WorldWideScience

Sample records for brain pharmacological characterization

  1. Some pharmacological properties of brain ganglioside

    Science.gov (United States)

    Bogoch, S.; Paasonen, M. K.; Trendelenburg, U.

    1962-01-01

    The effects of a preparation of purified brain ganglioside and of neuraminic acid have been studied on various pharmacological test preparations. In concentrations of 10 μg/ml. or more, ganglioside stimulates the isolated guinea-pig ileum; graded responses are usually obtained. Various substances, known to antagonize the actions of other stimulant substances, fail to affect the response to ganglioside. Ganglioside and neuraminic acid neither stimulate the superior cervical ganglion of the cat nor do they affect ganglionic transmission. Ganglioside and neuraminic acid did not change the response of the frog rectus abdominis muscle to acetylcholine, nor did they affect the blood pressure of the cat. Ganglioside (2 μg/ml. or more) stimulates the isolated heart of Venus mercenaria, but the response, which develops slowly, decreases with repeated administration of ganglioside. The response is not blocked by 2-bromo-lysergic acid diethylamide and there is no indication that it is due to the liberation of endogenous 5-hydroxytryptamine or related indole compounds. For both the heart of Venus mercenaria and guinea-pig ileum, the activity demonstrated by brain ganglioside is specifically a property of the whole molecule, since neither neuraminic acid itself nor a preparation of brain ganglioside from which only two-thirds of its neuraminic acid had been removed are active. PMID:13870595

  2. Brain connectivity in pathological and pharmacological coma

    Directory of Open Access Journals (Sweden)

    Quentin Noirhomme

    2010-12-01

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

  3. Brain Connectivity in Pathological and Pharmacological Coma

    Science.gov (United States)

    Noirhomme, Quentin; Soddu, Andrea; Lehembre, Rémy; Vanhaudenhuyse, Audrey; Boveroux, Pierre; Boly, Mélanie; Laureys, Steven

    2010-01-01

    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 frontoparietal “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

  4. Brain connectivity in pathological and pharmacological coma.

    Science.gov (United States)

    Noirhomme, Quentin; Soddu, Andrea; Lehembre, Rémy; Vanhaudenhuyse, Audrey; Boveroux, Pierre; Boly, Mélanie; Laureys, Steven

    2010-01-01

    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 frontoparietal "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. PMID:21191476

  5. Histamine receptors coupled to [3H]cAMP accumulation in brain: pharmacological characterization in a vesicular preparation of guinea pig cortex

    International Nuclear Information System (INIS)

    The histamine-stimulated accumulation of [3H]cAMP (formed by prelabeling with [3H]adenine) was characterized pharmacologically in a vesicular preparation of guinea pig cortex. The H2 antagonist cimetidine maximally blocked 80% of the response, whereas only 45% of the response could be inhibited by H1 antagonists. A combination of H1 and H2 antagonists completely abolished the response. These and other findings show that both H1 and H2 receptors mediate the response, but 25% of the response may require simultaneous activation of both receptors. A role for adenosine as a mediator of the histamine response was investigated. Adenosine deaminase (EC 3.5.4.4., 2.5 units/ml) decreased basal [3H]cAMP levels, abolished the cimetidine-resistant component of the histamine response, and reduced maximal H1 antagonism of the histamine response to 30%. Treatment with a combination of adenosine deaminase and the calcium chelator EGTA (2 mM) appeared to eliminate the H1 component completely. Under these latter conditions only H2 receptors appeared to mediate the histamine response. Thus, both H1 and H2 receptors stimulate [3H]cAMP accumulation in the vesicular preparation, but the H1 response seems to require either concomitant adenosine or H2 receptor stimulation and may be calcium dependent. These findings differ from those found in broken cell membrane preparations, where only H2 receptors appear to be coupled to adenylate cyclase activation

  6. [Pharmacological neuroenhancement and brain doping : Chances and risks].

    Science.gov (United States)

    Franke, A G; Lieb, K

    2010-08-01

    Pharmacological neuroenhancement refers to the use of psychoactive substances by healthy subjects with the purpose of cognitive enhancement, e.g., vigilance, concentration, memory, or mood. "Brain doping", however, refers to the illicit use of a subcategory of these substances such as prescription drugs. This subcategory includes psychostimulants (e.g., amphetamines, methylphenidate), modafinil, antidementia drugs (acetylcholine-esterase inhibitors, memantine), and antidepressants (selective serotonin reuptake inhibitors) which are being prescribed for the treatment of ADHD (attention deficit/hyperactivity disorder), Alzheimer's disease, and depression. Only psychostimulants and modafinil show significant effects on concentration, attentiveness, and vigilance in healthy subjects. However, a general use by healthy persons can not be justified because of relevant side effects and safety risks. Caffeine for pharmacological neuroenhancement can be seen as an equally effective alternative. "Brain doping" raises numerous ethical and social concerns that require a continued discussion. Demands of liberalization should be critically questioned. PMID:20700786

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1989-11-01

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

  10. [{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.

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

    International Nuclear Information System (INIS)

    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 [11C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [11C]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 [11C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38±11% of the control value. Furthermore, no metabolites of [11C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [11C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain

  12. 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...... 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 to the...

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Valentina ePieramico

    2014-09-01

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

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

    OpenAIRE

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

    2010-01-01

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

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    International Nuclear Information System (INIS)

    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)

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

    Science.gov (United States)

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

    2016-10-20

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

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

    OpenAIRE

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

    2016-01-01

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

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

    International Nuclear Information System (INIS)

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

  2. 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)

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

    Science.gov (United States)

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

    2016-07-01

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

  4. 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....

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1994-05-01

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

  7. 2-(/sup 125/I)iodomelatonin binding sites in hamster brain membranes: pharmacological characteristics and regional distribution

    Energy Technology Data Exchange (ETDEWEB)

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

    1988-05-01

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

  8. 2-[125I]iodomelatonin binding sites in hamster brain membranes: pharmacological characteristics and regional distribution

    International Nuclear Information System (INIS)

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

  9. Effects of ionizing radiation on the blood brain barrier permeability to pharmacologically active substances

    Energy Technology Data Exchange (ETDEWEB)

    Trnovec, T.; Kallay, Z.; Bezek, S. (Institute of Experimental Pharmacology, Bratislava (Yugoslavia))

    1990-12-01

    Ionizing radiation can impair the integrity of the blood brain barrier (BBB). Data on early and late damage after brain irradiation are usually reported separately, yet a gradual transition between these two types has become evident. Signs appearing within 3 weeks after irradiation are considered to be early manifestations. The mechanism of radiation-effected integrity impairment of the BBB is discussed in relation to changes in morphological structures forming the BBB, the endothelium of intracerebral vessels, and in the surrounding astrocytes. Alterations in the function of the BBB are manifested in the endothelium by changes in the ultrastructural location of the activity of phosphatases and by the activation of pinocytotic vesicular transport, and in astrocyte cytoplasm by glycogen deposition. The changes in ultrastructure were critically surveyed with regard to increasing doses of radiation to the brain in the range of 5 Gy to 960 Gy. The qualitative as well as the semiquantitative and quantitative observations on the passage of substances across the damaged BBB were treated separately. Qualitative changes are based mainly on findings of extravasation of vital stains and of labelled proteins. The quantitative studies established differences in radiation-induced changes in the permeability of the BBB depending on the structure and physico-chemical properties of the barrier penetrating tracers. Indirect evaluation of radiation-induced BBB changes is based on studies of pharmacological effects of substances acting on the CNS. In conclusion, radiation impairs significantly the integrity of the BBB following single irradiation of the brain with a dose exceeding 10-15 Gy. The response of the BBB to ionizing radiation is dependent both on the dose to which the brain is exposed and on specific properties of the tracer. 68 references.

  10. Synthesis and pharmacological characterization of certain baclofen analogues

    DEFF Research Database (Denmark)

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

    2013-01-01

    (RS)-4-Amino-3-(4-chlorophenyl)butanoic acid (baclofen, 2) is the prototypic selective GABAR agonist and is used clinically for the treatment of spasticity associated with brain and spinal cord injuries. Synthesis and GABA receptor agonist activity of certain amino acids structurally related to...... baclofen (2) are reported. (RS)-4-amino-3-(4- ethynylphenyl)butanoic acid hydrochloride (1b) showed GABA receptor agonist activity with EC = 240 µM whereas (RS)-4-amino-3-(4-iodophenyl)butanoic acid hydrochloride (1c) emerged as the best GABAB receptor agonist congener in the synthesized compounds with ED...

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

    Directory of Open Access Journals (Sweden)

    Christian eGiaume

    2013-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Stefaan W. van Gool

    2013-08-01

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

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

    Science.gov (United States)

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

    2016-05-01

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

  14. 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...... distributed brain responses identified two brain networks with modulations of activity related to face emotion and serotonin level. The first network included the left amygdala, bilateral striatum, and fusiform gyri. During the Control session this network responded only to fearful faces; increasing serotonin...... is critical for maintaining a differentiated brain response to threatening face emotions. Lower serotonin leads to a broadening of a normally fear-specific response to anger, and higher levels reduce the differentiated brain response to aversive face emotions....

  15. Pharmacological characterization of histamine receptors in the human temporal artery.

    OpenAIRE

    Ottosson, A; Jansen, I.; Edvinsson, L.

    1989-01-01

    1. The subtypes of histamine-receptors which mediate dilatation of small human temporal arteries have been characterized in vitro using 'selective' agonists and antagonists. 2. Dilatory responses were studied after preconstriction with prostaglandin F2 alpha since contraction was not seen at histamine concentrations up to 10(-4) M. Histamine caused a concentration-related relaxation of cerebral vessels with an IC50 value of 2.8 +/- 0.6 X 10(-7) M. 3. Cimetidine caused a parallel shift to the ...

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

    Directory of Open Access Journals (Sweden)

    Hammad Ismail

    2015-01-01

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

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

    Science.gov (United States)

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

    2016-09-01

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

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

    OpenAIRE

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

    2009-01-01

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

  19. Characterization using FLIPR of rat vanilloid receptor (rVR1) pharmacology

    OpenAIRE

    Jerman, J C; Brough, S J; Prinjha, R; Harries, M H; Davis, J. B.; Smart, D

    2000-01-01

    The vanilloid receptor (VR1) is a ligand-gated ion channel, which plays an important role in nociceptive processing. Therefore, a pharmacological characterization of the recently cloned rat VR1 (rVR1) was undertaken.HEK293 cells stable expressing rVR1 (rVR1-HEK293) were loaded with Fluo-3AM and then incubated at 25°C for 30 min with or without various antagonists or signal transduction modifying agents. Then intracellular calcium concentrations ([Ca2+]i) were monitored using FLIPR, before and...

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

    OpenAIRE

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

    1999-01-01

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

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

    OpenAIRE

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

    2014-01-01

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

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

    International Nuclear Information System (INIS)

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

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

    International Nuclear Information System (INIS)

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2002-10-01

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

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

    Science.gov (United States)

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

    2016-05-01

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

  7. 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.

