confirm that the MOP...

  2. Iomazenil: pharmacological and animal data

    International Nuclear Information System (INIS)

    Beer, H.F.; Blaeuenstein, P.A.; Hasler, P.H.; Schubiger, P.A.; Hunkeler, W.; Bibettu, E.P.; Pieri, L.; Grayson Richards, J.

    1990-01-01

    The flumazenil analogue Ro 16-0154 (Iomazenil), a benzodiazepine partial inverse agonist, has been labelled by halogen exchange to enable SPECT investigations of central benzodiazepine receptors in human brain. The purified 123 I-Ro 16-0154 was found to be stable in rat brain preparations and to be metabolized in rat liver preparations. Its pharmacological properties were comparable to those of flumazenil with the exception of the antagonism of diazepam versus pentylenetetrazol. Biodistribution in rats (1 h p.i.) resulted in a high brain to blood ratio of 16. Clinical studies revealed images of the bezodiazepine receptor density in the brain. (author) 9 figs., 3 tabs., 27 refs

  3. Pharmacological characterization of lipidized analogs of prolactin-releasing peptide with a modified C-terminal aromatic ring

    Czech Academy of Sciences Publication Activity Database

    Pražienková, Veronika; Tichá, Anežka; Blechová, Miroslava; Špolcová, Andrea; Železná, Blanka; Maletínská, Lenka

    2016-01-01

    Roč. 67, č. 1 (2016), s. 121-128 ISSN 0867-5910 R&D Projects: GA ČR(CZ) GA15-08679S Institutional support: RVO:61388963 Keywords : prolactin-releasing peptide * blood-brain barrier * food intake * lipidization * phenylalanine derivatives Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 2.883, year: 2016 http://www.jpp.krakow.pl/journal/archive/02_16/articles/11_article.html

  4. Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation

    Directory of Open Access Journals (Sweden)

    Yuming Wang

    2016-03-01

    Full Text Available Cockayne syndrome (CS is a severe neurodevelopmental disorder characterized by growth abnormalities, premature aging, and photosensitivity. Mutation of Cockayne syndrome B (CSB affects neuronal gene expression and differentiation, so we attempted to bypass its function by expressing downstream target genes. Intriguingly, ectopic expression of Synaptotagmin 9 (SYT9, a key component of the machinery controlling neurotrophin release, bypasses the need for CSB in neuritogenesis. Importantly, brain-derived neurotrophic factor (BDNF, a neurotrophin implicated in neuronal differentiation and synaptic modulation, and pharmacological mimics such as 7,8-dihydroxyflavone and amitriptyline can compensate for CSB deficiency in cell models of neuronal differentiation as well. SYT9 and BDNF are downregulated in CS patient brain tissue, further indicating that sub-optimal neurotrophin signaling underlies neurological defects in CS. In addition to shedding light on cellular mechanisms underlying CS and pointing to future avenues for pharmacological intervention, these data suggest an important role for SYT9 in neuronal differentiation.

  5. Characterizing Resting-State Brain Function Using Arterial Spin Labeling

    Science.gov (United States)

    Jann, Kay; Wang, Danny J.J.

    2015-01-01

    Abstract Arterial spin labeling (ASL) is an increasingly established magnetic resonance imaging (MRI) technique that is finding broader applications in studying the healthy and diseased brain. This review addresses the use of ASL to assess brain function in the resting state. Following a brief technical description, we discuss the use of ASL in the following main categories: (1) resting-state functional connectivity (FC) measurement: the use of ASL-based cerebral blood flow (CBF) measurements as an alternative to the blood oxygen level-dependent (BOLD) technique to assess resting-state FC; (2) the link between network CBF and FC measurements: the use of network CBF as a surrogate of the metabolic activity within corresponding networks; and (3) the study of resting-state dynamic CBF-BOLD coupling and cerebral metabolism: the use of dynamic CBF information obtained using ASL to assess dynamic CBF-BOLD coupling and oxidative metabolism in the resting state. In addition, we summarize some future challenges and interesting research directions for ASL, including slice-accelerated (multiband) imaging as well as the effects of motion and other physiological confounds on perfusion-based FC measurement. In summary, this work reviews the state-of-the-art of ASL and establishes it as an increasingly viable MRI technique with high translational value in studying resting-state brain function. PMID:26106930

  6. [Pharmacological treatment].

    Science.gov (United States)

    Arriola Manchola, Enrique; Álaba Trueba, Javier

    2016-06-01

    Alzheimer's disease (AD) is a chronic degenerative and inflammatory process leading to synapticdysfunction and neuronal death. A review about the pharmacological treatment alternatives is made: acetylcholinesterase inhibitors (AChEI), a nutritional supplement (Souvenaid) and Ginkgo biloba. A special emphasis on Ginkgo biloba due to the controversy about its use and the approval by the European Medicines Agency is made. Copyright © 2016 Sociedad Española de Geriatría y Gerontología. Publicado por Elsevier España, S.L.U. All rights reserved.

  7. Characterization of glioma stem cells through multiple stem cell markers and their specific sensitization to double-strand break-inducing agents by pharmacological inhibition of ataxia telangiectasia mutated protein.

    Science.gov (United States)

    Raso, Alessandro; Vecchio, Donatella; Cappelli, Enrico; Ropolo, Monica; Poggi, Alessandro; Nozza, Paolo; Biassoni, Roberto; Mascelli, Samantha; Capra, Valeria; Kalfas, Fotios; Severi, Paolo; Frosina, Guido

    2012-09-01

    Previous studies have shown that tumor-driving glioma stem cells (GSC) may promote radio-resistance by constitutive activation of the DNA damage response started by the ataxia telangiectasia mutated (ATM) protein. We have investigated whether GSC may be specifically sensitized to ionizing radiation by inhibiting the DNA damage response. Two grade IV glioma cell lines (BORRU and DR177) were characterized for a number of immunocytochemical, karyotypic, proliferative and differentiative parameters. In particular, the expression of a panel of nine stem cell markers was quantified by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry. Overall, BORRU and DR177 displayed pronounced and poor stem phenotypes, respectively. In order to improve the therapeutic efficacy of radiation on GSC, the cells were preincubated with a nontoxic concentration of the ATM inhibitors KU-55933 and KU-60019 and then irradiated. BORRU cells were sensitized to radiation and radio-mimetic chemicals by ATM inhibitors whereas DR177 were protected under the same conditions. No sensitization was observed after cell differentiation or to drugs unable to induce double-strand breaks (DSB), indicating that ATM inhibitors specifically sensitize glioma cells possessing stem phenotype to DSB-inducing agents. In conclusion, pharmacological inhibition of ATM may specifically sensitize GSC to DSB-inducing agents while sparing nonstem cells. © 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.

  8. 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

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

    International Nuclear Information System (INIS)

    Zeng Zhizhen; O'Brien, Julie A.; Lemaire, Wei; O'Malley, Stacey S.; Miller, Patricia J.; Zhao Zhijian; Wallace, Michael A.; Raab, Conrad; Lindsley, Craig W.; Sur, Cyrille; Williams, David L.

    2008-01-01

    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 [ 35 S](S)-2-amino-4-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl) ethyl)benzamide ([ 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 [ 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 d =1.9 nM), selective, GlyT1 inhibitor that, when radiolabeled with [ 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 [ 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 positron emission

  10. Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone

    Directory of Open Access Journals (Sweden)

    Sergio Perez-Alvarez

    2012-01-01

    Full Text Available Previously, we have shown that SH-SY5Y cells exposed to high concentrations of methadone died due to a necrotic-like cell death mechanism related to delayed calcium deregulation (DCD. In this study, we show that, in terms of their Ca2+ responses to 0.5 mM methadone, SH-SY5Y cells can be pooled into four different groups. In a broad pharmacological survey, the relevance of different Ca2+-related mechanisms on methadone-induced DCD was investigated including extracellular calcium, L-type Ca2+ channels, μ-opioid receptor, mitochondrial inner membrane potential, mitochondrial ATP synthesis, mitochondrial Ca2+/2Na+-exchanger, reactive oxygen species, and mitochondrial permeability transition. Only those compounds targeting mitochondria such as oligomycin, FCCP, CGP 37157, and cyclosporine A were able to amend methadone-induced Ca2+ dyshomeostasis suggesting that methadone induces DCD by modulating the ability of mitochondria to handle Ca2+. Consistently, mitochondria became dramatically shorter and rounder in the presence of methadone. Furthermore, analysis of oxygen uptake by isolated rat liver mitochondria suggested that methadone affected mitochondrial Ca2+ uptake in a respiratory substrate-dependent way. We conclude that methadone causes failure of intracellular Ca2+ homeostasis, and this effect is associated with morphological and functional changes of mitochondria. Likely, this mechanism contributes to degenerative side effects associated with methadone treatment.

  11. Dopamine D2 receptors in the cerebral cortex: Distribution and pharmacological characterization with [3H]raclopride

    International Nuclear Information System (INIS)

    Lidow, M.S.; Goldman-Rakic, P.S.; Rakic, P.; Innis, R.B.

    1989-01-01

    An apparent involvement of dopamine in the regulation of cognitive functions and the recognition of a widespread dopaminergic innervation of the cortex have focused attention on the identity of cortical dopamine receptors. However, only the presence and distribution of dopamine D 1 receptors in the cortex have been well documented. Comparable information on cortical D 2 sites is lacking. The authors report here the results of binding studied in the cortex and neostriatum of rat and monkey using the D 2 selective antagonist [ 3 H]raclopride. In both structures [ 3 H]raclopride bound in a sodium-dependent and saturable manner to a single population of sites with pharmacological profiles of dopamine D 2 receptors. D 2 sites were present in all regions of the cortex, although their density was much lower than in the neostriatum. The density of these sites in both monkey and, to a lesser extent, rat cortex displayed a rostral-caudal gradient with highest concentrations in the prefrontal and lowest concentrations in the occipital cortex, corresponding to dopamine levels in these areas. Thus, the present study established the presence and widespread distribution of dopamine D 2 receptors in the cortex

  12. Pharmacological characterization of Tc-99m(CN-t-butyl)/sub 6//sup +/: A potential heart agent

    International Nuclear Information System (INIS)

    Pendleton, D.B.; Delano, M.L.; Sands, H.; Gallagher, B.M.; Liteplo, M.P.; Camin, L.L.; Subramanyam, V.

    1984-01-01

    The authors have investigated the pharmacological behavior of hexakis (t-butylisonitrile)Tc(I) and evaluated it as a potential myocardial perfusion radiopharmaceutical. This complex produces good to excellent heart images in rats, guinea pigs, rabbits, cats, dogs, pigs and baboons. Good heart uptake in guinea pigs, cats and pigs may be predictive of good myocardial imaging in man, since the hearts of these three species extract Tl-201, but not Tc-99m(dmpe)/sub 2/-Cl/sub 2//sup +/ (similar to man, but unlike other animal species). Biodistribution studies reveal initial heart uptake of 1.3 to 2.2% of the injected activity. Imaging and biodistribution show significant initial lung activity which clears substantially during the first hour after injection. Little or no myocardial washout is observed. In rabbits with ischemia induced by coronary artery ligation, the complex distributes as a function of blood flow. Simultaneous injection of Tl-201 and Tc-99m (CN-t-butyl)/sub 6//sup +/ with subsequent dual isotope imaging shows that their initial distribution is a similar. The complex is extracted 100% by isolated rabbit and guinea pig hearts perfused with buffer. When human blood is mixed and co-injected with the complex, myocardial extraction is reduced, but remains high (73-75%). Uptake of the complex by rat myocytes in culture is not inhibited by either ouabain or K/sup +/. These results suggest that this complex may be a promising myocardial perfusion agent and should be tested in man

  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. Characterization of glycolipid galactosyltransferases from embryonic chicken brain

    International Nuclear Information System (INIS)

    Kyle, J.W.

    1985-01-01

    Glycolipid galactosyltransferases (GalT-3 and GalT-4) were solubilized from a membrane fraction isolated from embryonic chicken brain. The profiles of specific activity and total units per brain of GalT-3 and GalT-4 varied with embryonic age. GalT-4 had the highest specific activity at 9 days of embryonic development and showed a steady decrease until hatching. GalT-3 showed a gradual increase in specific activity. Both GalT3 and GalT-4 showed a steady increase in total units per brain throughout embryonic development. The solubilized enzymes could be separated using gel filtration, ion exchange chromatography or affinity chromatography on α-lactalbumin-agarose. Data obtained in the study imply that GalT-4 is involved in both glycoprotein and glycolipid biosynthesis. Glycosphingolipid products from GalT-3 and GalT-4 catalyzed reactions labeled with [ 14 C]galactose comigrated with authentic GMI and nLcOse 4 Cer, when examined by thin layer chromatography and autoradiography. Studies with galactosidases revealed that all of the enzyme products formed by GalT-3 and GalT-4 contained a [ 14 C]-galactose in a β anomeric linkage. Periodate oxidation studies of Gal-[ 14 C]GlcNAc, formed by purified GalT-4 using [ 14 C]GlcNAc as the acceptor, demonstrated that approximately 70% of the linkage formed was Galβ1-4GlcNAc and 30% was Galβ1-3GlcNAc. Studies on the susceptibility of [ 14 C]Gal-GlcNAc to base catalyzed β-elimination also suggested the presence of approximately 30% Galβ1-3GlcNAc

  15. The Mechanisms of Pharmacological Preconditioning of the Brain and the Comparative Efficacy of the Drugs — Direct- and Indirect-Acting Glycogen Synthase Kinase-3β Inhibitors: Experimental Study

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    V. V. Likhvantsev

    2012-01-01

    Full Text Available Objective: to investigate the activity of sevoflurane, dalargin, and lithium chloride in protecting the rat brain from total ischemia/reperfusion and to define whether the GSK=3^ deposphorylation contributes to the mechanism of pharmacological preconditioning. Materials and methods. Experiments were carried out on 80 male albino rats in which temporary circulatory arrest (CA was simulated by ligating the cardiovascular fascicle for 10 and 20 minutes. The animals were revived by mechanical ventilation external cardiac massage, and the intratracheal injection of adrenaline (epinephrine, Moscow Endocrinology Plant at a dose of 0.1 mg/kg. Animals were divided into 9 groups and sevorane (sevoflurane, Abbott Laboratories, dalargin (Microgen Research-and-Production Association, or lithium chloride (Sigma Chemical Co. were separately given with and without CA. Brain tissue homogenate specimens were obtained from euthanized animals. The concentration of total glycogen synthase kinase-3^ (GSK-3^ was colorimetrically determined using a Hitachi-557 spectrophotometer (Hitachi Ltd., Japan. The content of phosphorylated GSK-3/3 (pGSK-3^ in brain homogenate was estimated by Western blotting. Results. The total level of GSK-3^ in each group was similar (80—90 relative units and remained unchanged throughout each experiment. Twenty-minute ischemia maximally activated GSK-30 through dephosphorylation. Ten-minute ischemia elevated pGSK-3^ levels by more than 5 times as compared to the baseline value revealing the «training» effect. The quantity of pGSK-3^ was unchanged in the ischemia/perfusion group during sevoflurane insufflation and was decreased by 27% during dalargin administration. Conclusion. The experimental model of total ischemia provided evidence that the test drugs had a pharmacological preconditioning effect on brain neurons. According to their increasing effect, the drugs were arranged in the following order: dalargin < sevoflurane < lithium

  16. In vitro pharmacological characterization of a novel TRPA1 antagonist and proof of mechanism in a human dental pulp model

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    Nyman E

    2013-01-01

    Full Text Available Eva Nyman,1,* Bo Franzén,1,* Andreas Nolting,1 Göran Klement,1 Gang Liu,1 Maria Nilsson,1 Annika Rosén,2 Charlotta Björk,3 Dirk Weigelt,4 Patrik Wollberg,1 Paul Karila,1 Patrick Raboisson11Neuroscience, Innovative Medicines CNS/Pain, AstraZeneca R&D, Södertälje, Sweden; 2Division of Oral and Maxillofacial Surgery, Karolinska Institute/Karolinska University Hospital, Huddinge, Sweden; 3Clinical TA NS Early Development, 4Medicinal Chemistry, Innovative Medicines CNS/Pain, AstraZeneca R&D, Södertälje, Sweden*These authors contributed equally to this workAbstract: AZ465 is a novel selective transient receptor potential cation channel, member A1 (TRPA1 antagonist identified during a focused drug discovery effort. In vitro, AZ465 fully inhibits activation by zinc, O-chlorobenzylidene malononitrile (CS, or cinnamaldehyde of the human TRPA1 channel heterologously expressed in human embryonic kidney cells. Our data using patch-clamp recordings and mouse/human TRPA1 chimeras suggest that AZ465 binds reversibly in the pore region of the human TRPA1 channel. Finally, in an ex vivo model measuring TRPA1 agonist-stimulated release of neuropeptides from human dental pulp biopsies, AZD465 was able to block 50%–60% of CS-induced calcitonin gene-related peptide release, confirming that AZ465 inhibits the native human TRPA1 channel in neuronal tissue.Keywords: pain, pharmacology, antagonist, chimeric proteins, dental pulp, inflammation, neuropeptide, calcitonin gene-related peptide, CGRP

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

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    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.

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

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    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

  19. 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.

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    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.

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

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    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.

  1. Pharmacological Characterization of H05, a Novel Serotonin and Noradrenaline Reuptake Inhibitor with Moderate 5-HT2A Antagonist Activity for the Treatment of Depression.

    Science.gov (United States)

    Xu, Xiangqing; Wei, Yaqin; Guo, Qiang; Zhao, Song; Liu, Zhiqiang; Xiao, Ting; Liu, Yani; Qiu, Yinli; Hou, Yuanyuan; Zhang, Guisen; Wang, KeWei

    2018-06-01

    Multitarget antidepressants selectively inhibiting monoaminergic transporters and 5-hydroxytryptamine (5-HT) 2A receptor have demonstrated higher efficacy and fewer side effects than selective serotonin reuptake inhibitors. In the present study, we synthesized a series of novel 3-(benzo[d][1,3]dioxol-4-yloxy)-3-arylpropyl amine derivatives, among which compound H05 was identified as a lead, exhibiting potent inhibitory effects on both serotonin ( K i = 4.81 nM) and norepinephrine (NE) ( K i = 6.72 nM) transporters and moderate 5-HT 2A antagonist activity (IC 50 = 60.37 nM). H05 was able to dose-dependently reduce the immobility duration in mouse forced swimming test and tail suspension test, with the minimal effective doses lower than those of duloxetine, and showed no stimulatory effect on locomotor activity. The administration of H05 (5, 10, and 20 mg/kg, by mouth) significantly shortened the immobility time of adrenocorticotropin-treated rats that serve as a model of treatment-resistant depression, whereas imipramine (30 mg/kg, by mouth) and duloxetine (30 mg/kg, by mouth) showed no obvious effects. Chronic treatment with H05 reversed the depressive-like behaviors in a rat model of chronic unpredictable mild stress and a mouse model of corticosterone-induced depression. Microdialysis analysis revealed that the administration of H05 at either 10 or 20 mg/kg increased the release of 5-HT and NE from the frontal cortex. The pharmacokinetic (PK) and brain penetration analyses suggest that H05 has favorable PK properties with good blood-brain penetration ability. Therefore, it can be concluded that H05, a novel serotonin and NE reuptake inhibitor with 5-HT 2A antagonist activity, possesses efficacious activity in the preclinical models of depression and treatment-resistant depression, and it may warrant further evaluation for clinical development. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  2. Orbitrap mass spectrometry characterization of hybrid chondroitin/dermatan sulfate hexasaccharide domains expressed in brain.

    Science.gov (United States)

    Robu, Adrian C; Popescu, Laurentiu; Munteanu, Cristian V A; Seidler, Daniela G; Zamfir, Alina D

    2015-09-15

    In the central nervous system, chondroitin/dermatan sulfate (CS/DS) glycosaminoglycans (GAGs) modulate neurotrophic effects and glial cell maturation during brain development. Previous reports revealed that GAG composition could be responsible for CS/DS activities in brain. In this work, for the structural characterization of DS- and CS-rich domains in hybrid GAG chains extracted from neural tissue, we have developed an advanced approach based on high-resolution mass spectrometry (MS) using nanoelectrospray ionization Orbitrap in the negative ion mode. Our high-resolution MS and multistage MS approach was developed and applied to hexasaccharides obtained from 4- and 14-week-old mouse brains by GAG digestion with chondroitin B and in parallel with AC I lyase. The expression of DS- and CS-rich domains in the two tissues was assessed comparatively. The analyses indicated an age-related structural variability of the CS/DS motifs. The older brain was found to contain more structures and a higher sulfation of DS-rich regions, whereas the younger brain was found to be characterized by a higher sulfation of CS-rich regions. By multistage MS using collision-induced dissociation, we also demonstrated the incidence in mouse brain of an atypical [4,5-Δ-GlcAGalNAc(IdoAGalNAc)2], presenting a bisulfated CS disaccharide formed by 3-O-sulfate-4,5-Δ-GlcA and 6-O-sulfate-GalNAc moieties. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Assessing anxiety in C57BL/6J mice: a pharmacological characterization of the open-field and light/dark tests.

    Science.gov (United States)

    Heredia, Luis; Torrente, Margarita; Colomina, María T; Domingo, José L

    2014-01-01

    In order to assess anxiety in mammals various tests and species are currently available. These current assays measure changes in anxiety-like behaviors. The open-field and the light/dark are anxiety tests based on the spontaneous behavior of the animals, with C57BL/6J mice being a frequently used strain in behavioral studies. However, the suitability of this strain as a choice in anxiety studies has been questioned. In this study, we performed two pharmacological characterizations of this strain in both the open-field and the light/dark tests. We examined the changes in the anxiety-like behaviors of C57BL/6J mice exposed to chlordiazepoxide (CDP), an anxiolytic drug, at doses of 5 and 10 mg/kg, picrotoxine (PTX), an anxiogenic drug, at doses of 0.5 and 1 mg/kg, and methylphenidate (MPH), a psychomotor stimulant drug, at doses of 5 and 10 mg/kg, in a first experiment. In a second experiment, we tested CDP at 2.5 mg/kg, PTX at 2 mg/kg and MPH at 2.5 mg/kg. Results showed an absence of anxiolytic-like effects of CDP in open-field and light/dark tests. Light/dark test was more sensitive to the anxiogenic effects of PTX than the open-field test. Finally, a clear anxiogenic effect of MPH was observed in the two tests. Although C57BL/6J mice could not be a sensitive model to study anxiolytic effects in pharmacological or behavioral interventions, it might be a suitable model to test anxiogenic effects. Further studies are necessary to corroborate these results. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Pharmacological Characterization of 30 Human Melanocortin-4 Receptor Polymorphisms with the Endogenous Proopiomelanocortin Derived Agonists, Synthetic Agonists, and the Endogenous Agouti-Related Protein (AGRP) Antagonist

    Science.gov (United States)

    Xiang, Zhimin; Proneth, Bettina; Dirain, Marvin L.; Litherland, Sally A.; Haskell-Luevano, Carrie

    2010-01-01

    The melanocortin-4 receptor (MC4R) is a G-protein coupled receptor (GPCR) that is expressed in the central nervous system and has a role in regulating feeding behavior, obesity, energy homeostasis, male erectile response, and blood pressure. Since the report of the MC4R knockout mouse in 1997, the field has been searching for links between this genetic bio marker and human obesity and type 2 diabetes. More then 80 single nucleotide polymorphisms (SNPs) have been identified from human patients, both obese and non-obese controls. Many significant studies have been performed examining the pharmacological characteristics of these hMC4R SNPs in attempts to identify a molecular defects/insights that might link a genetic factor to the obese phenotype observed in patients possessing these mutations. Our laboratory has previously reported the pharmacological characterization of 40 of these polymorphic hMC4 receptors with multiple endogenous and synthetic ligands. The goal of the current study is to perform a similar comprehensive side-by-side characterization of 30 additional human hMC4R with single nucleotide polymorphisms using multiple endogenous agonists [α-, β, γ2-melanocyte stimulating hormones (MSH) and adrenocorticotropin (ACTH)], the antagonist agouti-related protein hAGRP(87-132), and synthetic agonists [NDP-MSH, MTII, and the tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 (JRH887-9)]. These in vitro data, in some cases, provide a putative molecular link between dysfunctional hMC4R's and human obesity. These 30 hMC4R SNPs include R7H, R18H, R18L, S36Y, P48S, V50M, F51L, E61K, I69T, D90N, S94R, G98R, I121T, A154D, Y157S, W174C, G181D, F202L, A219V, I226T, G231S, G238D, N240S, C271R, S295P, P299L, E308K, I317V, L325F and 750DelGA. All but the N240S hMC4R were identified in obese patients. Additionally, we have characterized a double I102T/V103I hMC4R. In addition to the pharmacological characterization, the hMC4R variants were evaluated for cell surface expression by flow

  5. Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist.

    Science.gov (United States)

    Xiang, Zhimin; Proneth, Bettina; Dirain, Marvin L; Litherland, Sally A; Haskell-Luevano, Carrie

    2010-06-08

    The melanocortin-4 receptor (MC4R) is a G-protein-coupled receptor (GPCR) that is expressed in the central nervous system and has a role in regulating feeding behavior, obesity, energy homeostasis, male erectile response, and blood pressure. Since the report of the MC4R knockout mouse in 1997, the field has been searching for links between this genetic biomarker and human obesity and type 2 diabetes. More then 80 single nucleotide polymorphisms (SNPs) have been identified from human patients, both obese and nonobese controls. Many significant studies have been performed examining the pharmacological characteristics of these hMC4R SNPs in attempts to identify a molecular defects/insights that might link a genetic factor to the obese phenotype observed in patients possessing these mutations. Our laboratory has previously reported the pharmacological characterization of 40 of these polymorphic hMC4 receptors with multiple endogenous and synthetic ligands. The goal of the current study is to perform a similar comprehensive side-by-side characterization of 30 additional human hMC4R with single nucleotide polymorphisms using multiple endogenous agonists [alpha-, beta-, and gamma(2)-melanocyte stimulating hormones (MSH) and adrenocorticotropin (ACTH)], the antagonist agouti-related protein hAGRP(87-132), and synthetic agonists [NDP-MSH, MTII, and the tetrapeptide Ac-His-dPhe-Arg-Trp-NH(2) (JRH887-9)]. These in vitro data, in some cases, provide a putative molecular link between dysfunctional hMC4R's and human obesity. These 30 hMC4R SNPs include R7H, R18H, R18L, S36Y, P48S, V50M, F51L, E61K, I69T, D90N, S94R, G98R, I121T, A154D, Y157S, W174C, G181D, F202L, A219 V, I226T, G231S, G238D, N240S, C271R, S295P, P299L, E308K, I317V, L325F, and 750DelGA. All but the N240S hMC4R were identified in obese patients. Additionally, we have characterized a double I102T/V103I hMC4R. In addition to the pharmacological characterization, the hMC4R variants were evaluated for cell surface

  6. Characterization of the phosphoproteome and sialoproteome in brain tissues by mass spectrometry

    DEFF Research Database (Denmark)

    Ibáñez-Vea, María; Kempf, Stefan J.; Larsen, Martin R.

    2017-01-01

    Mass spectrometry is an essential tool for the characterization of proteins within neuroscience. The development of faster instruments enables neuroscientists to investigate a large proportion of the proteome in the brain in only short analysis time. Yet, a detailed functional investigation of th...

  7. The pharmacology of regenerative medicine.

    Science.gov (United States)

    Christ, George J; Saul, Justin M; Furth, Mark E; Andersson, Karl-Erik

    2013-07-01

    Regenerative medicine is a rapidly evolving multidisciplinary, translational research enterprise whose explicit purpose is to advance technologies for the repair and replacement of damaged cells, tissues, and organs. Scientific progress in the field has been steady and expectations for its robust clinical application continue to rise. The major thesis of this review is that the pharmacological sciences will contribute critically to the accelerated translational progress and clinical utility of regenerative medicine technologies. In 2007, we coined the phrase "regenerative pharmacology" to describe the enormous possibilities that could occur at the interface between pharmacology, regenerative medicine, and tissue engineering. The operational definition of regenerative pharmacology is "the application of pharmacological sciences to accelerate, optimize, and characterize (either in vitro or in vivo) the development, maturation, and function of bioengineered and regenerating tissues." As such, regenerative pharmacology seeks to cure disease through restoration of tissue/organ function. This strategy is distinct from standard pharmacotherapy, which is often limited to the amelioration of symptoms. Our goal here is to get pharmacologists more involved in this field of research by exposing them to the tools, opportunities, challenges, and interdisciplinary expertise that will be required to ensure awareness and galvanize involvement. To this end, we illustrate ways in which the pharmacological sciences can drive future innovations in regenerative medicine and tissue engineering and thus help to revolutionize the discovery of curative therapeutics. Hopefully, the broad foundational knowledge provided herein will spark sustained conversations among experts in diverse fields of scientific research to the benefit of all.

  8. 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.

  9. Characterization of the regulatory subunit from brain cyclic AMP-dependent protein kinase II

    International Nuclear Information System (INIS)

    Stein, J.C.

    1985-01-01

    Tryptic peptides derived from the regulatory subunits of brain and heart cAMP-dependent protein kinase II were mapped by reverse phase HPLC. At 280 nm, 15 unique peptides were found only in the heart RII digest, while 5 other peptides were obtained only from brain RII. At 210 nm, 13 brain-RII specific and 15 heart-RII specific tryptic peptides were identified and resolved. Two-dimensional mapping analyses revealed that several 37 P-labeled tryptic fragments derived from the autophosphorylation and the photoaffinity labeled cAMP-binding sites of brain RII were separate and distinct from the 32 P-peptides isolated from similarly treated heart RII. The tryptic phosphopeptide containing the autophosphorylation site in brain RII was purified. The sequence and phosphorylation site is: Arg-Ala-Ser(P)-Val-Cys-Ala-Glu-Ala-Tyr-Asn-Pro-Asp-Glu-Glu-Glu-Asp-Asp-Ala-Glu. Astrocytes and neurons exhibit high levels of the brain RII enzyme, while oligodendrocytes contain the heart RII enzyme. Monoclonal antibodies to bovine cerebral cortex RII were made and characterized. The antibodies elucidated a subtle difference between membrane-associated and cytosolic RII from cerebral cortex

  10. Brain perivascular macrophages: characterization and functional roles in health and disease.

    Science.gov (United States)

    Faraco, Giuseppe; Park, Laibaik; Anrather, Josef; Iadecola, Costantino

    2017-11-01

    Perivascular macrophages (PVM) are a distinct population of resident brain macrophages characterized by a close association with the cerebral vasculature. PVM migrate from the yolk sac into the brain early in development and, like microglia, are likely to be a self-renewing cell population that, in the normal state, is not replenished by circulating monocytes. Increasing evidence implicates PVM in several disease processes, ranging from brain infections and immune activation to regulation of the hypothalamic-adrenal axis and neurovascular-neurocognitive dysfunction in the setting of hypertension, Alzheimer disease pathology, or obesity. These effects involve crosstalk between PVM and cerebral endothelial cells, interaction with circulating immune cells, and/or production of reactive oxygen species. Overall, the available evidence supports the idea that PVM are a key component of the brain-resident immune system with broad implications for the pathogenesis of major brain diseases. A better understanding of the biology and pathobiology of PVM may lead to new insights and therapeutic strategies for a wide variety of brain diseases.

  11. 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

  12. Chemical characterization of a red raspberry fruit extract and evaluation of its pharmacological effects in experimental models of acute inflammation and collagen-induced arthritis.

    Science.gov (United States)

    Figueira, M E; Câmara, M B; Direito, R; Rocha, J; Serra, A T; Duarte, C M M; Fernandes, A; Freitas, M; Fernandes, E; Marques, M C; Bronze, M R; Sepodes, B

    2014-12-01

    Berries are an important dietary source of fibres, vitamins, minerals and some biologically active non-nutrients. A red raspberry fruit extract was characterized in terms of phenolic content and the anti-inflammatory properties and protective effects were evaluated in two experimental models of inflammation. The antioxidant potential of the extract, the cellular antioxidant activity and the effects over neutrophils' oxidative burst were also studied to provide a mechanistic insight for the anti-inflammatory effects observed. The extract was administered in a dose of 15 mg kg(-1), i.p. and significantly inhibited paw oedema formation in the rat. The same dose was administered via i.p. and p.o. routes in the collagen-induced arthritis model in the rat. The extract showed pharmacological activity and was able to significantly reduce the development of clinical signs of arthritis and markedly reduce the degree of bone resorption, soft tissue swelling and osteophyte formation, preventing articular destruction in treated animals.

  13. Colorization and automated segmentation of human T2 MR brain images for characterization of soft tissues.

    Directory of Open Access Journals (Sweden)

    Muhammad Attique

    Full Text Available Characterization of tissues like brain by using magnetic resonance (MR images and colorization of the gray scale image has been reported in the literature, along with the advantages and drawbacks. Here, we present two independent methods; (i a novel colorization method to underscore the variability in brain MR images, indicative of the underlying physical density of bio tissue, (ii a segmentation method (both hard and soft segmentation to characterize gray brain MR images. The segmented images are then transformed into color using the above-mentioned colorization method, yielding promising results for manual tracing. Our color transformation incorporates the voxel classification by matching the luminance of voxels of the source MR image and provided color image by measuring the distance between them. The segmentation method is based on single-phase clustering for 2D and 3D image segmentation with a new auto centroid selection method, which divides the image into three distinct regions (gray matter (GM, white matter (WM, and cerebrospinal fluid (CSF using prior anatomical knowledge. Results have been successfully validated on human T2-weighted (T2 brain MR images. The proposed method can be potentially applied to gray-scale images from other imaging modalities, in bringing out additional diagnostic tissue information contained in the colorized image processing approach as described.

  14. Characterization of a sequential pipeline approach to automatic tissue segmentation from brain MR Images

    International Nuclear Information System (INIS)

    Hou, Zujun; Huang, Su

    2008-01-01

    Quantitative analysis of gray matter and white matter in brain magnetic resonance imaging (MRI) is valuable for neuroradiology and clinical practice. Submission of large collections of MRI scans to pipeline processing is increasingly important. We characterized this process and suggest several improvements. To investigate tissue segmentation from brain MR images through a sequential approach, a pipeline that consecutively executes denoising, skull/scalp removal, intensity inhomogeneity correction and intensity-based classification was developed. The denoising phase employs a 3D-extension of the Bayes-Shrink method. The inhomogeneity is corrected by an improvement of the Dawant et al.'s method with automatic generation of reference points. The N3 method has also been evaluated. Subsequently the brain tissue is segmented into cerebrospinal fluid, gray matter and white matter by a generalized Otsu thresholding technique. Intensive comparisons with other sequential or iterative methods have been carried out using simulated and real images. The sequential approach with judicious selection on the algorithm selection in each stage is not only advantageous in speed, but also can attain at least as accurate segmentation as iterative methods under a variety of noise or inhomogeneity levels. A sequential approach to tissue segmentation, which consecutively executes the wavelet shrinkage denoising, scalp/skull removal, inhomogeneity correction and intensity-based classification was developed to automatically segment the brain tissue into CSF, GM and WM from brain MR images. This approach is advantageous in several common applications, compared with other pipeline methods. (orig.)

  15. Cellular characterization of the peritumoral edema zone in malignant brain tumors

    International Nuclear Information System (INIS)

    Engelhorn, T.; Schwarz, M.A.; Savaskan, N.E.

    2009-01-01

    Brain edema is a hallmark of human malignant brain tumors and contributes to the clinical course and outcome of brain tumor patients. The so-called perifocal edema or brain swelling imposes in T2-weighted MR scans as high intensity areas surrounding the bulk tumor mass. The mechanisms of this increased fluid attraction and the cellular composition of the microenvironment are only partially understood. In this study, we focus on imaging perifocal edema in orthotopically implanted gliomas in rodents and correlate perifocal edema with immunohistochemical markers. We identified that areas of perifocal edema not only include the tumor invasion zone, but also are associated with increased glial fibrillary acidic protein (GFAP) and aquaporin-4 expression surrounding the bulk tumor mass. Moreover, a high number of activated microglial cells expressing CD11b and macrophage migration inhibitory factor (MIF) accumulate at the tumor border. Thus, the area of perifocal edema is mainly dominated by reactive changes of vital brain tissue. These data corroborate that perifocal edema identified in T2-weighted MR scans are characterized with alterations in glial cell distribution and marker expression forming an inflammatory tumor microenvironment. (author)

  16. 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

  17. 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, P.; Penninx, B.W.J.H.; Kenis, G.; Prickaerts, J.; Voshaar, R.C.O.; 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,

  18. Determination of pharmacological levels of harmane, harmine and harmaline in mammalian brain tissue, cerebrospinal fluid and plasma by high-performance liquid chromatography with fluorimetric detection.

    Science.gov (United States)

    Moncrieff, J

    1989-11-24

    Increased blood aldehyde levels, as occur in alcohol intoxication, could lead to the formation of beta-carbolines such as harmane by condensation with indoleamines. Endogenous beta-carbolines, therefore, should occur in specific brain areas where indoleamine concentrations are high, whilst exogenous beta-carbolines should exhibit an even distribution. The author presents direct and sensitive methods for assaying the beta-carbolines harmane, harmine and harmaline in brain tissue, cerebrospinal fluid and plasma at picogram sample concentrations using reversed-phase high-performance liquid chromatography with fluorimetric detection and minimal sample preparation. Using these assay methods, it was found that the distribution of beta-carbolines from a source exogenous to the brain results in a relatively even distribution within the brain tissue.

  19. 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. Copyright © 2016. Published by Elsevier Ltd.

  20. Characterizing brain structures and remodeling after TBI based on information content, diffusion entropy.

    Science.gov (United States)

    Fozouni, Niloufar; Chopp, Michael; Nejad-Davarani, Siamak P; Zhang, Zheng Gang; Lehman, Norman L; Gu, Steven; Ueno, Yuji; Lu, Mei; Ding, Guangliang; Li, Lian; Hu, Jiani; Bagher-Ebadian, Hassan; Hearshen, David; Jiang, Quan

    2013-01-01

    To overcome the limitations of conventional diffusion tensor magnetic resonance imaging resulting from the assumption of a Gaussian diffusion model for characterizing voxels containing multiple axonal orientations, Shannon's entropy was employed to evaluate white matter structure in human brain and in brain remodeling after traumatic brain injury (TBI) in a rat. Thirteen healthy subjects were investigated using a Q-ball based DTI data sampling scheme. FA and entropy values were measured in white matter bundles, white matter fiber crossing areas, different gray matter (GM) regions and cerebrospinal fluid (CSF). Axonal densities' from the same regions of interest (ROIs) were evaluated in Bielschowsky and Luxol fast blue stained autopsy (n = 30) brain sections by light microscopy. As a case demonstration, a Wistar rat subjected to TBI and treated with bone marrow stromal cells (MSC) 1 week after TBI was employed to illustrate the superior ability of entropy over FA in detecting reorganized crossing axonal bundles as confirmed by histological analysis with Bielschowsky and Luxol fast blue staining. Unlike FA, entropy was less affected by axonal orientation and more affected by axonal density. A significant agreement (r = 0.91) was detected between entropy values from in vivo human brain and histologically measured axonal density from post mortum from the same brain structures. The MSC treated TBI rat demonstrated that the entropy approach is superior to FA in detecting axonal remodeling after injury. Compared with FA, entropy detected new axonal remodeling regions with crossing axons, confirmed with immunohistological staining. Entropy measurement is more effective in distinguishing axonal remodeling after injury, when compared with FA. Entropy is also more sensitive to axonal density than axonal orientation, and thus may provide a more accurate reflection of axonal changes that occur in neurological injury and disease.

  1. Characterizing Brain Structures and Remodeling after TBI Based on Information Content, Diffusion Entropy

    Science.gov (United States)

    Fozouni, Niloufar; Chopp, Michael; Nejad-Davarani, Siamak P.; Zhang, Zheng Gang; Lehman, Norman L.; Gu, Steven; Ueno, Yuji; Lu, Mei; Ding, Guangliang; Li, Lian; Hu, Jiani; Bagher-Ebadian, Hassan; Hearshen, David; Jiang, Quan

    2013-01-01

    Background To overcome the limitations of conventional diffusion tensor magnetic resonance imaging resulting from the assumption of a Gaussian diffusion model for characterizing voxels containing multiple axonal orientations, Shannon's entropy was employed to evaluate white matter structure in human brain and in brain remodeling after traumatic brain injury (TBI) in a rat. Methods Thirteen healthy subjects were investigated using a Q-ball based DTI data sampling scheme. FA and entropy values were measured in white matter bundles, white matter fiber crossing areas, different gray matter (GM) regions and cerebrospinal fluid (CSF). Axonal densities' from the same regions of interest (ROIs) were evaluated in Bielschowsky and Luxol fast blue stained autopsy (n = 30) brain sections by light microscopy. As a case demonstration, a Wistar rat subjected to TBI and treated with bone marrow stromal cells (MSC) 1 week after TBI was employed to illustrate the superior ability of entropy over FA in detecting reorganized crossing axonal bundles as confirmed by histological analysis with Bielschowsky and Luxol fast blue staining. Results Unlike FA, entropy was less affected by axonal orientation and more affected by axonal density. A significant agreement (r = 0.91) was detected between entropy values from in vivo human brain and histologically measured axonal density from post mortum from the same brain structures. The MSC treated TBI rat demonstrated that the entropy approach is superior to FA in detecting axonal remodeling after injury. Compared with FA, entropy detected new axonal remodeling regions with crossing axons, confirmed with immunohistological staining. Conclusions Entropy measurement is more effective in distinguishing axonal remodeling after injury, when compared with FA. Entropy is also more sensitive to axonal density than axonal orientation, and thus may provide a more accurate reflection of axonal changes that occur in neurological injury and disease

  2. Patient Characterization Protocols for Psychophysiological Studies of Traumatic Brain Injury and Post-TBI Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Paul E. Rapp

    2013-07-01

    Full Text Available Psychophysiological investigations of traumatic brain injury (TBI are being conducted for several reasons, including the objective of learning more about the underlying physiological mechanisms of the pathological processes that can be initiated by a head injury. Additional goals include the development of objective physiologically based measures that can be used to monitor the response to treatment and to identify minimally symptomatic individuals who are at risk of delayed onset neuropsychiatric disorders following injury. Research programs studying TBI search for relationships between psychophysiological measures, particularly ERP component properties (e.g. timing, amplitude, scalp distribution, and a participant’s clinical condition. Moreover, the complex relationships between brain injury and psychiatric disorders are receiving increased research attention, and ERP technologies are making contributions to this effort. This review has two objectives supporting such research efforts. The first is to review evidence indicating that traumatic brain injury is a significant risk factor for post-injury neuropsychiatric disorders. The second objective is to introduce ERP researchers who are not familiar with neuropsychiatric assessment to the instruments that are available for characterizing traumatic brain injury, post-concussion syndrome, and psychiatric disorders. Specific recommendations within this very large literature are made. We have proceeded on the assumption that, as is typically the case in an ERP laboratory, the investigators are not clinically qualified and that they will not have access to participant medical records.

  3. Isolation of murine postnatal brain microglia for phenotypic characterization using magnetic cell separation technology.