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

    Science.gov (United States)

    Masliah, E; Díez-Tejedor, E

    2012-04-01

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

  9. Pharmacological manipulation of cyclic GMP levels in brain restores learning ability in animal models of hepatic encephalopathy: therapeutic implications

    Science.gov (United States)

    Rodrigo, Regina; Monfort, Pilar; Cauli, Omar; Erceg, Slaven; Felipo, Vicente

    2006-01-01

    Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome present in patients with liver disease that includes impaired intellectual function. To develop therapeutic treatments to restore cognitive function, it is important to understand the molecular mechanisms that impair cognitive function in HE. This review summarizes data showing that: (a) cognitive function and learning are impaired in patients with liver disease and in animal models of chronic liver failure or hyperammonemia; (b) the glutamate–NO–cGMP pathway modulates some forms of learning; and (c) the function of this pathway is impaired in brain in vivo in rats with chronic hyperammonemia or liver failure and from patients who died from HE. Learning ability of hyperammonemic rats was restored by increasing cGMP by: (1) continuous intracerebral administration of zaprinast, an inhibitor of the cGMP-degrading phosphodiesterase; (2) chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that crosses the blood–brain barrier; and (3) continuous intracerebral administration of cGMP. The data summarized indicate that impairment of learning ability in rats with chronic liver failure or hyperammonemia is due to impairment of the glutamate–NO–cGMP pathway. Moreover, increasing extracellular cGMP by pharmacological means may be a new therapeutic approach to improve cognitive function in patients with HE. PMID:19412446

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

    Institute of Scientific and Technical Information of China (English)

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

    2013-01-01

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

  11. Pharmacological Characterization of Novel A3 Adenosine Receptor-selective Antagonists

    OpenAIRE

    Jacobson, Kenneth A.; Park, Kyung-Sun; JIANG, JI-LONG; KIM, YONG-CHUL; Olah, Mark E.; Stiles, Gary L.; Ji, Xiao-duo

    1997-01-01

    The effects of putative A3 adenosine receptor antagonists of three diverse chemical classes (the flavonoid MRS 1067, the 6-phenyl-1,4-dihydropyridines MRS 1097 and MRS 1191, and the triazoloquinazo-line MRS 1220) were characterized in receptor binding and functional assays. MRS1067, MRS 1191 and MRS 1220 were found to be competitive in saturation binding studies using the agonist radioligand [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide) at cloned human brain A3 recep...

  12. Pharmacological treatments inhibiting levodopa-induced dyskinesias in MPTP-lesioned monkeys: brain glutamate biochemical correlates

    Directory of Open Access Journals (Sweden)

    NicolasMorin

    2014-08-01

    Full Text Available Antiglutamatergic drugs can relieve Parkinson’s disease (PD symptoms and decrease L-3,4-dihydroxyphenylalanine (L-DOPA-induced dyskinesias (LID. This review reports relevant studies investigating glutamate receptor subtypes in relation to motor complications in PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-lesioned monkeys. Antagonists of the ionotropic glutamate receptors, such as NMDA and AMPA receptors, display antidyskinetic activity in PD patients and animal models such as the MPTP monkey. Metabotropic glutamate 5 (mGlu5 receptor antagonists were shown to reduce the severity of LID in PD patients as well as in already dyskinetic non-human primates and to prevent the development of LID in de novo treatments in non-human primates. An increase in striatal post-synaptic NMDA, AMPA and mGlu5 receptors is documented in PD patients and MPTP monkeys with LID. This increase can be prevented in MPTP monkeys with the addition of a specific glutamate receptor antagonist to the L-DOPA treatment and also with drugs of various pharmacological specificities suggesting multiple receptor interactions. This is yet to be well documented for presynaptic mGlu4 and mGlu2/3 and offers additional new promising avenues.

  13. Mutual Amide Prodrug of Etodolac-glucosamine: Synthesis, Characterization and Pharmacological Screening

    Directory of Open Access Journals (Sweden)

    Preeti Pandey

    2013-01-01

    Full Text Available Etodolac, a nonsteroidal antiinflammatory drug, widely used in arthritis is associated with gastric ulceration and irritation due to presence of free carboxylic group. The current investigation reports synthesis of mutual amide prodrug of etodolac by masking free carboxylic group with glucosamine, a nutritional supplement for treatment of arthritis. Confirmation and characterization of the structure of the synthesized prodrug done by elemental and spectroscopy analysis, melting point, determination of migration parameters (R f , R M , and R t by using thin layer chromatography and high performance liquid chromatography, respectively. Partition coefficient and solubility study confirms its lipophilic character so can be suitable candidate for controlled release delivery. In vitro hydrolytic studies of prodrug confirms good rate of hydrolysis in blood plasma, fecal matter, and simulated intestinal fluid while stable in gastric simulated fluid. In vivo pharmacological screening performed on animals. Prodrug with respect to etodolac shows good analgesic, antiinflammatory, and antiarthritic activity. The prodrug was assessed for their probable damaging effects by ulcerogeniticity and histopathological analysis. The histopathological studies showed less ulceration in the gastric region when treated with prodrug, thereby proving the prodrug to be better in action as compared to etodolac and are advantageous in having less gastrointestinal side effects.

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

    Science.gov (United States)

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

    2008-09-01

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

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

    Science.gov (United States)

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

    1997-11-01

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

  16. 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.

  17. Principles of Safety Pharmacology

    OpenAIRE

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

    2008-01-01

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

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

    Science.gov (United States)

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

    2000-04-01

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

  19. Immunochemical characterization of rat brain protein kinase

    International Nuclear Information System (INIS)

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

  20. Development and characterization of positively selected brain-adapted SIV

    Directory of Open Access Journals (Sweden)

    Burdo Tricia H

    2005-05-01

    Full Text Available Abstract HIV is found in the brains of most infected individuals but only 30% develop neurological disease. Both viral and host factors are thought to contribute to the motor and cognitive disorders resulting from HIV infection. Here, using the SIV/rhesus monkey system, we characterize the salient characteristics of the virus from the brain of animals with neuropathological disorders. Nine unique molecular clones of SIV were derived from virus released by microglia cultured from the brains of two macaques with SIV encephalitis. Sequence analysis revealed a remarkably high level of similarity between their env and nef genes as well as their 3' LTR. As this genotype was found in the brains of two separate animals, and it encoded a set of distinct amino acid changes from the infecting virus, it demonstrates the convergent evolution of the virus to a unique brain-adapted genotype. This genotype was distinct from other macrophage-tropic and neurovirulent strains of SIV. Functional characterization of virus derived from representative clones showed a robust in vitro infection of 174xCEM cells, primary macrophages and primary microglia. The infectious phenotype of this virus is distinct from that shown by other strains of SIV, potentially reflecting the method by which the virus successfully infiltrates and infects the CNS. Positive in vivo selection of a brain-adapted strain of SIV resulted in a near-homogeneous strain of virus with distinct properties that may give clues to the viral basis of neuroAIDS.

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

    Science.gov (United States)

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

    1994-01-01

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

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

    Science.gov (United States)

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

    2011-08-01

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

  3. Studies in neuroendocrine pharmacology

    Science.gov (United States)

    Maickel, R. P.

    1976-01-01

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

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

    International Nuclear Information System (INIS)

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

  5. 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.

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

    Science.gov (United States)

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

    2016-03-01

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

  7. Pharmacological characterization of axonally transported (125I)-alpha-bungatoxin binding sites in rat sciatic nerve

    International Nuclear Information System (INIS)

    The authors attempt to label the putative receptors as they are axonally transported in peripheral nerves. With the use of an innovative autoradiographic technique, this approach as enabled the investigation of the pharmacological properties of the toxin-binding site interaction. The tissue sections from adult male rat sciatic nerves were incubated for 60 min at room temperature in phosphate buffer saline containing 2 nM I 125-alpha-BuTX with or without displacer. A bright field micrograph as well as dark field autoradiograph is illustrated of a ligated (12 hr.) rat sciatic nerve section incubated with I 125-alpha-BuTX. If one presumes that axonally transported I 125-alpha-BuTX binding sites correspond to receptors whose destination is the presynaptic membrane, then the data presented in this study may provide a pharmacological basis for differentiating pre- and postsynaptic sites of action of cholinergic drugs on the mammalian neuromuscular junction

  8. Characterization of pressure distribution in penetrating traumatic brain injuries.

    Science.gov (United States)

    Davidsson, Johan; Risling, Mårten

    2015-01-01

    Severe impacts to the head commonly lead to localized brain damage. Such impacts may also give rise to temporary pressure changes that produce secondary injuries in brain volumes distal to the impact site. Monitoring pressure changes in a clinical setting is difficult; detailed studies into the effect of pressure changes in the brain call for the development and use of animal models. The aim of this study is to characterize the pressure distribution in an animal model of penetrating traumatic brain injuries (pTBI). This data may be used to validate mathematical models of the animal model and to facilitate correlation studies between pressure changes and pathology. Pressure changes were measured in rat brains while subjected to pTBI for a variety of different probe velocities and shapes; pointy, blunt, and flat. Experiments on ballistic gel samples were carried out to study the formation of any temporary cavities. In addition, pressure recordings from the gel experiments were compared to values recorded in the animal experiments. The pTBI generated short lasting pressure changes in the brain tissue; the pressure in the contralateral ventricle (CLV) increased to 8 bar followed by a drop to 0.4 bar when applying flat probes. The pressure changes in the periphery of the probe, in the Cisterna Magna, and the spinal canal, were significantly less than those recorded in the CLV or the vicinity of the skull base. High-speed videos of the gel samples revealed the formation of spherically shaped cavities when flat and spherical probes were applied. Pressure changes in the gel were similar to those recorded in the animals, although amplitudes were lower in the gel samples. We concluded cavity expansion rate rather than cavity size correlated with pressure changes in the gel or brain secondary to probe impact. The new data can serve as validation data for finite element models of the trauma model and the animal and to correlate physical measurements with secondary injuries

  9. A High Rate Tension Device for Characterizing Brain Tissue

    CERN Document Server

    Rashid, Badar; Gilchrist, Michael; 10.1177/1754337112436900

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Aneta Radziwon-Balicka

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

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

    Science.gov (United States)

    Niimi, Kimie; Takahashi, Eiki

    2014-01-01

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

  12. Characterization of Amyloid-β Deposits in Bovine Brains.

    Science.gov (United States)

    Vallino Costassa, Elena; Fiorini, Michele; Zanusso, Gianluigi; Peletto, Simone; Acutis, Pierluigi; Baioni, Elisa; Maurella, Cristiana; Tagliavini, Fabrizio; Catania, Marcella; Gallo, Marina; Faro, Monica Lo; Chieppa, Maria Novella; Meloni, Daniela; D'Angelo, Antonio; Paciello, Orlando; Ghidoni, Roberta; Tonoli, Elisa; Casalone, Cristina; Corona, Cristiano

    2016-02-10

    Amyloid-β (Aβ) deposits are seen in aged individuals of many mammalian species that possess the same aminoacid sequence as humans. This study describes Aβ deposition in 102 clinically characterized cattle brains from animals aged 0 to 20 years. Extracellular and intracellular Aβ deposition was detected with 4G8 antibody in the cortex, hippocampus, and cerebellum. X-34 staining failed to stain Aβ deposits, indicating the non β-pleated nature of these deposits. Western blot analysis and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry revealed in Tris, Triton, and formic acid fractions the presence of different Aβ peptides, characterized mainly by C-terminally truncated forms. Exploration of the genetic variability of APOE, PSEN1, and PSEN2 genes involved in Alzheimer's disease pathogenesis revealed several previously unreported polymorphisms. This study demonstrates certain similarities between Aβ deposition patterns exhibited in cattle brains and those in the human brain in early stages of aging. Furthermore, the identification of the same Aβ peptides reported in humans, but unable to form aggregates, supports the hypothesis that cattle may be protected against amyloid plaque formation. PMID:26890772

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-11-20

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

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

    Science.gov (United States)

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

    1997-01-01

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

  15. 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 in...... AP across 12 different countries participated in a Delphi survey. Over four Delphi rounds, the panel identified and ranked the most important goals of AP, behaviours of AP (the actions people take to meet the goal of AP), strategies to change behaviour in AP, and contextual factors that should be...... acknowledged when instructing AP. Additionally, topics for future research on AP were formulated and prioritized. RESULTS: The Delphi panel prioritized 9 goals, 11 behaviours, 9 strategies to change behaviour, and 10 contextual factors of AP. These items were integrated into a consensual list containing the...