    Science.gov (United States)

    Harms, Ashley S; Tansey, Malú G

    2013-01-01

    To shorten the time between brain harvesting and microglia isolation, and characterization, we utilized the MACS(®) neural dissociation kit followed by OctoMACS(®) CD11b magnetic bead isolation technique to positively select for brain microglia expressing the pan-microglial marker CD11b, a key subunit of the membrane attack complex (MAC). This protocol yields a viable and highly pure (>95%) microglial population of approximately 500,000 cells per pup that is amenable for in vitro characterization within hours or days after being harvested from brain tissue. Primary microglia from C57Bl/6 mice were plated for next-day analyses of morphology and cellular markers by immunocytochemistry or for analysis of gene expression under resting or LPS-stimulated conditions. The ease of isolation enables investigators to perform molecular and cellular analyses without having to wait 1-2 weeks to isolate microglia by conventional methods involving mechanical agitation to dislodge these from astrocyte beds.

  4. Further In-vitro Characterization of an Implantable Biosensor for Ethanol Monitoring in the Brain

    Directory of Open Access Journals (Sweden)

    Gaia Rocchitta

    2013-07-01

    Full Text Available Ethyl alcohol may be considered one of the most widespread central nervous system (CNS depressants in Western countries. Because of its toxicological and neurobiological implications, the detection of ethanol in brain extracellular fluid (ECF is of great importance. In a previous study, we described the development and characterization of an implantable biosensor successfully used for the real-time detection of ethanol in the brain of freely-moving rats. The implanted biosensor, integrated in a low-cost telemetry system, was demonstrated to be a reliable device for the short-time monitoring of exogenous ethanol in brain ECF. In this paper we describe a further in-vitro characterization of the above-mentioned biosensor in terms of oxygen, pH and temperature dependence in order to complete its validation. With the aim of enhancing ethanol biosensor performance, different enzyme loadings were investigated in terms of apparent ethanol Michaelis-Menten kinetic parameters, viz. IMAX, KM and linear region slope, as well as ascorbic acid interference shielding. The responses of biosensors were studied over a period of 28 days. The overall findings of the present study confirm the original biosensor configuration to be the best of those investigated for in-vivo applications up to one week after implantation.

  5. Characterizing Focused-Ultrasound Mediated Drug Delivery to the Heterogeneous Primate Brain In Vivo with Acoustic Monitoring

    Science.gov (United States)

    Wu, Shih-Ying; Sanchez, Carlos Sierra; Samiotaki, Gesthimani; Buch, Amanda; Ferrera, Vincent P.; Konofagou, Elisa E.

    2016-11-01

    Focused ultrasound with microbubbles has been used to noninvasively and selectively deliver pharmacological agents across the blood-brain barrier (BBB) for treating brain diseases. Acoustic cavitation monitoring could serve as an on-line tool to assess and control the treatment. While it demonstrated a strong correlation in small animals, its translation to primates remains in question due to the anatomically different and highly heterogeneous brain structures with gray and white matteras well as dense vasculature. In addition, the drug delivery efficiency and the BBB opening volume have never been shown to be predictable through cavitation monitoring in primates. This study aimed at determining how cavitation activity is correlated with the amount and concentration of gadolinium delivered through the BBB and its associated delivery efficiency as well as the BBB opening volume in non-human primates. Another important finding entails the effect of heterogeneous brain anatomy and vasculature of a primate brain, i.e., presence of large cerebral vessels, gray and white matter that will also affect the cavitation activity associated with variation of BBB opening in different tissue types, which is not typically observed in small animals. Both these new findings are critical in the primate brain and provide essential information for clinical applications.

  6. Characterization of rat brain NCAM mRNA using DNA oligonucleotide probes

    DEFF Research Database (Denmark)

    Andersson, A M; Gaardsvoll, H; Giladi, E

    1990-01-01

    A number of different isoforms of the neural cell adhesion molecule (NCAM) have been identified. The difference between these is due to alternative splicing of a single NCAM gene. In rat brain NCAM mRNAs with sizes of 7.4, 6.7, 5.2, 4.3 and 2.9 kb have been reported. We have synthesized six DNA...... oligonucleotides, that hybridize to different exons in the NCAM gene. Furthermore we have constructed three oligonucleotides, that exclusively hybridize to mRNAs lacking certain exons, by letting them consist of sequences adjacent to both sides of the splice sites. By means of these probes we have characterized...... the five NCAM mRNAs in rat brain....

  7. Characterization of Novel Cytoplasmic PARP in the Brain of Octopus vulgaris

    Science.gov (United States)

    DE LISA, EMILIA; DE MAIO, ANNA; MOROZ, LEONID L.; MOCCIA, FRANCESCO; MENNELLA, MARIA ROSARIA FARAONE; DI COSMO, ANNA

    2014-01-01

    Recent investigation has focused on the participation of the poly (ADP-ribose) polymerase (PARP) reaction in the invertebrate central nervous system (CNS) during the process of long-term memory (LTM). In this paper, we characterize, localize, and assign a possible role to a cytoplasmic PARP in the brain of Octopus vulgaris. PARP activity was assayed in optic lobes, supraesophageal mass, and optic nerves. The highest levels of enzyme were found in the cytoplasmic fraction. Hyper-activation of the enzyme was detected in Octopus brain after visual discrimination training. Finally, cytoplasmic PARP was found to inhibit Octopus vulgaris actin polymerization. We propose that the cytoplasmic PARP plays a role in vivo to induce the cytoskeletonal reorganization that occurs during learning-induced neuronal plasticity. PMID:22815366

  8. Phytochemical and pharmacological overview on Liriopes radix

    African Journals Online (AJOL)

    Department of Pharmacology and Toxicology, Metabolic Diseases Research Laboratory, School of Dentistry, Kyung Hee. University ... has been used as a therapeutic drug for the treatment of ..... Alzheimer's disease (AD) is characterized by.

  9. Poloxamer 407/188 binary thermosensitive hydrogels as delivery systems for infiltrative local anesthesia: Physico-chemical characterization and pharmacological evaluation

    International Nuclear Information System (INIS)

    Akkari, Alessandra C.S.; Papini, Juliana Z. Boava; Garcia, Gabriella K.; Franco, Margareth K.K. Dias; Cavalcanti, Leide P.; Gasperini, Antonio; Alkschbirs, Melissa Inger; Yokaichyia, Fabiano; Paula, Eneida de; Tófoli, Giovana R.; Araujo, Daniele R. de

    2016-01-01

    In this study, we reported the development and the physico-chemical characterization of poloxamer 407 (PL407) and poloxamer 188 (PL188) binary systems as hydrogels for delivering ropivacaine (RVC), as drug model, and investigate their use in infiltrative local anesthesia for applications on the treatment of post-operative pain. We studied drug-micelle interaction and micellization process by light scattering and differential scanning calorimetry (DSC), the sol-gel transition and hydrogel supramolecular structure by small-angle-X-ray scattering (SAXS) and morphological evaluation by Scanning Electron Microscopy (SEM). In addition, we have presented the investigation of drug release mechanisms, in vitro/in vivo toxic and analgesic effects. Micellar dimensions evaluation showed the formation of PL407-PL188 mixed micelles and the drug incorporation, as well as the DSC studies showed increased enthalpy values for micelles formation after addition of PL 188 and RVC, indicating changes on self-assembly and the mixed micelles formation evoked by drug incorporation. SAXS studies revealed that the phase organization in hexagonal structure was not affected by RVC insertion into the hydrogels, maintaining their supramolecular structure. SEM analysis showed similar patterns after RVC addition. The RVC release followed the Higuchi model, modulated by the PL final concentration and the insertion of PL 188 into the system. Furthermore, the association PL407-PL188 induced lower in vitro cytotoxic effects, increased the duration of analgesia, in a single-dose model study, without evoking in vivo inflammation signs after local injection. - Highlights: • We present the development and relationships between physico-chemical and biopharmaceutical/pharmacological parameters for the PL407-PL188 binary hydrogel, as well as its use for infiltrative local anesthesia • The addition of PL188 and RVC evoked changes on enthalpy values, self-assembly and the mixed micelles formation • The

  10. 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

  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. Poloxamer 407/188 binary thermosensitive hydrogels as delivery systems for infiltrative local anesthesia: Physico-chemical characterization and pharmacological evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Akkari, Alessandra C.S. [Human and Natural Sciences Center, ABC Federal University, Santo André, SP (Brazil); Papini, Juliana Z. Boava [São Francisco University, Bragança Paulista, São Paulo (Brazil); Garcia, Gabriella K. [Human and Natural Sciences Center, ABC Federal University, Santo André, SP (Brazil); Franco, Margareth K.K. Dias [Nuclear and Energy Research Institute, São Paulo, SP (Brazil); Cavalcanti, Leide P. [School of Chemical Engineering, University of Campinas, SP (Brazil); Gasperini, Antonio; Alkschbirs, Melissa Inger [Brazilian Synchrotron Light Laboratory, Campinas, SP (Brazil); Yokaichyia, Fabiano [Department Quantum Phenomena in Novel Materials Helmholtz-Zentrum Berlin für Materialien und Energie GmbH, Berlin (Germany); Paula, Eneida de [Department of Biochemistry, Institute of Biology, State University of Campinas, Campinas, SP (Brazil); Tófoli, Giovana R. [Faculty of Dentistry São Leopoldo Mandic, Campinas, São Paulo (Brazil); Araujo, Daniele R. de, E-mail: daniele.araujo@ufabc.edu.br [Human and Natural Sciences Center, ABC Federal University, Santo André, SP (Brazil)

    2016-11-01

    In this study, we reported the development and the physico-chemical characterization of poloxamer 407 (PL407) and poloxamer 188 (PL188) binary systems as hydrogels for delivering ropivacaine (RVC), as drug model, and investigate their use in infiltrative local anesthesia for applications on the treatment of post-operative pain. We studied drug-micelle interaction and micellization process by light scattering and differential scanning calorimetry (DSC), the sol-gel transition and hydrogel supramolecular structure by small-angle-X-ray scattering (SAXS) and morphological evaluation by Scanning Electron Microscopy (SEM). In addition, we have presented the investigation of drug release mechanisms, in vitro/in vivo toxic and analgesic effects. Micellar dimensions evaluation showed the formation of PL407-PL188 mixed micelles and the drug incorporation, as well as the DSC studies showed increased enthalpy values for micelles formation after addition of PL 188 and RVC, indicating changes on self-assembly and the mixed micelles formation evoked by drug incorporation. SAXS studies revealed that the phase organization in hexagonal structure was not affected by RVC insertion into the hydrogels, maintaining their supramolecular structure. SEM analysis showed similar patterns after RVC addition. The RVC release followed the Higuchi model, modulated by the PL final concentration and the insertion of PL 188 into the system. Furthermore, the association PL407-PL188 induced lower in vitro cytotoxic effects, increased the duration of analgesia, in a single-dose model study, without evoking in vivo inflammation signs after local injection. - Highlights: • We present the development and relationships between physico-chemical and biopharmaceutical/pharmacological parameters for the PL407-PL188 binary hydrogel, as well as its use for infiltrative local anesthesia • The addition of PL188 and RVC evoked changes on enthalpy values, self-assembly and the mixed micelles formation • The

  13. Characterizing amide proton transfer imaging in haemorrhage brain lesions using 3T MRI

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Ha-Kyu [Philips Korea, Seoul (Korea, Republic of); Korea Basic Science Institute, Chungcheongbuk-do (Korea, Republic of); Han, Kyunghwa [Yonsei University College of Medicine, Department of Radiology and Research Institute of Radiological Science, Seodaemun-gu, Seoul (Korea, Republic of); Yonsei University College of Medicine, Yonsei Biomedical Research Institute, Seoul (Korea, Republic of); Zhou, Jinyuan [Johns Hopkins University School of Medicine, Division of MRI Research, Department of Radiology, Baltimore, MD (United States); Zhao, Yansong [Philips Healthcare, MR Clinical Science, Cleveland, OH (United States); Choi, Yoon Seong; Lee, Seung-Koo; Ahn, Sung Soo [Yonsei University College of Medicine, Department of Radiology and Research Institute of Radiological Science, Seodaemun-gu, Seoul (Korea, Republic of)

    2017-04-15

    The aim of this study was to characterize amide proton transfer (APT)-weighted signals in acute and subacute haemorrhage brain lesions of various underlying aetiologies. Twenty-three patients with symptomatic haemorrhage brain lesions including tumorous (n = 16) and non-tumorous lesions (n = 7) were evaluated. APT imaging was performed and analyzed with magnetization transfer ratio asymmetry (MTR{sub asym}). Regions of interest were defined as the enhancing portion (when present), acute or subacute haemorrhage, and normal-appearing white matter based on anatomical MRI. MTR{sub asym} values were compared among groups and components using a linear mixed model. MTR{sub asym} values were 3.68 % in acute haemorrhage, 1.6 % in subacute haemorrhage, 2.65 % in the enhancing portion, and 0.38 % in normal white matter. According to the linear mixed model, the distribution of MTR{sub asym} values among components was not significantly different between tumour and non-tumour groups. MTR{sub asym} in acute haemorrhage was significantly higher than those in the other regions regardless of underlying pathology. Acute haemorrhages showed high MTR{sub asym} regardless of the underlying pathology, whereas subacute haemorrhages showed lower MTR{sub asym} than acute haemorrhages. These results can aid in the interpretation of APT imaging in haemorrhage brain lesions. (orig.)

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

    International Nuclear Information System (INIS)

    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 ( 3 H-AVP) was used to localize and characterize putative AVT receptors in the brain of this amphibian. Binding of 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

  15. 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.

  16. Identification and in vitro pharmacological characterization of a novel and selective α7 nicotinic acetylcholine receptor agonist, Br-IQ17B.

    Science.gov (United States)

    Tang, Jing-shu; Xie, Bing-xue; Bian, Xi-ling; Xue, Yu; Wei, Ning-ning; Zhou, Jing-heng; Hao, Yu-chen; Li, Gang; Zhang, Liang-ren; Wang, Ke-wei

    2015-07-01

    Alpha7-nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca(2+)-permeable ion channel implicated in cognition and neuropsychiatric disorders. Activation of α7 nAChR improves learning, memory, and sensory gating in animal models. To identify novel α7 nAChR agonists, we synthesized a series of small molecules and characterized a representative compound, Br-IQ17B, N-[(3R)-1-azabicyclo[2,2,2]oct-3-yl]-5-bromoindolizine-2-carboxamide, which specifically activates α7 nAChR. Two-electrode voltage clamp (TEVC) recordings were primarily used for screening in Xenopus oocytes expressing human α7 nAChR. Assays, including radioisotope ligand binding, Western blots, whole-cell recordings of hippocampal culture neurons, and spontaneous IPSC recordings of brain slices, were also utilized to evaluate and confirm the specific activation of α7 nAChR by Br-IQ17B. Br-IQ17B potently activates α7 nAChR with an EC50 of 1.8±0.2 μmol/L. Br-IQ17B is selective over other subtypes such as α4β2 and α3β4, but it blocks 5-HT3A receptors. Br-IQ17B displaced binding of the α7 blocker [(3)H]-MLA to hippocampal crude membranes with a Ki of 14.9±3.2 nmol/L. In hippocampal neurons, Br-IQ17B evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 PAM PNU-120596. In brain slice recordings, Br-IQ17B enhanced GABAergic synaptic transmission in CA1 neurons. Mechanistically, Br-IQ17B increased ERK1/2 phosphorylation that was MLA-sensitive. We identified the novel, potent, and selective α7 agonist Br-IQ17B, which enhances synaptic transmission. Br-IQ17B may be a helpful tool to understand new aspects of α7 nAChR function, and it also has potential for being developed as therapy for schizophrenia and cognitive deficits.

  17. Pharmacologic and radioimmunologic studies on the role of the dopaminergic system in the brain for the regulation of adenohypophyseal adrenocorticotropic function

    Energy Technology Data Exchange (ETDEWEB)

    Boyadzhieva, N; Milkov, V; Milanov, S [Meditsinska Akademiya, Sofia (Bulgaria). Nauchen Inst. po Rentgenologiya i Radiobiologiya

    1990-01-01

    The studies were performed in three experimental setups after single and repeated (5, 10, 20 and 30 times daily) application of dopamine agonists and antagonists (levodopa, bromcryptine, apomorphine hydrochloride, levodopa + carbidopa combination and haloperidol) for determining the changes in the serum ACTH level in rats. In stress-free conditions and in the presence of stress effects dopamine agonists were shown to exert inhibiting effect on ACTH release. The independent role of the brain dopaminergic system was studied on combined application of agents (obsidan, phentolamine and piperoxan) blocking the central alpha- and beta-receptors and dopamine agonists and antagonists, accordingly under stress-free conditions and after cold-induced stress. The results pointed out the participation of the dopaminergic system in the complex neuro-meditary mechanism of controlling the production and release of ACTH from the adenohypophysis both under stress-free and stress conditions. A hypothesis is advanced that the brain dopaminergic system is implicated in the regulation of the adrenocorticotropic function in suppressed adrenergic system. 3 figs, 7 refs.

  18. Pharmacologic and radioimmunologic studies on the role of the dopaminergic system in the brain for the regulation of adenohypophyseal adrenocorticotropic function

    International Nuclear Information System (INIS)

    Boyadzhieva, N.; Milkov, V.; Milanov, S.

    1990-01-01

    The studies were performed in three experimental setups after single and repeated (5, 10, 20 and 30 times daily) application of dopamine agonists and antagonists (levodopa, bromcryptine, apomorphine hydrochloride, levodopa + carbidopa combination and haloperidol) for determining the changes in the serum ACTH level in rats. In stress-free conditions and in the presence of stress effects dopamine agonists were shown to exert inhibiting effect on ACTH release. The independent role of the brain dopaminergic system was studied on combined application of agents (obsidan, phentolamine and piperoxan) blocking the central alpha- and beta-receptors and dopamine agonists and antagonists, accordingly under stress-free conditions and after cold-induced stress. The results pointed out the participation of the dopaminergic system in the complex neuro-meditary mechanism of controlling the production and release of ACTH from the adenohypophysis both under stress-free and stress conditions. A hypothesis is advanced that the brain dopaminergic system is implicated in the regulation of the adrenocorticotropic function in suppressed adrenergic system. 3 figs, 7 refs

  19. Advances in the nutritional and pharmacological management of phenylketonuria

    Science.gov (United States)

    Ney, Denise M.; Blank, Robert D.; Hansen, Karen E.

    2014-01-01

    Structural Abstract Purpose of review The purpose is to discuss advances in the nutritional and pharmacological management of phenylketonuria (PKU). Recent findings Glycomacropeptide (GMP), a whey protein produced during cheese production, is a low-phe intact protein that represents a new dietary alternative to synthetic amino acids (AAs) for people with PKU. Skeletal fragility is a long-term complication of PKU that based on murine research, appears to result from both genetic and nutritional factors. Skeletal fragility in murine PKU is attenuated with the GMP diet, compared with an AA diet, allowing greater radial bone growth. Pharmacologic therapy with tetrahydrobiopterin (BH4), acting as a molecular chaperone for phenylalanine hydroxylase, increases tolerance to dietary phe in some individuals. Large neutral AAs (LNAA) inhibit phe transport across the intestinal mucosa and blood brain barrier; LNAA are most effective for individuals unable to comply with the low-phe diet. Summary Although a low-phe synthetic AA diet remains the mainstay of PKU management, new nutritional and pharmacological treatment options offer alternative approaches to maintain lifelong low phe concentrations. GMP medical foods provide an alternative to AA formula that may improve bone health, and BH4 permits some individuals with PKU to increase tolerance to dietary phe. Further research is needed to characterize the long-term efficacy of these new approaches for PKU management. PMID:24136088

  20. (+)- and (-)-N-allylnormetazocine binding sites in mouse brain: in vitro and in vivo characterization and regional distribution

    International Nuclear Information System (INIS)

    Compton, D.R.; Bagley, R.B.; Katzen, J.S.; Martin, B.R.

    1987-01-01

    In vivo and in vitro binding studies, both in whole brain and in selected areas, indicate that non-identical (+)- and (-)-NANM sites exist in the mouse brain, and each exhibits a different regional distribution. The in vivo binding of (+)- 3 H-NANM was found to be saturable at pharmacologically relevant doses, and represents a relatively small (10 - 22%) portion of total brain (+)- 3 H-NANM concentrations. The in vivo binding of (+)- 3 H-NANM was selectively displaced by (+)-NANM and PCP, and more sensitive to haloperidol and (+)-ketocyclazocine than the (-)- 3 H-NANM site. The in vivo binding of (-)- 3 H-NANM was selectively displaced by (-)-NANM, and more sensitive to naloxone and (-) ketocyclazocine than the (+)- 3 H-NANM site, and insensitive to PCP. This study indicates that the investigation of NANM binding sites is possible using in vivo binding techniques, and that each isomer apparently binds, in the mouse brain, to a single class of distinct sites. 32 references, 4 figures, 2 tables

  1. 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)

    Wagner, J.A.

    1987-01-01

    This dissertation provides molecular evidence for a diversity of Ca 2+ channels in neuronal and non-neuronal tissues. First, I demonstrated specific, reversible, saturable binding sites for omega [ 125 I]conotoxin GVIA (omega[ 125 I]CTX) in rat brain and rabbit sympathetic ganglion. Omega [ 125 I]CTX binding has a unique pharmacology, ion selectivity, and anatomical distribution in rat brain. Omega [ 125 I]CTX binding was solubilized, retaining an appropriate pharmacology and ion selectivity. Omega[ 125 I]CTX binding may be associated with a Ca 2+ channel because the K/sub D/ of omega [ 125 I]CTX is similar to the IC 50 of inhibition of depolarization-induced 45 Ca 2+ flux into rat brain synaptosomes. Specific (-)[ 3 H]desmethoxyverapamil ((-)[ 3 H]DMV) binding sites were demonstrated on osteoblast-like osteosarcoma cell membranes

  2. Characterization of TEM1/endosialin in human and murine brain tumors

    International Nuclear Information System (INIS)

    Carson-Walter, Eleanor B; Walter, Kevin A; Winans, Bethany N; Whiteman, Melissa C; Liu, Yang; Jarvela, Sally; Haapasalo, Hannu; Tyler, Betty M; Huso, David L; Johnson, Mahlon D

    2009-01-01

    TEM1/endosialin is an emerging microvascular marker of tumor angiogenesis. We characterized the expression pattern of TEM1/endosialin in astrocytic and metastatic brain tumors and investigated its role as a therapeutic target in human endothelial cells and mouse xenograft models. In situ hybridization (ISH), immunohistochemistry (IH) and immunofluorescence (IF) were used to localize TEM1/endosialin expression in grade II-IV astrocytomas and metastatic brain tumors on tissue microarrays. Changes in TEM1/endosialin expression in response to pro-angiogenic conditions were assessed in human endothelial cells grown in vitro. Intracranial U87MG glioblastoma (GBM) xenografts were analyzed in nude TEM1/endosialin knockout (KO) and wildtype (WT) mice. TEM1/endosialin was upregulated in primary and metastatic human brain tumors, where it localized primarily to the tumor vasculature and a subset of tumor stromal cells. Analysis of 275 arrayed grade II-IV astrocytomas demonstrated TEM1/endosialin expression in 79% of tumors. Robust TEM1/endosialin expression occurred in 31% of glioblastomas (grade IV astroctyomas). TEM1/endosialin expression was inversely correlated with patient age. TEM1/endosialin showed limited co-localization with CD31, αSMA and fibronectin in clinical specimens. In vitro, TEM1/endosialin was upregulated in human endothelial cells cultured in matrigel. Vascular Tem1/endosialin was induced in intracranial U87MG GBM xenografts grown in mice. Tem1/endosialin KO vs WT mice demonstrated equivalent survival and tumor growth when implanted with intracranial GBM xenografts, although Tem1/endosialin KO tumors were significantly more vascular than the WT counterparts. TEM1/endosialin was induced in the vasculature of high-grade brain tumors where its expression was inversely correlated with patient age. Although lack of TEM1/endosialin did not suppress growth of intracranial GBM xenografts, it did increase tumor vascularity. The cellular localization of TEM1

  3. Characterization of Nanodiamond-based anti-HIV drug Delivery to the Brain.

    Science.gov (United States)

    Roy, Upal; Drozd, Vadym; Durygin, Andriy; Rodriguez, Jesse; Barber, Paul; Atluri, Venkata; Liu, Xiaohua; Voss, Thomas G; Saxena, Surendra; Nair, Madhavan

    2018-01-25

    Human Immunodeficiency Virus Type 1 (HIV-1) remains one of the leading causes of death worldwide. Present combination antiretroviral therapy has substantially improved HIV-1 related pathology. However, delivery of therapeutic agents to the HIV reservoir organ like Central nervous system (CNS) remains a major challenge primarily due to the ineffective transmigration of drugs through Blood Brain Barrier (BBB). The recent advent of nanomedicine-based drug delivery has stimulated the development of innovative systems for drug delivery. In this regard, particular focus has been given to nanodiamond due to its natural biocompatibility and non-toxic nature-making it a more efficient drug carrier than other carbon-based materials. Considering its potential and importance, we have characterized unmodified and surface-modified (-COOH and -NH 2 ) nanodiamond for its capacity to load the anti-HIV-1 drug efavirenz and cytotoxicity, in vitro. Overall, our study has established that unmodified nanodiamond conjugated drug formulation has significantly higher drug loading capacity than surface-modified nanodiamond with minimum toxicity. Further, this nanodrug formulation was characterized by its drug dissolution profile, transmigration through the BBB, and its therapeutic efficacy. The present biological characterizations provide a foundation for further study of in-vivo pharmacokinetics and pharmacodynamics of nanodiamond-based anti-HIV drugs.

  4. A Tyrosine-Hydroxylase Characterization of Dopaminergic Neurons in the Honey Bee Brain

    Directory of Open Access Journals (Sweden)

    Stevanus R. Tedjakumala

    2017-07-01

    Full Text Available Dopamine (DA plays a fundamental role in insect behavior as it acts both as a general modulator of behavior and as a value system in associative learning where it mediates the reinforcing properties of unconditioned stimuli (US. Here we aimed at characterizing the dopaminergic neurons in the central nervous system of the honey bee, an insect that serves as an established model for the study of learning and memory. We used tyrosine hydroxylase (TH immunoreactivity (ir to ensure that the neurons detected synthesize DA endogenously. We found three main dopaminergic clusters, C1–C3, which had been previously described; the C1 cluster is located in a small region adjacent to the esophagus (ES and the antennal lobe (AL; the C2 cluster is situated above the C1 cluster, between the AL and the vertical lobe (VL of the mushroom body (MB; the C3 cluster is located below the calyces (CA of the MB. In addition, we found a novel dopaminergic cluster, C4, located above the dorsomedial border of the lobula, which innervates the visual neuropils of the bee brain. Additional smaller processes and clusters were found and are described. The profuse dopaminergic innervation of the entire bee brain and the specific connectivity of DA neurons, with visual, olfactory and gustatory circuits, provide a foundation for a deeper understanding of how these sensory modules are modulated by DA, and the DA-dependent value-based associations that occur during associative learning.

  5. Biochemical Characterization of Bovine Brain Myristoyl-CoA:Protein N-Myristoyltransferase Type 2

    Directory of Open Access Journals (Sweden)

    Ponniah Selvakumar

    2009-01-01

    Full Text Available Protein N-myristoylation is a lipidic modification which refers to the covalent attachment of myristate, a 14-carbon saturated fatty acid, to the N-terminal glycine residue of a number of mammalian, viral, and fungal proteins. In this paper, we have cloned the gene coding for myristoyl-CoA:protein N-myristoyltransferase (NMT from Bos tarus brain. The open reading frame codes for a 410-amino-acid protein and overexpressed in Escherichia coli. Kinetic studies suggested that bovine brain NMT2 and human NMT1 show significant differences in their peptide substrate specificities. The metal ion Ca2+ had stimulatory effects on NMT2 activity while Mn2+ and Zn2+ inhibited the enzyme activity. In addition, NMT2 activity was inhibited by various organic solvents and other detergents while NMT1 had a stimulatory effect. Biochemical characterization suggested that both forms of NMT have unique characteristics. Further analysis towards functional role NMT2 will lead the development of therapeutic target for the progression of various diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases.

  6. In vivo pharmacological characterization of (+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thiophenol hydrochloride (SIB-1553A), a novel cholinergic ligand: microdialysis studies.

    Science.gov (United States)

    Rao, Tadimeti S; Reid, Richard T; Correa, Lucia D; Santori, Emily M; Gardner, Michael F; Sacaan, Aida I; Lorrain, Daniel; Vernier, Jean-Michel

    2003-10-03

    SIB-1553A ((+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thiophenol HCl) is a neuronal nicotinic acetylcholine receptor (nAChR) ligand which is active in rodent and primate models of cognition. In functional assays, SIB-1553A exhibits marked subtype selectivity for nAChRs as compared to nicotine. In addition SIB-1553A also exhibits affinities to histaminergic (H3) and serotonergic (5-HT1 and 5HT2) receptors and sigma binding sites. In the present investigation, we characterized SIB-1553A-induced neurotransmitter release in vivo. Following subcutaneous injection (s.c., 10 mg/kg), SIB-1553A rapidly entered the brain achieving concentration of approximately 20 microM 15 min post-injection and was eliminated from plasma with a terminal half-life of approximately 32 min. In freely moving rats, SIB-1553A (1-40 mg/kg, s.c.), markedly increased ACh release in the hippocampus and prefrontal cortex. In both regions, the magnitude of SIB-1553A-induced ACh release was greater than that seen with the prototypical nAChR agonist, nicotine (0.4 mg/kg, s.c.). Both isomers of SIB-1553A induced similar levels of increase in hippocampal ACh release. Increased hippocampal ACh release was also observed following oral administration of SIB-1553A (40 mg/kg) or after local perfusion into the hippocampus (1 mM). SIB-1553A-induced hippocampal ACh release was significantly attenuated by two nAChR antagonists, mecamylamine (MEC) and dihydro-beta-erythroidine (DHbetaE), and by the dopamine (DA) (D1) antagonist, SCH-23390, arguing that ACh release, in part, involves activation of nAChRs and a permissive DA synapse. In contrast to its robust effects on ACh release, SIB-1553A (40 mg/kg, s.c.) modestly increased striatal DA release (approximately 180% of baseline). Due to the proposed role of cholinergic pathways in learning and memory, the neurochemical profile of SIB-1553A suggests a potential for it to treat cognitive dysfunction.

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

    OpenAIRE

    Elisabeth eJonckers; Disha eShah; Julie eHamaide; Marleen eVerhoye; Annemie eVan Der Linden

    2015-01-01

    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 stimu...

  8. Characterization of the L-glutamate clearance pathways across the blood-brain barrier and the effect of astrocytes in an in vitro blood-brain barrier model

    DEFF Research Database (Denmark)

    Helms, Hans CC; Aldana, Blanca I; Groth, Simon

    2017-01-01

    The aim was to characterize the clearance pathways for L-glutamate from the brain interstitial fluid across the blood-brain barrier using a primary in vitro bovine endothelial/rat astrocyte co-culture. Transporter profiling was performed using uptake studies of radiolabeled L-glutamate with co...... brain to blood via the concerted action of abluminal and luminal transport proteins, but the total brain clearance is highly dependent on metabolism in astrocytes and endothelial cells followed by transport of metabolites....

  9. Brain SPECT in children

    International Nuclear Information System (INIS)

    Guyot, M.; Baulieu, J.L.

    1996-01-01

    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)

  10. Mapping and characterization of positive and negative BOLD responses to visual stimulation in multiple brain regions at 7T

    NARCIS (Netherlands)

    Jorge, João; Figueiredo, Patrícia; Gruetter, Rolf; Van der Zwaag, W.

    External stimuli and tasks often elicit negative BOLD responses in various brain regions, and growing experimental evidence supports that these phenomena are functionally meaningful. In this work, the high sensitivity available at 7T was explored to map and characterize both positive (PBRs) and

  11. Characterization of melanocortin receptor ligands on cloned brain melanocortin receptors and on grooming behavior in the rat

    NARCIS (Netherlands)

    Gispen, W.H.; Adan, R.A.H.; Szklarczyk, A.W.; Oosterom, J.; Brakkee, J.H.; Nijenhuis, W.A.; Schaaper, W.M.; Meloen, R.H.

    1999-01-01

    Since the melanocortin MC3 and melanocortin MC4 receptors are the main melanocortin receptor subtypes expressed in rat brain, we characterized the activity and affinity of nine melanocortin receptor ligands using these receptors in vitro, as well as their activity in a well-defined

  12. Characterization of Noise Signatures of Involuntary Head Motion in the Autism Brain Imaging Data Exchange Repository

    Science.gov (United States)

    Caballero, Carla; Mistry, Sejal; Vero, Joe; Torres, Elizabeth B

    2018-01-01

    The variability inherently present in biophysical data is partly contributed by disparate sampling resolutions across instrumentations. This poses a potential problem for statistical inference using pooled data in open access repositories. Such repositories combine data collected from multiple research sites using variable sampling resolutions. One example is the Autism Brain Imaging Data Exchange repository containing thousands of imaging and demographic records from participants in the spectrum of autism and age-matched neurotypical controls. Further, statistical analyses of groups from different diagnoses and demographics may be challenging, owing to the disparate number of participants across different clinical subgroups. In this paper, we examine the noise signatures of head motion data extracted from resting state fMRI data harnessed under different sampling resolutions. We characterize the quality of the noise in the variability of the raw linear and angular speeds for different clinical phenotypes in relation to age-matched controls. Further, we use bootstrapping methods to ensure compatible group sizes for statistical comparison and report the ranges of physical involuntary head excursions of these groups. We conclude that different sampling rates do affect the quality of noise in the variability of head motion data and, consequently, the type of random process appropriate to characterize the time series data. Further, given a qualitative range of noise, from pink to brown noise, it is possible to characterize different clinical subtypes and distinguish them in relation to ranges of neurotypical controls. These results may be of relevance to the pre-processing stages of the pipeline of analyses of resting state fMRI data, whereby head motion enters the criteria to clean imaging data from motion artifacts. PMID:29556179

  13. Characterization of Noise Signatures of Involuntary Head Motion in the Autism Brain Imaging Data Exchange Repository

    Directory of Open Access Journals (Sweden)

    Carla Caballero

    2018-03-01

    Full Text Available The variability inherently present in biophysical data is partly contributed by disparate sampling resolutions across instrumentations. This poses a potential problem for statistical inference using pooled data in open access repositories. Such repositories combine data collected from multiple research sites using variable sampling resolutions. One example is the Autism Brain Imaging Data Exchange repository containing thousands of imaging and demographic records from participants in the spectrum of autism and age-matched neurotypical controls. Further, statistical analyses of groups from different diagnoses and demographics may be challenging, owing to the disparate number of participants across different clinical subgroups. In this paper, we examine the noise signatures of head motion data extracted from resting state fMRI data harnessed under different sampling resolutions. We characterize the quality of the noise in the variability of the raw linear and angular speeds for different clinical phenotypes in relation to age-matched controls. Further, we use bootstrapping methods to ensure compatible group sizes for statistical comparison and report the ranges of physical involuntary head excursions of these groups. We conclude that different sampling rates do affect the quality of noise in the variability of head motion data and, consequently, the type of random process appropriate to characterize the time series data. Further, given a qualitative range of noise, from pink to brown noise, it is possible to characterize different clinical subtypes and distinguish them in relation to ranges of neurotypical controls. These results may be of relevance to the pre-processing stages of the pipeline of analyses of resting state fMRI data, whereby head motion enters the criteria to clean imaging data from motion artifacts.

  14. Pharmacological characterization of RS-1259, an orally active dual inhibitor of acetylcholinesterase and serotonin transporter, in rodents: possible treatment of Alzheimer's disease.

    Science.gov (United States)

    Abe, Yasuyuki; Aoyagi, Atsushi; Hara, Takao; Abe, Kazumi; Yamazaki, Reina; Kumagae, Yoshihiro; Naruto, Shunji; Koyama, Kazuo; Marumoto, Shinji; Tago, Keiko; Toda, Narihiro; Takami, Kazuko; Yamada, Naho; Ori, Mayuko; Kogen, Hiroshi; Kaneko, Tsugio

    2003-09-01

    A dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT), RS-1259 (4-[1S)-methylamino-3-(4-nitrophenoxy)]propylphenyl N,N-dimethylcarbamate (fumaric acid)(1/2)salt), was newly synthesized. RS-1259 simultaneously inhibited AChE and SERT in the brain following an oral administration in mice and rats. Actual simultaneous elevation of extracellular levels of 5-HT and ACh in the rat hippocampus was confirmed by microdialysis. The compound was as effective as SERT inhibitors such as fluoxetine and fluvoxamine in a 5-hydroxytryptophan-enhancing test in mice. Spatial memory deficits in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake episodes in the daytime electroencephalogram of rats. Although RS-1259 was weaker than donepezil in enhancing central cholinergic transmission, as observed by ACh elevation in the hippocampus and memory enhancement in aged rats, the efficacy of RS-1259 on the consciousness level, which reflects the whole activity in the brain, was almost the same as that of donepezil. These results suggest that both cholinergic and serotonergic systems are involved in maintaining brain arousal and that a dual inhibitor of AChE and SERT may be useful for the treatment of cognitive disorders associated with reduced brain activity such as in Alzheimer's disease.

  15. Multimodal Characterization of the Late Effects of Traumatic Brain Injury: A Methodological Overview of the Late Effects of Traumatic Brain Injury Project.

    Science.gov (United States)

    Edlow, Brian L; Keene, C Dirk; Perl, Daniel P; Iacono, Diego; Folkerth, Rebecca D; Stewart, William; Mac Donald, Christine L; Augustinack, Jean; Diaz-Arrastia, Ramon; Estrada, Camilo; Flannery, Elissa; Gordon, Wayne A; Grabowski, Thomas J; Hansen, Kelly; Hoffman, Jeanne; Kroenke, Christopher; Larson, Eric B; Lee, Patricia; Mareyam, Azma; McNab, Jennifer A; McPhee, Jeanne; Moreau, Allison L; Renz, Anne; Richmire, KatieRose; Stevens, Allison; Tang, Cheuk Y; Tirrell, Lee S; Trittschuh, Emily H; van der Kouwe, Andre; Varjabedian, Ani; Wald, Lawrence L; Wu, Ona; Yendiki, Anastasia; Young, Liza; Zöllei, Lilla; Fischl, Bruce; Crane, Paul K; Dams-O'Connor, Kristen

    2018-05-03

    Epidemiological studies suggest that a single moderate-to-severe traumatic brain injury (TBI) is associated with an increased risk of neurodegenerative disease, including Alzheimer's disease (AD) and Parkinson's disease (PD). Histopathological studies describe complex neurodegenerative pathologies in individuals exposed to single moderate-to-severe TBI or repetitive mild TBI, including chronic traumatic encephalopathy (CTE). However, the clinicopathological links between TBI and post-traumatic neurodegenerative diseases such as AD, PD, and CTE remain poorly understood. Here, we describe the methodology of the Late Effects of TBI (LETBI) study, whose goals are to characterize chronic post-traumatic neuropathology and to identify in vivo biomarkers of post-traumatic neurodegeneration. LETBI participants undergo extensive clinical evaluation using National Institutes of Health TBI Common Data Elements, proteomic and genomic analysis, structural and functional magnetic resonance imaging (MRI), and prospective consent for brain donation. Selected brain specimens undergo ultra-high resolution ex vivo MRI and histopathological evaluation including whole-mount analysis. Co-registration of ex vivo and in vivo MRI data enables identification of ex vivo lesions that were present during life. In vivo signatures of postmortem pathology are then correlated with cognitive and behavioral data to characterize the clinical phenotype(s) associated with pathological brain lesions. We illustrate the study methods and demonstrate proof of concept for this approach by reporting results from the first LETBI participant, who despite the presence of multiple in vivo and ex vivo pathoanatomic lesions had normal cognition and was functionally independent until her mid-80s. The LETBI project represents a multidisciplinary effort to characterize post-traumatic neuropathology and identify in vivo signatures of postmortem pathology in a prospective study.

  16. 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.

  17. 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.

  18. Biological and Pharmacological properties

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Biological and Pharmacological properties. NOEA inhibits Ceramidase. Anandamide inhibits gap junction conductance and reduces sperm fertilizing capacity. Endogenous ligands for Cannabinoid receptors (anandamide and NPEA). Antibacterial and antiviral ...

  19. 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.

  20. 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)

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

    2010-01-01

    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.

  1. 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

  2. Pharmacology and function of melatonin receptors

    International Nuclear Information System (INIS)

    Dubocovich, M.L.

    1988-01-01

    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

  3. Pharmacological treatment of sleep disorders and its relationship with neuroplasticity.

    Science.gov (United States)

    Abad, Vivien C; Guilleminault, Christian

    2015-01-01

    Sleep and wakefulness are regulated by complex brain circuits located in the brain stem, thalamus, subthalamus, hypothalamus, basal forebrain, and cerebral cortex. Wakefulness and NREM and REM sleep are modulated by the interactions between neurotransmitters that promote arousal and neurotransmitters that promote sleep. Various lines of evidence suggest that sleep disorders may negatively affect neuronal plasticity and cognitive function. Pharmacological treatments may alleviate these effects but may also have adverse side effects by themselves. This chapter discusses the relationship between sleep disorders, pharmacological treatments, and brain plasticity, including the treatment of insomnia, hypersomnias such as narcolepsy, restless legs syndrome (RLS), obstructive sleep apnea (OSA), and parasomnias.

  4. Crystal structure and pharmacological characterization of a novel N-methyl-D-aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site

    DEFF Research Database (Denmark)

    Kvist, Trine; Steffensen, Thomas Bielefeldt; Greenwood, Jeremy R

    2013-01-01

    NMDA receptors are ligand-gated ion channels that mediate excitatory neurotransmission in the brain. They are tetrameric complexes composed of glycine-binding GluN1 and GluN3 subunits together with glutamate-binding GluN2 subunits. Subunit-selective antagonists that discriminate between the glyci...... screening. Furthermore, the structure reveals that the imino acetamido group of TK40 acts as an α-amino acid bioisostere, which could be of importance in bioisosteric replacement strategies for future ligand design....

  5. 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.

  6. Affinity purification and partial characterization of the zonulin/zonula occludens toxin (Zot) receptor from human brain.

    Science.gov (United States)

    Lu, R; Wang, W; Uzzau, S; Vigorito, R; Zielke, H R; Fasano, A

    2000-01-01

    The intercellular tight junctions (TJs) of endothelial cells represent the limiting structure for the permeability of the blood-brain barrier (BBB). Although the BBB has been recognized as being the interface between the bloodstream and the brain, little is known about its regulation. Zonulin and its prokaryotic analogue, zonula occludens toxin (Zot) elaborated by Vibrio cholerae, both modulate intercellular TJs by binding to a specific surface receptor with subsequent activation of an intracellular signaling pathway involving phospholipase C and protein kinase C activation and actin polymerization. Affinity column purification revealed that human brain plasma membrane preparations contain two Zot binding proteins of approximately 55 and approximately 45 kDa. Structural and kinetic studies, including saturation and competitive assays, identified the 55-kDa protein as tubulin, whereas the 45-kDa protein represents the zonulin/Zot receptor. Biochemical characterization provided evidence that this receptor is a glycoprotein containing multiple sialic acid residues. Comparison of the N-terminal sequence of the zonulin/Zot receptor with other protein sequences by BLAST analysis revealed a striking similarity with MRP-8, a 14-kDa member of the S-100 family of calcium binding proteins. The discovery and characterization of this receptor from human brain may significantly contribute to our knowledge on the pathophysiological regulation of the BBB.

  7. 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

    In earlier studies insects were proposed as suitable models for vertebrate blood–brain barrier (BBB) permeability prediction and useful in early drug discovery. Here we provide transcriptome and functional data demonstrating the presence of a P-glycoprotein (Pgp) efflux transporter in the brain b...... has the potential to act as a robust and convenient model for assessing BBB permeability in early drug discovery.......In earlier studies insects were proposed as suitable models for vertebrate blood–brain barrier (BBB) permeability prediction and useful in early drug discovery. Here we provide transcriptome and functional data demonstrating the presence of a P-glycoprotein (Pgp) efflux transporter in the brain...

  8. Characterization of the Distance Relationship Between Localized Serotonin Receptors and Glia Cells on Fluorescence Microscopy Images of Brain Tissue.

    Science.gov (United States)

    Jacak, Jaroslaw; Schaller, Susanne; Borgmann, Daniela; Winkler, Stephan M

    2015-08-01

    We here present two new methods for the characterization of fluorescent localization microscopy images obtained from immunostained brain tissue sections. Direct stochastic optical reconstruction microscopy images of 5-HT1A serotonin receptors and glial fibrillary acidic proteins in healthy cryopreserved brain tissues are analyzed. In detail, we here present two image processing methods for characterizing differences in receptor distribution on glial cells and their distribution on neural cells: One variant relies on skeleton extraction and adaptive thresholding, the other on k-means based discrete layer segmentation. Experimental results show that both methods can be applied for distinguishing classes of images with respect to serotonin receptor distribution. Quantification of nanoscopic changes in relative protein expression on particular cell types can be used to analyze degeneration in tissues caused by diseases or medical treatment.

  9. Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: Design, characterization and in vivo pharmacokinetic evaluation.

    Science.gov (United States)

    Đorđević, Sanela M; Cekić, Nebojša D; Savić, Miroslav M; Isailović, Tanja M; Ranđelović, Danijela V; Marković, Bojan D; Savić, Saša R; Timić Stamenić, Tamara; Daniels, Rolf; Savić, Snežana D

    2015-09-30

    This paper describes design and evaluation of parenteral lecithin-based nanoemulsions intended for brain delivery of risperidone, a poorly water-soluble psychopharmacological drug. The nanoemulsions were prepared through cold/hot high pressure homogenization and characterized regarding droplet size, polydispersity, surface charge, morphology, drug-vehicle interactions, and physical stability. To estimate the simultaneous influence of nanoemulsion formulation and preparation parameters--co-emulsifier type, aqueous phase type, homogenization temperature--on the critical quality attributes of developed nanoemulsions, a general factorial experimental design was applied. From the established design space and stability data, promising risperidone-loaded nanoemulsions (mean size about 160 nm, size distribution Solutol(®) HS15 as co-emulsifier, were produced by hot homogenization and their ability to improve risperidone delivery to the brain was assessed in rats. Pharmacokinetic study demonstrated erratic brain profiles of risperidone following intraperitoneal administration in selected nanoemulsions, most probably due to their different droplet surface properties (different composition of the stabilizing layer). Namely, polysorbate 80-costabilized nanoemulsion showed increased (1.4-7.4-fold higher) risperidone brain availability compared to other nanoemulsions and drug solution, suggesting this nanoemulsion as a promising carrier worth exploring further for brain targeting. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. 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.

  11. Characterization of children hospitalized with traumatic brain injuries after building falls.

    Science.gov (United States)

    Loftus, Kirsten V; Rhine, Tara; Wade, Shari L; Pomerantz, Wendy J

    2018-04-10

    Unintentional falls cause a substantial proportion of pediatric traumatic brain injury (TBI), with building falls carrying particularly high risk for morbidity and mortality. The cohort of children sustaining building fall-related TBI has not been well-examined. We sought to characterize children hospitalized with building fall-related TBIs and evaluate if specific factors distinguished these children from children hospitalized with TBI due to other fall mechanisms. We secondarily assessed if TBI severity among children injured due to a building fall varied between children from urban versus non-urban areas. This was a secondary analysis of the Pediatric Health Information System (PHIS), an administrative database from pediatric hospitals. We identified children codes. Urban versus non-urban status was determined using PHIS-assigned Rural-Urban Commuting Area codes. Injury severity (i.e. Injury Severity Score (ISS) and head Abbreviated Injury Scale (AIS) score) were calculated. Head AIS scores were dichotomized into minor/moderate (1-2) and serious/severe (3-6) for analysis. Frequencies, descriptive statistics, Chi-square analysis, and Mann-Whitney U analysis characterized populations and determined group differences. The study cohort included 23,813 children, of whom 933 (3.9%) fell from buildings. Within the building fall cohort, 707 (75.8%) resided in urban areas, 619 (66.3%) were male, 513 (55.0%) were white, and 528 (56.6%) had government insurance; the mean age was 3.8 years (SD 2.9). There was a larger proportion of children with serious/severe TBI among those injured from building falls relative to other falls (63.4% vs 53.9%, p building falls, those from non-urban areas were more likely to sustain a serious/severe TBI relative to urban children (58.9% vs 53.6%, p buildings falls with TBI sustained more severe injuries relative to other fall types. Although a majority of children hospitalized with building fall related-TBIs were from urban areas, those

  12. H-1 chemical shift imaging characterization of human brain tumor and edema

    NARCIS (Netherlands)

    Sijens, PE; Oudkerk, M

    Longitudinal (T1) and transverse (T2) relaxation times of metabolites in human brain tumor, peritumoral edema, and unaffected brain tissue were assessed from point resolved spectroscopy (PRESS) H-1 chemical shift imaging results at different repetition times (TR = 1500 and 5000 ms; T1: n = 19) and

  13. Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics.

    Science.gov (United States)

    Chen, Xiao-Wen; Sun, Yuan-Yuan; Fu, Lei; Li, Jian-Qi

    2016-11-10

    A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  14. Pharmacologic modeling of primary mitochondrial respiratory chain dysfunction in zebrafish.

    Science.gov (United States)

    Byrnes, James; Ganetzky, Rebecca; Lightfoot, Richard; Tzeng, Michael; Nakamaru-Ogiso, Eiko; Seiler, Christoph; Falk, Marni J

    2017-07-18

    Mitochondrial respiratory chain (RC) disease is a heterogeneous and highly morbid group of energy deficiency disorders for which no proven effective therapies exist. Robust vertebrate animal models of primary RC dysfunction are needed to explore the effects of variation in RC disease subtypes, tissue-specific manifestations, and major pathogenic factors contributing to each disorder, as well as their pre-clinical response to therapeutic candidates. We have developed a series of zebrafish (Danio rerio) models that inhibit, to variable degrees, distinct aspects of RC function, and enable quantification of animal development, survival, behaviors, and organ-level treatment effects as well as effects on mitochondrial biochemistry and physiology. Here, we characterize four pharmacologic inhibitor models of mitochondrial RC dysfunction in early larval zebrafish, including rotenone (complex I inhibitor), azide (complex IV inhibitor), oligomycin (complex V inhibitor), and chloramphenicol (mitochondrial translation inhibitor that leads to multiple RC complex dysfunction). A range of concentrations and exposure times of each RC inhibitor were systematically evaluated on early larval development, animal survival, integrated behaviors (touch and startle responses), organ physiology (brain death, neurologic tone, heart rate), and fluorescence-based analyses of mitochondrial physiology in zebrafish skeletal muscle. Pharmacologic RC inhibitor effects were validated by spectrophotometric analysis of Complex I, II and IV enzyme activities, or relative quantitation of ATP levels in larvae. Outcomes were prioritized that utilize in vivo animal imaging and quantitative behavioral assessments, as may optimally inform the translational potential of pre-clinical drug screens for future clinical study in human mitochondrial disease subjects. The RC complex inhibitors each delayed early embryo development, with short-term exposures of these three agents or chloramphenicol from 5 to 7 days

  15. In vitro pharmacological characterization of (+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB-1553A), a nicotinic acetylcholine receptor ligand.

    Science.gov (United States)

    Rao, Tadimeti S; Adams, Pamala B; Correa, Lucia D; Santori, Emily M; Sacaan, Aida I; Reid, Richard T; Suto, Carla M; Vernier, Jean Michel

    2003-08-15

    SIB-1553A ((+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol HCl) is a neuronal nicotinic acetylcholine receptor (nAChR) ligand which displaced the binding of [3H]nicotine (NIC) to the rat brain nAChRs with an IC(50) value of 110 nM with no appreciable affinity to the alpha7 nAhRs. SIB-1553A showed modest affinity for histaminergic (H3) and serotonergic (5-HT1 and 5-HT2) receptors, and sigma binding sites. In calcium flux assays, SIB-1553A (0.1-5 microM), in contrast to nicotine, showed a greater selectivity for beta4-subunit containing recombinant hnAChRs (alpha2beta4, alpha3beta4 and alpha4beta4) vs. beta2-subunit containing nAChRs (alpha4beta2 and alpha3beta2) both in terms of efficacy and potency. While NIC (10-30 microM) and epibatidine (0.01-0.1 microM) fully activated human muscle-type AChRs expressed by RD cell line, SIB-1553A was virtually ineffective for up to >100 microM and elicited less than 10% of the response due to suberyldicholine. SIB-1553A (< or =30 microM) evoked [3H]DA release from striatum, olfactory tubercles and prefrontal cortex (PFC), and [3H]NE release from hippocampus and PFC, and this evoked release was sensitive to mecamylamine (MEC). SIB-1553A-evoked neurotransmitter release exhibited region- and transmitter-specific antagonism by dehydro-beta-erythroidine (DHbetaE). SIB-1553A was less efficacious than NIC at evoking [3H]NE from the rat hippocampus and antagonized NIC response upon co-application implying partial agonist properties. SIB-1553A did not evoke basal [3H]ACh release from the rat striatum or hippocampus, but attenuated NMDA-evoked [3H]ACh release from the rat striatum. SIB-1553A did not inhibit rat brain cholinesterase for up to 1 mM. Multiple receptor affinities and release of several neurotransmitters may underlie the cognitive-enhancing effects of SIB-1553A documented in rodent and primate models.

  16. Development, Characterization, and Implementation of a System for Focused Ultrasound-Mediated Blood-Brain Barrier Opening in Mice

    Science.gov (United States)

    Valdez, Michael Aaron

    therapeutic effect, molecules of pharmacologically-relevant sizes were delivered to brain with a novel, multispectral approach. Results demonstrated that the device was able to safely open the BBB, and macromolecule delivery showed that both molecule size and FUS pressure both influence the amount and distribution of molecules in the brain. Using different ultrasound pressures, the threshold for BBB opening was found to be ≥ 180 kPa (0.13 MI). The threshold for damage was found to be ≥ 420 kPa (0.30 MI), and was minor at this pressure, but extensive for higher pressure (870 kPa, 0.62 MI), in which minor damage was caused by this pressure. Performing a novel implementation of a diffusion model on the fluorescence images of 500, 70, and 3 kDa dextran resulted in calculated diffusion coefficients of 0.032 +/- 0.015, 12 +/- 6.0, and 0.13 +/- 0.094 square microns per second, respectively.

  17. CLINICAL PHARMACOLOGY OF DIURETICS

    Directory of Open Access Journals (Sweden)

    I. V. Soldatenko

    2014-06-01

    Full Text Available Clinical pharmacology of diuretics in the international system of ATC (anatomic-therapeutic-chemical is presented. Classification of this group by the action mechanism and caused effects is provided. Pharmacokinetics and pharmacodynamics features, indications and principles of diuretics usage in clinics are considered. Contraindications, side effects and interaction with other drugs of this group are discussed in detail.

  18. 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...

  19. Identification and characterization of an ATP.Mg-dependent protein phosphatase from pig brain

    International Nuclear Information System (INIS)

    Yang, S.D.; Fong, Y.L.

    1985-01-01

    Substantial amounts of ATP.Mg-dependent phosphorylase phosphatase (Fc. M) and its activator (kinase FA) were identified and extensively purified from pig brain, in spite of the fact that glycogen metabolism in the brain is of little importance. The brain Fc.M was completely inactive and could only be activated by ATP.Mg and FA, isolated either from rabbit muscle or pig brain. Kinetical analysis of the dephosphorylation of endogenous brain protein indicates that Fc.M could dephosphorylate 32 P-labeled myelin basic protein (MBP) and [ 32 P]phosphorylase alpha at a comparable rate and moreover, this associated MBP phosphatase activity was also strictly kinase FA/ATP.Mg-dependent, demonstrating that MBP is a potential substrate for Fc.M in the brain. By manipulating MBP and inhibitor-2 as specific potent phosphorylase phosphatase inhibitors, we further demonstrate that 1) Fc.M contains two distinct catalytic sites to dephosphorylate different substrates, and 2) brain MBP may be a physiological trigger involved in the regulation of protein phosphatase substrate specificity in mammalian nervous tissues

  20. Mechanical characterization of the P56 mouse brain under large-deformation dynamic indentation

    Science.gov (United States)

    MacManus, David B.; Pierrat, Baptiste; Murphy, Jeremiah G.; Gilchrist, Michael D.

    2016-02-01

    The brain is a complex organ made up of many different functional and structural regions consisting of different types of cells such as neurons and glia, as well as complex anatomical geometries. It is hypothesized that the different regions of the brain exhibit significantly different mechanical properties, which may be attributed to the diversity of cells and anisotropy of neuronal fibers within individual brain regions. The regional dynamic mechanical properties of P56 mouse brain tissue in vitro and in situ at velocities of 0.71-4.28 mm/s, up to a deformation of 70 μm are presented and discussed in the context of traumatic brain injury. The experimental data obtained from micro-indentation measurements were fit to three hyperelastic material models using the inverse Finite Element method. The cerebral cortex elicited a stiffer response than the cerebellum, thalamus, and medulla oblongata regions for all velocities. The thalamus was found to be the least sensitive to changes in velocity, and the medulla oblongata was most compliant. The results show that different regions of the mouse brain possess significantly different mechanical properties, and a significant difference also exists between the in vitro and in situ brain.

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

    International Nuclear Information System (INIS)

    Gazdzinski, Lisa M.; Cormier, Kyle; Lu, Fred G.; Lerch, Jason P.; Wong, C. Shun; Nieman, Brian J.

    2012-01-01

    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.

  2. 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.

  3. Characterization and distribution of receptors for the atrial natriuretic peptides in mammalian brain

    International Nuclear Information System (INIS)

    Quirion, R.; Dalpe, M.; Dam, T.V.

    1986-01-01

    Both rat 125 I-labeled atrial natriuretic polypeptide [ 125 I-ANP or atrial natriuretic factor fragment ANF-(99-126)] and human 125 I-α-ANP or human ANF-(99-126)] bind with high specificity and affinity to an apparent single class of sites in guinea pig brain. Similar results have been reported in peripheral tissues, which indicate that central and peripheral ANP binding sites have fairly similar structural requirements. In vitro receptor autoradiography shows that in the guinea pig brain, 125 I-ANP binding sites are highly concentrated in the external plexiform layer of the olfactory bulb, subfornical organ, various thalamic nuclei, medial geniculate nucleus, and cerebellum. Lower densities are found in the central nucleus of the amygdala, dentate gyrus, hippocampus, and area postrema. Most remaining regions contain much lower densities of sites. In rat brain 125 I-ANP binding sites are differentially distributed, with high densities in the subfornical organ, area postrema, and linings of ventricles but low densities in the thalamus and cerebellum. In monkey brain, 125 I-ANP binding sites are concentrated in the cerebellum. The presence of high densities of 125 I-ANP binding sites in various brain regions strongly suggests the existence of a family of brain-heart peptides, in analogy to the well-known brain-gut peptides. Moreover, the extensive distribution of 125 I-ANP binding sites in mammalian brain suggests that the possible roles of ANP/ANF-like peptides in brain are not restricted to the central regulation of cardiovascular parameters

  4. Characterization of piRNAs across postnatal development in mouse brain

    KAUST Repository

    Ghosheh, Yanal; Seridi, Loqmane; Ryu, Tae Woo; Takahashi, Hazuki; Orlando, Valerio; Carninci, Piero; Ravasi, Timothy

    2016-01-01

    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.

  5. 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.

  6. Pharmacological management of panic disorder

    Directory of Open Access Journals (Sweden)

    Carlo Marchesi

    2008-03-01

    Full Text Available Carlo MarchesiPsychiatric Section, Department of Neuroscience, University of Parma, Parma, ItalyAbstract: Panic disorder (PD is a disabling condition which appears in late adolescence or early adulthood and affects more frequently women than men. PD is frequently characterized by recurrences and sometimes by a chronic course and, therefore, most patients require longterm treatments to achieve remission, to prevent relapse and to reduce the risks associated with comorbidity. Pharmacotherapy is one of the most effective treatments of PD. In this paper, the pharmacological management of PD is reviewed. Many questions about this effective treatment need to be answered by the clinician and discussed with the patients to improve her/his collaboration to the treatment plan: which is the drug of choice; when does the drug become active; which is the effective dose; how to manage the side effects; how to manage nonresponse; and how long does the treatment last. Moreover, the clinical use of medication in women during pregnancy and breastfeeding or in children and adolescents was reviewed and its risk-benefit balance discussed.Keywords: panic disorder, pharmacological treatment, treatment guidelines

  7. Identification and characterization of insulin receptors on foetal-mouse brain-cortical cells.

    OpenAIRE

    Van Schravendijk, C F; Hooghe-Peters, E L; De Meyts, P; Pipeleers, D G

    1984-01-01

    The occurrence of insulin receptors was investigated in freshly dissociated brain-cortical cells from mouse embryos. By analogy with classical insulin-binding cell types, binding of 125I-insulin to foetal brain-cortical cells was time- and pH-dependent, only partially reversible, and competed for by unlabelled insulin and closely related peptides. Desalanine-desasparagine-insulin, pig proinsulin, hagfish insulin and turkey insulin were respectively 2%, 4%, 2% and 200% as potent as bovine insu...

  8. The formulation, characterization and in vivo evaluation of a magnetic carrier for brain delivery of NIR dye

    Energy Technology Data Exchange (ETDEWEB)

    Raut, S L; Kirthivasan, B; Bommana, M M; Squillante, E; Sadoqi, M, E-mail: squillae@stjohns.edu, E-mail: sadoqim@stjohns.edu [College of Pharmacy and Allied Health Professions, St John' s University, Queens, NY 11439 (United States)

    2010-10-01

    This work reports the targeting of the near infrared (NIR) dye indocyanine green (ICG) to the brain using composite nanoparticles. Thermal decomposition of iron pentacarbonyl was used to synthesize monodisperse oleic acid coated magnetic nanoparticles (OAMNP). Synthesized OAMNP and ICG were encapsulated in a poly (lactide-co-glycolide) matrix using an emulsion evaporation method. Different batches containing OAMNP:PLGA ratios (1:4, 1:2 and 3:4) were prepared with ICG (group B-1, 2, 3) and without ICG (group A-1, 2, 3) loading. All the formulations were characterized in terms of morphology, particle size, zeta potential, magnetic content, ICG encapsulation efficiency and the spectral properties of ICG. The optimized formulation showed an encapsulation efficiency of 56 {+-} 4.6% for ICG and 57 {+-} 1.37% for OAMNP. The biodistribution and brain targeting study involved three groups of six animals, each with 0.4 mg kg{sup -1} equivalent of ICG, given as neat ICG solution, composite nanoparticles without the aid of a magnetic field, and composite nanoparticles under the influence of a magnetic field (8000 G) to groups 1, 2 and 3 respectively. The tissue analysis and microscopy images revealed a significantly higher brain concentration of ICG (p < 0.05) for group 3 than the two control groups. These results are encouraging for the brain delivery of hydrophilic dyes/drugs using this method for biomedical applications.

  9. Pharmacological characterization of LY233053: A structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action

    International Nuclear Information System (INIS)

    Schoepp, D.D.; Ornstein, P.L.; Leander, J.D.; Lodge, D.; Salhoff, C.R.; Zeman, S.; Zimmerman, D.M.

    1990-01-01

    This study reports the activity of a structurally novel excitatory amino acid receptor antagonist, LY233053 [cis-(+-)-4-[(2H-tetrazol-5-yl)methyl]piperidine-2-carboxylic acid], the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of [3H] CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or [3H]kainate binding assays was observed (IC50 values greater than 10,000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats, LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons, LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However, a dose of 160 mg/kg, i.m., was required to produce phencyclidine-like catalepsy in pigeons. In mice, LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary, the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity

  10. Pharmacological treatment and BBB-targeted genetic therapy for MCT8-dependent hypomyelination in zebrafish

    Directory of Open Access Journals (Sweden)

    David Zada

    2016-11-01

    Full Text Available Hypomyelination is a key symptom of Allan-Herndon-Dudley syndrome (AHDS, a psychomotor retardation associated with mutations in the thyroid-hormone (TH transporter MCT8 (monocarboxylate transporter 8. AHDS is characterized by severe intellectual deficiency, neuromuscular impairment and brain hypothyroidism. In order to understand the mechanism for TH-dependent hypomyelination, we developed an mct8 mutant (mct8−/− zebrafish model. The quantification of genetic markers for oligodendrocyte progenitor cells (OPCs and mature oligodendrocytes revealed reduced differentiation of OPCs into oligodendrocytes in mct8−/− larvae and adults. Live imaging of single glial cells showed that the number of oligodendrocytes and the length of their extensions are reduced, and the number of peripheral Schwann cells is increased, in mct8−/− larvae compared with wild type. Pharmacological analysis showed that TH analogs and clemastine partially rescued the hypomyelination in the CNS of mct8−/− larvae. Intriguingly, triiodothyronine (T3 treatment rescued hypomyelination in mct8−/− embryos before the maturation of the blood–brain barrier (BBB, but did not affect hypomyelination in older larvae. Thus, we expressed Mct8-tagRFP in the endothelial cells of the vascular system and showed that even relatively weak mosaic expression completely rescued hypomyelination in mct8−/− larvae. These results suggest potential pharmacological treatments and BBB-targeted gene therapy that can enhance myelination in AHDS and possibly in other TH-dependent brain disorders.

  11. Brain Targeted Intranasal Zaleplon Nano-emulsion: In-Vitro Characterization and Assessment of Gamma Aminobutyric Acid Levels in rabbits' Brain and Plasma at low and high Doses.

    Science.gov (United States)

    Abd-Elrasheed, Eman; El-Helaly, Sara Nageeb; El-Ashmoony, Manal M; Salah, Salwa

    2017-11-30

    Zaleplon is a pyrazolopyrimidin derivative hypnotic drug indicated for the short-term management of insomnia. Zaleplon belongs to Class II drugs, according to the biopharmaceutical classification system (BCS), showing poor solubility and high permeability. It undergoes extensive first-pass hepatic metabolism after oral absorption, with only 30% of Zaleplon being systemically available. It is available in tablet form which is unable to overcome the previous problems. The aim of this study is to enhance solubility and bioavailability via utilizing nanotechnology in the formulation of intranasal Zaleplon nano-emulsion (ZP-NE) to bypass the barriers and deliver an effective therapy to the brain. Screening studies were carried out wherein the solubility of zaleplon in various oils, surfactants(S) and co-surfactants(CoS) were estimated. Pseudo-ternary phase diagrams were constructed and various nano-emulsion formulations were prepared. These formulations were subjected to thermodynamic stability, in-vitro characterization, histopathological studies and assessment of the gamma aminobutyric acid (GABA) level in plasma and brain in rabbits compared to the market product (Sleep aid®). Stable NEs were successfully developed with a particle size range of 44.57±3.351 to 136.90±1.62 nm. A NE composed of 10% Miglyol® 812, 40%Cremophor® RH40 40%Transcutol® HP and 10% water successfully enhanced the bioavailability and brain targeting in the rabbits, showing a three to four folds increase than the marketed product. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. 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

    )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......-ylethynyl)-benzene, nitrogen atoms in ortho positions], with an IC(50) value in the nanomolar range, is significantly more potent than the 3- and 4-pyridyl analogs. Mutational analysis, directed by a previously published mGluR5 homology model, was used to determine key residues for the ligand...... that the higher potency of 2-BisPEB is due to hydrogen bonding to Ser809 because the S809A mutation made 2-BisPEB equipotent to 3- and 4-BisPEB (IC(50), 1-2.5 µM). The potency of MPEP was also greatly affected by S809A (52-fold), suggesting that a Ser809-mediated hydrogen bond is also a key interaction between...

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

    International Nuclear Information System (INIS)

    Grams, M; Wilson, Z; Sio, T; Beltran, C; Tryggestad, E; Gupta, S; Blackwell, C; McCollough, K; Sarkaria, J; Furutani, K

    2014-01-01

    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

  14. ¹H MRS characterization of neurochemical profiles in orthotopic mouse models of human brain tumors.

    Science.gov (United States)

    Hulsey, Keith M; Mashimo, Tomoyuki; Banerjee, Abhishek; Soesbe, Todd C; Spence, Jeffrey S; Vemireddy, Vamsidhara; Maher, Elizabeth A; Bachoo, Robert M; Choi, Changho

    2015-01-01

    Glioblastoma (GBM), the most common primary brain tumor, is resistant to currently available treatments. The development of mouse models of human GBM has provided a tool for studying mechanisms involved in tumor initiation and growth as well as a platform for preclinical investigation of new drugs. In this study we used (1) H MR spectroscopy to study the neurochemical profile of a human orthotopic tumor (HOT) mouse model of human GBM. The goal of this study was to evaluate differences in metabolite concentrations in the GBM HOT mice when compared with normal mouse brain in order to determine if MRS could reliably differentiate tumor from normal brain. A TE =19 ms PRESS sequence at 9.4 T was used for measuring metabolite levels in 12 GBM mice and 8 healthy mice. Levels for 12 metabolites and for lipids/macromolecules at 0.9 ppm and at 1.3 ppm were reliably detected in all mouse spectra. The tumors had significantly lower concentrations of total creatine, GABA, glutamate, total N-acetylaspartate, aspartate, lipids/macromolecules at 0.9 ppm, and lipids/macromolecules at 1.3 ppm than did the brains of normal mice. The concentrations of glycine and lactate, however, were significantly higher in tumors than in normal brain. Copyright © 2014 John Wiley & Sons, Ltd.

  15. Taste Reward Circuitry Related Brain Structures Characterize Ill and Recovered Anorexia Nervosa and Bulimia Nervosa

    Science.gov (United States)

    Frank, Guido K.; Shott, Megan E.; Hagman, Jennifer O.; Mittal, Vijay A.

    2013-01-01

    Objective The pathophysiology of the eating disorder anorexia nervosa remains obscure, but structural brain alterations could be functionally important biomarkers. Here we assessed taste pleasantness and reward sensitivity in relation to brain structure, which might be related to food avoidance commonly seen in eating disorders. Method We used structural magnetic resonance brain imaging to study gray and white matter volumes in individuals with restricting type currently ill (n = 19) or recovered-anorexia nervosa (n = 24), bulimia nervosa (n= 19) and healthy control women (n=24). Results All eating disorder groups showed increased gray matter volume of the medial orbitofrontal cortex (gyrus rectus). Manually tracing confirmed larger gyrus rectus volume, and predicted taste pleasantness across all groups. The analyses also indicated other morphological differences between diagnostic categories: Ill and recovered-anorexia nervosa had increased right, while bulimia nervosa had increased left antero-ventral insula gray matter volumes compared to controls. Furthermore, dorsal striatum volumes were reduced in recovered-anorexia and bulimia nervosa, and predicted sensitivity to reward in the eating disorder groups. The eating disorder groups also showed reduced white matter in right temporal and parietal areas when compared to healthy controls. Notably, the results held when controlling for a range of covariates (e.g., age, depression, anxiety, medications). Conclusion Brain structure in medial orbitofrontal cortex, insula and striatum is altered in eating disorders and suggests altered brain circuitry that has been associated with taste pleasantness and reward value. PMID:23680873

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

    International Nuclear Information System (INIS)

    Amit, Moran; Laider-Trejo, Leonor; Shalom, Vardit; Shabtay-Orbach, Ayelet; Krelin, Yakov; Gil, Ziv

    2013-01-01

    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 μm 2 vs. 4617 μm 2 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

  17. Pharmacological interactions of vasoconstrictors.

    Science.gov (United States)

    Gómez-Moreno, Gerardo; Guardia, Javier; Cutando, Antonio; Calvo-Guirado, José Luis

    2009-01-01

    This article is the first of a series on pharmacological interactions involving medicaments commonly prescribed and/or used in odontology: vasoconstrictors in local anaesthetics and anti-inflammatory and anti-microbial analgesics. The necessity for the odontologist to be aware of adverse reactions as a result of the pharmacological interactions is due to the increase in medicament consumption by the general population. There is a demographic change with greater life expectancy and patients have increased chronic health problems and therefore have increased medicament intake. The presence of adrenaline (epinephrine) and other vasoconstrictors in local odontological anaesthetics is beneficial in relation to the duration and depth of anaesthesia and reduces bleeding and systemic toxicity of the local anaesthetic. However, it might produce pharmacological interactions between the injected vasoconstrictors and the local anaesthetic and adrenergic medicament administered exogenically which the odontologist should be aware of, especially because of the risk of consequent adverse reactions. Therefore the importance of conducting a detailed clinical history of the general state of health and include all medicaments, legal as well as illegal, taken by the patient.

  18. Pharmacological effects of biotin.

    Science.gov (United States)

    Fernandez-Mejia, Cristina

    2005-07-01

    In the last few decades, more vitamin-mediated effects have been discovered at the level of gene expression. Increasing knowledge on the molecular mechanisms of these vitamins has opened new perspectives that form a connection between nutritional signals and the development of new therapeutic agents. Besides its role as a carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. The vitamin regulates genes that are critical in the regulation of intermediary metabolism: Biotin has stimulatory effects on genes whose action favors hypoglycemia (insulin, insulin receptor, pancreatic and hepatic glucokinase); on the contrary, biotin decreases the expression of hepatic phosphoenolpyruvate carboxykinase, a key gluconeogenic enzyme that stimulates glucose production by the liver. The findings that biotin regulates the expression of genes that are critical in the regulation of intermediary metabolism are in agreement with several observations that indicate that biotin supply is involved in glucose and lipid homeostasis. Biotin deficiency has been linked to impaired glucose tolerance and decreased utilization of glucose. On the other hand, the diabetic state appears to be ameliorated by pharmacological doses of biotin. Likewise, pharmacological doses of biotin appear to decrease plasma lipid concentrations and modify lipid metabolism. The effects of biotin on carbohydrate metabolism and the lack of toxic effects of the vitamin at pharmacological doses suggest that biotin could be used in the development of new therapeutics in the treatment of hyperglycemia and hyperlipidemia, an area that we are actively investigating.

  19. Characterization of macromolecular baseline of human brain using metabolite cycled semi-LASER at 9.4T.

    Science.gov (United States)

    Giapitzakis, Ioannis-Angelos; Avdievich, Nikolai; Henning, Anke

    2018-08-01

    Macromolecular resonances (MM) arise mainly from cytosolic proteins and overlap with metabolites, influencing metabolite quantification. Macromolecules can serve as valuable biomarkers for diseases and pathologies. The objectives of this study were to characterize MM at 9.4T in the human brain (occipital and left parietal lobe) and to describe the RF coil setup used for MM acquisition in the two regions. An adiabatic inversion pulse was optimised for metabolite nulling at 9.4T using double inversion recovery and was combined for the first time with metabolite cycled (MC) semi-LASER and appropriate coil configuration. MM spectra (seven volunteers) from two brain locations were averaged and smoothed creating MM templates, which were then parametrized using simulated Voigt-shaped lines within LCModel. Quantification was performed on individual data sets, including corrections for different tissue composition and the T 1 and T 2 relaxation of water. Our coil configuration method resulted in efficient B1+ (>30 T/√kW) for both brain regions. The 15 MM components were detected and quantified in MM baselines of the two brain areas. No significant differences in concentration levels of MM between different regions were found. Two new MM peaks were reported (M7 & M8). Double inversion, which was combined with MC semi-LASER, enabled the acquisition of high spectral resolution MM spectra for both brain regions at 9.4T. The 15 MM components were detected and quantified. Two new MM peaks were reported for the first time (M7 & M8) and preliminarily assigned to β-methylene protons of aspartyl-groups. Magn Reson Med 80:462-473, 2018. © 2018 International Society for Magnetic Resonance in Medicine. © 2018 International Society for Magnetic Resonance in Medicine.

  20. Poloxamer 407/188 binary thermosensitive hydrogels as delivery systems for infiltrative local anesthesia: Physico-chemical characterization and pharmacological evaluation.

    Science.gov (United States)

    Akkari, Alessandra C S; Papini, Juliana Z Boava; Garcia, Gabriella K; Franco, Margareth K K Dias; Cavalcanti, Leide P; Gasperini, Antonio; Alkschbirs, Melissa Inger; Yokaichyia, Fabiano; de Paula, Eneida; Tófoli, Giovana R; de Araujo, Daniele R

    2016-11-01

    In this study, we reported the development and the physico-chemical characterization of poloxamer 407 (PL407) and poloxamer 188 (PL188) binary systems as hydrogels for delivering ropivacaine (RVC), as drug model, and investigate their use in infiltrative local anesthesia for applications on the treatment of post-operative pain. We studied drug-micelle interaction and micellization process by light scattering and differential scanning calorimetry (DSC), the sol-gel transition and hydrogel supramolecular structure by small-angle-X-ray scattering (SAXS) and morphological evaluation by Scanning Electron Microscopy (SEM). In addition, we have presented the investigation of drug release mechanisms, in vitro/in vivo toxic and analgesic effects. Micellar dimensions evaluation showed the formation of PL407-PL188 mixed micelles and the drug incorporation, as well as the DSC studies showed increased enthalpy values for micelles formation after addition of PL 188 and RVC, indicating changes on self-assembly and the mixed micelles formation evoked by drug incorporation. SAXS studies revealed that the phase organization in hexagonal structure was not affected by RVC insertion into the hydrogels, maintaining their supramolecular structure. SEM analysis showed similar patterns after RVC addition. The RVC release followed the Higuchi model, modulated by the PL final concentration and the insertion of PL 188 into the system. Furthermore, the association PL407-PL188 induced lower in vitro cytotoxic effects, increased the duration of analgesia, in a single-dose model study, without evoking in vivo inflammation signs after local injection. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. 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.

  2. Characterization of the gamma-aminobutyric acid receptor system in human brain gliomas

    International Nuclear Information System (INIS)

    Frattola, L.; Ferrarese, C.; Canal, N.; Gaini, S.M.; Galluso, R.; Piolti, R.; Trabucchi, M.

    1985-01-01

    The properties of [ 3 H]-gamma-aminobutyric acid [( 3 H]GABA) binding were studied in biopsied specimens from normal human brain and from 18 cases of human brain gliomas, made up of 6 astrocytomas, 6 glioblastomas, 3 oligodendrogliomas, and 3 medulloblastomas. In fresh membranes obtained from normal gray and white matter one population of Na+-dependent GABA receptors was observed, while in the frozen Triton X-100-treated membranes two distinct populations of Na+-independent binding sites were detected. Specific GABA binding sites in brain gliomas were shown only in frozen Triton X-100-treated membranes. As in normal tissue, these receptors are Na+-independent and bind [ 3 H]GABA with two distinct affinity components. The biochemical profiles of [ 3 H]GABA binding to membranes obtained from different tumors of glial origin are quite similar and cannot be related to the degree of malignancy of the neoplasia

  3. Characterization and visualization of cholecystokinin receptors in rat brain using [3H]pentagastrin

    International Nuclear Information System (INIS)

    Gaudreau, P.; Quirion, R.; St Pierre, S.; Pert, C.B.

    1983-01-01

    [ 3 H]Pentagastrin binds specifically to an apparent single class of CCK receptors on slide-mounted sections of rat brain (KD . 5.6 nM; Bmax . 36.6 fmol/mg protein). This specific binding is temperature-dependent and regulated by ions and nucleotides. The relative potencies of C-terminal fragments of CCK-8(SO 3 H), benzotript and proglumide in inhibiting specific [ 3 H]pentagastrin binding to CCK brain receptors reinforce the concept of different brain and pancreas CCK receptors. CCK receptors were visualized by using tritium-sensitive LKB film analyzed by computerized densitometry. CCK receptors are highly concentrated in the cortex, dentate gyrus, granular and external plexiform layers of the olfactory bulb, anterior olfactory nuclei, olfactory tubercle, claustrum, accumbens nucleus, some nuclei of the amygdala, thalamus and hypothalamus

  4. Molecular and functional characterization of riboflavin specific transport system in rat brain capillary endothelial cells

    Science.gov (United States)

    Patel, Mitesh; Vadlapatla, Ramya Krishna; Pal, Dhananjay; Mitra, Ashim K.

    2012-01-01

    Riboflavin is an important water soluble vitamin (B2) required for metabolic reactions, normal cellular growth, differentiation and function. Mammalian brain cells cannot synthesize riboflavin and must import from systemic circulation. However, the uptake mechanism, cellular translocation and intracellular trafficking of riboflavin in brain capillary endothelial cells are poorly understood. The primary objective of this study is to investigate the existence of riboflavin-specific transport system and delineate the uptake and intracellular regulation of riboflavin in immortalized rat brain capillary endothelial cells (RBE4). The uptake of [3H]-Riboflavin is sodium, temperature and energy dependent but pH independent. [3H]-Riboflavin uptake is saturable with Km and Vmax values of 19 ± 3 µM and 0.235 ± 0.012 picomoles/min/mg protein, respectively. The uptake process is inhibited by unlabelled structural analogs (lumiflavin, lumichrome) but not by structurally unrelated vitamins. Ca++/calmodulin and protein kinase A (PKA) pathways are found to play an important role in the intracellular regulation of [3H]-Riboflavin. Apical and baso-lateral uptake of [3H]-Riboflavin clearly indicate that riboflavin specific transport system is predominantly localized on the apical side of RBE4 cells. A 628 bp band corresponding to riboflavin transporter is revealed in RT-PCR analysis. These findings, for the first time report the existence of a specialized and high affinity transport system for riboflavin in RBE4 cells. Blood-brain barrier (BBB) is a major obstacle limiting drug transport inside the brain as it regulates drug permeation from systemic circulation. This transporter can be utilized for targeted delivery in enhancing brain permeation of highly potent drugs on systemic administration. PMID:22683359

  5. Specific labelling of serotonin 5-HT(1B) receptors in rat frontal cortex with the novel, phenylpiperazine derivative, [3H]GR125,743. A pharmacological characterization.

    Science.gov (United States)

    Millan, M J; Newman-Tancredi, A; Lochon, S; Touzard, M; Aubry, S; Audinot, V

    2002-04-01

    Although several tritiated agonists have been used for radiolabelling serotonin (5-hydroxytryptamine, 5-HT)(1B) receptors in rats, data with a selective, radiolabelled antagonist have not been presented. Inasmuch as [3H]GR125,743 specifically labels cloned, human and native guinea pig 5-HT(1B) receptors and has been employed for characterization of cerebral 5-HT(1B) receptor in the latter species [Eur. J. Pharmacol. 327 (1997) 247.], the present study evaluated its utility for characterization of native, cerebral 5-HT(1B) sites in the rat. In homogenates of frontal cortex, [3H]GR125,743 (0.8 nM) showed rapid association (t(1/2)=3.4 min), >90% specific binding and high affinity (K(d)=0.6 nM) for a homogeneous population of receptors with a density (B(max)) of 160 fmol/mg protein. In competition binding studies, affinities were determined for 15 chemically diverse 5-HT(1B) agonists, including 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl]ethylamine (L694,247; pK(i), 10.4), 5-carboxamidotryptamine (5-CT; 9.7), 3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxybenzyl)acrylamide (GR46,611; 9.6), 5-methoxy-3-(1,2,5,6-tetrahydro-4-pyridinyl)-1H-indole (RU24,969; 9.5), dihydroergotamine (DHE; 8.6), 5-H-pyrrolo[3,2-b]pyridin-5-one,1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl (CP93,129; 8.4), anpirtoline (7.9), sumatriptan (7.4), 1-[2-(3-fluorophenyl)ethyl]-4-[3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]piperazine (L775,606; 6.4) and (minus sign)-1(S)-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-N-methyl-3,4-dihydro-1H-2-benzopyran-6-carboxamide (PNU109,291; <5.0). Similarly, affinities were established for 13 chemically diverse antagonists, including N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide (GR125,743; pK(i), 9.1), (-)cyanopindolol (9.0), (-)-tertatolol (8.2), N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiozol-3-yl)biphenyl-4-carboxamide (GR127,935; 8.2), N-[3

  6. Brain-targeted solid lipid nanoparticles containing riluzole: preparation, characterization and biodistribution.

    Science.gov (United States)

    Bondì, Maria Luisa; Craparo, Emanuela Fabiola; Giammona, Gaetano; Drago, Filippo

    2010-01-01

    Developments within nanomedicine have revealed a great potential for drug delivery to the brain. In this study nanoparticulate systems as drug carriers for riluzole, with sufficiently high loading capacity and small particle size, were prepared to a reach therapeutic drug level in the brain. Solid lipid nanoparticles containing riluzole have great potential as drug-delivery systems for amyotrophic lateral sclerosis and were produced by using the warm oil-in-water microemulsion technique. The resulting systems obtained were approximately 88 nm in size and negatively charged. Drug-release profiles demonstrated that a drug release was dependent on medium pH. Biodistribution of riluzole blended into solid lipid nanoparticles was carried out after administration to rats and the results were compared with those obtained by riluzole aqueous dispersion administration. Rats were sacrificed at time intervals of 8, 16 and 30 h, and the riluzole concentration in the blood and organs such as the brain, liver, spleen, heart and kidney was determined. It was demonstrated that these solid lipid nanoparticles were able to successfully carry riluzole into the CNS. Moreover, a low drug biodistribution in organs such as the liver, spleen, heart, kidneys and lung was found when riluzole was administered as drug-loaded solid lipid nanoparticles. Riluzole-loaded solid lipid nanoparticles showed colloidal size and high drug loading, a greater efficacy than free riluzole in rats, a higher capability to carry the drug into the brain and a lower indiscriminate biodistribution.

  7. Characterizing the optical properties of human brain tissue with high numerical aperture optical coherence tomography.