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

    DEFF Research Database (Denmark)

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

    2001-01-01

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

  17. Pharmacological characterization and autoradiographic localization and dopamine receptors in the human adrenal cortex

    International Nuclear Information System (INIS)

    The pharmacological characteristics and the anatomical localization of dopamine D1-like and D2-like receptors were studied in sections of the human adrenal cortex using radioligand binding and autoradiographic techniques. [3H]SCH 23390 was used as a ligand of D1-like receptors, whereas [3H]spiroperidol was used to label D2-like receptors. No specific [3H]SCH 23390 binding was detectable in sections of the human adrenal cortex. On the other hand, [3H]spiroperidol was bound to sections of the adrenal gland in a manner consistent with the labelling of dopamine D2-like receptor sites. The binding was time, temperature and concentration dependent, belonging in the range of concentrations of the radioligand used for a single class of high-affinity sites. The dissociation constant (Kd) averaged 2.7 nmol/l, whereas the maximum density of binding sites (Bmax) was 160 nmol/mg tissue. Experiments on the pharmacological specificity of [3H]spiroperidol binding to sections of the human adrenal cortex revealed that clozapine was the most powerful displacer of [3H]spiroperidol from sections of the human adrenal cortex. This suggests the presence in the human adrenal cortex of dopamine receptors of the D4 subtype. Light microscope autoradiography showed the highest density of specific [3H]spiroperidol binding sites in the zona glomerulosa and to a lesser extent in the zona reticularis. Only sparse [3H]spiroperidol binding sites were localized in the zona fasciculata. The possible functional consequences of this localization of dopamine D2-like receptor sites in the human adrenal cortex are discussed. 37 refs., 3 figs., 1 tab

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

    Science.gov (United States)

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

    2016-04-01

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

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

    Science.gov (United States)

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

    1981-04-30

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

  20. Pharmacological characterization of ergotamine-induced inhibition of the cardioaccelerator sympathetic outflow in pithed rats.

    Science.gov (United States)

    Cobos-Puc, Luis E; Villalón, Carlos M; Sánchez-López, Araceli; Ramírez-Rosas, Martha B; Lozano-Cuenca, Jair; Pertz, Heinz H; Görnemann, Tilo; Centurión, David

    2009-02-01

    Ergotamine inhibits the sympathetically-induced tachycardia in pithed rats. The present study identified the pharmacological profile of this response. Male Wistar rats were pithed and prepared to stimulate the preganglionic (C(7)-T(1)) cardiac sympathetic outflow. Intravenous continuous infusions of ergotamine dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. Using several antagonists, the sympatho-inhibition to ergotamine was: (1) partially blocked by rauwolscine (alpha(2)), haloperidol (D(1/2)-like) or rauwolscine plus GR127935 (5-HT(1B/1D)); (2) abolished by rauwolscine plus haloperidol; and (3) unaffected by either saline or GR127935. In animals systematically pretreated with haloperidol, this sympatho-inhibition was: (1) unaffected by BRL44408 (alpha(2A)), partially antagonized by MK912 (alpha(2C)); and (3) abolished by BRL44408 plus MK912. These antagonists failed to modify the sympathetically induced tachycardic responses per se. Thus, the cardiac sympatho-inhibition by ergotamine may be mainly mediated by alpha(2A)/alpha(2C)-adrenoceptors, D(2)-like receptors and, to a lesser extent, by 5-HT(1B/1D) receptors. PMID:18779954

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

    Science.gov (United States)

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

    2009-01-01

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

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

    International Nuclear Information System (INIS)

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

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

    International Nuclear Information System (INIS)

    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 [125I][Sar1-Ile8]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. (author)

  4. Impact of pharmacological treatments on cognitive and behavioral outcome in the postacute stages of adult traumatic brain injury: a meta-analysis.

    Science.gov (United States)

    Wheaton, Patricia; Mathias, Jane L; Vink, Robert

    2011-12-01

    Pharmacological treatments that are administered to adults in the postacute stage after a traumatic brain injury (TBI) (≥4 weeks after injury) have the potential to reduce persistent cognitive and behavioral problems. While a variety of treatments have been examined, the findings have yet to be consolidated, hampering advances in the treatment of TBI. A meta-analysis of research that has investigated the cognitive and behavioral effects of pharmacological treatments administered in the later stage after TBI was therefore conducted. The PubMed and PsycINFO databases were searched, and Cohen d effect sizes, percent overlap, and failsafe N statistics were calculated for each treatment. Both randomized controlled trials and open-label studies (prospective and retrospective) were included. Nineteen treatments were investigated by 30 independent studies, comprising 395 participants with TBI in the treatment groups and 137 control subjects. When treated in the postacute period, 1 dopaminergic agent (methylphenidate) improved behavior (anger/aggression, psychosocial function) and 1 cholinergic agent (donepezil) improved cognition (memory, attention). In addition, when the injury-to-treatment interval was broadened to include studies that administered treatment just before the postacute period, 2 dopaminergic agents (methylphenidate, amantadine) showed clinically useful treatment benefits for behavior, whereas 1 serotonergic agent (sertraline) markedly impaired cognition and psychomotor speed. PMID:22020351

  5. Brain targeted solid lipid nanoparticles for brain ischemia: preparation and in vitro characterization.

    Science.gov (United States)

    Morsi, Nadia M; Ghorab, Dalia M; Badie, Hany A

    2013-01-01

    This study aims at formulating solid lipid nanoparticles (SLNs) of Vinpocetine (VIN) to be used as a brain targeted sustained drug-delivery system. VIN is a derivative of vincamine alkaloid, used for chronic cerebral vascular ischemia. However, it suffers from low bioavailability and short half-life. Its oral bioavailability is recorded to be between 7 and 55%. Its elimination half-life is 1-2 h so it would be a good candidate for a sustained drug-delivery system. VIN SLNs were prepared using modified high shear homogenization followed by ultrasonication technique. The effect of incorporating different lipids at different concentrations of various surfactants was investigated. The VIN SLNs were characterized by entrapment efficiency percent (EE%), particle size distribution, zeta-potential, and cumulative released percent after 96 h. The EE% ranged between 83.34% ± 0.95-94.56% ± 0.11 due to the lipophilic character of VIN. The mean particle size measured ranged from 123 nm-464 nm. The cumulative released percent after 96 h ranged from 23.55% to 75.67% showing a controlled release profile. Formula (F32) composed of 5% glyceryl monostearate (GMS) and stabilized by 2% surfactant mixture [Tween 80, Pluronic F 68 (1:1)] was the most appropriate formula for brain delivery having EE% of 89.09% ± 1.49, zero-order release kinetics with cumulative released percent of 72.12% after 96 h, zeta-potential of -11.3 ± 0.97 mV. It showed a unimodal size distribution with particle size ≈ 90 nm and polydispersity index of 0.121. The formula of choice in this study exhibited a zero-order sustained release profile and met the requirement for a brain targeted SLN so it could be a promising formula to deliver VIN to the brain. PMID:23477526

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

    Science.gov (United States)

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

    2004-12-01

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

  7. 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 (...

  8. Pharmacologic characterization of the oxytocin receptor in human uterine smooth muscle cells

    OpenAIRE

    Tahara, Atsuo; Tsukada, Junko; Tomura, Yuichi; Wada, Koh-ichi; Kusayama, Toshiyuki; Ishii, Noe; Yatsu, Takeyuki; Uchida, Wataru; Tanaka, Akihiro

    2000-01-01

    [3H]-oxytocin was used to characterize the oxytocin receptor found in human uterine smooth muscle cells (USMC). Specific binding of [3H]-oxytocin to USMC plasma membranes was dependent upon time, temperature and membrane protein concentration.Scatchard plot analysis of equilibrium binding data revealed the existence of a single class of high-affinity binding sites with an apparent equilibrium dissociation constant (Kd) of 0.76 nM and a maximum receptor density (Bmax) of 153 fmol mg−1 protein....

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

    Science.gov (United States)

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

    2016-03-01

    Migraine is a highly prevalent neurovascular disorder in the brain. An optimal therapy for migraine has not yet been developed. Gastrodin (Gas), the main effective constitute from Gastrodiae Rhizoma (Tianma in Chinese), has been indicated for migraine treatment and prophylaxis more than 30years, with demonstrated safety. However, Gas is a phenolic glycoside, with relatively low concentrations and weak efficacy in the central nervous system. To develop more effective anti-migraine agents, we synthesized a novel Gas derivative (Gas-D). In the present study, comparative pharmacodynamic evaluations of Gas and Gas-D were performed in a model of nitroglycerin (NTG)-induced migraine in rats and the hot-plate test in mice. Following behavioral testing in this migraine model, external jugular vein blood and the trigeminal nucleus caudalis (TNC) were collected to analyze plasma nitric oxide (NO) and calcitonin gene-related peptide (CGRP) concentrations and c-Fos expression in the TNC. The acute oral toxicity of Gas and Gas-D was also examined. We found that Gas-D had potent anti-migraine effects, likely attributable to inhibition of both trigeminal nerve activation at central sites and the peripheral release of CGRP following NO scavenging. Additionally, Gas-D exerted significant anti-nociceptive effect in response to thermal pain compared with Gas. Furthermore, a single dose of 2.048g/kg Gas or Gas-D presented no acute oral toxicity in mice. Altogether, the potent anti-migraine and anti-hyperalgesic effects of Gas-D suggest that it might be a potentially novel drug candidate for migraine treatment or prophylaxis. PMID:26704993

  10. 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.

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

    Science.gov (United States)

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

    1994-03-01

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

  12. 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

  13. Noradrenergic system in cultured aggregates of fetal rat brain cells: morphology of the aggregates and pharmacological indices of noradrenergic neurons

    Energy Technology Data Exchange (ETDEWEB)

    Majocha, R.E.; Pearse, R.N.; Baldessarini, R.J.; Delong, G.R.; Walton, K.G. (Harvard Medical School, Boston, MA (USA))

    1981-12-28

    Spherical aggregates formed rapidly in culture by re-aggregation of trypsin-dissociated brain cells from the 17-day-old fetal rat. Over about 10 days an initially random distribution of cells evolved into a 3-layered arrangement; cells with characteristics of neurons were found largely in the intermediate layer. The survival of neuronal and glial cell types was evaluated histologically and verified by electron microscopy, which revealed synaptic and myelin structures that rapidly increased in number after 18 days in culture. Levels of norepinephrine (NE) and dopamine (DA) reached peaks of 9.5 and 4.4 ng/mg protein, respectively, at culture day 21. Uptake of (/sup 3/H)NE paralleled these amine levels and was blocked by desipramine or pretreatment with either reserpine or 6-OH-DA. Autoradiographs of aggregates labeled with (/sup 3/H)NE showed a high density of silver grains over cells, apparently neurons, with branching processes traced for 120 ..mu..m. Previously accumulated (/sup 3/H)NE was released under depolarizing conditions (high (K/sup +/) or vertridine) only in the presence of Ca/sup 2 +/. Release was induced to a lesser extent by kainic > glutamic acid. Thus, such aggregates appear to contain catecholaminergic neurons capable of synthesis, uptake and release of NE. The time course of development of these functions supports suggestions that aggregate preparations might be useful in studying neurochemical or morphological aspects of brain development and function in vitro.