    Science.gov (United States)

    Wang, Hui; Magnain, Caroline; Sakadžić, Sava; Fischl, Bruce; Boas, David A

    2017-12-01

    Quantification of tissue optical properties with optical coherence tomography (OCT) has proven to be useful in evaluating structural characteristics and pathological changes. Previous studies primarily used an exponential model to analyze low numerical aperture (NA) OCT measurements and obtain the total attenuation coefficient for biological tissue. In this study, we develop a systematic method that includes the confocal parameter for modeling the depth profiles of high NA OCT, when the confocal parameter cannot be ignored. This approach enables us to quantify tissue optical properties with higher lateral resolution. The model parameter predictions for the scattering coefficients were tested with calibrated microsphere phantoms. The application of the model to human brain tissue demonstrates that the scattering and back-scattering coefficients each provide unique information, allowing us to differentially identify laminar structures in primary visual cortex and distinguish various nuclei in the midbrain. The combination of the two optical properties greatly enhances the power of OCT to distinguish intricate structures in the human brain beyond what is achievable with measured OCT intensity information alone, and therefore has the potential to enable objective evaluation of normal brain structure as well as pathological conditions in brain diseases. These results represent a promising step for enabling the quantification of tissue optical properties from high NA OCT.

  8. 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 pathogens...

  9. 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.

  10. Support vector machine classification and characterization of age-related reorganization of functional brain networks.

    Science.gov (United States)

    Meier, Timothy B; Desphande, Alok S; Vergun, Svyatoslav; Nair, Veena A; Song, Jie; Biswal, Bharat B; Meyerand, Mary E; Birn, Rasmus M; Prabhakaran, Vivek

    2012-03-01

    Most of what is known about the reorganization of functional brain networks that accompanies normal aging is based on neuroimaging studies in which participants perform specific tasks. In these studies, reorganization is defined by the differences in task activation between young and old adults. However, task activation differences could be the result of differences in task performance, strategy, or motivation, and not necessarily reflect reorganization. Resting-state fMRI provides a method of investigating functional brain networks without such confounds. Here, a support vector machine (SVM) classifier was used in an attempt to differentiate older adults from younger adults based on their resting-state functional connectivity. In addition, the information used by the SVM was investigated to see what functional connections best differentiated younger adult brains from older adult brains. Three separate resting-state scans from 26 younger adults (18-35 yrs) and 26 older adults (55-85) were obtained from the International Consortium for Brain Mapping (ICBM) dataset made publically available in the 1000 Functional Connectomes project www.nitrc.org/projects/fcon_1000. 100 seed-regions from four functional networks with 5mm(3) radius were defined based on a recent study using machine learning classifiers on adolescent brains. Time-series for every seed-region were averaged and three matrices of z-transformed correlation coefficients were created for each subject corresponding to each individual's three resting-state scans. SVM was then applied using leave-one-out cross-validation. The SVM classifier was 84% accurate in classifying older and younger adult brains. The majority of the connections used by the classifier to distinguish subjects by age came from seed-regions belonging to the sensorimotor and cingulo-opercular networks. These results suggest that age-related decreases in positive correlations within the cingulo-opercular and default networks, and decreases in

  11. Pharmacological Profile of Quinoxalinone

    Directory of Open Access Journals (Sweden)

    Youssef Ramli

    2014-01-01

    Full Text Available Quinoxalinone and its derivatives are used in organic synthesis for building natural and designed synthetic compounds and they have been frequently utilized as suitable skeletons for the design of biologically active compound. This review covers updated information on the most active quinoxalinone derivatives that have been reported to show considerable pharmacological actions such as antimicrobial, anti-inflammatory, antidiabetic, antiviral, antitumor, and antitubercular activity. It can act as an important tool for chemists to develop newer quinoxalinone derivatives that may prove to be better agents in terms of efficacy and safety.

  12. 99mTc-Daunorubicin a potential brain imaging and theranostic agent: synthesis, quality control, characterization, biodistribution and scintigraphy

    International Nuclear Information System (INIS)

    Faheem, A.R.; Bokhari, T.H.; Roohi, S.; Mushtaq, A.; Sohaib, M.

    2013-01-01

    Daunorubicin is a chemotherapeutic antibiotic of the anthracycline family used for the treatment of many type of cancers when doxorubicin or other less effective drugs cannot be used. The aim of the present study was labeling of Daunorubicin with 99m Tc, quality control, characterization, and biodistribution of radiolabeled Daunorubicin. Labeling efficiency was determined by ascending paper chromatography. All the experiments were performed at room temperature (25 °C ± 2 °C). More than 96% labeling efficiency with 99m Tc was achieved at pH 5–6, 2–4 μg stannous chloride and 300 μg of ligand in few minutes. The characterization of the compound was performed by using HPLC, electrophoresis and shake flask assay. Electrophoresis indicates that Tc-99 m-Daunorubicin is neutral, HPLC confirms the single specie of the labeled compound, while shake flask assay confirms high lipophilicity. The biodistribution studies of 99m Tc-Daunorubicin were performed in rats. Significantly higher accumulation of 99m Tc-Daunorubicin was seen in brain of normal rats. Scintigraphy was also indicating higher accumulation of 99m Tc-Daunorubicin in brain of normal rabbits.

  13. Development and characterization of glutathione-conjugated albumin nanoparticles for improved brain delivery of hydrophilic fluorescent marker.

    Science.gov (United States)

    Patel, Prerak J; Acharya, Niyati S; Acharya, Sanjeev R

    2013-01-01

    The glutathione-conjugated bovine serum albumin (BSA) nanoparticles were constructed in the present exploration as a novel biodegradable carrier for brain-specific drug delivery with evaluation of its in vitro and in vivo delivery properties. BSA nanocarriers were activated and conjugated to the distal amine functions of the glutathione via carbodiimide chemistry using EDAC as a mediator. These nanoparticles were characterized for particle shape, average size, SPAN value, drug entrapment and in vitro drug release. Further, presence of glutathione on the surface of BSA nanoparticles was confirmed by Ellman's assay, which has suggested that approximately 750 units of glutathione were conjugated per BSA nanoparticle. To evaluate the brain delivery properties of the glutathione-conjugated BSA nanoparticles fluorescein sodium was used as a model hydrophilic compound. Permeability and neuronal uptake properties of developed formulations were evaluated against the MDCK-MDR1 endothelial and neuro-glial cells, respectively. The permeability of glutathione-conjugated BSA nanoparticles across the monolayer of MDCK-MDR1 endothelial tight junction was shown significantly higher than that of unconjugated nanoparticles and fluorescein sodium solution. Similarly, glutathione-conjugated nanoparticles exhibited considerably higher uptake by neuro-glial cells which was inferred by high fluorescence intensity under microscope in comparison to unconjugated nanoparticles and fluorescein sodium solution. Following an intravenous administration, nearly three folds higher fluorescein sodium was carried to the rat brain by glutathione-conjugated nanoparticles as compared to unconjugated nanoparticles. The significant in vitro and in vivo results suggest that glutathione-conjugated BSA nanoparticles is a promising brain drug delivery system with low toxicity.

  14. Mapping and characterization of positive and negative BOLD responses to visual stimulation in multiple brain regions at 7T.

    Science.gov (United States)

    Jorge, João; Figueiredo, Patrícia; Gruetter, Rolf; van der Zwaag, Wietske

    2018-02-20

    External stimuli and tasks often elicit negative BOLD responses in various brain regions, and growing experimental evidence supports that these phenomena are functionally meaningful. In this work, the high sensitivity available at 7T was explored to map and characterize both positive (PBRs) and negative BOLD responses (NBRs) to visual checkerboard stimulation, occurring in various brain regions within and beyond the visual cortex. Recently-proposed accelerated fMRI techniques were employed for data acquisition, and procedures for exclusion of large draining vein contributions, together with ICA-assisted denoising, were included in the analysis to improve response estimation. Besides the visual cortex, significant PBRs were found in the lateral geniculate nucleus and superior colliculus, as well as the pre-central sulcus; in these regions, response durations increased monotonically with stimulus duration, in tight covariation with the visual PBR duration. Significant NBRs were found in the visual cortex, auditory cortex, default-mode network (DMN) and superior parietal lobule; NBR durations also tended to increase with stimulus duration, but were significantly less sustained than the visual PBR, especially for the DMN and superior parietal lobule. Responses in visual and auditory cortex were further studied for checkerboard contrast dependence, and their amplitudes were found to increase monotonically with contrast, linearly correlated with the visual PBR amplitude. Overall, these findings suggest the presence of dynamic neuronal interactions across multiple brain regions, sensitive to stimulus intensity and duration, and demonstrate the richness of information obtainable when jointly mapping positive and negative BOLD responses at a whole-brain scale, with ultra-high field fMRI. © 2018 Wiley Periodicals, Inc.

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

    International Nuclear Information System (INIS)

    Rey, A.; Manta, E.; Leon, A.; Papadopoulos, M.; Pirmettis, Y.; Raptopoulou, C.; Chiotellis, E.; Leon, E.; Mallo, L.

    1998-01-01

    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 99m Tc 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 99m Tc-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. 99 Tc 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)

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

    Energy Technology Data Exchange (ETDEWEB)

    John, Christy S. E-mail: radcsj@gwumc.edu; Bowen, Wayne D.; Fisher, Susan J.; Lim, Benjamin B.; Geyer, Brian C.; Vilner, Bertold J.; Wahl, Richard 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[{sup 125}I]-4-methoxybenzamide (P[{sup 125}I]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[{sup 125}I]MBA with Tc-99m sestamibi were made in a rat mammary tumor model. Sigma-1 affinity (K{sub i}) for PIMBA in guinea pig brain membranes using [{sup 3}H](+)pentazocine was found to be 11.82{+-}0.68 nM, whereas sigma-2 affinity in rat liver using [{sup 3}H]DTG (1,3-o-di-tolylguanidine) was 206{+-}11 nM. Sites in guinea pig brain membranes labeled by P[{sup 125}I]MBA showed high affinity for haloperidol, (+)-pentazocine, BD1008, and PIMBA (K{sub i}=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. K{sub i} values for the inhibition of P[{sup 125}I]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[{sup 125}I]MBA in T47D cells as studied by Scatchard analysis showed saturable binding, with a K{sub d}=94{+-}7 nM and a B{sub max}=2035{+-}305 fmol/mg of proteins. Biodistribution studies in Sprague-Dawley rats showed a rapid clearance of P[{sup 125}I]MBA from the normal organs. The potential of PIMBA in imaging breast cancer was

  17. 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

    International Nuclear Information System (INIS)

    John, Christy S.; Bowen, Wayne D.; Fisher, Susan J.; Lim, Benjamin B.; Geyer, Brian C.; Vilner, Bertold J.; Wahl, Richard L.

    1999-01-01

    The goal of this study was to investigate the potential use of a radioiodinated benzamide, N-[2-(1'-piperidinyl)ethyl]-3-iodo[ 125 I]-4-methoxybenzamide (P[ 125 I]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[ 125 I]MBA with Tc-99m sestamibi were made in a rat mammary tumor model. Sigma-1 affinity (K i ) for PIMBA in guinea pig brain membranes using [ 3 H](+)pentazocine was found to be 11.82±0.68 nM, whereas sigma-2 affinity in rat liver using [ 3 H]DTG (1,3-o-di-tolylguanidine) was 206±11 nM. Sites in guinea pig brain membranes labeled by P[ 125 I]MBA showed high affinity for haloperidol, (+)-pentazocine, BD1008, and PIMBA ( K i =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. K i values for the inhibition of P[ 125 I]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[ 125 I]MBA in T47D cells as studied by Scatchard analysis showed saturable binding, with a K d =94±7 nM and a B max =2035±305 fmol/mg of proteins. Biodistribution studies in Sprague-Dawley rats showed a rapid clearance of P[ 125 I]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 closely mimics

  18. 3D perfused brain phantom for interstitial ultrasound thermal therapy and imaging: design, construction and characterization

    International Nuclear Information System (INIS)

    Martínez, José M; Jarosz, Boguslaw J

    2015-01-01

    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)

  19. Diffusion MRI processing for multi-compartment characterization of brain pathology

    International Nuclear Information System (INIS)

    Hedouin, Renaud

    2017-01-01

    Diffusion weighted imaging (DWI) is a specific type of MRI acquisition based on the direction of diffusion of the brain water molecules. It allows, through several acquisitions, to model the brain microstructure, as white matter, which is significantly smaller than the voxel-resolution. To acquire a large number of images in a clinical setting, very-fast acquisition techniques are required as single-shot imaging. However these acquisitions suffer locally large distortions. We propose a block-matching registration method based on the acquisition of images with opposite phase-encoding directions (PED). This technique specially designed for Echo-Planar Images (EPI) robustly correct images and provides a deformation field. This field is applicable to an entire DWI series from only one reversed EPI allowing distortion correction with a minimal acquisition time cost. This registration algorithm has been validated both on phantom and on in vivo data and is available in our source medical image processing toolbox Anima. From these diffusion images, we are able to construct multi-compartments models (MCM) which can represent complex brain microstructure. Doing registration, averaging and atlas creation on these MCM images is required to perform studies and statistic analyses. We propose a general method to interpolate MCM as a simplification problem based on spectral clustering. This technique, which is adaptable for any MCM, has been validated on both synthetic and real data. Then, from a registered dataset, we performed a patient to population analysis at a voxel-level computing statistics on MCM parameters. Specifically designed tractography can also be used to make analysis, following tracks, based on individual anisotropic compartments. All these tools are designed and used on real data and contribute to the search of bio-markers for brain diseases such as multiple sclerosis. (author)

  20. Molecular characterization and temporal expression profiling of presenilins in the developing porcine brain

    DEFF Research Database (Denmark)

    Madsen, Lone B.; Thomsen, Bo; Larsen, Knud

    2007-01-01

    Background: The transmembrane presenilin (PSEN) protein, PSEN1 and PSEN2, have been proposed to be the catalytic components of the ¿-secretase protein complex, which is an intramembranous multimeric protease involved in development, cell regulatory processes, and neurodegeneration in Alzheimer...... similarity and colocatalization of PSEN1 and PSEN2 in brain tissue reflect a certain degree of fucntional redundancy. The data show that pigs may provide a new animal model for detailed analysis of the developmental functions of the PSENs....

  1. Amtyr1: characterization of a gene from honeybee (Apis mellifera) brain encoding a functional tyramine receptor.

    Science.gov (United States)

    Blenau, W; Balfanz, S; Baumann, A

    2000-03-01

    Biogenic amine receptors are involved in the regulation and modulation of various physiological and behavioral processes in both vertebrates and invertebrates. We have cloned a member of this gene family from the CNS of the honeybee, Apis mellifera. The deduced amino acid sequence is homologous to tyramine receptors cloned from Locusta migratoria and Drosophila melanogaster as well as to an octopamine receptor cloned from Heliothis virescens. Functional properties of the honeybee receptor were studied in stably transfected human embryonic kidney 293 cells. Tyramine reduced forskolin-induced cyclic AMP production in a dose-dependent manner with an EC50 of approximately 130 nM. A similar effect of tyramine was observed in membrane homogenates of honeybee brains. Octopamine also reduced cyclic AMP production in the transfected cell line but was both less potent (EC50 of approximately 3 microM) and less efficacious than tyramine. Receptor-encoding mRNA has a wide-spread distribution in the brain and subesophageal ganglion of the honeybee, suggesting that this tyramine receptor is involved in sensory signal processing as well as in higher-order brain functions.

  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. Synthesis, characterization and pharmacological evaluation of ...

    African Journals Online (AJOL)

    microscope (SEM), mass spectrometry (EI-MS), ultraviolet-visible (UV-Vis) spectrophotometry, ... The new compounds were also investigated for their alkaline phosphatase (ALPs) inhibition, .... The antimicrobial properties of OMZ, HQL and.

  4. Synthesis, characterization and pharmacological evaluation of ...

    African Journals Online (AJOL)

    electrolytes. Ni(II) complex exhibited antioxidant activity (30.48 ± 0.32 μM) higher than those of BHT (standard) and other complexes. Stronger inhibition of ALPs by Ni (II) mixed ligand complex compared to the other complexes was evident.

  5. Characterization of tumor vasculature in mouse brain by USPIO contrast-enhanced MRI.

    NARCIS (Netherlands)

    Gambarota, G.; Leenders, W.P.J.

    2011-01-01

    Detailed characterization of the tumor vasculature provides a better understanding of the complex mechanisms associated with tumor development and is especially important to evaluate responses to current therapies which target the tumor vasculature. Magnetic resonance imaging (MRI) studies of tumors

  6. 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.

  7. Attitudes toward pharmacological cognitive enhancement-a review

    NARCIS (Netherlands)

    Schelle, K.J.; Faulmüller, N.; 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

  8. Characterization of TLX expression in neural stem cells and progenitor cells in adult brains.

    Directory of Open Access Journals (Sweden)

    Shengxiu Li

    Full Text Available 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 analog labeling approach, we showed that almost all of the self-renewing neural stem cells expressed TLX. Interestingly, most of the TLX-positive cells in the SVZ represented the thymidine analog-negative, relatively quiescent neural stem cell population. Using cell type markers and short-term BrdU labeling, we demonstrated that TLX was also expressed in the Mash1+ rapidly dividing type C cells. Furthermore, loss of TLX expression dramatically reduced BrdU label-retaining neural stem cells and the actively dividing neural progenitor cells in the SVZ, but substantially increased GFAP staining and extended GFAP processes. These results suggest that TLX is essential to maintain the self-renewing neural stem cells in the SVZ and that the GFAP+ cells in the SVZ lose neural stem cell property upon loss of TLX expression. Understanding the cellular distribution of TLX and its function in specific cell types may provide insights into the development of therapeutic tools for neurodegenerative diseases by targeting TLX in neural stem/progenitors cells.

  9. Characterization of TLX expression in neural stem cells and progenitor cells in adult brains.

    Science.gov (United States)

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

    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 analog labeling approach, we showed that almost all of the self-renewing neural stem cells expressed TLX. Interestingly, most of the TLX-positive cells in the SVZ represented the thymidine analog-negative, relatively quiescent neural stem cell population. Using cell type markers and short-term BrdU labeling, we demonstrated that TLX was also expressed in the Mash1+ rapidly dividing type C cells. Furthermore, loss of TLX expression dramatically reduced BrdU label-retaining neural stem cells and the actively dividing neural progenitor cells in the SVZ, but substantially increased GFAP staining and extended GFAP processes. These results suggest that TLX is essential to maintain the self-renewing neural stem cells in the SVZ and that the GFAP+ cells in the SVZ lose neural stem cell property upon loss of TLX expression. Understanding the cellular distribution of TLX and its function in specific cell types may provide insights into the development of therapeutic tools for neurodegenerative diseases by targeting TLX in neural stem/progenitors cells.

  10. Characterization of cholinergic muscarinic receptor-stimulated phosphoinositide metabolism in brain from immature rats

    International Nuclear Information System (INIS)

    Balduini, W.; Murphy, S.D.; Costa, L.G.

    1990-01-01

    Hydrolysis of phosphoinositides elicited by stimulation of cholinergic muscarinic receptors has been studied in brain from neonatal (7-day-old) rats in order to determine: (1) whether the neonatal rat could provide a good model system to study this signal-transduction pathway; and (2) whether potential differences with adult nerve tissue would explain the differential, age-related effects of cholinergic agonists. Accumulation of [3H] inositol phosphates in [3H]inositol prelabeled slices from neonatal and adult rats was measured as an index of phosphoinositide metabolism. Full (acetylcholine, methacholine, carbachol) and partial (oxotremorine, bethanechol) agonists had qualitatively similar, albeit quantitatively different, effects in neonatal and adult rats. Atropine and pirenzepine effectively blocked the carbachol-induced response with inhibition constants of 1.2 and 20.7 nM, respectively. In all brain areas, response to all agonists was higher in neonatal than adult rats, and in hippocampus and cerebral cortex the response was higher than in cerebellum or brainstem. The relative intrinsic activity of partial agonists was higher in the latter two areas (0.6-0.7) than in the former two (0.3-0.4). Carbachol-stimulated phosphoinositide metabolism in brain areas correlated well with the binding of [3H]QNB (r2 = 0.627) and, particularly, with [3H]pirenzepine (r2 = 0.911). In cerebral cortex the effect of carbachol was additive to that of norepinephrine and glutamate. The presence of calcium (250-500 microM) was necessary for maximal response to carbachol to be elicited; the EC50 value for Ca2+ was 65.4 microM. Addition of EDTA completely abolished the response. Removal of sodium ions from the incubation medium reduced the response to carbachol by 50%

  11. Purification and characterization of a polyisoprenyl phosphate phosphatase from pig brain. Possible dual specificity.

    Science.gov (United States)

    Frank, D W; Waechter, C J

    1998-05-08

    Microsomal fractions from pig and calf brain catalyze the enzymatic dephosphorylation of endogenous and exogenous dolichyl monophosphate (Dol-P) (Sumbilla, C. A., and Waechter, C. J. (1985) Methods Enzymol. 111, 471-482). The Dol-P phosphatase (EC 3.1.3.51) has been solubilized by extracting pig brain microsomes with the nonionic detergent Nonidet P-40 and purified approximately 1,107-fold by a combination of anion exchange chromatography, polyethylene glycol fractionation, dye-ligand chromatography, and wheat germ agglutinin affinity chromatography. Treatment of the enzyme with neuraminidase prevented binding to wheat germ agglutinin-Sepharose, indicating the presence of one or more N-acetylneuraminyl residues per molecule of enzyme. When the highly purified polyisoprenyl phosphate phosphatase was analyzed by SDS-polyacrylamide gel electrophoresis, a major 33-kDa polypeptide was observed. Enzymatic dephosphorylation of Dol-P by the purified phosphatase was 1) optimal at pH 7; 2) potently inhibited by F-, orthovanadate, and Zn2+ > Co2+ > Mn2+ but unaffected by Mg2+; 3) exhibited an approximate Km for C95-Dol-P of 45 microM; and 4) was sensitive to N-ethylmaleimide, phenylglyoxal, and diethylpyrocarbonate. The pig brain phosphatase did not dephosphorylate glucose 6-phosphate, mannose 6-phosphate, 5'-AMP, or p-nitrophenylphosphate, but it dephosphorylated dioleoyl-phosphatidic acid at initial rates similar to those determined for Dol-P. Based on the virtually identical sensitivity of Dol-P and phosphatidic acid dephosphorylation by the highly purified enzyme to N-ethylmaleimide, F-, phenylglyoxal, and diethylpyrocarbonate, both substrates appear to be hydrolyzed by a single enzyme with an apparent dual specificity. This is the first report of the purification of a neutral Dol-P phosphatase from mammalian tissues. Although the enzyme is Mg2+-independent and capable of dephosphorylating Dol-P and PA, several enzymological properties distinguish this lipid

  12. Quantitative Apparent Diffusion Coefficients in the Characterization of Brain Tumors and Associated Peritumoral Edema

    International Nuclear Information System (INIS)

    Server, A.; Schellhorn, T.; Nakstad, P.H.; Kulle, B.; Maehlen, J.; Kumar, T.; Josefsen, R.; Langberg, C.W.

    2009-01-01

    Background: Conventional magnetic resonance (MR) imaging has a number of limitations in the diagnosis of the most common intracranial brain tumors, including tumor specification and the detection of tumoral infiltration in regions of peritumoral edema. Purpose: To prospectively assess if diffusion-weighted MR imaging (DWI) could be used to differentiate between different types of brain tumors and to distinguish between peritumoral infiltration in high-grade gliomas, lymphomas, and pure vasogenic edema in metastases and meningiomas. Material and Methods: MR imaging and DWI was performed on 93 patients with newly diagnosed brain tumors: 59 patients had histologically verified high-grade gliomas (37 glioblastomas multiforme, 22 anaplastic astrocytomas), 23 patients had metastatic brain tumors, five patients had primary cerebral lymphomas, and six patients had meningiomas. Apparent diffusion coefficient (ADC) values of tumor (enhancing regions or the solid portion of tumor) and peritumoral edema, and ADC ratios (ADC of tumor or peritumoral edema to ADC of contralateral white matter, ADC of tumor to ADC of peritumoral edema) were compared with the histologic diagnosis. ADC values and ratios of high-grade gliomas, primary cerebral lymphomas, metastases, and meningiomas were compared by using ANOVA and multiple comparisons. Optimal thresholds of ADC values and ADC ratios for distinguishing high-grade gliomas from metastases were determined by receiver operating characteristic (ROC) curve analysis. Results: Statistically significant differences were found for minimum and mean of ADC tumor and ADC tumor ratio values between metastases and high-grade gliomas when including only one factor at a time. Including a combination of in total four parameters (mean ADC tumor, and minimum, maximum and mean ADC tumor ratio) resulted in sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of 72.9, 82.6, 91.5, and 54.3% respectively. In the ROC curve analysis

  13. Characterization of [(3)H]harmane binding to rat whole brain membranes.

    Science.gov (United States)

    Anderson, N J; Robinson, E S J; Husbands, S M; Delagrange, P; Nutt, D J; Hudson, A L

    2003-12-01

    This study investigates the binding of [(3)H]harmane to rat whole brain homogenates. Saturation studies revealed [(3)H]harmane labels a single, saturable, high-capacity population with high affinity. All the test compounds displaced [(3)H]harmane completely and in an apparently monophasic manner. The displacement profile of the test ligands indicated labeling of MAO-A. Given the high level of MAO-A binding, it is unlikely that a low-capacity I(2) site would be distinguishable from the total [(3)H]harmane population.

  14. Effect of brain-derived neurotrophic factor on activity-regulated cytoskeleton-associated protein gene expression in primary frontal cortical neurons. Comparison with NMDA and AMPA

    DEFF Research Database (Denmark)

    El-Sayed, Mona; Hofman-Bang, Jacob; Mikkelsen, Jens D

    2011-01-01

    The effect of brain-derived neurotrophic factor (BDNF) on activity-regulated cytoskeleton-associated protein (Arc) mRNA levels in primary neuronal cultures of rat frontal cortex was characterized pharmacologically and compared to the effect on expression of c-fos, bdnf, neuritin, cox-2 as examples...

  15. Quantitative autoradiography of ligands for dopamine receptors and transporters in brain of Göttingen minipig

    DEFF Research Database (Denmark)

    Minuzzi, Luciano; Olsen, Aage Kristian; Bender, Dirk

    2006-01-01

    The pig has been used as animal model for positron emission tomography (PET) studies of dopamine (DA) receptors and pharmacological perturbations of DA neurotransmission. However, the binding properties of DA receptors and transporters in pig brain have not been characterized in vitro. Therefore...... in young and old pigs, and were close to those reported for rat and human brain. Furthermore, gradients in the concentrations of D1 and D2/3 sites in striatum measured in vitro agreed with earlier findings in PET studies. However, the dopamine transporter (DAT) ligand [3H]GBR12935 did not bind in pig brain...

  16. Pharmacological therapy for amblyopia

    Directory of Open Access Journals (Sweden)

    Anupam Singh

    2017-01-01

    Full Text Available Amblyopia is the most common cause of preventable blindness in children and young adults. Most of the amblyopic visual loss is reversible if detected and treated at appropriate time. It affects 1.0 to 5.0% of the general population. Various treatment modalities have been tried like refractive correction, patching (both full time and part time, penalization and pharmacological therapy. Refractive correction alone improves visual acuity in one third of patients with anisometropic amblyopia. Various drugs have also been tried of which carbidopa & levodopa have been popular. Most of these agents are still in experimental stage, though levodopa-carbidopa combination therapy has been widely studied in human amblyopes with good outcomes. Levodopa therapy may be considered in cases with residual amblyopia, although occlusion therapy remains the initial treatment choice. Regression of effect after stoppage of therapy remains a concern. Further studies are therefore needed to evaluate the full efficacy and side effect profile of these agents.

  17. Pharmacological therapy for amblyopia

    Science.gov (United States)

    Singh, Anupam; Nagpal, Ritu; Mittal, Sanjeev Kumar; Bahuguna, Chirag; Kumar, Prashant

    2017-01-01

    Amblyopia is the most common cause of preventable blindness in children and young adults. Most of the amblyopic visual loss is reversible if detected and treated at appropriate time. It affects 1.0 to 5.0% of the general population. Various treatment modalities have been tried like refractive correction, patching (both full time and part time), penalization and pharmacological therapy. Refractive correction alone improves visual acuity in one third of patients with anisometropic amblyopia. Various drugs have also been tried of which carbidopa & levodopa have been popular. Most of these agents are still in experimental stage, though levodopa-carbidopa combination therapy has been widely studied in human amblyopes with good outcomes. Levodopa therapy may be considered in cases with residual amblyopia, although occlusion therapy remains the initial treatment choice. Regression of effect after stoppage of therapy remains a concern. Further studies are therefore needed to evaluate the full efficacy and side effect profile of these agents. PMID:29018759

  18. 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.

  19. 31P NMR characterization of graded traumatic brain injury in rats

    International Nuclear Information System (INIS)

    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 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

  20. Characterizing brain patterns in conversion from mild cognitive impairment (MCI) to Alzheimer's disease

    Science.gov (United States)

    Silva R., Santiago S.; Giraldo, Diana L.; Romero, Eduardo

    2017-11-01

    Structural Magnetic Resonance (MR) brain images should provide quantitative information about the stage and progression of Alzheimer's disease. However, the use of MRI is limited and practically reduced to corroborate a diagnosis already performed with neuropsychological tools. This paper presents an automated strategy for extraction of relevant anatomic patterns related with the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) using T1-weighted MR images. The process starts by representing each of the possible classes with models generated from a linear combination of volumes. The difference between models allows us to establish which are the regions where relevant patterns might be located. The approach searches patterns in a space of brain sulci, herein approximated by the most representative gradients found in regions of interest defined by the difference between the linear models. This hypothesis is assessed by training a conventional SVM model with the found relevant patterns under a leave-one-out scheme. The resultant AUC was 0.86 for the group of women and 0.61 for the group of men.

  1. Serotonergic modulation of reward and punishment: evidence from pharmacological fMRI studies.

    Science.gov (United States)

    Macoveanu, Julian

    2014-03-27

    Until recently, the bulk of research on the human reward system was focused on studying the dopaminergic and opioid neurotransmitter systems. However, extending the initial data from animal studies on reward, recent pharmacological brain imaging studies on human participants bring a new line of evidence on the key role serotonin plays in reward processing. The reviewed research has revealed how central serotonin availability and receptor specific transmission modulates the neural response to both appetitive (rewarding) and aversive (punishing) stimuli in putative reward-related brain regions. Thus, serotonin is suggested to be involved in behavioral control when there is a prospect of reward or punishment. The new findings may have implications in understanding psychiatric disorders such as major depression which is characterized by abnormal serotonergic function and reward-related processing and may also provide a neural correlated for the emotional blunting observed in the clinical treatment of psychiatric disorders with selective serotonin reuptake inhibitors. Given the unique profile of action of each serotonergic receptor subtype, future pharmacological studies may favor receptor specific investigations to complement present research mainly focused on global serotonergic manipulations. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. 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

  3. Characterizing genes with distinct methylation patterns in the context of protein-protein interaction network: application to human brain tissues.

    Science.gov (United States)

    Li, Yongsheng; Xu, Juan; Chen, Hong; Zhao, Zheng; Li, Shengli; Bai, Jing; Wu, Aiwei; Jiang, Chunjie; Wang, Yuan; Su, Bin; Li, Xia

    2013-01-01

    DNA methylation is an essential epigenetic mechanism involved in transcriptional control. However, how genes with different methylation patterns are assembled in the protein-protein interaction network (PPIN) remains a mystery. In the present study, we systematically dissected the characterization of genes with different methylation patterns in the PPIN. A negative association was detected between the methylation levels in the brain tissues and topological centralities. By focusing on two classes of genes with considerably different methylation levels in the brain tissues, namely the low methylated genes (LMGs) and high methylated genes (HMGs), we found that their organizing principles in the PPIN are distinct. The LMGs tend to be the center of the PPIN, and attacking them causes a more deleterious effect on the network integrity. Furthermore, the LMGs express their functions in a modular pattern and substantial differences in functions are observed between the two types of genes. The LMGs are enriched in the basic biological functions, such as binding activity and regulation of transcription. More importantly, cancer genes, especially recessive cancer genes, essential genes, and aging-related genes were all found more often in the LMGs. Additionally, our analysis presented that the intra-classes communications are enhanced, but inter-classes communications are repressed. Finally, a functional complementation was revealed between methylation and miRNA regulation in the human genome. We have elucidated the assembling principles of genes with different methylation levels in the context of the PPIN, providing key insights into the complex epigenetic regulation mechanisms.

  4. Establishment, characterization, virus susceptibility and transfection of cell lines from cobia, Rachycentron canadum (L.), brain and fin.

    Science.gov (United States)

    Cheng, T-C; Lai, Y-S; Lin, I-Y; Wu, C-P; Chang, S-L; Chen, T-I; Su, M-S

    2010-02-01

    Establishment and characterization of two cobia, Rachycentron canadum, cell lines derived from cobia brain (CB) and cobia fin (CF) are described. Caudal fin and brain from juvenile cobia were dissociated for 30 and 10 min, respectively, in phosphate-buffered saline containing 0.25% trypsin at 25 degrees C. The optimal culture condition for both dissociated cells (primary cell culture) was at 28 degrees C in Leibovitz-15 medium containing 10% foetal bovine serum. The cells have been sub-cultured at a ratio of 1:2 for more than 160 passages over a period of 3 years. Origin of the cultured cells was verified by comparison of their sequences of mitochondrial cytochrome oxidase subunit I genes (cox I) with the cox 1 sequence from cobia muscle tissue. The cell lines showed polyploidy. No mycoplasma contamination was detected. Susceptibility to grouper iridovirus was observed for the CB cell line but not the CF cell line. Both cell lines expressed green fluorescent protein after being transfected with green fluorescent reporter gene driven by the cytomegalovirus promoter.

  5. Pharmacological Aspects of Neuro-Immune Interactions.

    Science.gov (United States)

    Tarasov, Vadim V; Kudryashov, Nikita V; Chubarev, Vladimir N; Kalinina, Tatiana S; Barreto, George E; Ashraf, Ghulam Md; Aliev, Gjumrakch

    2018-01-01

    The use of systematic approach for the analysis of mechanism of action of drugs at different levels of biological organization of organisms is an important task in experimental and clinical pharmacology for drug designing and increasing the efficacy and safety of drugs. The analysis of published data on pharmacological effects of psychotropic drugs possessing immunomodulatory and/or antiviral properties have shown a correlation between central effects of examined drugs associated with the impact on the processes of neurogenesis of adult brain and survival of neurons, and their ability to alter levels of key proinflammatory cytokines. The changes that occur as a result of the influence of pharmacological agents at one of the systems should inevitably lead to the functional reorganization at another. Integrative mechanisms underlying the neuro-immune interactions may explain the "pleiotropic" pharmacological effects of some antiviral and immunomodulatory drugs. Amantadine, which was originally considered as an antiviral agent, was approved as anti-parkinsonic drug after its wide medical use. The prolonged administration of interferon alpha caused depression in 30-45% of patients, thus limiting its clinical use. The antiviral drug "Oseltamivir" may provoke the development of central side effects, including abnormal behavior, delirium, impaired perception and suicides. Anti-herpethetical drug "Panavir" shows pronounced neuroprotective properties. The purpose of this review is to analyze the experimental and clinical data related to central effects of drugs with antiviral or/and immunotropic activity, and to discover the relationship of these effects with changes in reactivity of immune system and proinflammatory response. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Characterization of solubilized human and rat brain US -endorphin-receptor complex

    Energy Technology Data Exchange (ETDEWEB)

    Helmeste, D.M.; Li, C.H.

    1986-01-01

    Opioid receptors have been solubilized from human striatal and rat whole-brain membranes by use of 3-((3-cholamidopropyl)dimethylammonio)-1-propanesulfonate (CHAPS). Tritiated human US -endorphin (TH-US /sub h/-EP) binding revealed high-affinity competition by morphine, naloxone, and various US -EP analogues. Lack of high-affinity competition by (+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl)benzeneacetamide methanesulfonate (U50-488, Upjohn) indicated that k sites were not labeled by TH-US -/sub h/-EP under these conditions. Affinities were similar in both soluble and membrane preparations except for (Met)enkephalin, which appears to be rapidly degraded by the solubilized extract. Size differences between human and rat solubilized TH-US /sub h/-EP-receptor complexes were revealed by exclusion chromatography.

  7. Purification and characterization of mu-specific opioid receptor from rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Hasegawa, J.; Cho, T.M.; Ge, B.L.; Loh, H.H.

    1986-03-05

    A mu-specific opioid receptor was purified to apparent homogeneity from rat brain membranes by 6-succinylmorphine affinity chromatography, Ultrogel filtration, wheat germ agglutinin affinity chromatography, and isoelectric focusing. The purified receptor had a molecular weight of 58,000 as determined by polyacrylamide gel electrophoresis, and was judged to be homogeneous by the following criteria: (1) a single band on the SDS gel; and (2) a specific opioid binding activity of 17,720 pmole/mg protein, close to the theoretical value. In addition, the 58,000 molecular weight value agrees closely with that determined by covalently labelling purified receptor with bromoacetyl-/sup 3/H-dihydromorphine or with /sup 125/I-beta-endorphin and dimethyl suberimidate. To their knowledge, this is the first complete purification of an opioid receptor that retains its ability to bind opiates.

  8. Blood biomarkers in moderate-to-severe traumatic brain injury: potential utility of a multimarker approach in characterizing outcome

    Directory of Open Access Journals (Sweden)

    Alex P Di Battista

    2015-05-01

    Full Text Available Background: Blood biomarkers are valuable tools for elucidating the complex cellular and molecular mechanisms underlying traumatic brain injury (TBI pathophysiology. Profiling distinct classes of biomarkers could aid in the identification and characterization of both initial injury and secondary pathological processes. The purpose of this study was to characterize the prognostic performance, both individually and combined, of a recently developed multimarker panel of circulating biomarkers reflecting specific pathogenic mechanisms including neuroinflammation, oxidative damage and neuroregeneration, in moderate-to-severe TBI patients. Materials and Methods: Peripheral blood samples were drawn from 85 isolated TBI patients (n=60 severe, n=25 moderate at hospital admission, 6-, 12-, and 24-h post-injury. Mortality and neurological outcome were assessed using the extended Glasgow Outcome Score (GOSE. A multiplex platform was designed on MULTI-SPOT® plates to simultaneously analyze human plasma levels of s100 calcium binding protein (s100B, glial fibrillary acidic protein (GFAP, neuron specific enolase (NSE, brain derived neurotrophic factor (BDNF, monocyte chemoattractant protein (MCP-1, intercellular adhesion molecule (ICAM-5, and peroxiredoxin (PRDX-6. Results: Unfavorable outcome was associated with elevations in s100B, GFAP and MCP-1. Mortality was related to differences in 6 of 7 markers analyzed. Combined admission concentrations of s100B, GFAP and MCP-1 were able to discriminate favorable versus unfavorable outcome (AUC = 0.83, and survival versus death (AUC = 0.87, although not significantly better than s100B alone (AUC = 0.82 and 0.86, respectively. Conclusion: The multimarker panel of TBI-related biomarkers performed well in discriminating between unfavorable and favorable outcomes in the acute period after moderate-to-severe TBI. However, these combined biomarkers did not outperform s100B alone.

  9. 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.

  10. Dosimetric characterization of hypofractionated Gamma Knife radiosurgery of large or complex brain tumors versus linear accelerator-based treatments.

    Science.gov (United States)

    Dong, Peng; Pérez-Andújar, Angélica; Pinnaduwage, Dilini; Braunstein, Steve; Theodosopoulos, Philip; McDermott, Michael; Sneed, Penny; Ma, Lijun

    2016-12-01

    OBJECTIVE Noninvasive Gamma Knife (GK) platforms, such as the relocatable frame and on-board imaging, have enabled hypofractionated GK radiosurgery of large or complex brain lesions. This study aimed to characterize the dosimetric quality of such treatments against linear accelerator-based delivery systems that include the CyberKnife (CK) and volumetric modulated arc therapy (VMAT). METHODS Ten patients treated with VMAT at the authors' institution for large brain tumors (> 3 cm in maximum diameter) were selected for the study. The median prescription dose was 25 Gy (range 20-30 Gy) in 5 fractions. The median planning target volume (PTV) was 9.57 cm 3 (range 1.94-24.81 cm 3 ). Treatment planning was performed using Eclipse External Beam Planning V11 for VMAT on the Varian TrueBeam system, Multiplan V4.5 for the CyberKnife VSI System, and Leksell GammaPlan V10.2 for the Gamma Knife Perfexion system. The percentage of the PTV receiving at least the prescription dose was normalized to be identical across all platforms for individual cases. The prescription isodose value for the PTV, conformity index, Paddick gradient index, mean and maximum doses for organs at risk, and normal brain dose at variable isodose volumes ranging from the 5-Gy isodose volume (V5) to the 15-Gy isodose volume (V15) were compared for all of the cases. RESULTS The mean Paddick gradient index was 2.6 ± 0.2, 3.2 ± 0.5, and 4.3 ± 1.0 for GK, CK, and VMAT, respectively (p 0.06). The average prescription isodose values were 52% (range 47%-69%), 60% (range 46%-68%), and 88% (range 70%-94%) for GK, CK, and VMAT, respectively, thus producing significant variations in dose hot spots among the 3 platforms. Furthermore, the mean V5 values for GK and CK were similar (p > 0.79) at 71.9 ± 36.2 cm 3 and 73.3 ± 31.8 cm 3 , respectively, both of which were statistically lower (p linear accelerator-based treatments. Such a result supports the use of a large number of isocenters or confocal beams for the

  11. [Pharmacological treatment of obesity].

    Science.gov (United States)

    Gomis Barbará, R

    2004-01-01

    The pharmacological treatment of obesity should be considered when cannot be achieved a 10% weight loss with diet therapy and physical activity. The drugs effective in obesity treatment may act by different mechanisms such as reduction in food intake, inhibition of fat absorption, increase of thermogenesis and stimulation of adipocyte apoptosis. At present, we only have two marketed drugs for obesity treatment. Sibutramine is an inhibitor of norepinephrine, dopamine and serotonina reuptake which inhibits food intake and increases thermogenesis. Sibutramine administration for a year can induce a weight loss of 4-7%. Its main side effects are hypertension, headache, insomnia and constipation. Orlistat is an inhibitor of pancreatic lipase which is able to block the absorption of 30% of ingested fat. Its administration induces weight loss and reduction of ulterior weight regain. Also, this drug improves hypertension dyslipdaemia and helps to prevent diabetes in 52% of cases when administered over four years. The increase in frequency of stools and interference with vitamin absorption are its main side effects. Glucagon-like peptide 1, which increases insulin sensitivity and satiety, adiponectin and PPAR-gamma agonists which reduce insulin resistance and modulates adipocyte generation are the basis for future therapeutic approaches of obesity. Phosphatase inhibitors induce PPAR-gamma phosphorylation and UCP-1 expression leading to an increase in thermogenesis and reduction in appetite.