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

    Directory of Open Access Journals (Sweden)

    Juha R Savinainen

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2012-06-01

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

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

    OpenAIRE

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

    2008-01-01

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

  18. Identification, functional characterization, and pharmacological profile of a serotonin type-2b receptor in the medically important insect, Rhodnius prolixus.

    Science.gov (United States)

    Paluzzi, Jean-Paul V; Bhatt, Garima; Wang, Chang-Hui J; Zandawala, Meet; Lange, Angela B; Orchard, Ian

    2015-01-01

    In the Chagas disease vector, Rhodnius prolixus, two diuretic hormones act synergistically to dramatically increase fluid secretion by the Malpighian tubules (MTs) during the rapid diuresis that is initiated upon engorgement of vertebrate blood. One of these diuretic hormones is the biogenic amine, serotonin (5-hydroxytryptamine, 5-HT), which controls a variety of additional activities including cuticle plasticization, salivary gland secretion, anterior midgut absorption, cardioacceleratory activity, and myotropic activities on a number of visceral tissues. To better understand the regulatory mechanisms linked to these various physiological actions of serotonin, we have isolated and characterized a serotonin type 2b receptor in R. prolixus, Rhopr5HTR2b, which shares sequence similarity to the vertebrate serotonin type 2 receptors. Rhopr5HTR2b transcript is enriched in well-recognized physiological targets of serotonin, including the MTs, salivary glands and dorsal vessel (i.e., insect heart). Notably, Rhopr5HTR2b was not enriched in the anterior midgut where serotonin stimulates absorption and elicits myotropic control. Using a heterologous functional receptor assay, we examined Rhopr5HTR2b activation characteristics and its sensitivity to potential agonists, antagonists, and other biogenic amines. Rhopr5HTR2b is dose-dependently activated by serotonin with an EC50 in the nanomolar range. Rhopr5HTR2b is sensitive to alpha-methyl serotonin and is inhibited by a variety of serotonin receptor antagonists, including propranolol, spiperone, ketanserin, mianserin, and cyproheptadine. In contrast, the cardioacceleratory activity of serotonin revealed a unique pharmacological profile, with no significant response induced by alpha-methyl serotonin and insensitivity to ketanserin and mianserin. This distinct agonist/antagonist profile indicates that a separate serotonin receptor type may mediate cardiomodulatory effects controlled by serotonin in R. prolixus. PMID:26041983

  19. 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.

  20. 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

  1. 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.

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

    Science.gov (United States)

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

    2006-09-01

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

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

    OpenAIRE

    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

    2015-01-01

    Mild traumatic brain injuries are frequent events in the general population and are associated with a severe neurodegenerative disease, chronic traumatic encephalopathy (CTE). This disease is characterized by abnormal accumulation of protein aggregates, primarily tau proteins, which accumulate in brain areas responsible for mood, fear, stress, and cognition. There is no definitive clinical diagnosis of CTE at the present time, and this new work shows how a tau-sensitive brain imaging agent, [...

  4. Brain

    Science.gov (United States)

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

  5. Pharmacologic Neuroimaging of the Ontogeny of Dopamine Receptor Function

    OpenAIRE

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

    2010-01-01

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

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  7. Pharmacological characterization of extracellular acidification rate responses in human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells

    OpenAIRE

    Coldwell, M C; Boyfield, I; Brown, A M; Stemp, G; Middlemiss, D. N.

    1999-01-01

    This study characterized pharmacologically the functional responses to agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) zreceptors separately expressed in cloned cells using the cytosensor microphysiometer.Dopaminergic receptor agonists caused increases in extracellular acidification rate in adherent Chinese hamster ovary (CHO) clones expressing hD2, hD3 or hD4 receptors. Acidification rate responses to agonists in other cell lines expressing these receptors were smaller tha...

  8. Iomazenil: pharmacological and animal data

    International Nuclear Information System (INIS)

    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 123I-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

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

    NARCIS (Netherlands)

    TIMMERMAN, W; ZWAVELING, J; WESTERINK, BHC

    1992-01-01

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

  10. Brain Signature Characterizing the Body-Brain-Mind Axis of Transsexuals

    Science.gov (United States)

    Chao, Hsiang-Tai; Tu, Pei-Chi; Li, Cheng-Ta; Cheng, Chou-Ming; Su, Tung-Ping; Lee, Ying-Chiao; Hsieh, Jen-Chuen

    2013-01-01

    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. PMID:23923023

  11. 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.

  12. 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

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

    International Nuclear Information System (INIS)

    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 [35S](S)-2-amino-4-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl) ethyl)benzamide ([35S]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 [14C]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 (Kd=1.9 nM), selective, GlyT1 inhibitor that, when radiolabeled with [35S], 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 [35S]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 tomography tracers

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

    Directory of Open Access Journals (Sweden)

    Kun Hyoe Rhoo

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, Karina Corleto

    2014-07-01

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

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

    OpenAIRE

    Gaia Rocchitta; Pier Andrea Serra; Robert D. O'Neill; Maria Speranza Desole; Rossana Migheli; Marco Pirisinu; Gianfranco Bazzu; Ylenia Spissu; Manuel Zinellu; Ottavio Secchi

    2013-01-01

    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 ...

  17. On the application of Quantitative EEG for characterizing autistic brain: a systematic review

    Directory of Open Access Journals (Sweden)

    Lucia Billeci

    2013-08-01

    Full Text Available Autism Spectrum Disorders (ASD are thought to be associated with abnormalities in neural connectivity at both the global and local levels. Quantitative electroencephalography (QEEG is a non-invasive technique that allows a highly precise measurement of brain function and connectivity. This review encompasses the key findings of QEEG application in subjects with ASD, in order to assess the relevance of this approach in characterizing brain function and clustering phenotypes. QEEG studies evaluating both the spontaneous brain activity and brain signals under controlled experimental stimuli were examined. Despite conflicting results, literature analysis suggests that QEEG features are sensitive to modification in neuronal regulation dysfunction which characterize autistic brain. QEEG may therefore help in detecting regions of altered brain function and connectivity abnormalities, in linking behavior with brain activity, and subgrouping affected individuals within the wide heterogeneity of ASD. The use of advanced techniques for the increase of the specificity and of spatial localization could allow finding distinctive patterns of QEEG abnormalities in ASD subjects, paving the way for the development of tailored intervention strategies.

  18. Pharmacology of Iron Transport

    OpenAIRE

    Byrne, Shaina L.; Krishnamurthy, Divya; Wessling-Resnick, Marianne

    2012-01-01

    Elucidating the molecular basis for the regulation of iron uptake, storage, and distribution is necessary to understand iron homeostasis. Pharmacological tools are emerging to identify and distinguish among different iron transport pathways. Stimulatory or inhibitory small molecules with effects on iron uptake can help characterize the mechanistic elements of iron transport and the roles of the transporters involved in these processes. In particular, iron chelators can serve as potential phar...

  19. Isolation and characterization of a factor from rat liver which inhibits 3H-nicotine binding to brain nicotine receptors

    International Nuclear Information System (INIS)

    In studies of 3H-nicotine binding sites in rat brain membranes, it was observed that crude rat liver homogenates are capable of inhibiting this binding. The purpose of this work was to isolate from the liver homogenate the factor (or factors) responsible for this nicotinelike activity and to identify it. Isolation procedures, including heat denaturation, ultrafiltration, and reverse phase high pressure liquid chromatography, resulted in an incompletely purified substance whose chemical properties were compatible with those of dimethylaminoethyl (DMAE) carbamate, as reflected in infrared, ultraviolet, NMR, and mass spectra; in HPLC elution characteristics into mobile phases; and in IC50's with respect to 3H-nicotine binding to neural membranes, although additional purification and characterization will be necessary to confirm or reject this identification. This compound has not previously been described in mammalian tissue, although its two component functional moieties, dimethylaminoethanol and carbamic acid, are present in the liver. The binding properties of DMAE carbamate are compared with those of structurally and pharmacological related compounds to assess its potential as an endogenous cholinergic ligand

  20. Isolation and characterization of human malignant glioma cells from histologically normal brain.

    Science.gov (United States)

    Silbergeld, D L; Chicoine, M R

    1997-03-01

    Brain invasion prevents complete surgical extirpation of malignant gliomas; however, invasive cells from distant, histologically normal brain previously have not been isolated, cultured, and characterized. To evaluate invasive human malignant glioma cells, the authors established cultures from gross tumor and histologically normal brain. Three men and one woman, with a mean age of 67 years, underwent two frontal and two temporal lobectomies for tumors, which yielded specimens of both gross tumor and histologically normal brain. Each specimen was acquired a minimum of 4 cm from the gross tumor. The specimens were split: a portion was sent for neuropathological evaluation (three glioblastomas multiforme and one oligodendroglioma) and a portion was used to establish cell lines. Morphologically, the specimens of gross tumor and histologically normal brain were identical in three of the four cell culture pairs. Histochemical staining characteristics were consistent both within each pair and when compared with the specimens sent for neuropathological evaluation. Cultures demonstrated anchorage-independent growth in soft agarose and neoplastic karyotypes. Growth rates in culture were greater for histologically normal brain than for gross tumor in three of the four culture pairs. Although the observed increases in growth rates of histologically normal brain cultures do not correlate with in vivo behavior, these findings corroborate the previously reported stem cell potential of invasive glioma cells. Using the radial dish assay, no significant differences in motility between cultures of gross tumor and histologically normal brain were found. In summary, tumor cells were cultured from histologically normal brain acquired from a distance greater than 4 cm from the gross tumor, indicating the relative insensitivity of standard histopathological identification of invasive glioma cells (and hence the inadequacy of frozen-section evaluation of resection margins). Cell lines

  1. 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. PMID:26123275

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

    Science.gov (United States)

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

    2016-09-25

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

  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: 2.386, year: 2014 http://www.jpp.krakow.pl/journal/archive/02_16/articles/11_article.html

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  6. 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.

  7. Pharmacological and physiological characterization of the tremulous jaw movement model of parkinsonian tremor: potential insights into the pathophysiology of tremor

    Directory of Open Access Journals (Sweden)

    Lyndsey E. Collins-Praino

    2011-07-01

    Full Text Available Tremor is a cardinal symptom of parkinsonism, occurring early on in the disease course and affecting more than 70% of patients. Parkinsonian resting tremor occurs in a frequency range of 3-7Hz and can be resistant to available pharmacotherapy. Despite its prevalence, and the significant decrease in quality of life associated with it, the pathophysiology of parkinsonian tremor is poorly understood. The tremulous jaw movement (TJM model is an extensively validated rodent model of tremor. TJMs are induced by conditions that also lead to parkinsonism in humans (i.e. striatal DA depletion, DA antagonism and cholinomimetic activity and reversed by several antiparkinsonian drugs (i.e. DA precursors, DA agonists, anticholinergics and adenosine A2A antagonists. TJMs occur in the same 3-7 Hz frequency range seen in parkinsonian resting tremor, a range distinct from that of dyskinesia (1-2 Hz and postural tremor (8-14 Hz. Overall, these drug-induced TJMs share many characteristics with human parkinsonian tremor, but do not closely resemble tardive dyskinesia. The current review discusses recent advances in the validation of the tremulous jaw movement model, and illustrates how this model is being used to develop novel therapeutic strategies, both surgical and pharmacological, for the treatment of parkinsonian resting tremor.

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

    OpenAIRE

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

    2010-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Jason M Meyer

    2012-01-01

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

  10. 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

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

    International Nuclear Information System (INIS)

    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 37P-labeled tryptic fragments derived from the autophosphorylation and the photoaffinity labeled cAMP-binding sites of brain RII were separate and distinct from the 32P-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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-11-01

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

  13. Characterization of normal brain and brain tumor pathology by chisquares parameter maps of diffusion-weighted image data

    International Nuclear Information System (INIS)

    Objective: To characterize normal and pathologic brain tissue by quantifying the deviation of diffusion-related signal from a simple monoexponential decay, when measured over a wider than usual range of b-factors. Methods and materials: Line scan diffusion imaging (LSDI), with diffusion weighting at multiple b-factors between 100 and 5000 s/mm2, was performed on 1.5 T clinical scanners. Diffusion data of single slice sections were acquired in five healthy subjects and 19 brain tumor patients. In-patients, conventional T2-weighted and contrast-enhanced T1-weighted images were obtained for reference purposes. The chisquare (χ2) error parameter associated with the monoexponential fits of the measured tissue water signals was then used to quantify the departure from a simple monoexponential signal decay on a pixel-by-pixel basis. Results: Diffusion-weighted images over a wider b-factor range than typically used were successfully obtained in all healthy subjects and patients. Normal and pathologic tissues demonstrated signal decays, which clearly deviate from a simple monoexponential behavior. The χ2 of cortical and deep grey matter was considerably lower than in white matter. In peritumoral edema, however, χ2 was 68% higher than in normal white matter. In highly malignant brain tumors, such as glioblastoma multiforme (GBM) or anaplastic astrocytoma, χ2 values were on average almost 400% higher than in normal white matter, while for one low grade astrocytoma and two cases of metastasis, χ2 was not profoundly different from the χ2 value of white matter. Maps of the χ2 values provide good visualization of spatial details. However, the tumor tissue contrast generated appeared in many cases to be different from the enhancement produced by paramagnetic contrast agents. For example, in cases where the contrast agent only highlighted the rim of the tumor, χ2 enhancement was present within the solid part of the tumor. Conclusion: The deviation from a purely

  14. Ocular pharmacology.

    Science.gov (United States)

    Novack, Gary D; Robin, Alan L

    2016-05-01

    Ophthalmic diseases include both those analogous to systemic diseases (eg, inflammation, infection, neuronal degeneration) and not analogous (eg, cataract, myopia). Many anterior segment diseases are treated pharmacologically through eye drops, which have an implied therapeutic index of local therapy. Unlike oral dosage forms administered for systemic diseases, eyedrops require patients not only to adhere to treatment, but to be able to accurately perform-ie, instill drops correctly. Anatomical and physiological barriers make topical delivery to the anterior chamber challenging-in some cases more challenging than absorption through the skin, nasal passages, or gut. Treatment of the posterior segment (eg, vitreous, retina, choroid, and optic nerve) is more challenging due to additional barriers. Recently, intravitreal injections have become a standard of care with biologics for the treatment of macular degeneration and other diseases. Although the eye has esterases, hydroxylases, and transporters, it has relatively little CYP450 enzymes. Because it is challenging to obtain drug concentrations at the target site, ocular clinical pharmacokinetics, and thus pharmacokinetic-pharmacodynamic interactions, are rarely available. Ophthalmic pharmaceuticals require consideration of solubility, physiological pH, and osmolarity, as well as sterility and stability, which in turn requires optimal pharmaceutics. Although applied locally, ocular medications may be absorbed systemically, which results in morbidity and mortality (eg, systemic hypotension, bronchospasm, and bradycardia). PMID:26360129

  15. Pharmacological characterization of mouse GPRC6A, an L-alpha-amino-acid receptor modulated by divalent cations

    DEFF Research Database (Denmark)

    Christiansen, B; Hansen, K B; Wellendorph, P; Bräuner-Osborne, Hans

    2007-01-01

    GPRC6A is a novel member of family C of G protein-coupled receptors with so far unknown function. We have recently described both human and mouse GPRC6A as receptors for L-alpha-amino acids. To date, functional characterization of wild-type GPRC6A has been impaired by the lack of activity in quan...

  16. Differentiation and characterization of human pluripotent stem cell-derived brain microvascular endothelial cells.

    Science.gov (United States)

    Stebbins, Matthew J; Wilson, Hannah K; Canfield, Scott G; Qian, Tongcheng; Palecek, Sean P; Shusta, Eric V

    2016-05-15

    The blood-brain barrier (BBB) is a critical component of the central nervous system (CNS) that regulates the flux of material between the blood and the brain. Because of its barrier properties, the BBB creates a bottleneck to CNS drug delivery. Human in vitro BBB models offer a potential tool to screen pharmaceutical libraries for CNS penetration as well as for BBB modulators in development and disease, yet primary and immortalized models respectively lack scalability and robust phenotypes. Recently, in vitro BBB models derived from human pluripotent stem cells (hPSCs) have helped overcome these challenges by providing a scalable and renewable source of human brain microvascular endothelial cells (BMECs). We have demonstrated that hPSC-derived BMECs exhibit robust structural and functional characteristics reminiscent of the in vivo BBB. Here, we provide a detailed description of the methods required to differentiate and functionally characterize hPSC-derived BMECs to facilitate their widespread use in downstream applications. PMID:26518252

  17. The microtubular cytoskeleton of olfactory neurons derived from patients with schizophrenia or with bipolar disorder: Implications for biomarker characterization, neuronal physiology and pharmacological screening.

    Science.gov (United States)

    Benítez-King, G; Valdés-Tovar, M; Trueta, C; Galván-Arrieta, T; Argueta, J; Alarcón, S; Lora-Castellanos, A; Solís-Chagoyán, H

    2016-06-01

    Schizophrenia (SZ) and Bipolar Disorder (BD) are highly inheritable chronic mental disorders with a worldwide prevalence of around 1%. Despite that many efforts had been made to characterize biomarkers in order to allow for biological testing for their diagnoses, these disorders are currently detected and classified only by clinical appraisal based on the Diagnostic and Statistical Manual of Mental Disorders. Olfactory neuroepithelium-derived neuronal precursors have been recently proposed as a model for biomarker characterization. Because of their peripheral localization, they are amenable to collection and suitable for being cultured and propagated in vitro. Olfactory neuroepithelial cells can be obtained by a non-invasive brush-exfoliation technique from neuropsychiatric patients and healthy subjects. Neuronal precursors isolated from these samples undergo in vitro the cytoskeletal reorganization inherent to the neurodevelopment process which has been described as one important feature in the etiology of both diseases. In this paper, we will review the current knowledge on microtubular organization in olfactory neurons of patients with SZ and with BD that may constitute specific cytoskeletal endophenotypes and their relation with alterations in L-type voltage-activated Ca(2+) currents. Finally, the potential usefulness of neuronal precursors for pharmacological screening will be discussed. PMID:26837043

  18. 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.

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

    Science.gov (United States)

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

    2015-01-01

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

  20. Co-translational formation and pharmacological characterization of beta1-adrenergic receptor/nanodisc complexes with different lipid environments.

    Science.gov (United States)

    Rues, Ralf-Bernhardt; Dötsch, Volker; Bernhard, Frank

    2016-06-01

    G protein-coupled receptors are of key significance for biomedical research. Streamlined approaches for their efficient recombinant production are of pivotal interest in order to explore their intrinsic conformational dynamics and complex ligand binding behavior. We have systematically optimized the co-translational association and folding of G protein-coupled receptors with defined membranes of nanodiscs by cell-free expression approaches. Each optimization step was quantified and the ligand binding active fraction of the receptor samples could drastically be improved. The strategy was exemplified with a stabilized and a non-stabilized derivative of the turkey beta1-adrenergic receptor. Systematic lipid screens with preformed nanodiscs revealed that generation of ligand binding active conformations of the analyzed beta1-adrenergic receptors strongly depends on lipid charge, flexibility and chain length. The lipid composition of the nanodisc membranes modulates the affinities to a variety of ligands of both receptor derivatives. In addition, the thermostabilization procedure had a significant impact on specific ligand affinities of the receptor and abolished or reduced the binding of certain antagonists. Both receptors were highly stable after purification with optimized nanodisc membranes. The procedure avoids any detergent contact of the receptors and sample production takes less than two days. Moreover, even non-stabilized receptors can be analyzed and their prior purification is not necessary for the formation of nanodisc complexes. The established process appears therefore to be suitable as a new platform for the functional or even structural characterization of recombinant G protein-coupled receptors associated with defined lipid environments. PMID:26922884

  1. Characterizing the spatial distribution of microhemorrhages resulting from Traumatic Brain Injury (TBI)

    Science.gov (United States)

    Li, Ningzhi; Chou, Yi-Yu; Shiee, Navid; Chan, Leighton; Pham, Dzung L.; Butman, John A.

    2014-03-01

    This study examines the spatial distribution of microhemorrhages defined using susceptibility weighted images (SWI) in 46 patients with Traumatic Brain Injury (TBI) and applying region of interest (ROI) analysis using a brain atlas. SWI and 3D T1-weighted images were acquired on a 3T clinical Siemens scanner. A neuroradiologist reviewed all SWI images and manually labeled all identified microhemorrhages. To characterize the spatial distribution of microhemorrhages in standard Montreal Neurological Institute (MNI) space, the T1-weighted images were nonlinearly registered to the MNI template. This transformation was then applied to the co-registered SWI images and to the microhemorrhage coordinates. The frequencies of microhemorrhages were determined in major structures from ROIs defined in the digital Talairach brain atlas and in white matter tracts defined using a diffusion tensor imaging atlas. A total of 629 microhemorrhages were found with an average of 22±42 (range=1-179) in the 24 positive TBI patients. Microhemorrhages mostly congregated around the periphery of the brain and were fairly symmetrically distributed, although a number were found in the corpus callosum. From Talairach ROI analysis, microhemorrhages were most prevalent in the frontal lobes (65.1%). Restricting the analysis to WM tracts, microhemorrhages were primarily found in the corpus callosum (56.9%).

  2. Pharmacological characterization of glycine-activated currents in HEK 293 cells expressing N-methyl-D-aspartate NR1 and NR3 subunits.