  12. Pharmacological therapy of spondyloarthritis.

    Science.gov (United States)

    Palazzi, Carlo; D'Angelo, Salvatore; Gilio, Michele; Leccese, Pietro; Padula, Angela; Olivieri, Ignazio

    2015-01-01

    The current pharmacological therapy of spondyloarthritis (SpA) includes several drugs: Non-steroidal anti-inflammatory drugs, corticosteroids, traditional disease-modifying antirheumatic drugs and biologic drugs. A systematic literature search was completed using the largest electronic databases (Medline, Embase and Cochrane), starting from 1995, with the aim to review data on traditional and biologic agents commercialised for SpA treatment. Randomised controlled trials and large observational studies were considered. In addition, studies performed in SpA patients treated with other, still unapproved, drugs (rituximab, anti-IL6 agents, apremilast, IL17 inhibitors and anakinra) were also taken into account. Biologic agents, especially anti-TNF drugs, have resulted in significant progress in improving clinical symptoms and signs, reducing inflammatory features in laboratory tests and imaging findings, and recovering all functional indexes. Anti-TNF drugs have radically changed the evolution of radiographic progression in peripheral joints; the first disappointing data concerning their efficacy on new bone formation of axial SpA has been recently challenged by studies enrolling patients who have been earlier diagnosed and treated. The opportunity to extend the interval of administration or to reduce the doses of anti-TNF agents can favourably influence the costs. Ustekinumab, the first non-anti-TNF biologic drug commercialised for psoriatic arthritis, offers new chances to patients that are unresponsive to anti-TNF.

  13. Pharmacology of midazolam.

    Science.gov (United States)

    Pieri, L; Schaffner, R; Scherschlicht, R; Polc, P; Sepinwall, J; Davidson, A; Möhler, H; Cumin, R; Da Prada, M; Burkard, W P; Keller, H H; Müller, R K; Gerold, M; Pieri, M; Cook, L; Haefely, W

    1981-01-01

    8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) is an imidazobenzodiazepine whose salts are soluble and stable in aqueous solution. It has a quick onset and, due to rapid metabolic inactivation, a rather short duration of action in all species studied. Midazolam has a similar pharmacologic potency and broad therapeutic range as diazepam. It produces all the characteristic effects of the benzodiazepine class, i.e., anticonvulsant, anxiolytic, sleep-inducing, muscle relaxant, and "sedative" effects. The magnitude of the anticonflict effect of midazolam is smaller than that of diazepam in rats and squirrel monkeys, probably because a more pronounced sedative component interferes with the increase of punished responses. In rodents, surgical anaesthesia is not attained with midazolam alone even in high i.v. doses, whereas this state is obtained in monkeys. The drug potentiates the effect of various central depressant agents. Midazolam is virtually free of effects on the cardiovascular system in conscious animals and produces only slight decreases in cardiac performance in dogs anaesthetized with barbiturates. No direct effects of the drugs on autonomic functions were found, however, stress-induced autonomic disturbances are prevented, probably by an effect on central regulatory systems. All animal data suggest the usefulness of midazolam as a sleep-inducer and i.v. anaesthetic of rapid onset and short duration.

  14. Pharmacology of pediatric resuscitation.

    Science.gov (United States)

    Ushay, H M; Notterman, D A

    1997-02-01

    The resuscitation of children from cardiac arrest and shock remains a challenging goal. The pharmacologic principles underlying current recommendations for intervention in pediatric cardiac arrest have been reviewed. Current research efforts, points of controversy, and accepted practices that may not be most efficacious have been described. Epinephrine remains the most effective resuscitation adjunct. High-dose epinephrine is tolerated better in children than in adults, but its efficacy has not received full analysis. The preponderance of data continues to point toward the ineffectiveness and possible deleterious effects of overzealous sodium bicarbonate use. Calcium chloride is useful in the treatment of ionized hypocalcemia but may harm cells that have experienced asphyxial damage. Atropine is an effective agent for alleviating bradycardia induced by increased vagal tone, but because most bradycardia in children is caused by hypoxia, improved oxygenation is the intervention of choice. Adenosine is an effective and generally well-tolerated agent for the treatment of supraventricular tachycardia. Lidocaine is the drug of choice for ventricular dysrhythmias, and bretylium, still relatively unexplored, is in reserve. Many pediatricians use dopamine for shock in the postresuscitative period, but epinephrine is superior. Most animal research on cardiac arrest is based on models with ventricular fibrillation that probably are not reflective of cardiac arrest situations most often seen in pediatrics.

  15. Characterization of a high affinity cocaine binding site in rat brain

    International Nuclear Information System (INIS)

    Calligaro, D.; Eldefrawi, M.

    1986-01-01

    Binding of [ 3 H]cocaine to synaptic membranes from whole rat brain was reversible and saturable. Nonlinear regression analysis of binding isotherms indicated two binding affinities: one with k/sub d/ = 16 nM, B/sub max/ = 0.65 pmoles/mg protein and the other with K/sub d/ = 660 nM, B/sub max/ = 5.1 pmoles/mg protein. The high-affinity binding of [ 3 H]cocaine was sensitive to the actions of trypsin and chymotrypsin but not carboxypeptidase, and was eliminated by exposure of the membranes to 95 0 C for 5 min. Specific binding at 2 nM was higher at pH 8.8 than at pH 7.0. Binding of [ 3 H]cocaine (15 nM) was inhibited by increasing concentrations of Na + ions. Several cocaine analogues, neurotransmitter uptake inhibitors and local anesthetics displaced specific [ 3 H]cocaine binding at 2 nM with various potencies. The cocaine analogue (-)-norcocaine was the most potent (IC 50 = 10 nM), while the local anesthetic tetracaine was the least potent in inhibiting [ 3 H]cocaine binding. Several biogenic amine uptake inhibitors, including tricyclic antidepressants and phencyclidine, had IC 50 values below μM concentrations

  16. Effects of anticancer drugs on glia-glioma brain tumor model characterized by acoustic impedance microscopy

    Science.gov (United States)

    Soon, Thomas Tiong Kwong; Chean, Tan Wei; Yamada, Hikari; Takahashi, Kenta; Hozumi, Naohiro; Kobayashi, Kazuto; Yoshida, Sachiko

    2017-07-01

    An ultrasonic microscope is a useful tool for observing living tissue without chemical fixation or histochemical processing. Two-dimensional (2D) acoustic impedance microscopy developed in our previous study for living cell observation was employed to visualize intracellular changes. We proposed a brain tumor model by cocultivating rat glial cells and C6 gliomas to quantitatively analyze the effects of two types of anticancer drugs, cytochalasin B (CyB) and temozolomide (TMZ), when they were applied. We reported that CyB treatment (25 µg/ml, T = 90 min) significantly reduced the acoustic impedance of gliomas and has little effect on glial cells. Meanwhile, TMZ treatment (2 mg/ml, T = 90 min) impacted both cells equally, in which both cells’ acoustic impedances were decreased. As CyB targets the actin filament polymerization of the cells, we have concluded that the decrease in acoustic impedance was in fact due to actin filament depolymerization and the data can be quantitatively assessed for future studies in novel drug development.

  17. STATISTICAL GROWTH MODELING OF LONGITUDINAL DT-MRI FOR REGIONAL CHARACTERIZATION OF EARLY BRAIN DEVELOPMENT.

    Science.gov (United States)

    Sadeghi, Neda; Prastawa, Marcel; Fletcher, P Thomas; Gilmore, John H; Lin, Weili; Gerig, Guido

    2012-01-01

    A population growth model that represents the growth trajectories of individual subjects is critical to study and understand neurodevelopment. This paper presents a framework for jointly estimating and modeling individual and population growth trajectories, and determining significant regional differences in growth pattern characteristics applied to longitudinal neuroimaging data. We use non-linear mixed effect modeling where temporal change is modeled by the Gompertz function. The Gompertz function uses intuitive parameters related to delay, rate of change, and expected asymptotic value; all descriptive measures which can answer clinical questions related to growth. Our proposed framework combines nonlinear modeling of individual trajectories, population analysis, and testing for regional differences. We apply this framework to the study of early maturation in white matter regions as measured with diffusion tensor imaging (DTI). Regional differences between anatomical regions of interest that are known to mature differently are analyzed and quantified. Experiments with image data from a large ongoing clinical study show that our framework provides descriptive, quantitative information on growth trajectories that can be directly interpreted by clinicians. To our knowledge, this is the first longitudinal analysis of growth functions to explain the trajectory of early brain maturation as it is represented in DTI.

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

    International Nuclear Information System (INIS)

    Luu, M.D.; Morrow, A.L.; Paul, S.M.; Schwartz, R.D.

    1987-01-01

    γ-Aminobutyric acid (GABA) receptor-mediated 36 chloride ( 36 Cl - ) uptake was measured in synaptoneurosomes from rat brain. GABA and GABA agonists stimulated 36 Cl - 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 36 Cl - 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 36 Cl - uptake was also dependent on the anion present in the media. The muscinol response varied in media containing the following anions: Br - >Cl - ≥NO 3 - >I - ≥SCN - >>C 3 H 5 OO - ≥ClO 4 - >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

  19. Pharmacology Portal: An Open Database for Clinical Pharmacologic Laboratory Services.

    Science.gov (United States)

    Karlsen Bjånes, Tormod; Mjåset Hjertø, Espen; Lønne, Lars; Aronsen, Lena; Andsnes Berg, Jon; Bergan, Stein; Otto Berg-Hansen, Grim; Bernard, Jean-Paul; Larsen Burns, Margrete; Toralf Fosen, Jan; Frost, Joachim; Hilberg, Thor; Krabseth, Hege-Merete; Kvan, Elena; Narum, Sigrid; Austgulen Westin, Andreas

    2016-01-01

    More than 50 Norwegian public and private laboratories provide one or more analyses for therapeutic drug monitoring or testing for drugs of abuse. Practices differ among laboratories, and analytical repertoires can change rapidly as new substances become available for analysis. The Pharmacology Portal was developed to provide an overview of these activities and to standardize the practices and terminology among laboratories. The Pharmacology Portal is a modern dynamic web database comprising all available analyses within therapeutic drug monitoring and testing for drugs of abuse in Norway. Content can be retrieved by using the search engine or by scrolling through substance lists. The core content is a substance registry updated by a national editorial board of experts within the field of clinical pharmacology. This ensures quality and consistency regarding substance terminologies and classification. All laboratories publish their own repertoires in a user-friendly workflow, adding laboratory-specific details to the core information in the substance registry. The user management system ensures that laboratories are restricted from editing content in the database core or in repertoires within other laboratory subpages. The portal is for nonprofit use, and has been fully funded by the Norwegian Medical Association, the Norwegian Society of Clinical Pharmacology, and the 8 largest pharmacologic institutions in Norway. The database server runs an open-source content management system that ensures flexibility with respect to further development projects, including the potential expansion of the Pharmacology Portal to other countries. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

  20. Development and Characterization of a Brain Endothelial Cell Phenotype using Human Induced Pluripotent Stem Cells

    DEFF Research Database (Denmark)

    Goldeman, Charlotte; Saaby, Lasse; Holst, Bjørn

    for experiments the following day. The model was monitored by measuring the trans-endothelial electrical resistance (TEER). RA had an inductive effect on the model, shown by an elevation in barrier tightness which correlated with the presence of tight junction proteins, shown by confocal microscopy images which...... be used to investigate drug transport in vitro, and screen candidates for permeation properties. One recent approach is to develop in vitro models of the BBB using human induced pluripotent stem cells (hIPSCs) as described by Stebbins et al. (2015).The aim of the present study was to investigate whether...... the published protocols were generically applicable and thus to develop and characterize in vitro models of the BBB using hIPSCs from different sources. Two stem cell lines, Bioni010-C and WTSli024-A, were seeded and maintained on Matrigel in mTesR1 media. Cells were then seeded as single cells at different...

  1. Fuzzy pharmacology: theory and applications.

    Science.gov (United States)

    Sproule, Beth A; Naranjo, Claudio A; Türksen, I Burhan

    2002-09-01

    Fuzzy pharmacology is a term coined to represent the application of fuzzy logic and fuzzy set theory to pharmacological problems. Fuzzy logic is the science of reasoning, thinking and inference that recognizes and uses the real world phenomenon that everything is a matter of degree. It is an extension of binary logic that is able to deal with complex systems because it does not require crisp definitions and distinctions for the system components. In pharmacology, fuzzy modeling has been used for the mechanical control of drug delivery in surgical settings, and work has begun evaluating its use in other pharmacokinetic and pharmacodynamic applications. Fuzzy pharmacology is an emerging field that, based on these initial explorations, warrants further investigation.

  2. The pharmacology of gynaecology.

    Science.gov (United States)

    Tothill, A

    1980-09-01

    Focus in this discussion of the pharmacology of gynecology is on the following: vaginal infections; genital herpes; genital warts; pelvic inflammatory disease; urinary infections; pruritus vulvae; menstrual problems; infertility; oral contraception; and hormone replacement therapy. Doctors in England working in Local Authority Family Planning Clinics are debarred from prescribing, and any patient with a vaginal infection has to be referred either to a special clinic or to her general practitioner which is often preferable as her medical history will be known. Vaginal discharge is a frequent complaint, and it is necessary to obtain full details. 1 of the most common infections is vaginal candidosis. Nystatin pessaries have always been a useful 1st-line treatment and are specific for this type of infection. Trichomonas infection also occurs frequently and responds well to metronidazole in a 200 mg dosage, 3 times daily for 7 days. It is necessary to treat the consort at the same time. Venereal diseases such as syphilis and gonorrhea always require vigorous treatment. Patients are now presenting with herpes genitalis far more often. The only treatment which is currently available, and is as good as any, is the application of warm saline to the vaginal area. Genital warts may be discovered on routine gynecological examination or may be reported to the doctor by the patient. 1 application of a 20% solution of podophyllum, applied carefully to each wart, usually effects a cure. Pelvic inflammatory disease seems to be on the increase. Provided any serious disease is ruled out a course of systemic antibiotics is often effective. Urinary infections are often seen in the gynecologic clinic, and many of these will respond well to 2 tablets of co-trimoxazole, 2 times daily for 14 days. In pruritus vulvae it is important to determine whether the cause is general or local. Menstrual problems regularly occur and have been increased by the IUD and the low-dose progesterone pill

  3. Morphometric brain characterization of refractory obsessive-compulsive disorder: diffeomorphic anatomic registration using exponentiated Lie algebra.

    Science.gov (United States)

    Tang, Wanjie; Li, Bin; Huang, Xiaoqi; Jiang, Xiaoyu; Li, Fei; Wang, Lijuan; Chen, Taolin; Wang, Jinhui; Gong, Qiyong; Yang, Yanchun

    2013-10-01

    Few studies have used neuroimaging to characterize treatment-refractory obsessive-compulsive disorder (OCD). This study sought to explore gray matter structure in patients with treatment-refractory OCD and compare it with that of healthy controls. A total of 18 subjects with treatment-refractory OCD and 26 healthy volunteers were analyzed by MRI using a 3.0-T scanner and voxel-based morphometry (VBM). Diffeomorphic anatomical registration using exponentiated Lie algebra (DARTEL) was used to identify structural changes in gray matter associated with treatment-refractory OCD. A partial correlation model was used to analyze whether morphometric changes were associated with Yale-Brown Obsessive-Compulsive Scale scores and illness duration. Gray matter volume did not differ significantly between the two groups. Treatment-refractory OCD patients showed significantly lower gray matter density than healthy subjects in the left posterior cingulate cortex (PCC) and mediodorsal thalamus (MD) and significantly higher gray matter density in the left dorsal striatum (putamen). These changes did not correlate with symptom severity or illness duration. Our findings provide new evidence of deficits in gray matter density in treatment-refractory OCD patients. These patients may show characteristic density abnormalities in the left PCC, MD and dorsal striatum (putamen), which should be verified in longitudinal studies. © 2013. Published by Elsevier Inc. All rights reserved.

  4. Precision pharmacology for Alzheimer's disease.

    Science.gov (United States)

    Hampel, Harald; Vergallo, Andrea; Aguilar, Lisi Flores; Benda, Norbert; Broich, Karl; Cuello, A Claudio; Cummings, Jeffrey; Dubois, Bruno; Federoff, Howard J; Fiandaca, Massimo; Genthon, Remy; Haberkamp, Marion; Karran, Eric; Mapstone, Mark; Perry, George; Schneider, Lon S; Welikovitch, Lindsay A; Woodcock, Janet; Baldacci, Filippo; Lista, Simone

    2018-04-01

    The complex multifactorial nature of polygenic Alzheimer's disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels - from molecules to organ systems - and through adaptation, to compensation, and decompensation to systems failure. Adaptation and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment. An individual vulnerability to stressors exists on the basis of individual triggers, drivers, and thresholds accounting for the initiation and failure of adaptive and compensatory responses. Consequently, the distinct pattern of AD pathophysiology in space and time must be investigated on the basis of the individual biological makeup. This requires the implementation of systems biology and neurophysiology to facilitate Precision Medicine (PM) and Precision Pharmacology (PP). The regulation of several processes at multiple levels of complexity from gene expression to cellular cycle to tissue repair and system-wide network activation has different time delays (temporal scale) according to the affected systems (spatial scale). The initial failure might originate and occur at every level potentially affecting the whole dynamic interrelated systems within an organism. Unraveling the spatial and temporal dynamics of non-linear pathophysiological mechanisms across the continuum of hierarchical self-organized systems levels and from systems homeostasis to systems failure is key to understand AD. Measuring and, possibly, controlling space- and time-scaled adaptive and compensatory responses occurring during AD will represent a crucial step to achieve the capacity to substantially modify the disease course and progression at the best suitable timepoints, thus counteracting disrupting critical pathophysiological inputs. This approach will provide the conceptual basis for effective

  5. [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

  6. The "brittle response" to Parkinson's disease medications: characterization and response to deep brain stimulation.

    Directory of Open Access Journals (Sweden)

    Daniel Martinez-Ramirez

    Full Text Available Formulate a definition and describe the clinical characteristics of PD patients with a "brittle response" (BR to medications versus a "non-brittle response" (NBR, and characterize the use of DBS for this population.An UF IRB approved protocol used a retrospective chart review of 400 consecutive PD patients presenting to the UF Center for Movement Disorders and Neurorestoration. Patient records were anonymized and de-identified prior to analysis. SPSS statistics were used to analyze data.Of 345 included patients, 19 (5.5% met criteria for BR PD. The BR group was comprised of 58% females, compared to 29% in the NBR group (P = .008. The former had a mean age of 63.4 compared to 68.1 in the latter. BR patients had lower mean weight (63.5 vs. 79.6, P = <.001, longer mean disease duration (12.6 vs. 8.9 years, P = .003, and had been on LD for more years compared to NBR patients (9.8 vs. 5.9, P = .001. UPDRS motor scores were higher (40.4 vs. 30.0, P = .001 in BR patients. No differences were observed regarding the Schwab and England scale, PDQ-39, and BDI-II. Sixty-three percent of the BR group had undergone DBS surgery compared to 18% (P = .001. Dyskinesias were more common, severe, and more often painful (P = <.001 in the BR group. There was an overall positive benefit from DBS.BR PD occurred more commonly in female patients with a low body weight. Patients with longer disease duration and longer duration of LD therapy were also at risk. The BR group responded well to DBS.

  7. Characterization of high affinity [3H]triazolam binding in rat brain

    International Nuclear Information System (INIS)

    Earle, M.; Concas, A.; Yamamura, H.I.

    1986-01-01

    The hypnotic Triazolam (TZ), a triazolo (1,4)-benzodiazepine, displays a short physiological half life and has been used for the treatment of insomnia related to anxiety states. Specific binding properties of this recently tritiated TZ were characterized. The authors major objectives were the direct measurement of the temperature dependence and the GABA effect on [ 3 H]TZ binding. Saturation studies showed a shift to lower affinity at 37 0 C (K/sub d/ = 0.25 +/- 0.01 nM at O 0 C; K/sub d/ = 1.46 +/- 0.03 nM at 37 0 C) while the B/sub max/ values remained unchanged (1003 +/- 37 fmoles/mg prot. at 0 0 C and 1001 +/- 43 fmoles/mg prot. at 37 0 C). Inhibition studies showed that [ 3 H]TZ binding displayed no GABA shift at 0 0 C(K/sub i/ 0.37 +/- 0.03 nM/- GABA and K/sub i/ = 0.55 +/- 0.13 nM/+GABA) but a nearly two-fold shift was apparent at 37 0 C (K/sub i/ = 2.92 +/- 0.2 nM/-GABA; K/sub i/ = 1.37 +/- 0.11 mM/+GABA). These results were also confirmed by saturation studies in the presence or absence of GABA showing a shift to higher affinity in the presence of GABA only at 37 0 C. In Ro 15-1788/[ 3 H]TZ competition experiments the presence of GABA did not affect the inhibitory potency of Ro 15-1788 on [ 3 H]TZ binding at both temperatures. In conclusion [ 3 H]TZ binding showed an extremely high affinity for benzodiazepine receptors. In contrast to reported literature, the findings suggest that TZ interacts with benzodiazepine receptors similar to other benzodiazepine agonists

  8. A multimodal MRI approach to identify and characterize microstructural brain changes in neuropsychiatric systemic lupus erythematosus.

    Science.gov (United States)

    Ercan, Ece; Ingo, Carson; Tritanon, Oranan; Magro-Checa, Cesar; Smith, Alex; Smith, Seth; Huizinga, Tom; van Buchem, Mark A; Ronen, Itamar

    2015-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement and results in neurological and psychiatric (NP) symptoms in up to 40% of the patients. To date, the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) poses a challenge due to the lack of neuroradiological gold standards. In this study, we aimed to better localize and characterize normal appearing white matter (NAWM) changes in NPSLE by combining data from two quantitative MRI techniques, diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI). 9 active NPSLE patients (37 ± 13 years, all females), 9 SLE patients without NP symptoms (44 ± 11 years, all females), and 14 healthy controls (HC) (40 ± 9 years, all females) were included in the study. MTI, DTI and fluid attenuated inversion recovery (FLAIR) images were collected from all subjects on a 3 T MRI scanner. Magnetization transfer ratio (MTR), mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) maps and white matter lesion maps based on the FLAIR images were created for each subject. MTR and DTI data were then co-analyzed using tract-based spatial statistics and a cumulative lesion map to exclude lesions. Significantly lower MTR and FA and significantly higher AD, RD and MD were found in NPSLE compared to HC in NAWM regions. The differences in DTI measures and in MTR, however, were only moderately co-localized. Additionally, significant differences in DTI measures, but not in MTR, were found between NPSLE and SLE patients, suggesting that the underlying microstructural changes detected by MD are linked to the onset of NPSLE. The co-analysis of the anatomical distribution of MTI and DTI measures can potentially improve the diagnosis of NPSLE and contribute to the understanding of the underlying microstructural damage.

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

    Energy Technology Data Exchange (ETDEWEB)

    Benyhe, S.; Varga, E.; Hepp, J.; Magyar, A.; Borsodi, A.; Wollemann, M.

    1990-09-01

    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.

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

    International Nuclear Information System (INIS)

    Benyhe, S.; Varga, E.; Hepp, J.; Magyar, A.; Borsodi, A.; Wollemann, M.

    1990-01-01

    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

  11. A diffusion model-free framework with echo time dependence for free-water elimination and brain tissue microstructure characterization.

    Science.gov (United States)

    Molina-Romero, Miguel; Gómez, Pedro A; Sperl, Jonathan I; Czisch, Michael; Sämann, Philipp G; Jones, Derek K; Menzel, Marion I; Menze, Bjoern H

    2018-03-23

    The compartmental nature of brain tissue microstructure is typically studied by diffusion MRI, MR relaxometry or their correlation. Diffusion MRI relies on signal representations or biophysical models, while MR relaxometry and correlation studies are based on regularized inverse Laplace transforms (ILTs). Here we introduce a general framework for characterizing microstructure that does not depend on diffusion modeling and replaces ill-posed ILTs with blind source separation (BSS). This framework yields proton density, relaxation times, volume fractions, and signal disentanglement, allowing for separation of the free-water component. Diffusion experiments repeated for several different echo times, contain entangled diffusion and relaxation compartmental information. These can be disentangled by BSS using a physically constrained nonnegative matrix factorization. Computer simulations, phantom studies, together with repeatability and reproducibility experiments demonstrated that BSS is capable of estimating proton density, compartmental volume fractions and transversal relaxations. In vivo results proved its potential to correct for free-water contamination and to estimate tissue parameters. Formulation of the diffusion-relaxation dependence as a BSS problem introduces a new framework for studying microstructure compartmentalization, and a novel tool for free-water elimination. © 2018 International Society for Magnetic Resonance in Medicine.

  12. Characterization of a purified nicotinic receptor from rat brain by using idiotypic and anti-idiotypic antibodies

    International Nuclear Information System (INIS)

    Abood, L.G.; Langone, J.J.; Bjercke, R.; Lu, X.; Banerjee, S.

    1987-01-01

    The availability of an anti-nicotine monoclonal antibody has made it possible to further establish the nature of the nicotine recognition proteins purified from rat brain by affinity chromatography and to provide a highly sensitive assay for determining [ 3 H]nicotine binding to the purified material. An enantiomeric analogue of nicotine. (-)-6-hydroxymethylnicotine, was used to prepare the affinity column. In addition, with the use of an anti-idiotypic monoclonal antibody, it was confirmed that the recognition site for nicotine resides on a protein complex composed of two components with molecular masses of 62 and 57 kDa. It was also demonstrated that the same two proteins could be purified by immunoaffinity chromatography with the use of an anti-idiotypic monoclonal antibody. With the use of the anti-nicotine antibody to measure [ 3 H]nicotine binding, the purified material was shown to bind 250 pmol/mg of protein. By utilizing a procedure in which the purified receptor protein was conjugated to membranes by disulfide bonds, a binding activity of 80 pmol/mg was obtained. With the availability of sterospecific monoclonal antibodies to (-)-nicotine as well as monoclonal anti-idiotypic antibodies derived when the anti-nicotine antibodies were used as immunogens, additional procedures became available for the further characterization of the purified nicotine receptor and examining its (-)-[ 3 H]nicotine-binding characteristics

  13. Pharmacology of antihistamines

    Directory of Open Access Journals (Sweden)

    Martin K Church

    2013-01-01

    Full Text Available H 1- antihistamines, the mainstay of treatment for urticaria, were developed from anticholinergic drugs more than 70 years ago. They act as inverse agonists rather than antagonists of histamine H 1 -receptors which are members of the G-protein family. The older first generation H 1- antihistamines penetrate readily into the brain to cause sedation, drowsiness, fatigue and impaired concentration and memory causing detrimental effects on learning and examination performance in children and on impairment of the ability of adults to work and drive. Their use should be discouraged. The newer second-generation H 1 -antihistamines are safer, cause less sedation and are more efficacious. Three drugs widely used for symptomatic relief in urticaria, desloratadine, levocetirizine and fexofenadine are highlighted in this review. Of these levocetirizine and fexofenadine are the most potent in humans in vivo. However, levocetirizine may cause somnolence in susceptible individuals, whereas fexofenadine has a relatively short duration of action and may be required to be given twice daily for all round daily protection. Although desloratadine is less potent, it has the advantages of rarely causing somnolence and having a long duration of action.

  14. Characterization of the concurrent metabolic changes in brain and plasma during insulin-induced moderate hypoglycemia using 1H NMR spectroscopy in juvenile rats.

    Science.gov (United States)

    Ennis, Kathleen; Lusczek, Elizabeth; Rao, Raghavendra

    2017-07-13

    Treatment of hypoglycemia in children is currently based on plasma glucose measurements. This approach may not ensure neuroprotection since plasma glucose does not reflect the dynamic state of cerebral energy metabolism. To determine whether cerebral metabolic changes during hypoglycemia could be better characterized using plasma metabolomic analysis, insulin-induced acute hypoglycemia was induced in 4-week-old rats. Brain tissue and concurrent plasma samples were collected from hypoglycemic (N=7) and control (N=7) rats after focused microwave fixation to prevent post-mortem metabolic changes. The concentration of 29 metabolites in brain and 34 metabolites in plasma were determined using 1 H NMR spectroscopy at 700MHz and examined using partial least squares-discriminant analysis. The sensitivity of plasma glucose for detecting cerebral energy failure was assessed by determining its relationship to brain phosphocreatine. The brain and plasma metabolite profiles of the hypoglycemia group were distinct from the control group (brain: R 2 =0.92, Q 2 =0.31; plasma: R 2 =0.95, Q 2 =0.74). Concentration differences in glucose, ketone bodies and amino acids were responsible for the intergroup separation. There was 45% concordance between the brain and plasma metabolite profiles. Brain phosphocreatine correlated with brain glucose (control group: R 2 =0.86; hypoglycemia group: R 2 =0.59; pplasma glucose. The results confirm that plasma glucose is an insensitive biomarker of cerebral energy changes during hypoglycemia and suggest that a plasma metabolite profile is superior for monitoring cerebral metabolism. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Quality management of pharmacology and safety pharmacology studies

    DEFF Research Database (Denmark)

    Spindler, Per; Seiler, Jürg P

    2002-01-01

    to safety pharmacology studies, and, when indicated, to secondary pharmacodynamic studies, does not influence the scientific standards of studies. However, applying formal GLP standards will ensure the quality, reliability and integrity of studies, which reflect sound study management. It is important...... to encourage a positive attitude among researchers and academics towards these lines, whenever possible. GLP principles applied to the management of non-clinical safety studies are appropriate quality standards when studies are used in the context of protecting public health, and these quality standards...... 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...

  16. 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.

  17. Nematode cholinergic pharmacology

    International Nuclear Information System (INIS)

    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 [ 3 H]N-methylscopolamine ([ 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

  18. Pharmacological interventions for unilateral spatial neglect after stroke.

    Science.gov (United States)

    Luvizutto, Gustavo José; Bazan, Rodrigo; Braga, Gabriel Pereira; Resende, Luiz Antônio de Lima; Bazan, Silméia Garcia Z; El Dib, Regina

    2015-11-06

    Unilateral spatial neglect (USN) is characterized by the inability to report or respond to people or objects presented on the side contralateral to the lesioned side of the brain and has been associated with poor functional outcomes and long stays in hospitals and rehabilitation centers. Pharmacological interventions (medical interventions only, use of drugs to improve the health condition), such as dopamine and noradrenergic agonists or pro-cholinergic treatment, have been used in people affected by USN after stroke, and effects of these treatments could provide new insights for health professionals and policy makers. To evaluate the effectiveness and safety of pharmacological interventions for USN after stroke. We searched the Cochrane Stroke Group Trials Register (April 2015), the Cochrane Central Register of Controlled Trials (April 2015), MEDLINE (1946 to April 2015), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to April 2015), EMBASE (1980 to April 2015), PsycINFO (1806 to April 2015) and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to April 2015). We also searched trials and research registers, screened reference lists, and contacted study authors and pharmaceutical companies (April 2015). We included randomized controlled trials (RCTs) and quasi-randomized controlled trials (quasi-RCTs) of pharmacological interventions for USN after stroke. Two review authors independently assessed risk of bias in the included studies and extracted data. We included in the review two studies with a total of 30 randomly assigned participants. We rated the quality of the evidence as very low as the result of study limitations, small numbers of events, and small sample sizes, with imprecision in the confidence interval (CI). We were not able to perform meta-analysis because of heterogeneity related to the different interventions evaluated between included studies. Very low-quality evidence from one trial (20 participants

  19. TMOD-05. MOLECULAR CHARACTERIZATION OF ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF PEDIATRIC BRAIN TUMORS AND THEIR USE IN PRECLINICAL EXPERIMENTS

    Science.gov (United States)

    Brabetz, Sebastian; Schmidt, Christin; Groebner, Susanne N.; Mack, Norman; Seker-Cin, Huriye; Jones, David T.W.; Chavez, Lukas; Milde, Till; Witt, Olaf; Leary, Sarah E.; Li, Xiao-Nan; Wechsler-Reya, Robert J.; Olson, James M.; Pfister, Stefan M.; Kool, Marcel

    2017-01-01

    Abstract Genomic studies have shown that multiple molecular subtypes of pediatric brain tumors exist that are biologically and clinically highly distinct. These findings ask for novel subtype specific treatments. To develop these we need more and better preclinical models that correctly reflect the proper tumor (sub)type. Orthotopic patient-derived xenograft (PDX) models generated by intracranial injection of primary patient material into the brain of NSG mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Prior to drug selection and testing, extensive molecular characterizations of PDX and matching primary tumor/blood (DNA methylation, DNA sequencing, and gene expression) are needed to see how the PDX represents the original disease and to learn about targetable oncogenic drivers in each model. In collaboration with several groups around the world we have generated and fully characterized thus far 75 PDX models reflecting 15 distinct subtypes of pediatric brain cancer. PDX models always retain their molecular subtype and in the vast majority of cases also mutations and copy number alterations compared to matching primary tumors. Most aggressive tumors, harboring MYC(N) amplifications, are overrepresented in the cohort, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines, such as Group 4 medulloblastoma, are included. All models and corresponding molecular data will become available for the community for preclinical research. Examples of such preclinical experiments will be presented. PDX models of pediatric brain tumors are still quite rare. Our repertoire of PDX models and corresponding molecular characterizations allow researchers all over the world to find the right models for their specific scientific questions. It will provide an unprecedented resource to study tumor biology and pave the way for

  20. How Do Health Care Providers Diagnose Traumatic Brain Injury (TBI)?

    Science.gov (United States)

    ... NICHD Research Information Find a Study More Information Pharmacology Condition Information NICHD Research Information Find a Study ... the brain, bruised brain tissue, and other damage. Magnetic resonance imaging (MRI). MRI uses magnets and radio waves to ...

  1. Clinical pharmacology of homoharringtonine

    International Nuclear Information System (INIS)

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

    1986-01-01

    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 [ 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 [ 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 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

  2. 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.

  3. Tinnitus: network pathophysiology-network pharmacology.

    Science.gov (United States)

    Elgoyhen, Ana B; Langguth, Berthold; Vanneste, Sven; De Ridder, Dirk

    2012-01-01

    Tinnitus, the phantom perception of sound, is a prevalent disorder. One in 10 adults has clinically significant subjective tinnitus, and for one 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 Food and Drug Administration (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 (CNS) 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 CNS 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. 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…

  5. 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,…

  6. 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....

  7. New approaches in analyzing the pharmacological properties of herbal extracts.

    Science.gov (United States)

    Hamburger, Matthias

    2007-01-01

    Herbal extracts are widely used and accepted in the population. The pharmacological characterization of such products meets some specific challenges, given the chemical complexity of the active ingredient. An overview is given on modern methods and approaches that can be used for that purpose. In particular, HPLC-based activity profiling is discussed as a means to identify pharmacologically active compounds in an extract, and expression profiling is described as a means for global assessment of effects exerted by multi-component mixtures such as extracts. These methods are illustrated with selected axamples from our labs, including woad (Isatis tinctoria), the traditional Chinese herb Danshen (Salvia miltiorrhiza) and black cohosh (Cimicifuga racemosa).

  8. Characterization of Streptococcus constellatus strains recovered from a brain abscess and periodontal pockets in an immunocompromised patient.

    Science.gov (United States)

    Marques da Silva, Rafael; Caugant, Dominique A; Josefsen, Roger; Tronstad, Leif; Olsen, Ingar

    2004-12-01

    There have been a number of reports of brain abscesses suggesting an odontogenic etiology. However, no efforts have been made to compare brain abscess isolates with isolates from the oral cavity using highly discriminative methods. We report a brain abscess caused by Streptococcus constellatus in an immunocompromised patient where oral infection (periodontitis) was suspected to be implicated. The brain abscess and oral isolates were compared by means of one phenotypic and three genetic (restriction fragment length polymorphism [RFLP], ribotyping, and random amplified polymorphic DNA [RAPD]) fingerprinting techniques. The phenotypic method and RFLP showed identical profiles between brain and periodontal isolates, while ribotyping and RAPD showed very close similarity, with only one band difference in one of the three ribotypes and in one of the three polymorphic RAPD. Gene transfer by genetic recombinational events in the periodontal pocket might have been responsible for the emergence of a strain variant of S. constellatus that had the potential to cause an abscess at a distant site (brain). The importance of odontogenic sources as potential foci of infection for brain abscesses is discussed.

  9. Early life environmental and pharmacological stressors result in persistent dysregulations of the serotonergic system

    Directory of Open Access Journals (Sweden)

    Peiyan eWong

    2015-04-01

    Full Text Available Dysregulations in the brain serotonergic system and exposure to environmental stressors have been implicated in the development of major depressive disorder. Here, we investigate the interactions between the stress and serotonergic systems by characterizing the behavioral and biochemical effects of chronic stress applied during early-life or adulthood in wild type (WT mice and mice with deficient tryptophan hydroxylase 2 (TPH2 function. We showed that chronic mild stress applied in adulthood did not affect the behaviors and serotonin levels of WT and TPH2 knock-in (KI mice. Whereas, maternal separation (MS stress increased anxiety- and depressive-like behaviors of WT mice, with no detectable behavioral changes in TPH2 KI mice. Biochemically, we found that MS WT mice had reduced brain serotonin levels, which was attributed to increased expression of monoamine oxidase A (MAO A. The increased MAO A expression was detected in MS WT mice at 4 weeks old and adulthood. No change in TPH2 expression was detected. To determine whether a pharmacological stressor, dexamethasone (Dex, will result in similar biochemical results obtained from MS, we used an in vitro system, SH-SY5Y cells, and found that Dex treatment resulted in increased MAO A expression levels. We then treated WT mice with Dex for 5 days, either during postnatal days 7-11 or adulthood. Both groups of Dex treated WT mice had reduced basal corticosterone and glucocorticoid receptors expression levels. However, only Dex treatment during PND7-11 resulted in reduced serotonin levels and increased MAO A expression. Just as with MS WT mice, TPH2 expression in PND7-11 Dex-treated WT mice was unaffected. Taken together, our findings suggest that both environmental and pharmacological stressors affect the expression of MAO A, and not TPH2, when applied during the critical postnatal period. This leads to long-lasting perturbations in the serotonergic system, and results in anxiety- and depressive

  10. Pharmacological Effects of Niacin on Acute Hyperlipemia.

    Science.gov (United States)

    la Paz, Sergio Montserrat-de; Bermudez, Beatriz; Naranjo, M Carmen; Lopez, Sergio; Abia, Rocio; Muriana, Francisco J G

    2016-01-01

    The well-known changes in modern lifestyle habits including over nutrition and physical inactivity have led to striking adverse effects on public health (e.g., obesity, diabetes, and metabolic syndrome) over recent decades. One noticeable consequence is exaggerated and prolonged state of postprandial hyperlipemia due to the ingestion of multiple fat-enriched meals during the course of a day. Postprandial (non-fasting) hyperlipemia is characterized by increased blood levels of exogenous triglycerides (TG) in the form of apolipoprotein (apo) B48-containing TG-rich lipoproteins (TRL), which have a causal role in the pathogenesis and progression of cardiovascular disease (CVD). The cardiovascular benefits of lifestyle modification (healthy diet and exercise) and conventional lipid-lowering therapies (e.g., statins, fibrates, and niacin) could involve their favourable effects on postprandial metabolism. Pharmacologically, niacin has been used as an athero-protective drug for five decades. Studies have since shown that niacin may decrease fasting levels of plasma verylow- density lipoproteins (VLDL), low-density lipoprotein cholesterol (LDL-C), and lipoprotein [a] (Lp[a]), while may increase high-density lipoprotein cholesterol (HDL-C). Herein, the purpose of this review was to provide an update on effects and mechanisms related to the pharmacological actions of niacin on acute hyperlipemia.

  11. 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

  12. Combined Effects of Primary and Tertiary Blast on Rat Brain: Characterization of a Model of Blast-induced Mild Traumatic Brain Injury

    Science.gov (United States)

    2015-03-01

    Prog Neurobiol. 2001;63:321-36. [34] Zador Z, Stiver S, Wang V, Manley GT. Role of aquaporin-4 in cerebral edema and stroke. Handb Exp Pharmacol. 2009...bullae were opened • Images were taken under microscope with a 20x magnification • Sham ( ll , 1R), 280Ps_S psi (2l, 2R), 2BOPs_12 psi (3l, 3R...8217 · ~~ lW . ll at 7 dafter double blast exposures (ID Effect of blast exposure on auditory cortex • Immunohistochemistry on brain sections • at 6 hand

  13. Combined Effects of Primary and Tertiary Blast on Rat Brain: Characterization of a Model of Blast-induced Mild Traumatic Brain Injury

    Science.gov (United States)

    2013-03-01

    injury in U.S. military personnel. N Engl J Med 364, 2091–2100 (2011) 27. Lu J, Ng KC , Ling GS, Wu J, Poon JF, Kan EM, Tan MH, Wu YJ, Li P...Moochhala S, Yap E, Lee LK, Teo AL, Yeh IB, Ser- gio DM, Chua F, Kumar SD, Ling EA: Effect of blast exposure on the brain structure and cognition in the...12689448] 32. Henderson D, Bielefeld EC, Harris KC , Hu BH. The role of oxidative stress in noise-induced hearing loss. Ear Hear. 2006;27(1):1–19. [PMID

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

    KAUST Repository

    Khoram, Nafiseh; Zayane, Chadia; Laleg-Kirati, Taous-Meriem; Djellouli, Rabia

    2014-01-01

    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

  15. 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.

  16. Characterizing acupuncture stimuli using brain imaging with FMRI--a systematic review and meta-analysis of the literature.

    Directory of Open Access Journals (Sweden)

    Wenjing Huang

    Full Text Available The mechanisms of action underlying acupuncture, including acupuncture point specificity, are not well understood. In the previous decade, an increasing number of studies have applied fMRI to investigate brain response to acupuncture stimulation. Our aim was to provide a systematic overview of acupuncture fMRI research considering the following aspects: 1 differences between verum and sham acupuncture, 2 differences due to various methods of acupuncture manipulation, 3 differences between patients and healthy volunteers, 4 differences between different acupuncture points.We systematically searched English, Chinese, Korean and Japanese databases for literature published from the earliest available up until September 2009, without any language restrictions. We included all studies using fMRI to investigate the effect of acupuncture on the human brain (at least one group that received needle-based acupuncture. 779 papers were identified, 149 met the inclusion criteria for the descriptive analysis, and 34 were eligible for the meta-analyses. From a descriptive perspective, multiple studies reported that acupuncture modulates activity within specific brain areas, including somatosensory cortices, limbic system, basal ganglia, brain stem, and cerebellum. Meta-analyses for verum acupuncture stimuli confirmed brain activity within many of the regions mentioned above. Differences between verum and sham acupuncture were noted in brain response in middle cingulate, while some heterogeneity was noted for other regions depending on how such meta-analyses were performed, such as sensorimotor cortices, limbic regions, and cerebellum.Brain response to acupuncture stimuli encompasses a broad network of regions consistent with not just somatosensory, but also affective and cognitive processing. While the results were heterogeneous, from a descriptive perspective most studies suggest that acupuncture can modulate the activity within specific brain areas, and the

  17. 99mTc-Hexamethyl Propyleneamine Oxime Brain Perfusion Single Photon Emission Computed Tomography in Characterization of Dementia: An Initial Experience in Indian Clinical Practice

    International Nuclear Information System (INIS)

    Santra, Amburanjan; Sinha, Gaurav Kumar; Neogi, Rajarshi; Thukral, Ramesh Kumar

    2014-01-01

    There is a growing health burden in developing countries due to recent trends of increasing incidence of neurodegenerative diseases. To reduce the healthcare cost and effective management of dementia illness, early diagnosis, accurate differentiation and their progression assessment is becoming crucially important. We are utilizing 99m Tc-d, l-hexamethyl propyleneamine oxime (HMPAO) brain perfusion single photon emission computed tomography (SPECT) to characterize dementia on the basis of perfusion patterns and observed significant improvement in their management. Eleven patients (median age of 60 years range of 53-83 years) with clinical suspicion of dementia underwent 99m Tc-HMPAO brain perfusion SPECT. SPECT-computed tomography acquisition done, data are reconstructed, reviewed in three view and further processed in “neurogam” to get voxel based analysis and the comparison with age based normal database and surface mapping. Final diagnosis was done with clinical correlation. Four patients are diagnosed as Alzheimer's disease, two as frontotemporal dementia, one as dementia of Lewy bodies, two as vascular dementia and two as pseudodementia. All imaging findings are well-correlated with clinical background. Brain perfusion SPECT with HMPAO was very helpful to us in characterizing the patients of dementia by its perfusion pattern

  18. 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.