    Science.gov (United States)

    Smothers, C Thetford; Woodward, John J

    2007-08-01

    N-Methyl-D-aspartate (NMDA) receptors are important targets for drugs of abuse such as ethanol, toluene, and ketamine. Ligand-gated ion channels assembled from the NR1 and NR3 subunits have functional and pharmacological properties that are distinct from those of conventional NMDA receptors containing NR2 subunits. In the present study we used voltage-clamp electrophysiology to characterize excitatory glycine-activated receptors assembled from NR1, NR3A, and NR3B subunits expressed in human embryonic kidney (HEK) 293 cells. These glycine-activated receptors were not stimulated by glutamate or kainic acid and were resistant to magnesium block. A wide variety of NMDA receptor antagonists including d-2-amino-5-phosphonovaleric acid, ifenprodil, memantine, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate (MK-801) or acamprosate did not inhibit glycine-activated NR1/NR3A/NR3B receptors. Likewise, these receptors were not affected by antagonists of inhibitory glycine receptors or glycine transporters. The NMDA receptor glycine site agonist, d-serine, partially activated NR1/NR3A/NR3B receptors, whereas the antagonist, 5,7-dichloro-kynurenic acid, inhibited receptor currents. Conversely, the antagonist, 7-chlorokynurenic acid, and the partial agonist, R-(+)-3-amino-1-hydroxy-2-pyrrolidinone (HA-966), potentiated glycine-stimulated currents of these receptors. NR1/NR3A/NR3B receptor currents were inhibited by 10 to 21% by ethanol and toluene but were relatively insensitive to ketamine. Ethanol inhibition was enhanced in receptors expressing the NR1(L819A) mutant, whereas those containing NR1(F639A) or NR1(M813A) showed no change relative to the wild-type NR1. The results of this study indicate that coexpression of NR1, NR3A, and NR3B subunits in HEK 293 cells results in glycineactivated receptors with novel functional and pharmacological properties. PMID:17502428

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

    OpenAIRE

    Grzegorz eBulaj

    2014-01-01

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

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

    DEFF Research Database (Denmark)

    Andersson, A M; Gaardsvoll, H; Giladi, E; Dahl, B; Bock, Elisabeth Marianne

    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...

  5. Development and characterization of enteric-coated microparticles of biochanin A for their beneficial pharmacological potential in estrogen deficient-hypertension.

    Science.gov (United States)

    Sachdeva, Chinu; Mishra, Neeraj; Sharma, Saurabh

    2016-07-01

    Enteric coating of microparticles prevents stomach degradation and enhances oral bioavailability of poorly soluble drugs. Thus, in the present study, enteric-coated microparticle (ECMP) of biochanin A was developed and their pharmacological potential was investigated in hypertensive ovariectomized rats (Ovx-HT). Biochanin A microparticles were prepared by using ionic gelation method and coating was done by ethyl cellulose using coacervation phase separation method. Surface modified microparticles were characterized on the basis of size, entrapment efficiency, polydispersity index, FTIR and zeta potential and percentage of in vitro release. Ovariectomized rats were administered deoxy corticosterone acetate (40 mg/kg, s.c. twice a week for 6 weeks) salt to induce Ovx-HT. Hypertension was assessed in terms of increase in systolic, diastolic, mean arterial blood pressure, lipid peroxidation level, tumor necrosis factor-alpha (TNF-α) level and decrease in serum nitrite and reduced glutathione (GSH) level. The optimized formulation of ECMP has shown significant increase in oral bioavailability assessed by high-performance liquid chromatography. Furthermore, these ECMPs significantly reduced the mean arterial blood pressure, systolic and diastolic blood pressure, reduced lipid peroxidation and TNF-α level and significantly increased the serum nitrite and reduced GSH level in Ovx-HT rats. However, L-NAME significantly prevented the ameliorative effect of ECMP. Thus, it may be concluded that ECMP of biochanin A has shown delayed release capacity, increase in oral bioavailability up to 6 folds than plain biochanin A and exerts antihypertensive effect in ovariectomized rats possibly in an eNOS dependent manner. PMID:26599817

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

    Science.gov (United States)

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

    2014-12-01

    Brain cholinesterases from four fish (Arapaima gigas, Colossoma macropomum, Rachycentron canadum and Oreochromis niloticus) were characterized using specific substrates and selective inhibitors. Parameters of catalytic efficiency such as activation energy (AE), k(cat) and k(cat)/k(m) as well as rate enhancements produced by these enzymes were estimated by a method using crude extracts described here. Despite the BChE-like activity, specific substrate kinetic analysis pointed to the existence of only acetylcholinesterase (AChE) in brain of the species studied. Selective inhibition suggests that C. macropomum brain AChE presents atypical activity regarding its behavior in the presence of selective inhibitors. AE data showed that the enzymes increased the rate of reactions up to 10(12) in relation to the uncatalyzed reactions. Zymograms showed the presence of AChE isoforms with molecular weights ranging from 202 to 299 kDa. Values of k(cat) and k(cat)/k(m) were similar to those found in the literature. PMID:24980148

  7. Distribution and characterization of two non-opiod peptides with morphine modulating activity in brain

    International Nuclear Information System (INIS)

    Two peptides which are immunoreactive to Phe-Met-Arg-Phe-NH2 (FMRF-NH2) antiserum were purified from bovine brain, chemically characterized and synthesized. These two peptides, octapeptide octadecapeptide, can reduce rat tail flick latencies; octapeptide can also attenuate morphine induced analgesia. The distribution of these two peptides in brain was studied by radioimmunoassay. Octapeptide antiserum shows high affinity for synthetic octapeptide, PYY and FMRF-NH2. The antiserum is almost totally inactive to γ1-MSH. Octadecapeptide antiserum shows high affinity for octadecapeptide, some cross-reaction for the octapeptide (50%), γ1-MSH (10%) and FMRF-NH2 (0.01%). NPY, PYY, Met5-Enk-Arg-Phe and CCk are inactive. Octa and Octadecapeptide immunoreactivities are unevenly distributed in bovine brain. The highest concentrations (pmol g-1) are found in dorsal spinal cord (9.8 and 16.4 respectively), periaqueductal gray (8.6 and 6.8) and pons medulla (7.0 and 8.9); non-detectable amounts in cortex and cerebellum. The enrichment of these peptides in dorsal cord and PAG, areas important in opoid-mediated pain perception, suggest that they may play a role in mediating antinociception. Furthermore, using these two antisera, it is now possible to differentiate mammalian FMRF-NH2-like and NPY

  8. Distribution and characterization of two non-opiod peptides with morphine modulating activity in brain

    Energy Technology Data Exchange (ETDEWEB)

    Majane, E.A.; Yang, H.Y.T.

    1986-03-05

    Two peptides which are immunoreactive to Phe-Met-Arg-Phe-NH/sub 2/ (FMRF-NH/sub 2/) antiserum were purified from bovine brain, chemically characterized and synthesized. These two peptides, octapeptide octadecapeptide, can reduce rat tail flick latencies; octapeptide can also attenuate morphine induced analgesia. The distribution of these two peptides in brain was studied by radioimmunoassay. Octapeptide antiserum shows high affinity for synthetic octapeptide, PYY and FMRF-NH/sub 2/. The antiserum is almost totally inactive to ..gamma../sub 1/-MSH. Octadecapeptide antiserum shows high affinity for octadecapeptide, some cross-reaction for the octapeptide (50%), ..gamma../sub 1/-MSH (10%) and FMRF-NH/sub 2/ (0.01%). NPY, PYY, Met/sup 5/-Enk-Arg-Phe and CCk are inactive. Octa and Octadecapeptide immunoreactivities are unevenly distributed in bovine brain. The highest concentrations (pmol g/sup -1/) are found in dorsal spinal cord (9.8 and 16.4 respectively), periaqueductal gray (8.6 and 6.8) and pons medulla (7.0 and 8.9); non-detectable amounts in cortex and cerebellum. The enrichment of these peptides in dorsal cord and PAG, areas important in opoid-mediated pain perception, suggest that they may play a role in mediating antinociception. Furthermore, using these two antisera, it is now possible to differentiate mammalian FMRF-NH/sub 2/-like and NPY.

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

    Science.gov (United States)

    Lahmiri, Salim

    2016-08-01

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

  10. Characterization of atrial natriuretic peptide receptors in brain microvessel endothelial cells

    Science.gov (United States)

    Whitson, P. A.; Huls, M. H.; Sams, C. F.

    1991-01-01

    Atrial natriuretic peptide (ANP) binding and ANP-induced increases in cyclic guanosine monophosphate (cGMP) levels have been observed in brain microvessels (Chabrier et al., 1987; Steardo and Nathanson, 1987), suggesting that this fluid-regulating hormone may play a role in the fluid homeostasis of the brain. This study was initiated to characterize the ANP receptors in primary cultures of brain microvessel endothelial cells (BMECs). The apparent equilibrium dissociation constant, Kd, for ANP increased from 0.25 nM to 2.5 nM, and the number of ANP binding sites as determined by Scatchard analysis increased from 7,100 to 170,000 sites/cell between 2 and 10 days of culture following monolayer formation. Time- and concentration-dependent studies on the stimulation of cGMP levels by ANP indicated that guanylate cyclase-linked ANP receptors were present in BMECs. The relative abilities of ANP, brain natriuretic peptide (BNP), and a truncated analog of ANP containing amino acids 5-27 (ANP 5-27) to modulate the accumulation of cGMP was found to be ANP greater than BNP much greater than ANP 5-27. Affinity cross-linking with disuccinimidyl suberate and radiolabeled ANP followed by gel electrophoresis under reducing conditions demonstrated a single band corresponding to the 60-70 kD receptor, indicating the presence of the nonguanylate cyclase-linked ANP receptor. Radiolabeled ANP binding was examined in the presence of various concentrations of either ANP, BNP, or ANP 5-27 and suggested that a large proportion of the ANP receptors present in blood-brain barrier endothelial cells bind all of these ligands similarly. These data indicate both guanylate cyclase linked and nonguanylate cyclase linked receptors are present on BMECs and that a higher proportion of the nonguanylate cyclase linked receptors is expressed. This in vitro culture system may provide a valuable tool for the examination of ANP receptor expression and function in blood-brain barrier endothelial cells.

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1987-06-01

    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 (+)-/sup 3/H-NANM was found to be saturable at pharmacologically relevant doses, and represents a relatively small (10 - 22%) portion of total brain (+)-/sup 3/H-NANM concentrations. The in vivo binding of (+)-/sup 3/H-NANM was selectively displaced by (+)-NANM and PCP, and more sensitive to haloperidol and (+)-ketocyclazocine than the (-)-/sup 3/H-NANM site. The in vivo binding of (-)-/sup 3/H-NANM was selectively displaced by (-)-NANM, and more sensitive to naloxone and (-) ketocyclazocine than the (+)-/sup 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.

  13. The pharmacological features of bilirubin: the question of the century.

    Science.gov (United States)

    Zahir, Farhana; Rabbani, Gulam; Khan, Rizwan Hasan; Rizvi, Shamim J; Jamal, Mohammad Sarwar; Abuzenadah, Adel M

    2015-09-01

    This review looks at the toxicity and metabolism of bilirubin in terms of its pharmacological potential. Its role has gained importance as more research has revealed the functional significance and interrelationship between the gasotransmitters nitric oxide and carbon monoxide. The biological actions of bilirubin have mostly been characterized in the high micromolar range where toxic effects occur. However, it could also prove to be an important cytoprotector for brain tissue, which is inherently less equipped for antioxidant defense. Plasma bilirubin levels negatively correlate to a number of disease states. Higher levels of bilirubin that are still within the normal range provide a protective effect to the body. The effects on various disorders could be tested using controlled pharmacological upregulation of the molecule with animal models. At nanomolar concentrations, considerable benefits have been obtained when the molecule was delivered pharmacologically under in vitro or in vivo test conditions, particularly in neurodegenerative disorders and after tissue or organ transplantation. The induction of heme oxygenase-1 (HMOX-1) via the activation of nuclear factor erythroid 2-related factor or the use of bile pigments in the harvesting of diseased tissue are novel applications, and like every new therapy, should be used with caution. HMOX-1 is tissue specific, and in exceptional states, such as schizophrenia and specific types of renal disorder, the same therapy may have disastrous effects. PMID:26208389

  14. Neuroimaging correlates of pharmacological and psychological treatments for specific phobia.

    Science.gov (United States)

    Linares, Ila M; Chags, Marcos H N; Machado-de-Sousa, João P; Crippa, José A S; Hallak, Jaime E C

    2014-01-01

    Specific phobia is an anxiety disorder characterized by irrational fear and avoidance of specific things or situations, interfering significantly with the patients' daily life. Treatment for the disorder consists of both pharmacological and psychological approaches, mainly cognitive behavioral therapy (CBT). Neuroimaging techniques have been used in an attempt to improve our understanding of the neurobiology of SP and of the effects of treatment options available. This review describes the design and results of eight articles investigating the neuroimaging correlates of pharmacological and psychological treatments for SP. The studies show that CBT is effective in SP, leading to a reduction of anxiety symptoms that is accompanied by functional alterations in the brain. The results of pharmacological interventions for SP are less uniform, but suggest that the partial agonist of the NMDA (N-methyl D-aspartate) receptor DCS (D-cycloserine) can be used in combination with psychotherapy techniques for the achievement of quicker treatment response and that DCS modulates the function of structures implicated in the neurobiology of SP. Further research should explore the augmentation of CBT treatment with DCS in controlled trials. PMID:24923351

  15. Further in-vitro characterization of an implantable biosensor for ethanol monitoring in the brain

    OpenAIRE

    Secchi, Ottavio; Zinellu, Manuel; Spissu, Ylenia; Pirisinu, Marco; Bazzu, Gianfranco; Migheli, Rossana; Desole, Maria Speranza; O'Neill, Robert D.; Serra, Pier Andrea; Rocchitta, Gaia Giovanna Maria

    2013-01-01

    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 ...

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

    International Nuclear Information System (INIS)

    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

  17. Clinical feasibility of using mean apparent propagator (MAP) MRI to characterize brain tissue microstructure.

    Science.gov (United States)

    Avram, Alexandru V; Sarlls, Joelle E; Barnett, Alan S; Özarslan, Evren; Thomas, Cibu; Irfanoglu, M Okan; Hutchinson, Elizabeth; Pierpaoli, Carlo; Basser, Peter J

    2016-02-15

    Diffusion tensor imaging (DTI) is the most widely used method for characterizing noninvasively structural and architectural features of brain tissues. However, the assumption of a Gaussian spin displacement distribution intrinsic to DTI weakens its ability to describe intricate tissue microanatomy. Consequently, the biological interpretation of microstructural parameters, such as fractional anisotropy or mean diffusivity, is often equivocal. We evaluate the clinical feasibility of assessing brain tissue microstructure with mean apparent propagator (MAP) MRI, a powerful analytical framework that efficiently measures the probability density function (PDF) of spin displacements and quantifies useful metrics of this PDF indicative of diffusion in complex microstructure (e.g., restrictions, multiple compartments). Rotation invariant and scalar parameters computed from the MAP show consistent variation across neuroanatomical brain regions and increased ability to differentiate tissues with distinct structural and architectural features compared with DTI-derived parameters. The return-to-origin probability (RTOP) appears to reflect cellularity and restrictions better than MD, while the non-Gaussianity (NG) measures diffusion heterogeneity by comprehensively quantifying the deviation between the spin displacement PDF and its Gaussian approximation. Both RTOP and NG can be decomposed in the local anatomical frame for reference determined by the orientation of the diffusion tensor and reveal additional information complementary to DTI. The propagator anisotropy (PA) shows high tissue contrast even in deep brain nuclei and cortical gray matter and is more uniform in white matter than the FA, which drops significantly in regions containing crossing fibers. Orientational profiles of the propagator computed analytically from the MAP MRI series coefficients allow separation of different fiber populations in regions of crossing white matter pathways, which in turn improves our

  18. Neurocomputational models of brain disorders

    NARCIS (Netherlands)

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

    2011-01-01

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

  19. 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

  20. Conus venom peptide pharmacology.

    Science.gov (United States)

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

    2012-04-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  2. 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.

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

    Directory of Open Access Journals (Sweden)

    Xiang-Xue Zhou

    2014-01-01

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

  4. Pharmacological disruption of maladaptive memory.

    Science.gov (United States)

    Taylor, Jane R; Torregrossa, Mary M

    2015-01-01

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

  5. Pharmacology Information System Ready

    Science.gov (United States)

    Chemical and Engineering News, 1973

    1973-01-01

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

  6. Curriculum Guidelines for Pharmacology.

    Science.gov (United States)

    Shaw, David H.; And Others

    1990-01-01

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

  7. Pharmacology of cannabinoids.

    Science.gov (United States)

    Grotenhermen, Franjo

    2004-01-01

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

  8. Development and characterization of non-resonant multiphoton photoacoustic spectroscopy (NMPPAS) for brain tumor margining

    Science.gov (United States)

    Dahal, Sudhir

    ) and healthy tissue with over 99% accuracy. NMPPAS spectral features showed evident differences between tumor and healthy tissues, and ratiometric analysis ensured that only a few wavelengths could be used for excitation instead of using numerous wavelength excitations to create spectra. This process would significantly reduce the analysis time while maintaining the same degree of accuracy. Tissue phantoms were fabricated in order to characterize the properties of NMPPAS. Scattering particles were doped into the phantoms to simulate their light scattering properties to real tissues. This allowed for better control over shape, size, reproducibility and doping in the sample while maintaining the light-tissue interaction properties of real tissue. To make NMPPAS viable for clinical applications, the technique was characterized to determine the spatial (lateral and longitudinal) resolution, depth of penetration and its ability to image in three-dimension through layers of tissue. Both resolutions were determined to be near-cellular level resolution (50-70 microm), obtained initially with the aid of the technique of multiphoton fluorescence, and later verified using NMPPAS imaging. Additionally, the maximum depth of penetration and detection was determined to be about 1.4cm, making the technique extremely suitable to margin tumors from underlying tissues in the brain. The capability of NMPPAS to detect and image layers that lie beneath other structures and blood vessels was also investigated. Three-dimensional images were obtained for the first time using NMPPAS. The images were obtained from different depths and structures were imaged through other layers of existing structures in the sample. This verified that NMPPAS was capable of detecting and imaging structures that lie embedded within the tissues. NMPPAS images of embedded structures were also obtained with the presence of hemoglobin, which is potentially the largest source of background in blood-perfused tissues

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

    Science.gov (United States)

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

    2013-10-01

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

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

    Science.gov (United States)

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

    2010-10-01

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

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

    International Nuclear Information System (INIS)

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

  12. 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.

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

    Directory of Open Access Journals (Sweden)

    Pooja Attri

    2011-01-01

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

  14. Statistics in Pharmacology

    OpenAIRE

    Spina, D.

    2007-01-01

    Statistics is an important tool in pharmacological research that is used to summarize (descriptive statistics) experimental data in terms of central tendency (mean or median) and variance (standard deviation, standard error of the mean, confidence interval or range) but more importantly it enables us to conduct hypothesis testing. This is of particular importance when attempting to determine whether the pharmacological effect of one drug is superior to another which clearly has implications f...

  15. Who needs pharmacologic therapy?

    Directory of Open Access Journals (Sweden)

    Christopher Porterfield; Rohit Malhotra

    2014-06-01

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

  16. Characterization and location of secretory phospholipase A2 groups IIE, V, and X in the rat brain

    DEFF Research Database (Denmark)

    Kolko, M.; Christoffersen, Nanna Rønbjerg; Barreiro, S.G.;

    2006-01-01

    cloned and characterized in various tissues and receptors have been identified. In the nervous system, sPLA2 groups IB, IIA, IIE, IIF, V, and XII have been identified, and binding sites for sPLA2 have been found. Here, we report sPLA2-IIE and sPLA2-X in rat brain as well as in neurons in primary culture....... We furthermore confirm the presence of sPLA2-V in rat brain and demonstrate the presence of sPLA2-V in primary neuronal cultures. The distribution of sPLA2-IIE, V, and -X seems to be mainly neuronal, with the highest abundance occurring in the cerebral cortex and hippocampus. We also find that sPLA2......-IIE, -V, and -X are differentially induced by kainic acid. This study supports the concept that sPLA2 heterogeneity in brain is functionally relevant and responsive to seizures....

  17. Non Pharmacological Cognitive Enhancers - Current Perspectives.

    Science.gov (United States)

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

    2015-07-01

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

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

    International Nuclear Information System (INIS)

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

  19. 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...... vertebrates, the locust brain–barrier function is morphologically confined to one specific cell layer and by using a whole-brain ex vivo drug exposure technique our locust model may retain the major cues that maintain and modulate the physiological function of the brain barrier. We show that the locust model...

  20. Pharmacological and clinical properties of curcumin

    Directory of Open Access Journals (Sweden)

    Huang S

    2011-06-01

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

  1. Eburnamine derivatives and the brain.

    Science.gov (United States)

    Vas, Adám; Gulyás, Balázs

    2005-11-01

    The Apocynaceae plant family contains a great number of so called eburnamine-vincamine alkaloids. Quite a few of these alkaloids exert varied pharmacological activities on the cell multiplication, cardiovascular system, and brain functions. Many derivatives were also synthesized to find pharmacologically active compounds better characterized and safer to be administered than the natural plant alkaloids themselves. We concentrate on the eburnamine structures with cerebral activities in this review. Vincamine, vinburnine, vindeburnol, apovincaminate, and vinpocetine (cis-ethyl-apovincaminate) all share modulatory effects on brain circulation and neuronal homeostasis, bear antihypoxic and neuroprotective potencies to various degrees. The most eminent compound of this class of alkaloids is vinpocetine. Since its introduction to the market as a neuroprotective agent many non clinical and clinical studies proved vinpocetine's effects on calmodulin dependent phosphodiesterase E1, on sodium, calcium channels, peripheral benzodiazepine receptor, and glutamate receptors as well as its clinical usefulness in the treatment of post-ischaemic stroke disease states and various disorders of cerebrovascular origin. Lately, positron emission tomography studies proved that vinpocetine has a rapid uptake in the primate and human brain with a heterogeneous distribution pattern (preference areas: thalamus, basal ganglia, and visual cortex) both after intravenous and oral administration. Vinpocetine exerts beneficial effects in cerebral glucose metabolism and regional cerebral blood flow in chronic post-stroke patients. PMID:16158388

  2. 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.

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

    OpenAIRE

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

    2016-01-01

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

  4. Understanding paroxysmal sympathetic hyperactivity after traumatic brain injury

    OpenAIRE

    Meyer, Kimberly S.

    2014-01-01

    Background: Paroxysmal sympathetic hyperactivity (PSH) is a condition occurring in a small percentage of patients with severe traumatic brain injury (TBI). It is characterized by a constellation of symptoms associated with excessive adrenergic output, including tachycardia, hypertension, tachypnea, and diaphoresis. Diagnosis is one of exclusion and, therefore, is often delayed. Treatment is aimed at minimizing triggers and pharmacologic management of symptoms. Methods: A literature review...