  19. New methods of minimally invasive brain modulation as therapies in psychiatry: TMS, MST, VNS and DBS.

    Science.gov (United States)

    George, Mark S

    2002-08-01

    Over the past 20 years, new methods have been developed that have allowed scientists to visualize the human brain in action. Initially positron emission tomography (PET) and now functional magnetic resonance imaging (fMRI) are causing a paradigm shift in psychiatry and the neurosciences. Psychiatry is abandoning the pharmacological model of 'brain as soup', used for much of the past 20 years. Instead, there is new realization that both normal and abnormal behavior arise from chemical processes that occur within parallel distributed networks in specific brain regions. Many of these pathological circuits are becoming well characterized, in disorders ranging from Parkinson's disease, to obsessive-compulsive disorder, to depression. Most recently, there has been an explosion of new techniques that allow for direct stimulation of these brain circuits, without the need for open craniotomy and neurosurgical ablation. The techniques include transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), vagus nerve stimulation (VNS), and deep brain stimulation (DBS). This review will describe these new tools, and overview their current and future potential for research and clinical neuropsychiatric use. The psychiatry of the future will be better grounded in a firm understanding of neuroanatomy and neurophysiology (as well as pharmacology). These brain stimulation tools, or their next iterations, will play an ever-larger role in clinical neuropsychiatric practice.

  20. 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

  1. The Relationship Between Dopamine Neurotransmitter Dynamics and the Blood-Oxygen-Level-Dependent (BOLD Signal: A Review of Pharmacological Functional Magnetic Resonance Imaging

    Directory of Open Access Journals (Sweden)

    Tyler J. Bruinsma

    2018-04-01

    Full Text Available Functional magnetic resonance imaging (fMRI is widely used in investigations of normal cognition and brain disease and in various clinical applications. Pharmacological fMRI (pharma-fMRI is a relatively new application, which is being used to elucidate the effects and mechanisms of pharmacological modulation of brain activity. Characterizing the effects of neuropharmacological agents on regional brain activity using fMRI is challenging because drugs modulate neuronal function in a wide variety of ways, including through receptor agonist, antagonist, and neurotransmitter reuptake blocker events. Here we review current knowledge on neurotransmitter-mediated blood-oxygen-level dependent (BOLD fMRI mechanisms as well as recently updated methodologies aimed at more fully describing the effects of neuropharmacologic agents on the BOLD signal. We limit our discussion to dopaminergic signaling as a useful lens through which to analyze and interpret neurochemical-mediated changes in the hemodynamic BOLD response. We also discuss the need for future studies that use multi-modal approaches to expand the understanding and application of pharma-fMRI.

  2. The pharmacology of lysergic acid diethylamide: a review.

    Science.gov (United States)

    Passie, Torsten; Halpern, John H; Stichtenoth, Dirk O; Emrich, Hinderk M; Hintzen, Annelie

    2008-01-01

    Lysergic acid diethylamide (LSD) was synthesized in 1938 and its psychoactive effects discovered in 1943. It was used during the 1950s and 1960s as an experimental drug in psychiatric research for producing so-called "experimental psychosis" by altering neurotransmitter system and in psychotherapeutic procedures ("psycholytic" and "psychedelic" therapy). From the mid 1960s, it became an illegal drug of abuse with widespread use that continues today. With the entry of new methods of research and better study oversight, scientific interest in LSD has resumed for brain research and experimental treatments. Due to the lack of any comprehensive review since the 1950s and the widely dispersed experimental literature, the present review focuses on all aspects of the pharmacology and psychopharmacology of LSD. A thorough search of the experimental literature regarding the pharmacology of LSD was performed and the extracted results are given in this review. (Psycho-) pharmacological research on LSD was extensive and produced nearly 10,000 scientific papers. The pharmacology of LSD is complex and its mechanisms of action are still not completely understood. LSD is physiologically well tolerated and psychological reactions can be controlled in a medically supervised setting, but complications may easily result from uncontrolled use by layman. Actually there is new interest in LSD as an experimental tool for elucidating neural mechanisms of (states of) consciousness and there are recently discovered treatment options with LSD in cluster headache and with the terminally ill.

  3. Characterization of the pharmacokinetics, brain distribution, and therapeutic efficacy of the adenosine A1 receptor partial agonist 2'-deoxy-N6-cyclopentyladenosine in sarin-poisoned rats

    International Nuclear Information System (INIS)

    Bueters, Tjerk J.H.; IJzerman, Ad P.; Helden, Herman P.M. van; Danhof, Meindert

    2003-01-01

    Characterization of the pharmacokinetics, brain distribution, and therapeutic efficacy of the adenosine A 1 receptor partial agonist 2'-deoxy-N 6 -cyclopentyladenosine in sarin-poisoned rats. Bueters, T.J.H., IJzerman, A.P., Van Helden, H.P.M., and Danhof, M. (2003). The objective of the present study was to determine (1) the influence of sarin poisoning (144 μg/kg sc) on the pharmacokinetics and brain distribution of the adenosine A 1 receptor partial agonist 2'-deoxy-N 6 -cyclopentyladenosine (2'dCPA), and (2) the effect of 2'dCPA (20 mg/kg iv) on the central acetylcholine (ACh) release and protection against sarin toxicity. A five-compartment model successfully described the pharmacokinetic profile of 2'dCPA in blood and brain microdialysate. A covariate analysis revealed that the volume of distribution of 2'dCPA in blood was different in sarin-poisoned rats, 177 ± 7 versus 148 ± 8 ml in control rats. However, the transport of 2'dCPA from blood to the brain was unaffected as reflected by the values of the intercompartmental transport clearances, 0.21 ± 0.02 and 0.21 ± 0.04 μl/min in control and sarin-poisoned rats, respectively. Also the area-under-curve (AUC) ratios of brain microdialysate and blood were identical with values of 0.02 ± 0.001 and 0.02 ± 0.002, respectively, demonstrating the restricted transport of 2'dCPA into the brain in both treatment groups. Treatment of sarin-poisoned rats by 2'dCPA did not adequately prevent the accumulation of ACh in the central nervous system. 2'dCPA delayed the emergence of concomitant symptoms compared to untreated rats, but eventually only 29% of the animals survived 24 h. In conclusion, the pharmacokinetic profile of 2'dCPA in blood was slightly changed by sarin, but not the distribution of 2'dCPA into the brain. The therapeutic efficacy of 2'dCPA against sarin was limited, presumably due to insufficient quantities of 2'dCPA reaching the brain

  4. Network-based Approaches in Pharmacology.

    Science.gov (United States)

    Boezio, Baptiste; Audouze, Karine; Ducrot, Pierre; Taboureau, Olivier

    2017-10-01

    In drug discovery, network-based approaches are expected to spotlight our understanding of drug action across multiple layers of information. On one hand, network pharmacology considers the drug response in the context of a cellular or phenotypic network. On the other hand, a chemical-based network is a promising alternative for characterizing the chemical space. Both can provide complementary support for the development of rational drug design and better knowledge of the mechanisms underlying the multiple actions of drugs. Recent progress in both concepts is discussed here. In addition, a network-based approach using drug-target-therapy data is introduced as an example. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Radioimmunoassay in basic and clinical pharmacology

    International Nuclear Information System (INIS)

    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

  6. Pharmacological Treatment for Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Kaoru Sugi, MD PhD

    2005-01-01

    Full Text Available Pharmacological treatment for atrial fibrillation has a variety of purposes, such as pharmacological defibrillation, maintenance of sinus rhythm, heart rate control to prevent congestive heart failure and prevention of both cerebral infarction and atrial remodeling. Sodium channel blockers are superior to potassium channel blockers for atrial defibrillation, while both sodium and potassium channel blockers are effective in the maintenance of sinus rhythm. In general, digitalis or Ca antagonists are used to control heart rate during atrial fibrillation to prevent congestive heart failure, while amiodarone or bepridil also reduce heart rates during atrial fibrillation. Anticoagulant therapy with warfarin is recommended to prevent cerebral infarction and angiotensin converting enzyme antagonists or angiotensin II receptor blockers are also used to prevent atrial remodeling. One should select appropriate drugs for treatment of atrial fibrillation according to the patient's condition.

  7. Pharmacological challenges in chronic pancreatitis

    OpenAIRE

    Olesen, Anne Estrup; Brokjaer, Anne; Fisher, Iben Wendelboe; Larsen, Isabelle Myriam

    2013-01-01

    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 ...

  8. 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

  9. Pharmacological and Non-pharmacological Therapies of Cognitive Impairment in Multiple Sclerosis.

    Science.gov (United States)

    Miller, Elzbieta; Morel, Agnieszka; Redlicka, Justyna; Miller, Igor; Saluk, Joanna

    2018-01-01

    Cognitive impairment is one of the most important clinical features of neurodegenerative disorders including multiple sclerosis (MS). Conducted research shows that up to 65 percent of MS patients have cognitive deficits such as episodic memory, sustained attention, reduced verbal fluency; however, the cognitive MS domain is information processing speed. It is the first syndrome of cognitive dysfunction and the most widely affected in MS. Occasionally these impairments occur even before the appearance of physical symptoms. Therefore, this review focused on the current status of our knowledge about possible methods of treatment cognitive impairment in MS patients including novel strategies. Research and online content was performed using Medline and EMBASE databases. The most recent research suggests that cognitive impairment is correlated with brain lesion volume and brain atrophy. The examination of the cognitive impairment is usually based on particular neuropsychological batteries. However, it can be not enough to make a precise diagnosis. This creates a demand to find markers that might be useful for identifying patients with risk of cognitive impairment at an early stage of the disease. Currently the most promising methods consist of neuroimaging indicators, such as diffusion tensor imaging, the magnetization transfer ratio, and N-acetyl aspartate levels. Diagnosis problems are strictly connected with treatment procedures. There are two main cognitive therapies: pharmacological (disease modifying drugs (DMD), symptomatic treatments) and non-pharmacological interventions that are focused on psychological and physical rehabilitation. Some trials have shown a positive association between physical activity and the cognitive function. This article is an overview of the current state of knowledge related to cognition impairment treatment in MS. Additionally, novel strategies for cognitive impairments such as cryostimulation and other complementary methods are

  10. Characterization of subtle brain abnormalities in a mouse model of Hedgehog pathway antagonist-induced cleft lip and palate.

    Science.gov (United States)

    Lipinski, Robert J; Holloway, Hunter T; O'Leary-Moore, Shonagh K; Ament, Jacob J; Pecevich, Stephen J; Cofer, Gary P; Budin, Francois; Everson, Joshua L; Johnson, G Allan; Sulik, Kathleen K

    2014-01-01

    Subtle behavioral and cognitive deficits have been documented in patient cohorts with orofacial clefts (OFCs). Recent neuroimaging studies argue that these traits are associated with structural brain abnormalities but have been limited to adolescent and adult populations where brain plasticity during infancy and childhood may be a confounding factor. Here, we employed high resolution magnetic resonance microscopy to examine primary brain morphology in a mouse model of OFCs. Transient in utero exposure to the Hedgehog (Hh) signaling pathway antagonist cyclopamine resulted in a spectrum of facial dysmorphology, including unilateral and bilateral cleft lip and palate, cleft of the secondary palate only, and a non-cleft phenotype marked by midfacial hypoplasia. Relative to controls, cyclopamine-exposed fetuses exhibited volumetric differences in several brain regions, including hypoplasia of the pituitary gland and olfactory bulbs, hyperplasia of the forebrain septal region, and expansion of the third ventricle. However, in affected fetuses the corpus callosum was intact and normal division of the forebrain was observed. This argues that temporally-specific Hh signaling perturbation can result in typical appearing OFCs in the absence of holoprosencephaly--a condition classically associated with Hh pathway inhibition and frequently co-occurring with OFCs. Supporting the premise that some forms of OFCs co-occur with subtle brain malformations, these results provide a possible ontological basis for traits identified in clinical populations. They also argue in favor of future investigations into genetic and/or environmental modulation of the Hh pathway in the etiopathogenesis of orofacial clefting.

  11. Current Enlightenment About Etiology and Pharmacological Treatment of Autism Spectrum Disorder

    Directory of Open Access Journals (Sweden)

    Nermin Eissa

    2018-05-01

    Full Text Available Autistic Spectrum Disorder (ASD is a complex neurodevelopmental brain disorder characterized by two core behavioral symptoms, namely impairments in social communication and restricted/repetitive behavior. The molecular mechanisms underlying ASD are not well understood. Recent genetic as well as non-genetic animal models contributed significantly in understanding the pathophysiology of ASD, as they establish autism-like behavior in mice and rats. Among the genetic causes, several chromosomal mutations including duplications or deletions could be possible causative factors of ASD. In addition, the biochemical basis suggests that several brain neurotransmitters, e.g., dopamine (DA, serotonin (5-HT, gamma-amino butyric acid (GABA, acetylcholine (ACh, glutamate (Glu and histamine (HA participate in the onset and progression of ASD. Despite of convincible understanding, risperidone and aripiprazole are the only two drugs available clinically for improving behavioral symptoms of ASD following approval by Food and Drug Administration (FDA. Till date, up to our knowledge there is no other drug approved for clinical usage specifically for ASD symptoms. However, many novel drug candidates and classes of compounds are underway for ASD at different phases of preclinical and clinical drug development. In this review, the diversity of numerous aetiological factors and the alterations in variety of neurotransmitter generation, release and function linked to ASD are discussed with focus on drugs currently used to manage neuropsychiatric symptoms related to ASD. The review also highlights the clinical development of drugs with emphasis on their pharmacological targets aiming at improving core symptoms in ASD.

  12. Current Enlightenment About Etiology and Pharmacological Treatment of Autism Spectrum Disorder.

    Science.gov (United States)

    Eissa, Nermin; Al-Houqani, Mohammed; Sadeq, Adel; Ojha, Shreesh K; Sasse, Astrid; Sadek, Bassem

    2018-01-01

    Autistic Spectrum Disorder (ASD) is a complex neurodevelopmental brain disorder characterized by two core behavioral symptoms, namely impairments in social communication and restricted/repetitive behavior. The molecular mechanisms underlying ASD are not well understood. Recent genetic as well as non-genetic animal models contributed significantly in understanding the pathophysiology of ASD, as they establish autism-like behavior in mice and rats. Among the genetic causes, several chromosomal mutations including duplications or deletions could be possible causative factors of ASD. In addition, the biochemical basis suggests that several brain neurotransmitters, e.g., dopamine (DA), serotonin (5-HT), gamma-amino butyric acid (GABA), acetylcholine (ACh), glutamate (Glu) and histamine (HA) participate in the onset and progression of ASD. Despite of convincible understanding, risperidone and aripiprazole are the only two drugs available clinically for improving behavioral symptoms of ASD following approval by Food and Drug Administration (FDA). Till date, up to our knowledge there is no other drug approved for clinical usage specifically for ASD symptoms. However, many novel drug candidates and classes of compounds are underway for ASD at different phases of preclinical and clinical drug development. In this review, the diversity of numerous aetiological factors and the alterations in variety of neurotransmitter generation, release and function linked to ASD are discussed with focus on drugs currently used to manage neuropsychiatric symptoms related to ASD. The review also highlights the clinical development of drugs with emphasis on their pharmacological targets aiming at improving core symptoms in ASD.

  13. Current Enlightenment About Etiology and Pharmacological Treatment of Autism Spectrum Disorder

    Science.gov (United States)

    Eissa, Nermin; Al-Houqani, Mohammed; Sadeq, Adel; Ojha, Shreesh K.; Sasse, Astrid; Sadek, Bassem

    2018-01-01

    Autistic Spectrum Disorder (ASD) is a complex neurodevelopmental brain disorder characterized by two core behavioral symptoms, namely impairments in social communication and restricted/repetitive behavior. The molecular mechanisms underlying ASD are not well understood. Recent genetic as well as non-genetic animal models contributed significantly in understanding the pathophysiology of ASD, as they establish autism-like behavior in mice and rats. Among the genetic causes, several chromosomal mutations including duplications or deletions could be possible causative factors of ASD. In addition, the biochemical basis suggests that several brain neurotransmitters, e.g., dopamine (DA), serotonin (5-HT), gamma-amino butyric acid (GABA), acetylcholine (ACh), glutamate (Glu) and histamine (HA) participate in the onset and progression of ASD. Despite of convincible understanding, risperidone and aripiprazole are the only two drugs available clinically for improving behavioral symptoms of ASD following approval by Food and Drug Administration (FDA). Till date, up to our knowledge there is no other drug approved for clinical usage specifically for ASD symptoms. However, many novel drug candidates and classes of compounds are underway for ASD at different phases of preclinical and clinical drug development. In this review, the diversity of numerous aetiological factors and the alterations in variety of neurotransmitter generation, release and function linked to ASD are discussed with focus on drugs currently used to manage neuropsychiatric symptoms related to ASD. The review also highlights the clinical development of drugs with emphasis on their pharmacological targets aiming at improving core symptoms in ASD. PMID:29867317

  14. A MARKOV RANDOM FIELD-BASED APPROACH TO CHARACTERIZING HUMAN BRAIN DEVELOPMENT USING SPATIAL-TEMPORAL TRANSCRIPTOME DATA.

    Science.gov (United States)

    Lin, Zhixiang; Sanders, Stephan J; Li, Mingfeng; Sestan, Nenad; State, Matthew W; Zhao, Hongyu

    2015-03-01

    Human neurodevelopment is a highly regulated biological process. In this article, we study the dynamic changes of neurodevelopment through the analysis of human brain microarray data, sampled from 16 brain regions in 15 time periods of neurodevelopment. We develop a two-step inferential procedure to identify expressed and unexpressed genes and to detect differentially expressed genes between adjacent time periods. Markov Random Field (MRF) models are used to efficiently utilize the information embedded in brain region similarity and temporal dependency in our approach. We develop and implement a Monte Carlo expectation-maximization (MCEM) algorithm to estimate the model parameters. Simulation studies suggest that our approach achieves lower misclassification error and potential gain in power compared with models not incorporating spatial similarity and temporal dependency.

  15. Developmental aspects of the rat brain insulin receptor: loss of sialic acid and fluctuation in number characterize fetal development

    International Nuclear Information System (INIS)

    Brennan, W.A. Jr.

    1988-01-01

    In this study, I have investigated the structure of the rat brain insulin receptor during fetal development. There is a progressive decrease in the apparent molecular size of the brain alpha-subunit during development: 130K on day 16 of gestation, 126K at birth, and 120K in the adult. Glycosylation was investigated as a possible reason for the observed differences in the alpha-subunit molecular size. The results show that the developmental decrease in the brain alpha-subunit apparent molecular size is due to a parallel decrease in sialic acid content. This was further confirmed by measuring the retention of autophosphorylated insulin receptors on wheat germ agglutinin (WGA)-Sepharose. An inverse correlation between developmental age and retention of 32 P-labeled insulin receptors on the lectin column was observed. Insulin binding increases 6-fold between 16 and 20 days of gestation [61 +/- 25 (+/- SE) fmol/mg protein and 364 +/- 42 fmol/mg, respectively]. Thereafter, binding in brain membranes decreases to 150 +/- 20 fmol/mg by 2 days after birth, then reaches the adult level of 63 +/- 15 fmol/mg. In addition, the degree of insulin-stimulated autophosphorylation closely parallels the developmental changes in insulin binding. Between 16 and 20 days of fetal life, insulin-stimulated phosphorylation of the beta-subunit increases 6-fold. Thereafter, the extent of phosphorylation decreases rapidly, reaching adult values identical with those in 16-day-old fetal brain. These results suggest that the embryonic brain possesses competent insulin receptors whose expression changes markedly during fetal development. This information should be important in defining the role of insulin in the developing nervous system

  16. Characterization of cortical neuronal and glial alterations during culture of organotypic whole brain slices from neonatal and mature mice.

    Science.gov (United States)

    Staal, Jerome A; Alexander, Samuel R; Liu, Yao; Dickson, Tracey D; Vickers, James C

    2011-01-01

    Organotypic brain slice culturing techniques are extensively used in a wide range of experimental procedures and are particularly useful in providing mechanistic insights into neurological disorders or injury. The cellular and morphological alterations associated with hippocampal brain slice cultures has been well established, however, the neuronal response of mouse cortical neurons to culture is not well documented. In the current study, we compared the cell viability, as well as phenotypic and protein expression changes in cortical neurons, in whole brain slice cultures from mouse neonates (P4-6), adolescent animals (P25-28) and mature adults (P50+). Cultures were prepared using the membrane interface method. Propidium iodide labeling of nuclei (due to compromised cell membrane) and AlamarBlue™ (cell respiration) analysis demonstrated that neonatal tissue was significantly less vulnerable to long-term culture in comparison to the more mature brain tissues. Cultures from P6 animals showed a significant increase in the expression of synaptic markers and a decrease in growth-associated proteins over the entire culture period. However, morphological analysis of organotypic brain slices cultured from neonatal tissue demonstrated that there were substantial changes to neuronal and glial organization within the neocortex, with a distinct loss of cytoarchitectural stratification and increased GFAP expression (pglial limitans and, after 14 DIV, displayed substantial cellular protrusions from slice edges, including cells that expressed both glial and neuronal markers. In summary, we present a substantial evaluation of the viability and morphological changes that occur in the neocortex of whole brain tissue cultures, from different ages, over an extended period of culture.

  17. Pharmacological chaperoning: a primer on mechanism and pharmacology.

    Science.gov (United States)

    Leidenheimer, Nancy J; Ryder, Katelyn G

    2014-05-01

    Approximately forty percent of diseases are attributable to protein misfolding, including those for which genetic mutation produces misfolding mutants. Intriguingly, many of these mutants are not terminally misfolded since native-like folding, and subsequent trafficking to functional locations, can be induced by target-specific, small molecules variably termed pharmacological chaperones, pharmacoperones, or pharmacochaperones (PCs). PC targets include enzymes, receptors, transporters, and ion channels, revealing the breadth of proteins that can be engaged by ligand-assisted folding. The purpose of this review is to provide an integrated primer of the diverse mechanisms and pharmacology of PCs. In this regard, we examine the structural mechanisms that underlie PC rescue of misfolding mutants, including the ability of PCs to act as surrogates for defective intramolecular interactions and, at the intermolecular level, overcome oligomerization deficiencies and dominant negative effects, as well as influence the subunit stoichiometry of heteropentameric receptors. Not surprisingly, PC-mediated structural correction of misfolding mutants normalizes interactions with molecular chaperones that participate in protein quality control and forward-trafficking. A variety of small molecules have proven to be efficacious PCs and the advantages and disadvantages of employing orthostatic antagonists, active-site inhibitors, orthostatic agonists, and allosteric modulator PCs are considered. Also examined is the possibility that several therapeutic agents may have unrecognized activity as PCs, and this chaperoning activity may mediate/contribute to therapeutic action and/or account for adverse effects. Lastly, we explore evidence that pharmacological chaperoning exploits intrinsic ligand-assisted folding mechanisms. Given the widespread applicability of PC rescue of mutants associated with protein folding disorders, both in vitro and in vivo, the therapeutic potential of PCs is vast

  18. Peptidomic analysis of the neurolysin-knockout mouse brain.

    Science.gov (United States)

    Castro, Leandro M; Cavalcanti, Diogo M L P; Araujo, Christiane B; Rioli, Vanessa; Icimoto, Marcelo Y; Gozzo, Fábio C; Juliano, Maria; Juliano, Luiz; Oliveira, Vitor; Ferro, Emer S

    2014-12-05

    A large number of intracellular peptides are constantly produced following protein degradation by the proteasome. A few of these peptides function in cell signaling and regulate protein-protein interactions. Neurolysin (Nln) is a structurally defined and biochemically well-characterized endooligopeptidase, and its subcellular distribution and biological activity in the vertebrate brain have been previously investigated. However, the contribution of Nln to peptide metabolism in vivo is poorly understood. In this study, we used quantitative mass spectrometry to investigate the brain peptidome of Nln-knockout mice. An additional in vitro digestion assay with recombinant Nln was also performed to confirm the identification of the substrates and/or products of Nln. Altogether, the data presented suggest that Nln is a key enzyme in the in vivo degradation of only a few peptides derived from proenkephalin, such as Met-enkephalin and octapeptide. Nln was found to have only a minor contribution to the intracellular peptide metabolism in the entire mouse brain. However, further studies appear necessary to investigate the contribution of Nln to the peptide metabolism in specific areas of the murine brain. Neurolysin was first identified in the synaptic membranes of the rat brain in the middle 80's by Frederic Checler and colleagues. Neurolysin was well characterized biochemically, and its brain distribution has been confirmed by immunohistochemical methods. The neurolysin contribution to the central and peripheral neurotensin-mediated functions in vivo has been delineated through inhibitor-based pharmacological approaches, but its genuine contribution to the physiological inactivation of neuropeptides remains to be firmly established. As a result, the main significance of this work is the first characterization of the brain peptidome of the neurolysin-knockout mouse. This article is part of a Special Issue entitled: Proteomics, mass spectrometry and peptidomics, Cancun 2013

  19. Characterization of amyloid beta peptides from brain extracts of transgenic mice overexpressing the London mutant of human amyloid precursor protein.

    Science.gov (United States)

    Pype, Stefan; Moechars, Dieder; Dillen, Lieve; Mercken, Marc

    2003-02-01

    Alzheimer's disease (AD) is marked by the presence of neurofibrillary tangles and amyloid plaques in the brain of patients. To study plaque formation, we report on further quantitative and qualitative analysis of human and mouse amyloid beta peptides (Abeta) from brain extracts of transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP). Using enzyme-linked immunosorbant assays (ELISAs) specific for either human or rodent Abeta, we found that the peptides from both species aggregated to form plaques. The ratios of deposited Abeta1-42/1-40 were in the order of 2-3 for human and 8-9 for mouse peptides, indicating preferential deposition of Abeta42. We also determined the identity and relative levels of other Abeta variants present in protein extracts from soluble and insoluble brain fractions. This was done by combined immunoprecipitation and mass spectrometry (IP/MS). The most prominent peptides truncated either at the carboxyl- or the amino-terminus were Abeta1-38 and Abeta11-42, respectively, and the latter was strongly enriched in the extracts of deposited peptides. Taken together, our data indicate that plaques of APP-London transgenic mice consist of aggregates of multiple human and mouse Abeta variants, and the human variants that we identified were previously detected in brain extracts of AD patients.

  20. 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.

    2008-01-01

    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. PMID:18378167

  1. Characterization of Proteins Present in Isolated Senile Plaques from Alzheimer's Diseased Brains by MALDI-TOF MS with MS/MS.

    Science.gov (United States)

    Kelley, Andrea R; Perry, George; Bach, Stephan B H

    2018-04-18

    The increase of insoluble senile plaques in the brain is a primary hallmark of Alzheimer's disease. The usefulness of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with tandem MS for the characterization of senile plaques from AD brains and the relevance of the components identified to furthering AD research using MS is discussed. Thirty-three components were reproducibly observed within tryptic aliquots of senile plaques from two different AD brains after sample preparation optimization. Additionally, this is one of the first accounts of LIFT being utilized for the direct sequencing of peptides from isolated senile plaques. While many of the species observed coisolated within senile plaques have been linked to AD etiology, if only speculatively, this is the first instance that many of them have been demonstrated to be a part of the plaques themselves. This work is the first step in determining the potential roles that the species may have in the aggregation or proliferation of the plaques.

  2. The Role of Medical Imaging in the Re-Characterization of Mild Traumatic Brain Injury Using Youth Sports as a Laboratory

    Directory of Open Access Journals (Sweden)

    Thomas M. Talavage

    2016-01-01

    Full Text Available The short- and long-term impact of mild traumatic brain injury is an increasingly vital concern for both military and civilian personnel. Such injuries produce significant social and financial burdens, and necessitate improved diagnostic and treatment methods. Recent integration of neuroimaging and biomechanical studies in youth collision-sport athletes has revealed that significant alterations in brain structure and function occur even in the absence of traditional clinical markers of concussion. While task performance is maintained, athletes exposed to repetitive head accelerations exhibit structural changes to the underlying white matter, altered glial cell metabolism, aberrant vascular response and marked changes in functional network behavior. Moreover, these changes accumulate with accrued years of exposure, suggesting a cumulative trauma mechanism that may culminate in categorization as concussion and long-term neurological deficits. The goal of this review is to elucidate the role of medical imaging in re-characterizing traumatic brain injury, as a whole, to better identify at-risk individuals and improve the development of preventative and interventional approaches.

  3. 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...

  4. Pharmacological approach to acute pancreatitis

    DEFF Research Database (Denmark)

    Bang, Ulrich-Christian; Semb, Synne; Nojgaard, Camilla

    2008-01-01

    -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...... pharmacological treatment of AP is limited and studies on the effect of potent anti-inflammatory drugs are warranted....... against tumor necrosis factor-alpha (TNF-alpha) have a potential as rescue therapy but no clinical trials are currently being conducted. The antibiotics beta-lactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis. Evidence based...

  5. Gaultheria: Phytochemical and Pharmacological Characteristics

    Directory of Open Access Journals (Sweden)

    Ren-Bing Shi

    2013-09-01

    Full Text Available The genus Gaultheria, comprised of approximately 134 species, is mostly used in ethnic drugs to cure rheumatism and relieve pain. Phytochemical investigations of the genus Gaultheria have revealed the presence of methyl salicylate derivatives, C6-C3 constituents, organic acids, terpenoids, steroids, and other compounds. Methyl salicylate glycoside is considered as a characteristic ingredient in this genus, whose anti-rheumatic effects may have a new mechanism of action. In this review, comprehensive information on the phytochemistry, volatile components and the pharmacology of the genus Gaultheria is provided to explore its potential and advance research.

  6. 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.

  7. 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

  8. Pharmacologic therapy for acute pancreatitis

    Science.gov (United States)

    Kambhampati, Swetha; Park, Walter; Habtezion, Aida

    2014-01-01

    While conservative management such as fluid, bowel rest, and antibiotics is the mainstay of current acute pancreatitis management, there is a lot of promise in pharmacologic therapies that target various aspects of the pathogenesis of pancreatitis. Extensive review of preclinical studies, which include assessment of therapies such as anti-secretory agents, protease inhibitors, anti-inflammatory agents, and anti-oxidants are discussed. Many of these studies have shown therapeutic benefit and improved survival in experimental models. Based on available preclinical studies, we discuss potential novel targeted pharmacologic approaches that may offer promise in the treatment of acute pancreatitis. To date a variety of clinical studies have assessed the translational potential of animal model effective experimental therapies and have shown either failure or mixed results in human studies. Despite these discouraging clinical studies, there is a great clinical need and there exist several preclinical effective therapies that await investigation in patients. Better understanding of acute pancreatitis pathophysiology and lessons learned from past clinical studies are likely to offer a great foundation upon which to expand future therapies in acute pancreatitis. PMID:25493000

  9. Initial Attempts of Development and Characterization of an In Vitro Blood Brain Barrier Model Derived from Human Pluripotent Stem Cells

    DEFF Research Database (Denmark)

    Goldeman, Charlotte; Saaby, Lasse; Hall, Vanessa Jane

    The human blood brain barrier has yet to be successfully replicated as an in vitro model. One of the more promising approaches has been to develop an in vitro model derived from human pluripotent stem cells. However, as promising as this model may be, a successful replication of the differentiation...... method on different kinds of pluripotent stem cell lines have yet to be accomplished. We try to approach the promising method as described by Stebbins et al. (2015) to differentiate human pluripotent stem cells into brain like endothelial cells (BECs). Five different human pluripotent stem cell lines...... configurations (mono culture, non-contact co-culture and contact co-culture) with primary rat astrocytes to induce barrier-like properties. Endothelial cell media supplemented with retinoic acid were then applied to the cells to ensure selective expansion of BECs. The different culture configurations were...

  10. Characterization of the binding of /sup 3/H-norzimeldine, a 5-HT uptake inhibitor, to rat brain homogenates

    Energy Technology Data Exchange (ETDEWEB)

    Hall, H. (Department of Biochemical Neuropharmacology, Research and Development Laboratories, Astra Laekemedel, Soedertaelje, Sweden)

    1984-01-01

    The binding of radiolabelled norzimeldine, a potent selective 5-HT reuptake inhibitor, to rat brain homogenates is described. /sup 3/H-Norzimeldine binds to a site with high affinity (Ksub(D) = 10.5 nM) in a saturable manner (Bsub(max) = 15.4 pmol/g wet weight in the cerebral cortex). The number of binding sites in the various regions of the brain parallels the capacity of the 5-HT reuptake mechanism. Drugs that inhibit the reuptake of 5-HT are also potent inhibitors of the /sup 3/H-norzimeldine binding, as are the tricyclic antidepressants, which are non-specific inhibitors of the noradrenaline and the 5-HT reuptake. Lesioning experiments using DSP4 (a NA neurotoxin) and p-chloroamphetamine (a 5-HT neurotoxin) suggest that the binding site is located on the presynaptic 5-HT nerve terminal, although a small component of the binding may be to noradrenergic uptake sites as well.

  11. Characterization of the binding of 3H-norzimeldine, a 5-HT uptake inhibitor, to rat brain homogenates

    International Nuclear Information System (INIS)

    Hall, H.

    1984-01-01

    The binding of radiolabelled norzimeldine, a potent selective 5-HT reuptake inhibitor, to rat brain homogenates is described. 3 H-Norzimeldine binds to a site with high affinity (Ksub(D) = 10.5 nM) in a saturable manner (Bsub(max) = 15.4 pmol/g wet weight in the cerebral cortex). The number of binding sites in the various regions of the brain parallels the capacity of the 5-HT reuptake mechanism. Drugs that inhibit the reuptake of 5-HT are also potent inhibitors of the 3 H-norzimeldine binding, as are the tricyclic antidepressants, which are non-specific inhibitors of the noradrenaline and the 5-HT reuptake. Lesioning experiments using DSP4 (a NA neurotoxin) and p-chloroamphetamine (a 5-HT neurotoxin) suggest that the binding site is located on the presynaptic 5-HT nerve terminal, although a small component of the binding may be to noradrenergic uptake sites as well.(author)

  12. High-density EEG characterization of brain responses to auditory rhythmic stimuli during wakefulness and NREM sleep.

    Science.gov (United States)

    Lustenberger, Caroline; Patel, Yogi A; Alagapan, Sankaraleengam; Page, Jessica M; Price, Betsy; Boyle, Michael R; Fröhlich, Flavio

    2018-04-01

    Auditory rhythmic sensory stimulation modulates brain oscillations by increasing phase-locking to the temporal structure of the stimuli and by increasing the power of specific frequency bands, resulting in Auditory Steady State Responses (ASSR). The ASSR is altered in different diseases of the central nervous system such as schizophrenia. However, in order to use the ASSR as biological markers for disease states, it needs to be understood how different vigilance states and underlying brain activity affect the ASSR. Here, we compared the effects of auditory rhythmic stimuli on EEG brain activity during wake and NREM sleep, investigated the influence of the presence of dominant sleep rhythms on the ASSR, and delineated the topographical distribution of these modulations. Participants (14 healthy males, 20-33 years) completed on the same day a 60 min nap session and two 30 min wakefulness sessions (before and after the nap). During these sessions, amplitude modulated (AM) white noise auditory stimuli at different frequencies were applied. High-density EEG was continuously recorded and time-frequency analyses were performed to assess ASSR during wakefulness and NREM periods. Our analysis revealed that depending on the electrode location, stimulation frequency applied and window/frequencies analysed the ASSR was significantly modulated by sleep pressure (before and after sleep), vigilance state (wake vs. NREM sleep), and the presence of slow wave activity and sleep spindles. Furthermore, AM stimuli increased spindle activity during NREM sleep but not during wakefulness. Thus, (1) electrode location, sleep history, vigilance state and ongoing brain activity needs to be carefully considered when investigating ASSR and (2) auditory rhythmic stimuli during sleep might represent a powerful tool to boost sleep spindles. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. 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. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Isolation of Neospora caninum from kidney and brain of a bovine foetus and molecular characterization in Brazil.

    Science.gov (United States)

    Locatelli Dittrich, Rosangela; Regidor-Cerrillo, Javier; Ortega-Mora, Luis Miguel; Oliveira Koch, Marília de; Busch, Ana Paula B; Gonçalves, Kamila Alcalá; Cruz, Amilcar A

    2018-02-01

    Bovine neosporosis has become a disease of international concern as it is among the main causes of abortion in cattle. Viable N. caninum has been isolated from brains of fetuses and neonatal calves, and there is no report of isolation of tachyzoites from kidney. Also, detailed information about the genetic diversity of N. caninum is scarce. N. caninum tachyzoites were isolated from the kidney and the brain of an aborted 4-month-old bovine foetus. The parasite was confirmed to be N. caninum by PCR. The tachyzoites of the new isolate, named BNC-PR4, were propagated in Vero cell cultures. Pathogenicity of the parasite was examined in BALB/c mice. Mice inoculated intraperitoneally with BNC-PR4 failed to yield clinical signs of disease and did not induce severe brain lesions, suggesting a bovine isolate with low virulence. The N. caninum-positive DNA sample was further analyzed by multilocus microsatellite (MS) genotyping for MS4, MS5, MS6A, MS6B, MS7, MS8, MS10, MS12, and MS21. Multilocus-microsatellite genotyping revealed a unique genetic profile that differed from previously reported isolates. Published by Elsevier Inc.

  15. Characterization of the Transcriptome and Gene Expression of Brain Tissue in Sevenband Grouper (Hyporthodus septemfasciatus in Response to NNV Infection

    Directory of Open Access Journals (Sweden)

    Jong-Oh Kim

    2017-01-01

    Full Text Available Grouper is one of the favorite sea food resources in Southeast Asia. However, the outbreaks of the viral nervous necrosis (VNN disease due to nervous necrosis virus (NNV infection have caused mass mortality of grouper larvae. Many aqua-farms have suffered substantial financial loss due to the occurrence of VNN. To better understand the infection mechanism of NNV, we performed the transcriptome analysis of sevenband grouper brain tissue, the main target of NNV infection. After artificial NNV challenge, transcriptome of brain tissues of sevenband grouper was subjected to next generation sequencing (NGS using an Illumina Hi-seq 2500 system. Both mRNAs from pooled samples of mock and NNV-infected sevenband grouper brains were sequenced. Clean reads of mock and NNV-infected samples were de novo assembled and obtained 104,348 unigenes. In addition, 628 differentially expressed genes (DEGs in response to NNV infection were identified. This result could provide critical information not only for the identification of genes involved in NNV infection, but for the understanding of the response of sevenband groupers to NNV infection.

  16. Human umbilical cord blood-derived stem cells and brain-derived neurotrophic factor protect injured optic nerve: viscoelasticity characterization

    Directory of Open Access Journals (Sweden)

    Xue-man Lv

    2016-01-01

    Full Text Available The optic nerve is a viscoelastic solid-like biomaterial. Its normal stress relaxation and creep properties enable the nerve to resist constant strain and protect it from injury. We hypothesized that stress relaxation and creep properties of the optic nerve change after injury. More-over, human brain-derived neurotrophic factor or umbilical cord blood-derived stem cells may restore these changes to normal. To validate this hypothesis, a rabbit model of optic nerve injury was established using a clamp approach. At 7 days after injury, the vitreous body re-ceived a one-time injection of 50 µg human brain-derived neurotrophic factor or 1 × 106 human umbilical cord blood-derived stem cells. At 30 days after injury, stress relaxation and creep properties of the optic nerve that received treatment had recovered greatly, with patho-logical changes in the injured optic nerve also noticeably improved. These results suggest that human brain-derived neurotrophic factor or umbilical cord blood-derived stem cell intervention promotes viscoelasticity recovery of injured optic nerves, and thereby contributes to nerve recovery.

  17. Pharmacological Treatment of Glutamate Excitotoxicity Following Traumatic Brain Injury

    Science.gov (United States)

    2009-01-14

    schizophrenia -like psychosis. TBI patients are also a higher risk for developing psychological problem many years post-injury. Cognitive symptoms of...promoting the propagation of action potentials. On the other hand, inhibitory neurotransmission mediated by GABA , causes the hyperpolarization of the...transporter contributes to neurotransmitter GABA synthesis and epilepsy. J Neurosci. 2002 Aug 1;22(15):6372-9. Shen M, Piser TM, Seybold VS, Thayer SA

  18. Pharmacological and non- pharmacological treatment of hypertension: A review article

    Directory of Open Access Journals (Sweden)

    Marjan Seyedmazhari

    2013-01-01

    Full Text Available BACKGROUND: Hypertension is a worldwide epidemic disease. It is more common and more severe in elderly persons. Various studies however have estimated 41.9 million men and 27.8 million women to have prehypertension. Diagnosis and early treatment of prehypertension are of utmost importance. Although hypertension is usually divided into 2 general categories of essential (primary and secondary hypertension, the initial treatment for hypertension often depends on its stage which is determined by systolic and diastolic blood pressure. Lifestyle modification is the first step in treating stage one hypertension. Pharmaceutical treatments including diuretics, angiotensin converting enzyme (ACE inhibitors, calcium blockers, beta blockers, and angiotensin receptor blockers will be recommended if lifestyle modification fails to control blood pressure.    METHODS: The PubMed database was searched by a number of keywords including hypertension, pharmaceutical treatment, and non-pharmaceutical treatment. The results were limited by determining a date range of 2008-11.    RESULTS: High blood pressure causes major health problems for many people around the world. It should be controlled because of its high mortality and morbidity. However, in order to select an appropriate treatment modality, it is initially important to diagnose the kinds and stages of hypertension. Pharmaceutical or non-pharmaceutical treatments can then be employed to control this serious disease.    CONCLUSION: Treating hypertension depends on the kinds and stages of this disease. Several tips should be considered when selecting a method of treatment.       Keywords: Hypertension, Pharmacological treatment, Non-pharmacological treatment

  19. 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

  20. Characterization of [(11)C]Cimbi-36 as an agonist PET radioligand for the 5-HT(2A) and 5-HT(2C) receptors in the nonhuman primate brain

    DEFF Research Database (Denmark)

    Finnema, Sjoerd J; Stepanov, Vladimir; Ettrup, Anders

    2014-01-01

    a more meaningful assessment of available receptors than antagonist radioligands. In the current study we characterized [(11)C]Cimbi-36 receptor binding in the primate brain. On five experimental days, a total of 14 PET measurements were conducted in three female rhesus monkeys. On each day, PET...... agonist radioligand suitable for examination of 5-HT2A receptors in the cortical regions and of 5-HT2C receptors in the choroid plexus of the primate brain....

  1. Lippia citrodora: a review on its phytochemistry and pharmacological activities

    Directory of Open Access Journals (Sweden)

    2017-11-01

    Full Text Available Background and objectives: Lippia citrodora commonly known as lemon verbena is a species of flowering plant in the verbena family, native to western South America. With its antioxidant effects, it is mostly used in folk medicine to treat anti-inflammatory diseases, and diseases associated with oxidative stress. This review has presented a summary on L. citordora’s phytochemistry and its pharmacological activities. It will also discuss gaps and challenges needed to be solved. Methods: Electronic database including Web of Science, PubMed, Science Direct and Google Scholar were searched for articles published between 1973 and 2017 regarding the phytochemistry and biological activities of L. citodora. Results: Traditional uses of this plant were specially related to coagulation system, digestive system and brain. Phytochemical investigations identified flavonoids, terpenes, iridois, lignins, phenylethanoid, as the main components of the plant. Antimicrobial, neuroprotective, antinociceptive, anti hyperpropulsive, sedative, anticolitis, anxiolytic, anticonvulsant, antihyperalgesic, and anticancer properties were among the pharmacological activities of L. citriodora. The plant extract and essential oil had also demonstrated high antioxidant activity. Conclusion: Modern pharmacological studies have now validated many traditional uses of L. citrodora. The data reviewed here revealed that this plant is a potential source for the treatment of a wide range of diseases specially inflammatory diseases and neurological dysfunctions. Future human studies are needed for further confirmation of the therapeutic activities of L. citriodora.

  2. The pharmacology of neurokinin receptors in addiction: prospects for therapy

    Directory of Open Access Journals (Sweden)

    Sandweiss AJ

    2015-09-01

    Full Text Available Alexander J Sandweiss, Todd W VanderahDepartment of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USAAbstract: Addiction is a chronic disorder in which consumption of a substance or a habitual behavior becomes compulsive and often recurrent, despite adverse consequences. Substance p (SP is an undecapeptide and was the first neuropeptide of the neurokinin family to be discovered. The subsequent decades of research after its discovery implicated SP and its neurokinin relatives as neurotransmitters involved in the modulation of the reward pathway. Here, we review the neurokinin literature, giving a brief historical perspective of neurokinin pharmacology, localization in various brain regions involved in addictive behaviors, and the functional aspects of neurokinin pharmacology in relation to reward in preclinical models of addiction that have shaped the rational drug design of neurokinin antagonists that could translate into human research. Finally, we will cover the clinical investigations using neurokinin antagonists and discuss their potential as a therapy for drug abuse.Keywords: reward, substance p, alcohol, morphine, cocaine, dopamine

  3. Pharmacological analyses of learning and memory in zebrafish (Danio rerio).

    Science.gov (United States)

    Bailey, Jordan M; Oliveri, Anthony N; Levin, Edward D

    2015-12-01

    Over the last decade, zebrafish (Danio rerio) have become valuable as a complementary model in behavioral pharmacology, opening a new avenue for understanding the relationships between drug action and behavior. This species offers a useful intermediate approach bridging the gap between in vitro studies and traditional mammalian models. Zebrafish offer great advantages of economy compared to their rodent counterparts, their complex brains and behavioral repertoire offer great translational potential relative to in vitro models. The development and validation of a variety of tests to measure behavior, including cognition, in zebrafish have set the stage for the use of this animal for behavioral pharmacology studies. This has led to research into the basic mechanisms of cognitive function as well as screening for potential cognition-improving drug therapies, among other lines of research. As with all models, zebrafish have limitations, which span pharmacokinetic challenges to difficulties quantifying behavior. The use, efficacy and limitations associated with a zebrafish model of cognitive function are discussed in this review, within the context of behavioral pharmacology. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Pharmacological challenges in chronic pancreatitis

    DEFF Research Database (Denmark)

    Olesen, Anne Estrup; Brokjaer, Anne; Fischer, Iben Wendelboe Deleuran

    2014-01-01

    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......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...

  5. Pharmacological challenges in chronic pancreatitis

    DEFF Research Database (Denmark)

    Olesen, Anne Estrup; Brokjaer, Anne; Fischer, Iben Wendelboe Deleuran

    2014-01-01

    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....... 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......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...

  6. MRI characterization of structural mouse brain changes in response to chronic exposure to the glufosinate ammonium herbicide.

    Science.gov (United States)

    Meme, Sandra; Calas, André-Guilhem; Montécot, Céline; Richard, Oliver; Gautier, Hélène; Gefflaut, Thierry; Doan, Bich Thuy; Même, William; Pichon, Jacques; Beloeil, Jean-Claude

    2009-10-01

    Glufosinate ammonium (GLA) is the active component of herbicides widely used in agriculture, truck farming, or public domains. GLA acts by inhibiting the plant glutamine synthetase (GlnS). It also inhibits mammalian GlnS in vitro and ex vivo. In the central nervous system this enzyme is exclusively localized in glial cells. Whereas acute neurotoxic effects of GLA are well documented, long-term effects during chronic exposure at low doses remain largely undisclosed. In the present work, C57BL/6J mice were treated intraperitoneally with 2.5, 5, and 10 mg/kg of GLA three times a week during 10 weeks. Cerebral magnetic resonance imaging (MRI) experiments were performed at high field (9.4 T) and the images were analyzed with four texture analysis (TA) methods. TA highlighted structural changes in seven brain structures after chronic GLA treatments. Changes are dose dependent and can be seen at a dose as low as 2.5 mg/kg for two areas, namely hippocampus and somatosensorial cortex. Glial fibrillary acidic protein (GFAP) expression in the same seven brain structures and GlnS activity in the hippocampus and cortex areas were also studied. The number of GFAP-positive cells is modified in six out of the seven areas examined. GlnS activity was significantly increased in the hippocampus but not in the cortex. These results indicate some kind of suffering at the cerebral level after chronic GLA treatment. Changes in TA were compared with the modification of the number of GFAP-positive astrocytes in the studied brain areas after GLA treatment. We show that the noninvasive MRI-TA is a sensitive method and we suggest that it would be a very helpful tool that can efficiently contribute to the detection of cerebral alterations in vivo during chronic exposure to xenobiotics.

  7. Neurochemical Characterization of PSA-NCAM+ Cells in the Human Brain and Phenotypic Quantification in Alzheimer's Disease Entorhinal Cortex.

    Science.gov (United States)

    Murray, Helen C; Swanson, Molly E V; Dieriks, B Victor; Turner, Clinton; Faull, Richard L M; Curtis, Maurice A

    2018-02-21

    Polysialylated neural cell adhesion molecule (PSA-NCAM) is widely expressed in the adult human brain and facilitates structural remodeling of cells through steric inhibition of intercellular NCAM adhesion. We previously showed that PSA-NCAM immunoreactivity is decreased in the entorhinal cortex in Alzheimer's disease (AD). Based on available evidence, we hypothesized that a loss of PSA-NCAM + interneurons may underlie this reduction. PSA-NCAM expression by interneurons has previously been described in the human medial prefrontal cortex. Here we used postmortem human brain tissue to provide further evidence of PSA-NCAM + interneurons throughout the human hippocampal formation and additional cortical regions. Furthermore, PSA-NCAM + cell populations were assessed in the entorhinal cortex of normal and AD cases using fluorescent double labeling and manual cell counting. We found a significant decrease in the number of PSA-NCAM + cells per mm 2 in layer II and V of the entorhinal cortex, supporting our previous description of reduced PSA-NCAM immunoreactivity. Additionally, we found a significant decrease in the proportion of PSA-NCAM + cells that co-labeled with NeuN and parvalbumin, but no change in the proportion that co-labeled with calbindin or calretinin. These results demonstrate that PSA-NCAM is expressed by a variety of interneuron populations throughout the brain. Furthermore, that loss of PSA-NCAM expression by NeuN + cells predominantly contributes to the reduced PSA-NCAM immunoreactivity in the AD entorhinal cortex. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Characterization of kappa opioid binding using dynorphin A1-13 and U69,593 in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Devlin, T.; Shoemaker, W.J. (Univ. of Connecticut Health Center, Farmington (USA))

    1990-05-01

    Previous studies of kappa opioid binding sites have suggested heterogeneous binding to this class of opioid receptors. To further investigate kappa receptor heterogeneity, we analyzed the binding properties of various kappa-selective ligands in rat brain homogenates. Displacement assays were carried out using (3H)bremazocine in the presence of various displacing ligands under mu and delta receptor-blocked conditions. Homologous displacement of (3H)bremazocine produced shallow displacement which best fit a two-site model of drug-receptor interaction. Dynorphin A1-13 and U69,593 exhibited similar biphasic displacement of (3H)bremazocine. Maximal displacement by these ligands, however, represented only approximately 55% of total (3H)bremazocine binding, which suggests the existence of a third component of (3H)bremazocine binding. Biphasic displacement by dynorphin A1-13 was detected in tissue throughout the brain and the spinal cord, whereas the dynorphin-resistant component of (3H)bremazocine binding was uniquely absent in the spinal cord. U50,488H, tifluadom and ethylketocyclazocine appeared to displace from additional, dynorphin-insensitive sites, as their maximal displacement exceeded that seen with either dynorphin A1-13 or U69,593. These results strongly suggest the existence of at least three components of non-mu, non-delta (3H)bremazocine binding in the rat brain: two with differential affinity for dynorphin A1-13 and U69-593 (kappa-1 and kappa-2 sites), and a third (termed here R1) that was further resolved into two binding sites by bremazocine. Preliminary analysis of the R1 component using naloxone revealed one high-affinity site, which may be opiate in nature, and a second site whose binding properties closely resemble those of the sigma receptor described by others.

  9. 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.

  10. Carotenoids: biochemistry, pharmacology and treatment.

    Science.gov (United States)

    Milani, Alireza; Basirnejad, Marzieh; Shahbazi, Sepideh; Bolhassani, Azam

    2017-06-01

    Carotenoids and retinoids have several similar biological activities such as antioxidant properties, the inhibition of malignant tumour growth and the induction of apoptosis. Supplementation with carotenoids can affect cell growth and modulate gene expression and immune responses. Epidemiological studies have shown a correlation between a high carotenoid intake in the diet with a reduced risk of breast, cervical, ovarian, colorectal cancers, and cardiovascular and eye diseases. Cancer chemoprevention by dietary carotenoids involves several mechanisms, including effects on gap junctional intercellular communication, growth factor signalling, cell cycle progression, differentiation-related proteins, retinoid-like receptors, antioxidant response element, nuclear receptors, AP-1 transcriptional complex, the Wnt/β-catenin pathway and inflammatory cytokines. Moreover, carotenoids can stimulate the proliferation of B- and T-lymphocytes, the activity of macrophages and cytotoxic T-cells, effector T-cell function and the production of cytokines. Recently, the beneficial effects of carotenoid-rich vegetables and fruits in health and in decreasing the risk of certain diseases has been attributed to the major carotenoids, β-carotene, lycopene, lutein, zeaxanthin, crocin (/crocetin) and curcumin, due to their antioxidant effects. It is thought that carotenoids act in a time- and dose-dependent manner. In this review, we briefly describe the biological and immunological activities of the main carotenoids used for the treatment of various diseases and their possible mechanisms of action. This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. © 2016 The British Pharmacological Society.

  11. Novel Regenerative Therapies Based on Regionally Induced Multipotent Stem Cells in Post-Stroke Brains: Their Origin, Characterization, and Perspective.

    Science.gov (United States)

    Takagi, Toshinori; Yoshimura, Shinichi; Sakuma, Rika; Nakano-Doi, Akiko; Matsuyama, Tomohiro; Nakagomi, Takayuki

    2017-12-01

    Brain injuries such as ischemic stroke cause severe neural loss. Until recently, it was believed that post-ischemic areas mainly contain necrotic tissue and inflammatory cells. However, using a mouse model of cerebral infarction, we demonstrated that stem cells develop within ischemic areas. Ischemia-induced stem cells can function as neural progenitors; thus, we initially named them injury/ischemia-induced neural stem/progenitor cells (iNSPCs). However, because they differentiate into more than neural lineages, we now refer to them as ischemia-induced multipotent stem cells (iSCs). Very recently, we showed that putative iNSPCs/iSCs are present within post-stroke areas in human brains. Because iNSPCs/iSCs isolated from mouse and human ischemic tissues can differentiate into neuronal lineages in vitro, it is possible that a clearer understanding of iNSPC/iSC profiles and the molecules that regulate iNSPC/iSC fate (e.g., proliferation, differentiation, and survival) would make it possible to perform neural regeneration/repair in patients following stroke. In this article, we introduce the origin and traits of iNSPCs/iSCs based on our reports and recent viewpoints. We also discuss their possible contribution to neurogenesis through endogenous and exogenous iNSPC/iSC therapies following ischemic stroke.

  12. Characterization of a cis-acting element involved in cell-specific expression of the zebrafish brain aromatase gene.

    Science.gov (United States)

    Le Page, Yann; Menuet, Arnaud; Kah, Olivier; Pakdel, Farzad

    2008-10-01

    The cytochrome P450 Aromatase is the key enzyme catalyzing the conversion of androgens into estrogens. In zebrafish, the brain aromatase is encoded by cyp19b. Expression of cyp19b is restricted to radial glial cells bordering forebrain ventricles and is strongly stimulated by estrogens during development. At the promoter level, we have previously shown that an estrogen responsive element (ERE) is required for induction by estrogens. Here, we investigated the role of ERE flanking regions in the control of cell-specific expression. First, we show that a 20 bp length motif, named G x RE (glial x responsive element), acts in synergy with the ERE to mediate the estrogenic induction specifically in glial cells. Second, we demonstrate that, in vitro, this sequence binds factors exclusively present in glial or neuro-glial cells and is able to confer a glial specificity to an artificial estrogen-dependent gene. Taken together, these results contribute to the understanding of the molecular mechanisms allowing cyp19b regulation by estrogens and allowed to identify a promoter sequence involved in the strong estrogen inducibility of cyp19b which is specific for glial cells. The exceptional aromatase activity measured in the brain of teleost fish could rely on such mechanisms.

  13. The associative brain at work

    DEFF Research Database (Denmark)

    Suppa, A.; Quartarone, A.; Siebner, H.

    2017-01-01

    with movement disorders and other neuropsychiatric diseases. The present review covers the physiology, pharmacology, pathology and motor effects of PAS. Further sections of the review focus on new protocols of “modified PAS” and possible future application of PAS in neuromorphic circuits designed for brain...

  14. Disrupted functional brain networks in autistic toddlers

    NARCIS (Netherlands)

    Boersma, M.; Kemner, C.; Reus, M.A. de; Collin, G; Snijders, T.M.; Hofman, D.; Buitelaar, J.K.; Stam, C.J.; Heuvel, M.P. van den

    2013-01-01

    Communication and integration of information between brain regions plays a key role in healthy brain function. Conversely, disruption in brain communication may lead to cognitive and behavioral problems. Autism is a neurodevelopmental disorder that is characterized by impaired social interactions

  15. An overview on Phyllanthus emblica: phytochemical and pharmacological investigations

    Directory of Open Access Journals (Sweden)

    Y. Amirazodi

    2017-11-01

    Full Text Available Background and objectives: Phyllanthus emblica L. (Phyllanthaceae, commonly known as Indian gooseberry, is an endemic plant to the tropical and subtropical areas in china, India and Thailand. The plant is extensively used in Chinese, Ayurveda, and traditional Persian medicine (TPM. In addition, there are numerous reports on pharmacological and clinical activities of gooseberry in current medicine. The present review was performed to compile the phytochemical and pharmacological data on P. emblica in order to draw a window for further research.  Methods: Databases such as Scopus, ScienceDirect and PubMed were searched for the term “P. emblica” up to 1st September, 2017. Papers concerning pharmacology and phytochemistry of the plant were gathered and analyzed. On the contrary, agriculture and genetic contents were excluded. Results: Over all, 80 papers were selected. The herb revealed to possess anti-diabetic, anti-oxidant, anti-proliferative, anti-inflammatory, antidepressant, larvicidal, anti-asthmatic, antiulcer, anti-aging, anti-carcinogenic, anti-tumor, anti-genotoxicity, anti-microbial, anticholinergic, antispasmodic, gastroprotective, anti-plasmodia, and antinociceptive activities as well as antidote effect against certain elements. The fruits are also useful in brain and gastrointestinal diseases and can be beneficial in hearth protection. Remarkably, many of those properties have been mentioned in TPM manuscripts.  Conclusion: Despite numerous pharmacological activities for P. emblica, there is still a gap between the in vivo and human studies which should be covered by more comprehensive and complementary studies. Many compounds have been isolated and elucidated from this plant which can be good candidates for various related activities and also as new natural medicaments in novel drug discovery.

  16. Black-bellied whistling duck (Dendrocygna autumnalis) brain cholinesterase characterization and diagnosis of anticholinesterase pesticide exposure in wild populations from Mexico.

    Science.gov (United States)

    Osten, Jaime Rendón-von; Soares, Amadeu M V M; Guilhermino, Lucia

    2005-02-01

    Rice is the main crop in the subbasin of the fluvial lagoon system of Palizada River (FLSPR) in the state of Campeche, Mexico. The pesticides used to control pests of this crop mainly are carbofuran, chlorpyrifos, and glyphosate. Black-bellied whistling duck (Dendrocygna autumnalis) is an ecologically and economically important species in the area. This duck is consumed by local inhabitants throughout the year, despite its potential exposure to pesticides. Due to its feeding habits, abundance, and nutritional value, D. autumnalis is a good indicator of environmental contamination and a potential route of human exposure to organophosphate and carbamate pesticides. In this study, the brain cholinesterase (ChE) in the frontal cerebral cortex of autochthonous ducks was characterized. In addition, the potential of the three locally used pesticides and mixtures to inhibit ChE activity was investigated and the exposure of the wild duck population during intensive pesticide applications in rice fields was evaluated. We found that acetylcholinesterase (AChE) seems to be the predominant ChE form in the biological fraction analyzed. Carbofuran was the most potent ChE inhibitor of D. autumnalis brain ChE activity from the three pesticides analyzed. Cholinesterase inhibition after exposure to pesticide mixtures predominantly was due to carbofuran. A decrease (p 30%) was apparent in wild ducks compared to reference ducks, with recovery of ChE inhibition in wild ducks occurring months later when no pesticides were applied in the field. Dendrocygna autumnalis brain ChE is a suitable parameter for inclusion in biomonitoring programs for both environmental protection and human safety.

  17. Apomorphine and piribedil in rats: biochemical and pharmacologic studies.

    Science.gov (United States)

    Butterworth, R F; Poignant, J C; Barbeau, A

    1975-01-01

    We studied the biochemical and pharmacologic modes of action of piribedil and apomorphine in the rat. Although both drugs have many points in common, they are also different in many of their manifestations. Apomorphine causes high-intensity, short-duration stereotyped behavior; it is distributed within the brain in uneven fashion, the striatum being the area of lowest concentration as measured by fluorometry. Direct stereotactic injection within the dopaminergic mesolimbic system, and particularly the tuberculum olfactorium, produced constant intense responses. All effects of apomorphine can be blocked by pimozide, but propanolol, a beta blocker, only reduces aggression and ferocity, leaving stereotyped behaviors intact. Finally, L-5-HTP tends to reduce aggression, ferocity, and to a lesser extent stereotypy; MIF or piribedil, as well as reserpine, potentiates the stereotyped behaviors induced by apomorphine, whereas L-DOPA usually decreases them. Piribedil, on the other hand, causes low-intensity, long-duration stereotyped behavior. It is distributed within the brain almost uniformly. Most effects of piribedil can be blocked by pimozide, but propanolol blocks only aggression and ferocity, leaving stereotyped behaviors intact. On the other hand, clonidine, an alpha-receptor agonist, blocks stereotyped behaviors induced by piribedil but markedly increases aggression, ferocity, and motor activity. L-5-HTP and L-DOPA have little effect on piribedil-induced manifestations. Reserpine decreases piribedil stereotypy. The main metabolite of piribedil, S 584, had no clear-cut pharmacologic action in our hands at the dosage used. It is concluded that both apomorphine and piribedil produce stereotyped behavior by modifying the physiologic balance between mesolimbic and nigrostriatal dopaminergic systems. The other actions of apomorphine and piribedil upon aggression, ferocity, and motor activity are not always in parallel and depend probably on the fact that piribedil is less

  18. 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

  19. Characterization and performance of monolithic detector blocks with a dedicated ASIC front-end readout for PET imaging of the human brain

    International Nuclear Information System (INIS)

    Rato Mendes, Pedro; Sarasola Martin, Iciar; Canadas, Mario; Garcia de Acilu, Paz; Cuypers, Robin; Perez, Jose Manuel; Willmott, Carlos

    2011-01-01

    We are developing a human brain PET scanner prototype compatible with MRI based on monolithic scintillator crystals, APD matrices and a dedicated ASIC front-end readout. In this work we report on the performance of individual detector modules and on the operation of such modules in PET coincidence. Results will be presented on the individual characterization of detector blocks and its ASIC front-end readout, with measured energy resolutions of 13% full-width half-maximum (FWHM) at 511 keV and spatial resolutions of the order of 2 mm FWHM. First results on PET coincidence performance indicate spatial resolutions as good as 2.1 mm FWHM for SSRB/FBP reconstruction of tomographic data obtained using a simple PET demonstrator based on a pair of monolithic detector blocks with ASIC readout.

  20. Pharmacologic treatment of depression in multiple sclerosis

    NARCIS (Netherlands)

    Koch, Marcus W.; Glazenborg, Arjon; Uyttenboogaart, Maarten; Mostert, Jop; De Keyser, Jacques

    2011-01-01

    Background Depression is a common problem in patients with multiple sclerosis (MS). It is unclear which pharmacologic treatment is the most effective and the least harmful. Objectives To investigate the efficacy and tolerability of pharmacologic treatments for depression in patients with MS. Search

  1. Complex Pharmacology of Free Fatty Acid Receptors

    DEFF Research Database (Denmark)

    Milligan, Graeme; Shimpukade, Bharat; Ulven, Trond

    2017-01-01

    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...

  2. The Dutch vision of clinical pharmacology

    NARCIS (Netherlands)

    Schellens, J H M; Grouls, R; Guchelaar, H J; Touw, D J; Rongen, G A; de Boer, A; Van Bortel, L M

    Recent position papers addressing the profession of clinical pharmacology have expressed concerns about the decline of interest in the field among clinicians and medical educators in the United Kingdom and other Western countries, whether clinical pharmacology is actually therapeutics, and whether

  3. Ayahuasca: Pharmacology, neuroscience and therapeutic potential.

    Science.gov (United States)

    Domínguez-Clavé, Elisabet; Soler, Joaquim; Elices, Matilde; Pascual, Juan C; Álvarez, Enrique; de la Fuente Revenga, Mario; Friedlander, Pablo; Feilding, Amanda; Riba, Jordi

    2016-09-01

    Ayahuasca is the Quechua name for a tea obtained from the vine Banisteriopsis caapi, and used for ritual purposes by the indigenous populations of the Amazon. The use of a variation of the tea that combines B. caapi with the leaves of the shrub Psychotria viridis has experienced unprecedented expansion worldwide for its psychotropic properties. This preparation contains the psychedelic 5-HT 2A receptor agonist N,N-dimethyltryptamine (DMT) from P. viridis, plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties from B. caapi. Acute administration induces a transient modified state of consciousness characterized by introspection, visions, enhanced emotions and recollection of personal memories. A growing body of evidence suggests that ayahuasca may be useful to treat substance use disorders, anxiety and depression. Here we review the pharmacology and neuroscience of ayahuasca, and the potential psychological mechanisms underlying its therapeutic potential. We discuss recent findings indicating that ayahuasca intake increases certain mindfulness facets related to acceptance and to the ability to take a detached view of one's own thoughts and emotions. Based on the available evidence, we conclude that ayahuasca shows promise as a therapeutic tool by enhancing self-acceptance and allowing safe exposure to emotional events. We postulate that ayahuasca could be of use in the treatment of impulse-related, personality and substance use disorders and also in the handling of trauma. More research is needed to assess the full potential of ayahuasca in the treatment of these disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Characterizing Signals within Lesions and Mapping Brain Network Connectivity After Traumatic Axonal Injury: A 7 Tesla Resting-State FMRI Study.

    Science.gov (United States)

    Lee, Seul; Polimeni, Jonathan R; Price, Collin M; Edlow, Brian L; McNab, Jennifer A

    2018-04-18

    Resting-state functional magnetic resonance imaging (RS-FMRI) has been widely used to map brain functional connectivity, but it is unclear how to probe connectivity within and around lesions. Here we characterize RS-FMRI signal time-course properties and evaluate different seed placements within and around hemorrhagic traumatic axonal injury lesions. RS-FMRI was performed on a 7 Tesla scanner in a patient who recovered consciousness after traumatic coma and in three healthy controls. Eleven lesions in the patient were characterized in terms of: 1) temporal signal-to-noise ratio (tSNR); 2) physiological noise, through comparison of noise regressors derived from the white matter (WM), cerebrospinal fluid (CSF) and gray matter (GM); and 3) seed-based functional connectivity. Temporal SNR at the center of the lesions was 38.3% and 74.1% lower compared to the same region in the contralesional hemisphere of the patient and in the ipsilesional hemispheres of the controls, respectively. Within the lesions, WM noise was more prominent than CSF and GM noise. Lesional seeds did not produce discernable networks, but seeds in the contralesional hemisphere revealed networks whose nodes appeared to be shifted or obscured due to overlapping or nearby lesions. Single-voxel seed analysis demonstrated that placing a seed within a lesion's periphery was necessary to identify networks associated with the lesion region. These findings provide evidence of resting-state network changes in the human brain after recovery from traumatic coma. Further, we show that seed placement within a lesion's periphery or in the contralesional hemisphere may be necessary for network identification in patients with hemorrhagic traumatic axonal injury.

  5. Electrosteric stealth Rivastigmine loaded liposomes for brain targeting: preparation, characterization, ex vivo, bio-distribution and in vivo pharmacokinetic studies.

    Science.gov (United States)

    Nageeb El-Helaly, Sara; Abd Elbary, Ahmed; Kassem, Mohamed A; El-Nabarawi, Mohamed A

    2017-11-01

    Being one of the highly effective drugs in treatment of Alzheimer's disease, Rivastigmine brain targeting is highly demandable, therefore liposomal dispersion of Rivastigmine was prepared containing 2 mol% PEG-DSPE added to Lecithin, Didecyldimethyl ammonium bromide (DDAB), Tween 80 in 1:0.02:0.25 molar ratio. A major challenge during the preparation of liposomes is maintaining a stable formulation, therefore the aim of our study was to increase liposomal stability by addition of DDAB to give an electrostatic stability and PEG-DSPE to increase stability by steric hindrance, yielding what we called an electrosteric stealth (ESS) liposomes. A medium nano-sized liposome (478 ± 4.94 nm) with a nearly neutral zeta potential (ZP, -8 ± 0.2 mV) and an entrapment efficiency percentage of 48 ± 6.22 was prepared. Stability studies showed no major alteration after three months storage period concerning particle size, polydispersity index, ZP, entrapment efficiency and in vitro release study confirming the successful formation of a stable liposomes. No histopathological alteration was recorded for ESS liposomes of the sheep nasal mucosa. While ESS liposomes showed higher % of drug permeating through the sheep nasal mucosa (48.6%) than the drug solution (28.7%). On completing the in vivo pharmacokinetic studies of 36 rabbits showed 424.2% relative bioavailability of the mean plasma levels of the formula ESS compared to that of RHT intranasal solution and 486% relative bioavailability of the mean brain levels.

  6. Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.

    Science.gov (United States)

    Bekker, Pirow; Dairaghi, Daniel; Seitz, Lisa; Leleti, Manmohan; Wang, Yu; Ertl, Linda; Baumgart, Trageen; Shugarts, Sarah; Lohr, Lisa; Dang, Ton; Miao, Shichang; Zeng, Yibin; Fan, Pingchen; Zhang, Penglie; Johnson, Daniel; Powers, Jay; Jaen, Juan; Charo, Israel; Schall, Thomas J

    2016-01-01

    The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773.

  7. Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.

    Directory of Open Access Journals (Sweden)

    Pirow Bekker

    Full Text Available The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan, an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773.

  8. 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

  9. Detailed characterization of the in vitro pharmacological and pharmacokinetic properties of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH), a highly selective and brain-penetrant 5-HT2A receptor agonist

    DEFF Research Database (Denmark)

    Jensen, Anders A; McCorvy, John D; Petersen, Sebastian Leth

    2017-01-01

    ]ketanserin/[3H]mesulergine, [3H]LSD and [3H]Cimbi-36 binding assays (Ki 2C/Ki 2A ratio range 52-81, Ki 2B/Ki 2A ratio 37). Moreover, in inositol phosphate and intracellular Ca2+ mobilization assays 25CN-NBOH exhibited 30- to 180-fold 5-HT2A/5-HT2C selectivities and 54-fold 5-HT2A/5-HT2B selectivity as measured...

  10. Future pharmacological therapy in hypertension.

    Science.gov (United States)

    Stewart, Merrill H; Lavie, Carl J; Ventura, Hector O

    2018-04-26

    Hypertension (HTN) is a widespread and growing disease, with medication intolerance and side-effect present among many. To address these obstacles novel pharmacotherapy is an active area of drug development. This review seeks to explore future drug therapy for HTN in the preclinical and clinical arenas. The future of pharmacological therapy in HTN consists of revisiting old pathways to find new targets and exploring wholly new approaches to provide additional avenues of treatment. In this review, we discuss the current status of the most recent drug therapy in HTN. New developments in well trod areas include novel mineralocorticoid antagonists, aldosterone synthase inhibitors, aminopeptidase-A inhibitors, natriuretic peptide receptor agonists, or the counter-regulatory angiotensin converting enzyme 2/angiotensin (Ang) (1-7)/Mas receptor axis. Neprilysin inhibitors popularized for heart failure may also still hold HTN potential. Finally, we examine unique systems in development never before used in HTN such as Na/H exchange inhibitors, vasoactive intestinal peptide agonists, and dopamine beta hydroxylase inhibitors. A concise review of future directions of HTN pharmacotherapy.

  11. [History and pharmacology of trazodone].

    Science.gov (United States)

    Agnoli, A

    1986-10-01

    Trazodone, a non-tricyclic molecule, represents the first of a new generation of antidepressants. It is currently marketed in a number of European countries, in the United States and in Latin America. The pharmacological and biochemical data, the mechanism of action and the preferential indications of trazodone are presented and compared to those of imipramine and other tricyclics. Unlike imipramine, trazodone inhibits the adrenergic system. The two molecules have anti-nociceptive properties, similar effects on the serotoninergic system and, after repeated administrations, they both reduce the density of beta-receptors. The clinical implications of the alpha-blocking activity of trazodone are reported. Trazodone is preferable to tricyclic anti-depressants in the treatment of depression in elderly subjects in general, and especially when they present closed angle glaucoma, prostatic hypertrophy, tremor or cardiovascular problems due to hyperactivity of the adrenergic system, as well as in organic depressions and in depression secondary to schizophrenia, alcoholism and in patients with Parkinson's disease.

  12. Cardiovascular Safety Pharmacology of Sibutramine.

    Science.gov (United States)

    Yun, Jaesuk; Chung, Eunyong; Choi, Ki Hwan; Cho, Dae Hyun; Song, Yun Jeong; Han, Kyoung Moon; Cha, Hey Jin; Shin, Ji Soon; Seong, Won-Keun; Kim, Young-Hoon; Kim, Hyung Soo

    2015-07-01

    Sibutramine is an anorectic that has been banned since 2010 due to cardiovascular safety issues. However, counterfeit drugs or slimming products that include sibutramine are still available in the market. It has been reported that illegal sibutramine-contained pharmaceutical products induce cardiovascular crisis. However, the mechanism underlying sibutramine-induced cardiovascular adverse effect has not been fully evaluated yet. In this study, we performed cardiovascular safety pharmacology studies of sibutramine systemically using by hERG channel inhibition, action potential duration, and telemetry assays. Sibutramine inhibited hERG channel current of HEK293 cells with an IC50 of 3.92 μM in patch clamp assay and increased the heart rate and blood pressure (76 Δbpm in heart rate and 51 ΔmmHg in blood pressure) in beagle dogs at a dose of 30 mg/kg (per oral), while it shortened action potential duration (at 10 μM and 30 μM, resulted in 15% and 29% decreases in APD50, and 9% and 17% decreases in APD90, respectively) in the Purkinje fibers of rabbits and had no effects on the QTc interval in beagle dogs. These results suggest that sibutramine has a considerable adverse effect on the cardiovascular system and may contribute to accurate drug safety regulation.

  13. Pharmacological challenges in chronic pancreatitis.

    Science.gov (United States)

    Olesen, Anne Estrup; Brokjaer, Anne; Fisher, Iben Wendelboe; Larsen, Isabelle Myriam

    2013-11-14

    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 are often prescribed as pain treatment. Opioids have intrinsic effects on gastrointestinal motility and hence can modify the absorption of other drugs taken at the same time. Furthermore, the increased fluid absorption caused by opioids will decrease water available for drug dissolution and may hereby affect absorption of the drug. As stated above many factors can influence drug absorption and metabolism in patients with chronic pancreatitis. The factors may not have clinical relevance, but may explain inter-individual variations in responses to a given drug, in patients with chronic pancreatitis.

  14. [Pharmacologic treatment of osteoporosis--2011].

    Science.gov (United States)

    Lakatos, Péter

    2011-08-14

    Osteoporosis affects approximately 9% of the population in Hungary resulting in about 100 000 osteoporotic fractures annually. Thirty-five percent of patients with hip fractures due to osteoporosis will die within 1 year. Direct costs of osteoporosis exceed 25 billion forints per year. Apparently, cost-effective reduction of bone loss and consequent fracture risk will add up to not only financial savings but improvement in quality of life, as well. A number of pharmacological modalities are available for this purpose. The mainstay of the treatment of osteoporosis is the bisphosphonate group that includes effective anti-resorptive compounds mitigating bone loss and fragility. The recently registered denosumab exhibits similar efficacy by neutralizing RANK ligand, however, marked differences can be observed between the two drug classes. Strontium has a unique mechanism of action by rebalancing bone turnover, and thus, providing an efficient treatment option for the not fast bone losers who are at high fracture risk. The purely anabolic teriparatide is available for the extremely severe osteoporotic patients and for those who do not respond to other types of therapy. Older treatment options such as hormone replacement therapy, raloxifene, tibolone or calcitonin may also have a restricted place in the management of osteoporosis.

  15. Pharmacological Fingerprints of Contextual Uncertainty.

    Directory of Open Access Journals (Sweden)

    Louise Marshall

    2016-11-01

    Full Text Available Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses.

  16. Brain Networks are Independently Modulated by Donepezil, Sleep, and Sleep Deprivation.

    Science.gov (United States)

    Wirsich, Jonathan; Rey, Marc; Guye, Maxime; Bénar, Christian; Lanteaume, Laura; Ridley, Ben; Confort-Gouny, Sylviane; Cassé-Perrot, Catherine; Soulier, Elisabeth; Viout, Patrick; Rouby, Franck; Lefebvre, Marie-Noëlle; Audebert, Christine; Truillet, Romain; Jouve, Elisabeth; Payoux, Pierre; Bartrés-Faz, David; Bordet, Régis; Richardson, Jill C; Babiloni, Claudio; Rossini, Paolo Maria; Micallef, Joelle; Blin, Olivier; Ranjeva, Jean-Philippe

    2018-05-01

    Resting-state connectivity has been widely studied in the healthy and pathological brain. Less well-characterized are the brain networks altered during pharmacological interventions and their possible interaction with vigilance. In the hopes of finding new biomarkers which can be used to identify cortical activity and cognitive processes linked to the effects of drugs to treat neurodegenerative diseases such as Alzheimer's disease, the analysis of networks altered by medication would be particularly interesting. Eleven healthy subjects were recruited in the context of the European Innovative Medicines Initiative 'PharmaCog'. Each underwent five sessions of simultaneous EEG-fMRI in order to investigate the effects of donepezil and memantine before and after sleep deprivation (SD). The SD approach has been previously proposed as a model for cognitive impairment in healthy subjects. By applying network based statistics (NBS), we observed altered brain networks significantly linked to donepezil intake and sleep deprivation. Taking into account the sleep stages extracted from the EEG data we revealed that a network linked to sleep is interacting with sleep deprivation but not with medication intake. We successfully extracted the functional resting-state networks modified by donepezil intake, sleep and SD. We observed donepezil induced whole brain connectivity alterations forming a network separated from the changes induced by sleep and SD, a result which shows the utility of this approach to check for the validity of pharmacological resting-state analysis of the tested medications without the need of taking into account the subject specific vigilance.

  17. 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.

  18. Characterization of the binding of the Ptychodiscus brevis neurotoxin T17 to sodium channels in rat brain synaptosomes

    International Nuclear Information System (INIS)

    Poli, M.A.

    1985-01-01

    The lipid-soluble polyether neurotoxins isolated from the marine dinoflagellate Ptychodiscus brevis (formerly Gymnodinium breve) have been determined to bind to a unique receptor site associated with the voltage-sensitive sodium channel in rat brain synaptosomes. Reduction of the C 42 aldehyde function of T34 to the alcohol function of T17 using NaB 3 H 4 yielded 3 H-T17 with a specific activity of 15 Ci;/mmol. Using this specific probe, binding to sodium channels was measured at 4 0 CC, 22 0 C, and 37 0 C. Rosenthal analysis of the binding data yielded a K/sub d/ of 2.9 nM and B/sub max/ of 6.8 pmoles 3 H-T17 per mg of synaptosomal protein at 4 0 C. Both K/sub d/ and B/sub max/ were found to be temperature dependent. Depolarization of the synaptosomes by osmotic lysis resulted in the loss of 34% of the available receptor sites, with no decrease in binding affinity. Unlabeled T17, T34, and synthetic T17 (reduced T34) were equipotent in their ability to displace 3 H-T17 from its specific receptor site. Competition experiments using natural toxin probes specific for sites I-IV on the voltage-sensitive sodium channel demonstrate that 3 H-T17 does not bind to any of the previously-described neurotoxin receptor sites. A fifth site is proposed

  19. Rat organic solute carrier protein 1 (rOscp1) mediated the transport of organic solutes in Xenopus laevis oocytes: isolation and pharmacological characterization of rOscp1.

    Science.gov (United States)

    Izuno, Hisanori; Kobayashi, Yasuna; Sanada, Yutaka; Nihei, Daisuke; Suzuki, Masako; Kohyama, Noriko; Ohbayashi, Masayuki; Yamamoto, Toshinori

    2007-09-22

    Rat organic solute carrier protein 1 (rOscp1) was isolated from a rat testis cDNA library. Isolated rOscp1 cDNA consisted of 1089 base pairs that encoded a 363-amino acid protein, and the amino acid sequence was 88% and 93% identical to that of human OSCP1 (hOSCP1) and mouse Oscp1 (mOscp1), respectively. The message for rOscp1 is highly detected in rat testis. When expressed in X. oocytes, rOscp1 mediated the high affinity transport of p-aminohippurate (PAH) with a Km value of 15.7+/-1.9 microM, and rOscp1-mediated organic solutes were exhibited in time- and Na+-independent manners. rOscp1 also transported various structurally heterogenous compounds such as testosterone, dehydroepiandrosterone sulfate (DHEA-S), and taurocholate with some differences in substrate specificity compared with hOSCP1. Immunohistochemical analysis revealed that the rOscp1 protein is localized in the basal membrane side of Sertoli cells as observed in mouse testis [Kobayashi et al., 2007; Kobayashi, Y., Tsuchiya, A., Hayashi, T., Kohyama, N., Ohbayashi, M., Yamamoto, T., 2007. Isolation and characterization of polyspecific mouse organic solute carrier protein 1 (mOscp1). Drug Metabolism and Disposition 35 (7), 1239-1245]. Thus, the present results indicate that a newly isolated cDNA clone, rOscp1, is a polyspecific organic solute carrier protein with some differences in substrate specificity compared with human and mouse OSCP1.

  20. 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

  1. Biodistribution study of [I-123] ADAM in mice brain using quantitative autoradiography

    International Nuclear Information System (INIS)

    Lin, K.J.; Yen, T.C.; Tzen, K.Y.; Ye, X.X.; Hwang, J.J.; Wey, S.P.; Ting, G.

    2002-01-01

    Aim: Autoradiography with radioluminography is a delicate method to characterize newly developed radiotracers and to apply them to pharmacological studies. Herein, we reported a biodistribution result of [I-123] ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5- iodophenylamine) in mice brain quantitatively using imaging plates. Materials and Methods: 1mCi [I-123] ADAM was injected into male ICR mice through tail veins. Brains were removed at sequential time points ranging from 0.5hr to 4hr after injection. The whole brain was cut into 14mm thick coronal sections using a cyrotome. The sections were thaw-mounted on glass plate and apposed placed on an imaging plate with filter paper standards for 24 hours. Imaging reading was done by a Fuji FLA5000 device. Regions of interest were placed on the globus pallidus, hypothalamus, substantia nigra, raphe nuclei and cerebellum corresponding to the sterotaxic atlas, and the PSL/mm 2 values were measured. The specific binding was expressed as the ratios of (targets - cerebellum) to cerebellum. Results: Autoradiography study of brain showed that the [I-123] ADAM was accumulated at serotonin transporter rich sites, including the olfactory tubercle, globus pallidus, thalamus nuclei, hypothalamus, substantia nigra, interpeduncular nucleus, amygdala and raphe nuclei. Biodistribution of [I-123] ADAM in mice brain using quantitative autoradiography method showed a high specific binding in the substantia nigra and hypothalamus and the time-activity curve peaked at 120 min post-injection. Compatible specific binding result was achieved in the region of hypothalamus as compared with previous study by other group using conventional tissue micro-dissection method (Synapse 38:403-412, 2000). However, higher specific binding was observed in certain small brain regions including substantia nigra, raphe nuclei due to improved spatial resolution of the quantitative autoradiography technique. Conclusion: Our result showed that the

  2. Review of the Chemistry and Pharmacology of 7-Methyljugulone ...

    African Journals Online (AJOL)

    Review of the Chemistry and Pharmacology of 7-Methyljugulone. ... Methods: The chemical and pharmacological data were retrieved from the well-known scientific websites such as Pubmed, Google Scholar, Reaxys, Scirus, Scopus, ... Keywords: 7-methyljugulone; biosynthesis; in vitro synthesis; pharmacology

  3. [PROFESSOR VLADIMIR V. NIKOLAEV AND RUSSIAN PHARMACOLOGY.

    Science.gov (United States)

    Bondarchuk, N G; Fisenko, V P

    2016-01-01

    Various stages of scientific research activity of Prof. Vladimir V. Nikolaev are analyzed. The importance of Prof. Nikolaev's discovery of the two-neuron parasympathetic nervous system and some new methods of pharmacological substances evaluation is shown. Prof. Nikolaev is known as the editor of the first USSR Pharmacopoeia. Peculiarities of pharmacology teaching at the First Moscow Medical institute under conditions of changing social demands are described. Successful research of Prof. Nikolaev with colleagues in studying new mechanisms of drug action and developing original pharmacological substances is summarized.

  4. Problems of pharmacological supply of disaster medicine

    International Nuclear Information System (INIS)

    Sabaev, V.V.; Il'ina, S.L.

    1995-01-01

    The paper reviews a number of pharmacological problems, being important for the disaster medicine, of theoretical and practical nature, the settlement of which would promote more efficient rendering emergency medical aid to the injured persons in the conditions of emergency situations and further expert medical care. On the example of radiation accidents there are studied methodical approaches to organization of drug prophylaxis and therapy of the injured persons in emergency situations. The authors have proved the necessity of arranging proper pharmacological supply of disaster medicine which is to settle the whole complex of scientific-applied and organizational questions relating to the competence of pharmacology and pharmacy. 17 refs

  5. [Contribution of animal experimentation to pharmacology].

    Science.gov (United States)

    Sassard, Jean; Hamon, Michel; Galibert, Francis

    2009-11-01

    Animal experimentation is of considerable importance in pharmacology and cannot yet be avoided when studying complex, highly integrated physiological functions. The use of animals has been drastically reduced in the classical phases of pharmacological research, for example when comparing several compounds belonging to the same pharmacological class. However, animal experiments remain crucial for generating and validating new therapeutic concepts. Three examples of such research, conducted in strict ethical conditions, will be used to illustrate the different ways in which animal experimentation has contributed to human therapeutics.

  6. 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.

  7. Characterization of basal gene expression trends over a diurnal cycle in Xiphophorus maculatus skin, brain and liver.

    Science.gov (United States)

    Lu, Yuan; Reyes, Jose; Walter, Sean; Gonzalez, Trevor; Medrano, Geraldo; Boswell, Mikki; Boswell, William; Savage, Markita; Walter, Ronald

    2018-06-01

    Evolutionarily conserved diurnal circadian mechanisms maintain oscillating patterns of gene expression based on the day-night cycle. Xiphophorus fish have been used to evaluate transcriptional responses after exposure to various light sources and it was determined that each source incites distinct genetic responses in skin tissue. However, basal expression levels of genes that show oscillating expression patterns in day-night cycle, may affect the outcomes of such experiments, since basal gene expression levels at each point in the circadian path may influence the profile of identified light responsive genes. Lack of knowledge regarding diurnal fluctuations in basal gene expression patterns may confound the understanding of genetic responses to external stimuli (e.g., light) since the dynamic nature of gene expression implies animals subjected to stimuli at different times may be at very different stages within the continuum of genetic homeostasis. We assessed basal gene expression changes over a 24-hour period in 200 select Xiphophorus gene targets known to transcriptionally respond to various types of light exposure. We identified 22 genes in skin, 36 genes in brain and 28 genes in liver that exhibit basal oscillation of expression patterns. These genes, including known circadian regulators, produced the expected expression patterns over a 24-hour cycle when compared to circadian regulatory genes identified in other species, especially human and other vertebrate animal models. Our results suggest the regulatory network governing diurnal oscillating gene expression is similar between Xiphophorus and other vertebrates for the three Xiphophorus organs tested. In addition, we were able to categorize light responsive gene sets in Xiphophorus that do, and do not, exhibit circadian based oscillating expression patterns. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Characterization of the binding of the Ptychodiscus brevis neurotoxin T17 to sodium channels in rat brain synaptosomes

    Energy Technology Data Exchange (ETDEWEB)

    Poli, M.A.

    1985-01-01

    The lipid-soluble polyether neurotoxins isolated from the marine dinoflagellate Ptychodiscus brevis (formerly Gymnodinium breve) have been determined to bind to a unique receptor site associated with the voltage-sensitive sodium channel in rat brain synaptosomes. Reduction of the C/sub 42/ aldehyde function of T34 to the alcohol function of T17 using NaB/sup 3/H/sub 4/ yielded /sup 3/H-T17 with a specific activity of 15 Ci;/mmol. Using this specific probe, binding to sodium channels was measured at 4/sup 0/CC, 22/sup 0/C, and 37/sup 0/C. Rosenthal analysis of the binding data yielded a K/sub d/ of 2.9 nM and B/sub max/ of 6.8 pmoles /sup 3/H-T17 per mg of synaptosomal protein at 4/sup 0/C. Both K/sub d/ and B/sub max/ were found to be temperature dependent. Depolarization of the synaptosomes by osmotic lysis resulted in the loss of 34% of the available receptor sites, with no decrease in binding affinity. Unlabeled T17, T34, and synthetic T17 (reduced T34) were equipotent in their ability to displace /sup 3/H-T17 from its specific receptor site. Competition experiments using natural toxin probes specific for sites I-IV on the voltage-sensitive sodium channel demonstrate that /sup 3/H-T17 does not bind to any of the previously-described neurotoxin receptor sites. A fifth site is proposed.

  9. Biochemical and pharmacological studies of native and irradiated crotamine with gamma radiation of Co60

    International Nuclear Information System (INIS)

    Mitake, M.B.

    2000-01-01

    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)

  10. 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 ...

  11. Ethnobotanical, phytochemical and pharmacological properties of ...

    African Journals Online (AJOL)

    Electronic search engines such as Google, Google scholar, publishing sites such as Elsevier .... A number of pharmacological activities of C. bulbispermum have been ..... bulbispermum using the direct plate method and minimum inhibitory ...

  12. Bioanalysis, metabolism & clinical pharmacology of antiretroviral drugs

    NARCIS (Netherlands)

    Heine, R. ter

    2009-01-01

    The aims of all studies described in this thesis were to develop new bioanalytical and more patient friendly methods for studying the clinical pharmacology of antiretroviral drugs and to ultimately improve antiretroviral treatment.

  13. Medicinal, Pharmacological and Phytochemical Potentials of ...

    African Journals Online (AJOL)

    Medicinal, Pharmacological and Phytochemical Potentials of Annona Comosus linn. ... Therapeutic plants, and the drugs derived from them, are the most important ... also as treatment to: diarrhea, indigestion, pneumonia, bronchitis, arthritis, ...

  14. Disrupting reconsolidation: pharmacological and behavioral manipulations

    NARCIS (Netherlands)

    Soeter, M.; Kindt, M.

    2011-01-01

    We previously demonstrated that disrupting reconsolidation by pharmacological manipulations "deleted" the emotional expression of a fear memory in humans. If we are to target reconsolidation in patients with anxiety disorders, the disruption of reconsolidation should produce content-limited

  15. Pharmaceutical and pharmacological approaches for bioavailability

    Indian Academy of Sciences (India)

    2014-01-27

    Jan 27, 2014 ... Etoposide posses high plasma protein binding (97%) and is degraded via ... The present article gives insight on pharmaceutical and pharmacological .... caprolactone and were found efficient as drug delivery vehicles.

  16. ORIGINAL ARTICLES Pharmacological testing in Horner's syndrome

    African Journals Online (AJOL)

    topical cocaine 10% in both eyes gave an odds ratio of 1 050:1 that. Horner's syndrome ... nerve endings and therefore do not stimulate the effector cells directly. ... Pharmacological testing in Horner's syndrome – a new paradigm. Derrick P ...

  17. 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....

  18. Pharmacological Activity and Clinical Use of PDRN

    Directory of Open Access Journals (Sweden)

    Francesco Squadrito

    2017-04-01

    Full Text Available PDRN is a proprietary and registered drug that possesses several activities: tissue repairing, anti-ischemic, and anti-inflammatory. These therapeutic properties suggest its use in regenerative medicine and in diabetic foot ulcers. PDRN holds a mixture of deoxyribonucleotides with molecular weights ranging between 50 and 1,500 KDa, it is derived from a controlled purification and sterilization process of Oncorhynchus mykiss (Salmon Trout or Oncorhynchus keta (Chum Salmon sperm DNA. The procedure guarantees the absence of active protein and peptides that may cause immune reactions. In vitro and in vivo experiments have suggested that PDRN most relevant mechanism of action is the engagement of adenosine A2A receptors. Besides engaging the A2A receptor, PDRN offers nucleosides and nucleotides for the so called “salvage pathway.” The binding to adenosine A2A receptors is a unique property of PDRN and seems to be linked to DNA origin, molecular weight and manufacturing process. In this context, PDRN represents a new advancement in the pharmacotherapy. In fact adenosine and dipyridamole are non-selective activators of adenosine receptors and they may cause unwanted side effects; while regadenoson, the only other A2A receptor agonist available, has been approved by the FDA as a pharmacological stress agent in myocardial perfusion imaging. Finally, defibrotide, another drug composed by a mixture of oligonucleotides, has different molecular weight, a DNA of different origin and does not share the same wound healing stimulating effects of PDRN. The present review analyses the more relevant experimental and clinical evidences carried out to characterize PDRN therapeutic effects.

  19. Pharmacological Activity and Clinical Use of PDRN

    Science.gov (United States)

    Squadrito, Francesco; Bitto, Alessandra; Irrera, Natasha; Pizzino, Gabriele; Pallio, Giovanni; Minutoli, Letteria; Altavilla, Domenica

    2017-01-01

    PDRN is a proprietary and registered drug that possesses several activities: tissue repairing, anti-ischemic, and anti-inflammatory. These therapeutic properties suggest its use in regenerative medicine and in diabetic foot ulcers. PDRN holds a mixture of deoxyribonucleotides with molecular weights ranging between 50 and 1,500 KDa, it is derived from a controlled purification and sterilization process of Oncorhynchus mykiss (Salmon Trout) or Oncorhynchus keta (Chum Salmon) sperm DNA. The procedure guarantees the absence of active protein and peptides that may cause immune reactions. In vitro and in vivo experiments have suggested that PDRN most relevant mechanism of action is the engagement of adenosine A2A receptors. Besides engaging the A2A receptor, PDRN offers nucleosides and nucleotides for the so called “salvage pathway.” The binding to adenosine A2A receptors is a unique property of PDRN and seems to be linked to DNA origin, molecular weight and manufacturing process. In this context, PDRN represents a new advancement in the pharmacotherapy. In fact adenosine and dipyridamole are non-selective activators of adenosine receptors and they may cause unwanted side effects; while regadenoson, the only other A2A receptor agonist available, has been approved by the FDA as a pharmacological stress agent in myocardial perfusion imaging. Finally, defibrotide, another drug composed by a mixture of oligonucleotides, has different molecular weight, a DNA of different origin and does not share the same wound healing stimulating effects of PDRN. The present review analyses the more relevant experimental and clinical evidences carried out to characterize PDRN therapeutic effects. PMID:28491036

  20. Progress and perspectives on targeting nanoparticles for brain drug delivery

    Institute of Scientific and Technical Information of China (English)

    Huile Gao

    2016-01-01

    Due to the ability of the blood–brain barrier(BBB) to prevent the entry of drugs into the brain, it is a challenge to treat central nervous system disorders pharmacologically. The development of nanotechnology provides potential to overcome this problem. In this review, the barriers to brain-targeted drug delivery are reviewed, including the BBB, blood–brain tumor barrier(BBTB), and nose-to-brain barrier. Delivery strategies are focused on overcoming the BBB, directly targeting diseased cells in the brain, and dual-targeted delivery. The major concerns and perspectives on constructing brain-targeted delivery systems are discussed.

  1. Progress and perspectives on targeting nanoparticles for brain drug delivery

    Directory of Open Access Journals (Sweden)

    Huile Gao

    2016-07-01

    Full Text Available Due to the ability of the blood–brain barrier (BBB to prevent the entry of drugs into the brain, it is a challenge to treat central nervous system disorders pharmacologically. The development of nanotechnology provides potential to overcome this problem. In this review, the barriers to brain-targeted drug delivery are reviewed, including the BBB, blood–brain tumor barrier (BBTB, and nose-to-brain barrier. Delivery strategies are focused on overcoming the BBB, directly targeting diseased cells in the brain, and dual-targeted delivery. The major concerns and perspectives on constructing brain-targeted delivery systems are discussed.

  2. Pharmacological potential of tocotrienols: a review.

    Science.gov (United States)

    Ahsan, Haseeb; Ahad, Amjid; Iqbal, Jahangir; Siddiqui, Waseem A

    2014-01-01

    Tocotrienols, members of the vitamin E family, are natural compounds found in a number of vegetable oils, wheat germ, barley, and certain types of nuts and grains. Like tocopherols, tocotrienols are also of four types viz. alpha, beta, gamma and delta. Unlike tocopherols, tocotrienols are unsaturated and possess an isoprenoid side chain. Tocopherols are lipophilic in nature and are found in association with lipoproteins, fat deposits and cellular membranes and protect the polyunsaturated fatty acids from peroxidation reactions. The unsaturated chain of tocotrienol allows an efficient penetration into tissues that have saturated fatty layers such as the brain and liver. Recent mechanistic studies indicate that other forms of vitamin E, such as γ-tocopherol, δ-tocopherol, and γ-tocotrienol, have unique antioxidant and anti-inflammatory properties that are superior to those of α-tocopherol against chronic diseases. These forms scavenge reactive nitrogen species, inhibit cyclooxygenase- and 5-lipoxygenase-catalyzed eicosanoids and suppress proinflammatory signalling, such as NF-κB and STAT. The animal and human studies show tocotrienols may be useful against inflammation-associated diseases. Many of the functions of tocotrienols are related to its antioxidant properties and its varied effects are due to it behaving as a signalling molecule. Tocotrienols exhibit biological activities that are also exhibited by tocopherols, such as neuroprotective, anti-cancer, anti-inflammatory and cholesterol lowering properties. Hence, effort has been made to compile the different functions and properties of tocotrienols in experimental model systems and humans. This article constitutes an in-depth review of the pharmacology, metabolism, toxicology and biosafety aspects of tocotrienols. Tocotrienols are detectable at appreciable levels in the plasma after supplementations. However, there is inadequate data on the plasma concentrations of tocotrienols that are sufficient to

  3. Pharmacological interventions for acute pancreatitis.

    Science.gov (United States)

    Moggia, Elisabetta; Koti, Rahul; Belgaumkar, Ajay P; Fazio, Federico; Pereira, Stephen P; Davidson, Brian R; Gurusamy, Kurinchi Selvan

    2017-04-21

    In people with acute pancreatitis, it is unclear what the role should be for medical treatment as an addition to supportive care such as fluid and electrolyte balance and organ support in people with organ failure. To assess the effects of different pharmacological interventions in people with acute pancreatitis. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 9), MEDLINE, Embase, Science Citation Index Expanded, and trial registers to October 2016 to identify randomised controlled trials (RCTs). We also searched the references of included trials to identify further trials. We considered only RCTs performed in people with acute pancreatitis, irrespective of aetiology, severity, presence of infection, language, blinding, or publication status for inclusion in the review. Two review authors independently identified trials and extracted data. We did not perform a network meta-analysis as planned because of the lack of information on potential effect modifiers and differences of type of participants included in the different comparisons, when information was available. We calculated the odds ratio (OR) with 95% confidence intervals (CIs) for the binary outcomes and rate ratios with 95% CIs for count outcomes using a fixed-effect model and random-effects model. We included 84 RCTs with 8234 participants in this review. Six trials (N = 658) did not report any of the outcomes of interest for this review. The remaining 78 trials excluded 210 participants after randomisation. Thus, a total of 7366 participants in 78 trials contributed to one or more outcomes for this review. The treatments assessed in these 78 trials included antibiotics, antioxidants, aprotinin, atropine, calcitonin, cimetidine, EDTA (ethylenediaminetetraacetic acid), gabexate, glucagon, iniprol, lexipafant, NSAIDs (non-steroidal anti-inflammatory drugs), octreotide, oxyphenonium, probiotics, activated protein C, somatostatin, somatostatin plus omeprazole, somatostatin

  4. Characterization of functional brain activity and connectivity using EEG and fMRI in patients with sickle cell disease.

    Science.gov (United States)

    Case, Michelle; Zhang, Huishi; Mundahl, John; Datta, Yvonne; Nelson, Stephen; Gupta, Kalpna; He, Bin

    2017-01-01

    Sickle cell disease (SCD) is a red blood cell disorder that causes many complications including life-long pain. Treatment of pain remains challenging due to a poor understanding of the mechanisms and limitations to characterize and quantify pain. In the present study, we examined simultaneously recording functional MRI (fMRI) and electroencephalogram (EEG) to better understand neural connectivity as a consequence of chronic pain in SCD patients. We performed independent component analysis and seed-based connectivity on fMRI data. Spontaneous power and microstate analysis was performed on EEG-fMRI data. ICA analysis showed that patients lacked activity in the default mode network (DMN) and executive control network compared to controls. EEG-fMRI data revealed that the insula cortex's role in salience increases with age in patients. EEG microstate analysis showed patients had increased activity in pain processing regions. The cerebellum in patients showed a stronger connection to the periaqueductal gray matter (involved in pain inhibition), and negative connections to pain processing areas. These results suggest that patients have reduced activity of DMN and increased activity in pain processing regions during rest. The present findings suggest resting state connectivity differences between patients and controls can be used as novel biomarkers of SCD pain.

  5. 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.

  6. Impaired cognition and attention in adults: pharmacological management strategies.

    Science.gov (United States)

    Allain, Hervé; Akwa, Yvette; Lacomblez, Lucette; Lieury, Alain; Bentué-Ferrer, Danièle

    2007-02-01

    Cognitive psychology has provided clinicians with specific tools for analyzing the processes of cognition (memory, language) and executive functions (attention-concentration, abstract reasoning, planning). Neuropsychology, coupled with the neurosciences (including neuroimaging techniques), has authenticated the existence of early disorders affecting the "superior or intellectual" functions of the human brain. The prevalence of cognitive and attention disorders is high in adults because all the diseases implicating the central nervous system are associated with cognitive correlates of variable intensity depending on the disease process and the age of the patient. In some pathologies, cognitive impairment can be a leading symptom such as in schizophrenia, posttraumatic stress disorder or an emblematic stigmata as in dementia including Alzheimer's disease. Paradoxically, public health authorities have only recognized as medications for improving cognitive symptoms those with proven efficacy in the symptomatic treatment of patients with Alzheimer's disease; the other cognitive impairments are relegated to the orphanage of syndromes and symptoms dispossessed of medication. The purpose of this review is to promote a true "pharmacology of cognition" based on the recent knowledge in neurosciences. Data from adult human beings, mainly concerning memory, language, and attention processes, will be reported. "Drug therapeutic strategies" for improving cognition (except for memory function) are currently rather scarce, but promising perspectives for a new neurobiological approach to cognitive pharmacology will be highlighted.

  7. Zebrafish neurotransmitter systems as potential pharmacological and toxicological targets.

    Science.gov (United States)

    Rico, E P; Rosemberg, D B; Seibt, K J; Capiotti, K M; Da Silva, R S; Bonan, C D

    2011-01-01

    Recent advances in neurobiology have emphasized the study of brain structure and function and its association with numerous pathological and toxicological events. Neurotransmitters are substances that relay, amplify, and modulate electrical signals between neurons and other cells. Neurotransmitter signaling mediates rapid intercellular communication by interacting with cell surface receptors, activating second messenger systems and regulating the activity of ion channels. Changes in the functional balance of neurotransmitters have been implicated in the failure of central nervous system function. In addition, abnormalities in neurotransmitter production or functioning can be induced by several toxicological compounds, many of which are found in the environment. The zebrafish has been increasingly used as an animal model for biomedical research, primarily due to its genetic tractability and ease of maintenance. These features make this species a versatile tool for pre-clinical drug discovery and toxicological investigations. Here, we present a review regarding the role of different excitatory and inhibitory neurotransmitter systems in zebrafish, such as dopaminergic, serotoninergic, cholinergic, purinergic, histaminergic, nitrergic, glutamatergic, glycinergic, and GABAergic systems, and emphasizing their features as pharmacological and toxicological targets. The increase in the global knowledge of neurotransmitter systems in zebrafish and the elucidation of their pharmacological and toxicological aspects may lead to new strategies and appropriate research priorities to offer insights for biomedical and environmental research. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. A quantitative magnetic resonance histology atlas of postnatal rat brain development with regional estimates of growth and variability.

    Science.gov (United States)

    Calabrese, Evan; Badea, Alexandra; Watson, Charles; Johnson, G Allan

    2013-05-01

    There has been growing interest in the role of postnatal brain development in the etiology of several neurologic diseases. The rat has long been recognized as a powerful model system for studying neuropathology and the safety of pharmacologic treatments. However, the complex spatiotemporal changes that occur during rat neurodevelopment remain to be elucidated. This work establishes the first magnetic resonance histology (MRH) atlas of the developing rat brain, with an emphasis on quantitation. The atlas comprises five specimens at each of nine time points, imaged with eight distinct MR contrasts and segmented into 26 developmentally defined brain regions. The atlas was used to establish a timeline of morphometric changes and variability throughout neurodevelopment and represents a quantitative database of rat neurodevelopment for characterizing rat models of human neurologic disease. Published by Elsevier Inc.

  9. Pharmacological treatment of actinic keratosis

    Directory of Open Access Journals (Sweden)

    Ewa Zwierzyńska

    2016-09-01

    Full Text Available Actinic keratosis (AK is a disease characterized by hyperkeratotic lesions on skin damaged by ultraviolet. radiation. These lesions may progress to squamous cell or basal cell carcinoma. Currently pharmacotherapy and different surgical procedures are used in AK therapy. The most common treatment options are 5-fluorouracil, imiquimod, diclofenac, ingenol mebutate, and first and third generation retinoids (retinol, adapalene, tazarotene. Furthermore, research is being carried out in order to test new medications including nicotinamide, resiquimod, piroxicam, potassium dobesilate and oleogel based on a triterpene extract (betulin, betulinic acid. Recently, the preventive effect of acetylsalicylic acid and celecoxib has also been investigated.

  10. Evaluation of the antagonism of nicotine by mecamylamine and pempidine in the brain

    International Nuclear Information System (INIS)

    Martin, T.J.

    1989-01-01

    Antagonists have been crucial in the characterization of nicotine's pharmacology. Initial evidence for the existence of central nicotinic receptors was based on the fact that nicotine produced a number of behavioral effects that were antagonized by ganglionic blockers that crossed the blood-brain barrier, such as mecamylamine and pempidine. These compounds are thought to be noncompetitive antagonists due to the fact that they do not compete for agonist binding to brain homogenate in vitro. However, pharmacological evidence in support of noncompetitive antagonism is lacking. Dose-response curves for nicotine were determined in the presence of various doses of pempidine for depression of spontaneous activity and antinociception in mice. Pempidine was found to shift the dose response curves for these effects of nicotine in a manner consistent with noncompetitive antagonism. A number of mecamylamine analogs were investigated for antagonism of these central effects of nicotine as well. These studies revealed that the N-, 2-, and 3-methyls were crucial for optimal efficacy and potency and suggests that these compounds possess a specific mechanism of action, possibly involving a receptor. Furthermore, the structure-activity relationships for the mecamylamine analogs were found to be different than that previously reported for the agonists, suggesting that they do not act at the same site. The binding of [ 3 H]-L-nicotine and [ 3 H]-pempidine was studied in vitro to mouse brain homogentate and in situ to rat brain slices. The in situ binding of [ 3 H]-L-nicotine to rat brain slices was quantitated autoradiographically to discrete brain areas in the presence and absence of 1, 10 and 100 μM nicotine and pempidine. Pempidine did not effectively displace [ 3 H]-L-nicotine binding

  11. A meta-analysis to determine the effect of pharmacological and non-pharmacological treatments on fibromyalgia symptoms comprising OMERACT-10 response criteria.

    Science.gov (United States)

    Papadopoulou, Despoina; Fassoulaki, Argyro; Tsoulas, Christos; Siafaka, Ioanna; Vadalouca, Athina

    2016-03-01

    Fibromyalgia is characterized by widespread pain, sleep problems, fatigue, functional impairment, psychological distress, and cognitive dysfunction. The objective of this meta-analysis is to synthesize the available data on the effectiveness of pharmacological and non-pharmacological interventions across all domains included in the Outcome Measures in Rheumatology Clinical Trials (OMERACT-10) fibromyalgia response definitions, and to examine response based on these definitions. We searched Cochrane, PubMed, Scopus, and the reference lists of articles for randomized controlled trials of any drug formulation or non-pharmacological intervention used for fibromyalgia treatment. We extracted efficacy data regarding pain, sleep, physical function, fatigue, anxiety, depression, and cognition. The available data were insufficient to draw definite conclusions regarding response. Indirect evidence indicates that it may be expected with the use of serotonin noradrenaline reuptake inhibitors (SNRIs), noradrenaline reuptake inhibitors (NRIs), and multidisciplinary treatment.

  12. David Ferrier: brain drawings and brain maps.

    Science.gov (United States)

    Lazar, J Wayne

    2013-01-01

    This chapter has two emphases, one is about the men who influenced the visual representations that David Ferrier (1843-1928) used to illustrate his work on localization of brain functions during the years 1873-1875, namely, Alexander Ecker, John C. Galton, and Ernest Waterlow, and the other is about the nature of medical representations and of Ferrier's illustrations in particular. Medical illustrations are characterized either as pictures, line drawings, or brain maps. Ferrier's illustrations will be shown to be increasingly sophisticated brain maps that contrast with early nineteenth-century standards of medical illustrations, as exemplified by John Bell (1763-1829). © 2013 Elsevier B.V. All rights reserved.

  13. From molecule to behavior: Brain aromatase (cyp19a1b) characterization, expression analysis and its relation with social status and male agonistic behavior in a Neotropical cichlid fish.

    Science.gov (United States)

    Ramallo, Martín R; Morandini, Leonel; Birba, Agustina; Somoza, Gustavo M; Pandolfi, Matías

    2017-03-01

    The enzyme aromatase, responsible for the conversion of C19 androgens to C18 estrogens, exists as two paralogue copies in teleost fish: Cyp19a1a mostly expressed in the gonads, referred as gonadal aromatase, and Cyp19a1b, mostly expressed in the brain, accordingly known as brain aromatase. The neural localization of Cyp19a1b is greatly contained within the social behavior network and mesolimbic reward system in fish, suggesting a strong role of estrogen synthesis in the regulation of social behavior. In this work we aimed to analyze the variation in cyp19a1b expression in brain and pituitary of males of a highly social cichlid, Cichlasoma dimerus (locally known as chanchita), and its relation with inter-individual variability in agonistic behavior in a communal social environment. We first characterized chanchita's cyp19a1b mRNA and deduced amino acid sequence, which showed a high degree of conservation when compared to other teleost brain aromatase sequences, and its tissue expression patterns. Within the brain, Cyp19a1b was solely detected at putative radial glial cells of the forebrain, close to the brain ventricles. We then studied the relative expression levels of cyp19a1b by Real Time PCR in the brain and pituitary of males of different social status, territorial vs. non-territorial, and its relationship with an index of agonistic behavior. We found that even though, brain aromatase expression did not differ between types of males, pituitary cyp19a1b expression levels positively correlated with the index of agonistic behavior. This suggests a novel role of the pituitary in the regulation of social behavior by local estrogen synthesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Biochemical and pharmacological characterization of Trimersurus malabaricus snake venom.

    Science.gov (United States)

    Gowda, Raghavendra; Rajaiah, Rajesh; Angaswamy, Nataraj; Krishna, Sharath; Bannikuppe Sannanayak, Vishwanath

    2018-03-12

    Trimeresurus malabaricus is a venomous pit viper species endemic to southwestern part of India. In earlier reports, we have shown that envenomation by T. malabaricus venom leading to strong local tissue damage but the mechanism of action is not clearly revealed. Local tissue damage affected by T. malabaricus venom is of great importance since the poison has serious systemic effects including death in the case of multiple attacks. The present study details the major manifestations of T. malabaricus venom and the induction of local tissue damage, which suggests that most toxins are present in the form of hydrolytic enzymes. Hydrolytic activity of the enzymes was measured and the data indicated that protease and phospholipase A 2 activity was high which is responsible for local tissue damage. Furthermore, the role of hydrolytic enzymes in the induction of pathological events such as hemorrhage, edema, myotoxicity, and blood coagulation examination were assessed through animal models. © 2018 Wiley Periodicals, Inc.

  15. Design, synthesis, and pharmacological characterization of polyamine toxin derivatives

    DEFF Research Database (Denmark)

    Jensen, Lars S; Bølcho, Ulrik; Egebjerg, Jan

    2006-01-01

    for memory formation and are involved in neurodegenerative diseases. Previous studies have demonstrated that modification of the polyamine moiety of philanthotoxins can lead to very potent and highly selective ligands for the AMPA receptor, as exemplified with philanthotoxin-56. Much less attention has been......Polyamine toxins, such as philanthotoxins, are low-molecular-weight compounds isolated from spiders and wasps, which modulate ligand-gated ion channels in the nervous system. Philanthotoxins bind to the pore-forming region of AMPA receptors, a subtype of glutamate receptors which are important...... paid to the importance of the aromatic head group of philanthotoxins, but herein we demonstrate that modification of this moiety leads to a significant improvement in potency relative to philanthotoxin-56 at cloned AMPA receptors. Interestingly, the incorporation of an adamantane moiety is particularly...

  16. An activity canyon characterization of the pharmacological topography.

    Science.gov (United States)

    Kulkarni, Varsha S; Wild, David J

    2016-01-01

    Highly chemically similar drugs usually possess similar biological activities, but sometimes, small changes in chemistry can result in a large difference in biological effects. Chemically similar drug pairs that show extreme deviations in activity represent distinctive drug interactions having important implications. These associations between chemical and biological similarity are studied as discontinuities in activity landscapes. Particularly, activity cliffs are quantified by the drop in similar activity of chemically similar drugs. In this paper, we construct a landscape using a large drug-target network and consider the rises in similarity and variation in activity along the chemical space. Detailed analysis of structure and activity gives a rigorous quantification of distinctive pairs and the probability of their occurrence. We analyze pairwise similarity (s) and variation (d) in activity of drugs on proteins. Interactions between drugs are quantified by considering pairwise s and d weights jointly with corresponding chemical similarity (c) weights. Similarity and variation in activity are measured as the number of common and uncommon targets of two drugs respectively. Distinctive interactions occur between drugs having high c and above (below) average d (s). Computation of predicted probability of distinctiveness employs joint probability of c, s and of c, d assuming independence of structure and activity. Predictions conform with the observations at different levels of distinctiveness. Results are validated on the data used and another drug ensemble. In the landscape, while s and d decrease as c increases, d maintains value more than s. c ∈ [0.3, 0.64] is the transitional region where rises in d are significantly greater than drops in s. It is fascinating that distinctive interactions filtered with high d and low s are different in nature. It is crucial that high c interactions are more probable of having above average d than s. Identification of distinctive interactions is better with high d than low s. These interactions belong to diverse classes. d is greatest between drugs and analogs prepared for treatment of same class of ailments but with different therapeutic specifications. In contrast, analogs having low s would treat ailments from distinct classes. Intermittent spikes in d along the axis of c represent canyons in the activity landscape. This new representation accounts for distinctiveness through relative rises in s and d. It provides a mathematical basis for predicting the probability of occurrence of distinctiveness. It identifies the drug pairs at varying levels of distinctiveness and non-distinctiveness. The predicted probability formula is validated even if data approximately satisfy the conditions of its construction. Also, the postulated independence of structure and activity is of little significance to the overall assessment. The difference in distinctive interactions obtained by s and d highlights the importance of studying both of them, and reveals how the choice of measurement can affect the interpretation. The methods in this paper can be used to interpret whether or not drug interactions are distinctive and the probability of their occurrence. Practitioners and researchers can rely on this identification for quantitative modeling and assessment.

  17. An activity canyon characterization of the pharmacological topography

    OpenAIRE

    Kulkarni, Varsha S.; Wild, David J.

    2016-01-01

    Background Highly chemically similar drugs usually possess similar biological activities, but sometimes, small changes in chemistry can result in a large difference in biological effects. Chemically similar drug pairs that show extreme deviations in activity represent distinctive drug interactions having important implications. These associations between chemical and biological similarity are studied as discontinuities in activity landscapes. Particularly, activity cliffs are quantified by th...

  18. Synthesis, spectroscopic characterization and pharmacological evaluation of oxazolone derivatives

    Directory of Open Access Journals (Sweden)

    Fareed Ghulam

    2013-01-01

    Full Text Available A series of 4-aryl methylidene-2-phenyl/methyl-5-(4H-oxazolone derivatives (2-7 have been synthesized using the reported method by condensation of aldehydes with N-benzoyl / N-acetyl glycine in the presence of zinc oxide as a catalyst and acetic anhydride at room temperature in ethanol. The compounds (2-6 are new derivatives. The structures of compounds were evaluated on the basis of 1H-NMR, 13C-NMR, EIMS, FT-IR and elemental analysis. All the compounds were screened for their antibacterial and urease inhibition activity. Antibacterial activity was tested by agar well diffusion method using Mueller Hinton Agar medium. Compound (2 showed excellent activity against S. aureus which has 16 mm (80% inhibition and above 24 mm (70% against S. typhi. The most active compound against E. coli was compound (6 having 20 mm (80% inhibition followed by compound (5 having above 18 mm (70% inhibition. Urease inhibition activity of all the compounds was determined by indophenol method. Compounds (3, 6 and (7 showed significant inhibition against Jacks bean urease.

  19. Synthesis, characterization and pharmacological evaluation of substituted phenoxy acetamide derivatives

    Directory of Open Access Journals (Sweden)

    Rani Priyanka

    2015-01-01

    Full Text Available A novel series of 2-(substituted phenoxy-N-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylacetamide and N-(2-bromocyclohexyl-2-(substituted phenoxyacetamide derivatives having cyclohexyl nucleus as common in both types were synthesized and assessed for their anti-inflammatory activity by a carrageenan induced rat paw oedema method, analgesic activity by Eddy’s hot plate method and antipyretic activity by brewer’s yeast induced pyrexia method. All the novel derivatives have been synthesized by the reaction of camphor and similar ketone having cyclohexane nucleus (e.g. 2-bromocyclohexanone with ammonium carbonate and formic acid resulting in the formation of aromatic amines (1a-b. These amines on further chloroacetylation with chloroacetylchloride give compounds (2a-b. Compounds (2a-b are converted to 2-(substituted phenoxy-N-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetamide and N-(2-bromocyclohexyl-2-(substituted phenoxyacetamide derivatives on treatment with substituted phenol. Among the series 3a-f, 3i, 3k, 3l compounds showed significant anti-inflammatory activity as compared to the standard drug diclofenac sodium and also compound 3a-f, 3h, 3j, 3k exhibit significant analgesic activity as compared to the standard drug. Compounds 3a-f and 3k showed antipyretic activity nearly to the standard drug indomethacin. Compounds 3a-f and 3k possess anti-inflammatory, analgesic and antipyretic activities near to the standard.

  20. A combination of experimental measurement, constitutive damage model, and diffusion tensor imaging to characterize the mechanical properties of the human brain.

    Science.gov (United States)

    Karimi, Alireza; Rahmati, Seyed Mohammadali; Razaghi, Reza

    2017-09-01

    Understanding the mechanical properties of the human brain is deemed important as it may subject to various types of complex loadings during the Traumatic Brain Injury (TBI). Although many studies so far have been conducted to quantify the mechanical properties of the brain, there is a paucity of knowledge on the mechanical properties of the human brain tissue and the damage of its axon fibers under the various types of complex loadings during the Traumatic Brain Injury (TBI). Although many studies so far have been conducted to quantify the mechanical properties of the brain, there is a paucity of knowledge on the mechanical properties of the human brain tissue and the damage of its axon fibers under the frontal lobe of the human brain. The constrained nonlinear minimization method was employed to identify the brain coefficients according to the axial and transversal compressive data. The pseudo-elastic damage model data was also well compared with that of the experimental data and it not only up to the primary loading but also the discontinuous softening could well address the mechanical behavior of the brain tissue.

  1. Pharmacological stress agents in nuclear cardiology

    International Nuclear Information System (INIS)

    Buscombe, J.R.

    2004-01-01

    Treadmill test combined with myocardial perfusion scintigraphy (MPS) is a commonly used technique in the assessment of coronary artery disease. However there are a group of patients who may not be able to undergo treadmill tests. Patients with underlying conditions like neuromuscular disease, musculoskeletal disorder, heart failure and end-stage renal disease (ESRD) on renal dialysis would find it difficult to perform exercise on a treadmill or bicycle ergometer. These conditions prevent them from performing adequate exercise. Such patients would benefit from pharmacological stress procedures combined with MPS. Nuclear medicine departments use various pharmacological agents while performing stress tests on cardiac patients. The most commonly used pharmacological agents for cardiac stress are coronary vasodilators and catecholamines. In addition to these agents, adjuvant use of nitrates and atropine is also a common practice in nuclear cardiology. This review addresses various physiological and pharmacological properties of the commonly used pharmacological stress agents in MPS and critically analyses their advantages and disadvantages, as well as their safety and efficacy. (author)

  2. Pharmacological screening technologies for venom peptide discovery.

    Science.gov (United States)

    Prashanth, Jutty Rajan; Hasaballah, Nojod; Vetter, Irina

    2017-12-01

    Venomous animals occupy one of the most successful evolutionary niches and occur on nearly every continent. They deliver venoms via biting and stinging apparatuses with the aim to rapidly incapacitate prey and deter predators. This has led to the evolution of venom components that act at a number of biological targets - including ion channels, G-protein coupled receptors, transporters and enzymes - with exquisite selectivity and potency, making venom-derived components attractive pharmacological tool compounds and drug leads. In recent years, plate-based pharmacological screening approaches have been introduced to accelerate venom-derived drug discovery. A range of assays are amenable to this purpose, including high-throughput electrophysiology, fluorescence-based functional and binding assays. However, despite these technological advances, the traditional activity-guided fractionation approach is time-consuming and resource-intensive. The combination of screening techniques suitable for miniaturization with sequence-based discovery approaches - supported by advanced proteomics, mass spectrometry, chromatography as well as synthesis and expression techniques - promises to further improve venom peptide discovery. Here, we discuss practical aspects of establishing a pipeline for venom peptide drug discovery with a particular emphasis on pharmacology and pharmacological screening approaches. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.' Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Only connect: the merger of BMC Pharmacology and BMC Clinical Pharmacology.

    Science.gov (United States)

    Moylan, Elizabeth C; Morrey, Christopher; Appleford-Cook, Joanne M

    2012-08-13

    This editorial celebrates the launch of BMC Pharmacology and Toxicology within the BMC series of journals published by BioMed Central. The scope of the journal is interdisciplinary encompassing toxicology, experimental and clinical pharmacology including clinical trials. In this editorial we discuss the origins of this new journal and the ethos and policies under which it will operate.

  4. 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...... demonstrated mixed results in controlled clinical trials. Although limited information is available, opioid antagonists and glutamatergic agents have demonstrated efficacious outcomes, especially for individuals with PG suffering from intense urges to engage in the behavior. CONCLUSIONS: Given that several...

  5. 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

    2014-01-01

    Summary 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

  6. Perinatal pharmacology: applications for neonatal neurology.

    Science.gov (United States)

    Smits, Anne; Allegaert, Karel

    2011-11-01

    The principles of clinical pharmacology also apply to neonates, but their characteristics warrant a tailored approach. We focus on aspects of both developmental pharmacokinetics (concentration/time relationship) and developmental pharmacodynamics (concentration/effect relationship) in neonates. We hereby aimed to link concepts used in clinical pharmacology with compound-specific observations (anti-epileptics, analgosedatives) in the field of neonatal neurology. Although in part anecdotal, we subsequently illustrate the relevance of developmental pharmacology in the field of neonatal neurology by a specific intervention (e.g. whole body cooling), specific clinical presentations (e.g. short and long term outcome following fetal exposure to antidepressive agents, the development of new biomarkers for fetal alcohol syndrome) and specific clinical needs (e.g. analgosedation in neonates, excitocytosis versus neuro-apoptosis/impaired synaptogenesis). Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  7. Functional pharmacology of cloned heterodimeric GABA-B receptors expressed in mammalian cells

    DEFF Research Database (Denmark)

    Bräuner-Osborne, Hans; Krogsgaard-Larsen, P

    1999-01-01

    reported in different tissues, and this study thus provides a functional assay of cloned GABAB receptors which should be a valuable tool for further characterization of GABAB ligands. Finally, we can conclude that the functional pharmacological profiles of the two GABABR1 splice variants are very similar....

  8. 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...

  9. 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...... 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...

  10. The Role of Wnt Signal in Glioblastoma Development and Progression: A Possible New Pharmacological Target for the Therapy of This Tumor.

    Science.gov (United States)

    Zuccarini, Mariachiara; Giuliani, Patricia; Ziberi, Sihana; Carluccio, Marzia; Iorio, Patrizia Di; Caciagli, Francesco; Ciccarelli, Renata

    2018-02-17

    Wnt is a complex signaling pathway involved in the regulation of crucial biological functions such as development, proliferation, differentiation and migration of cells, mainly stem cells, which are virtually present in all embryonic and adult tissues. Conversely, dysregulation of Wnt signal is implicated in development/progression/invasiveness of different kinds of tumors, wherein a certain number of multipotent cells, namely "cancer stem cells", are characterized by high self-renewal and aggressiveness. Hence, the pharmacological modulation of Wnt pathway could be of particular interest, especially in tumors for which the current standard therapy results to be unsuccessful. This might be the case of glioblastoma multiforme (GBM), one of the most lethal, aggressive and recurrent brain cancers, probably due to the presence of highly malignant GBM stem cells (GSCs) as well as to a dysregulation of Wnt system. By examining the most recent literature, here we point out several factors in the Wnt pathway that are altered in human GBM and derived GSCs, as well as new molecular strategies or experimental drugs able to modulate/inhibit aberrant Wnt signal. Altogether, these aspects serve to emphasize the existence of alternative pharmacological targets that may be useful to develop novel therapies for GBM.

  11. Evaluation and Computational Characterization of the Faciliated Transport of Glc Carbon C-1 Oxime Reactivators Across a Blood Brain Barrier Model

    Science.gov (United States)

    2013-01-01

    blood brain barrier (BBB) to reactivate inhibited brain acetylcholinesterase (AChE). We selected glucose (Glc) transporters (GLUT) for this purpose as...Eur. J. Pharm. 332 (1997) 43–52. [4] N.J. Abbott , L. Ronnback, E. Hansson, Astrocyte-endothelial interactions at the blood –brain barrier, Nat. Rev...5a. CONTRACT NUMBER oxime reactivators across a blood brain barrier model 5b. GRANT NUMBER 1.E005.08.WR 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S

  12. 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 ...

  13. Systems pharmacology - Towards the modeling of network interactions.

    Science.gov (United States)

    Danhof, Meindert

    2016-10-30

    Mechanism-based pharmacokinetic and pharmacodynamics (PKPD) and disease system (DS) models have been introduced in drug discovery and development research, to predict in a quantitative manner the effect of drug treatment in vivo in health and disease. This requires consideration of several fundamental properties of biological systems behavior including: hysteresis, non-linearity, variability, interdependency, convergence, resilience, and multi-stationarity. Classical physiology-based PKPD models consider linear transduction pathways, connecting processes on the causal path between drug administration and effect, as the basis of drug action. Depending on the drug and its biological target, such models may contain expressions to characterize i) the disposition and the target site distribution kinetics of the drug under investigation, ii) the kinetics of target binding and activation and iii) the kinetics of transduction. When connected to physiology-based DS models, PKPD models can characterize the effect on disease progression in a mechanistic manner. These models have been found useful to characterize hysteresis and non-linearity, yet they fail to explain the eff