  5. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets

    Science.gov (United States)

    Santagata, Sandro; Cahill, Daniel P.; Taylor-Weiner, Amaro; Jones, Robert T.; Van Allen, Eliezer M.; Lawrence, Michael S.; Horowitz, Peleg M.; Cibulskis, Kristian; Ligon, Keith L.; Tabernero, Josep; Seoane, Joan; Martinez-Saez, Elena; Curry, William T.; Dunn, Ian F.; Paek, Sun Ha; Park, Sung-Hye; McKenna, Aaron; Chevalier, Aaron; Rosenberg, Mara; Barker, Frederick G.; Gill, Corey M.; Van Hummelen, Paul; Thorner, Aaron R.; Johnson, Bruce E.; Hoang, Mai P.; Choueiri, Toni K.; Signoretti, Sabina; Sougnez, Carrie; Rabin, Michael S.; Lin, Nancy U.; Winer, Eric P.; Stemmer-Rachamimov, Anat; Meyerson, Matthew; Garraway, Levi; Gabriel, Stacey; Lander, Eric S.; Beroukhim, Rameen; Batchelor, Tracy T.; Baselga, Jose; Louis, David N.

    2016-01-01

    Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases. PMID:26410082

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

    Science.gov (United States)

    Hipp, Dustin M; Ely, E Wesley

    2012-01-01

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

  7. 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.

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

    Science.gov (United States)

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

    2016-01-01

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

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

    DEFF Research Database (Denmark)

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

    2001-01-01

    Homobaclofen (5-amino-3-(4-chlorophenyl) pentanoic acid) is a homologue of the classical GABA(B) receptor agonist baclofen. In a recent study, the two enantiomers of this compound were tested in a GABA(B) receptor selective [3H]gamma-aminobutyric acid ([3H]GABA) binding assay using rat brain...... 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...... between the data obtained in this study and those from the guinea pig ileum model could be ascribed to differences in amino acid sequence or receptor splicing of GABA(B) receptors between the two species. Another explanation for the observation is the possible existence of a novel yet uncloned GABA...

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

    International Nuclear Information System (INIS)

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

  11. 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.

  12. Biomedical Science, Unit IV: The Nervous System in Health and Medicine. The Nervous System; Disorders of the Brain and Nervous System; Application of Computer Science to Diagnosis; Drugs and Pharmacology; The Human Senses; Electricity. Student Text. Revised Version, 1976.

    Science.gov (United States)

    Biomedical Interdisciplinary Curriculum Project, Berkeley, CA.

    This unit consists of four sequences. The first considers the brain, the nervous system, and disorders of the brain. The second sequence deals with applications of the computer in diagnosis of brain disorders along with mathematical and statistical principles used in health applications. The third sequence is concerned with drugs and their effects…

  13. Integrated proteomic platforms for the comparative characterization of medulloblastoma and pilocytic astrocytoma pediatric brain tumors: a preliminary study.

    Science.gov (United States)

    Martelli, Claudia; Iavarone, Federica; D'Angelo, Luca; Arba, Morena; Vincenzoni, Federica; Inserra, Ilaria; Delfino, Daniela; Rossetti, Diana Valeria; Caretto, Marta; Massimi, Luca; Tamburrini, Gianpiero; Di Rocco, Concezio; Caldarelli, Massimo; Messana, Irene; Castagnola, Massimo; Sanna, Maria Teresa; Desiderio, Claudia

    2015-06-01

    A top-down/bottom-up integrated proteomic approach based on LC-MS and 2-DE analysis was applied for comparative characterization of medulloblastoma and pilocytic astrocytoma posterior cranial fossa pediatric brain tumor tissues. Although rare, primary brain tumors are the most frequent solid tumors in the pediatric age. Among them the medulloblastoma is the prevalent malignant tumor in childhood while pilocytic astrocytoma is the most common, rarely showing a malignant progression. Due to the limited availability of this kind of sample, the study was applied to pooled tumor tissues for a preliminary investigation. The results showed different proteomic profiles of the two tumors and evidenced interesting differential expression of several proteins and peptides. Top-down proteomics of acid-soluble fractions of brain tumor homogenates ascribed a potential biomarker role of malignancy to β- and α-thymosins and their truncated proteoforms and to C-terminal truncated (des-GG) ubiquitin, resulting exclusively detected or over-expressed in the highly malignant medulloblastoma. The bottom-up proteomics of the acid-soluble fraction identified several proteins, some of them in common with 2-DE analysis of acid-insoluble pellets. Peroxiredoxin-1, peptidyl-prolyl cis-trans isomerase A, triosephosphate isomerase, pyruvate kinase PKM, tubulin beta and alpha chains, heat shock protein HSP-90-beta and different histones characterized the medulloblastoma while the Ig kappa chain C region, serotransferrin, tubulin beta 2A chain and vimentin the pilocytic astrocytoma. The two proteomic strategies, with their pros and cons, well complemented each other in characterizing the proteome of brain tumor tissues and in disclosing potential disease biomarkers to be validated in a future study on individual samples of both tumor histotypes. PMID:25909245

  14. 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.

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

    OpenAIRE

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

    2012-01-01

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

  16. Pharmacologic Therapies in Anticoagulation.

    Science.gov (United States)

    Ferreira, Joana Lima; Wipf, Joyce E

    2016-07-01

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

  17. Mitochondrial biogenesis: pharmacological approaches.

    Science.gov (United States)

    Valero, Teresa

    2014-01-01

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

  18. 1H chemical shift imaging characterization of human brain tumor and edema

    International Nuclear Information System (INIS)

    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) 1H chemical shift imaging results at different repetition times (TR=1500 and 5000 ms; T1: n=19) and echo times (TE=135 and 270 ms; T2: n=7). Metabolite T1 and T2 relaxation times in unaffected brain tissue corresponded with those published for healthy volunteers. T2 relaxation times were reduced in tumor (choline, N-acetyl aspartate) and edema (choline, creatine) compared with unaffected brain tissue (p1H chemical shift imaging is most suited in the use of choline elevation as tumor marker. (orig.)

  19. In vivo modeling and molecular characterization: a path towards targeted therapy of melanoma brain metastasis

    Directory of Open Access Journals (Sweden)

    AvitalGaziel-Sovran

    2013-05-01

    Full Text Available Brain metastasis from melanoma remains mostly incurable and the main cause of death from the disease. Early stage clinical trials and case studies show some promise for targeted therapies in the treatment of melanoma brain metastasis. However, the progression-free survival for currently available therapies, although significantly improved, is still very short. The development of new potent agents to eradicate melanoma brain metastasis relies on the elucidation of the molecular mechanisms that drive melanoma cells to reach and colonize the brain. The discovery of such mechanisms depends heavily on pre-clinical models that enable the testing of candidate factors and therapeutic agents in vivo. In this review we summarize the effects of available targeted therapies on melanoma brain metastasis in the clinic. We provide an overview of existing pre-clinical models to study the disease and discuss specific molecules and mechanisms reported to modulate different aspects of melanoma brain metastasis and finally, by integrating both clinical and basic data, we summarize both opportunities and challenges currently presented to researchers in the field.

  20. Social Pharmacology: Expanding horizons

    Directory of Open Access Journals (Sweden)

    Rituparna Maiti

    2014-01-01

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

  1. 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...

  2. Molecular pharmacology of human NMDA receptors

    DEFF Research Database (Denmark)

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

    2012-01-01

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

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

    Science.gov (United States)

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

    2015-07-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-06-01

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

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

    International Nuclear Information System (INIS)

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

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

    International Nuclear Information System (INIS)

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

  7. Brain effects of melanocortins.

    Science.gov (United States)

    Bertolini, Alfio; Tacchi, Raffaella; Vergoni, Anna Valeria

    2009-01-01

    The melanocortins (alpha, beta and gamma-melanocyte-stimulating hormones: MSHs; adrenocorticotrophic hormone: ACTH), a family of pro-opiomelanocortin (POMC)-derived peptides having in common the tetrapeptide sequence His-Phe-Arg-Trp, have progressively revealed an incredibly wide range of extra-hormonal effects, so to become one of the most promising source of innovative drugs for many, important and widespread pathological conditions. The discovery of their effects on some brain functions, independently made by William Ferrari and David De Wied about half a century ago, led to the formulation of the term "neuropeptide" at a time when no demonstration of the actual production of peptide molecules by neurons, in the brain, was still available, and there were no receptors characterized for these molecules. In the course of the subsequent decades it came out that melanocortins, besides inducing one of the most complex and bizarre behavioural syndromes (excessive grooming, crises of stretchings and yawnings, repeated episodes of spontaneous penile erection and ejaculation, increased sexual receptivity), play a key role in functions of fundamental physiological importance as well as impressive therapeutic effects in different pathological conditions. If serendipity had been an important determinant in the discovery of the above-mentioned first-noticed extra-hormonal effects of melanocortins, many of the subsequent discoveries in the pharmacology of these peptides (feeding inhibition, shock reversal, role in opiate tolerance/withdrawal, etc.) have been the result of a planned research, aimed at testing the "pro-nociceptive/anti-nociceptive homeostatic system" hypothesis. The discovery of melanocortin receptors, and the ensuing synthesis of selective ligands with agonist or antagonist activity, is generating completely innovative drugs for the treatment of a potentially very long list of important and widespread pathological conditions: sexual impotence, frigidity

  8. Kinetic characterization of hexokinase isoenzymes from glioma cells: Implications for FDG imaging of human brain tumors

    Energy Technology Data Exchange (ETDEWEB)

    Muzi, Mark E-mail: muzi@u.washington.edu; Freeman, Scott D.; Burrows, Robert C.; Wiseman, Robert W.; Link, Jeanne M.; Krohn, Kenneth A.; Graham, Michael M.; Spence, Alexander M

    2001-02-01

    Quantitative imaging of glucose metabolism of human brain tumors with PET utilizes 2-[{sup 18}F]-fluorodeoxy-D-glucose (FDG) and a conversion factor called the lumped constant (LC), which relates the metabolic rate of FDG to glucose. Since tumors have greater uptake of FDG than would be predicted by the metabolism of native glucose, the characteristic of tumors that governs the uptake of FDG must be part of the LC. The LC is chiefly determined by the phosphorylation ratio (PR), which is comprised of the kinetic parameters (Km and Vmax) of hexokinase (HK) for glucose as well as for FDG (LC {proportional_to} (Km{sub glc} {center_dot} Vmax{sub FDG})/(Km{sub FDG} {center_dot} Vmax{sub glc})). The value of the LC has been estimated from imaging studies, but not validated in vitro from HK kinetic parameters. In this study we measured the kinetic constants of bovine and 36B-10 rat glioma HK I (predominant in normal brain) and 36B-10 glioma HK II (increased in brain tumors) for the hexose substrates glucose, 2-deoxy-D-glucose (2DG) and FDG. Our principal results show that the KmGlc < KmFDG << Km2DG and that PR2DG < PRFDG. The FDG LC calculated from our kinetic parameters for normal brain, possessing predominantly HK I, would be higher than the normal brain LC predicted from animal studies using 2DG or human PET studies using FDG or 2DG. These results also suggest that a shift from HK I to HK II, which has been observed to increase in brain tumors, would have little effect on the value of the tumor LC.

  9. Kinetic characterization of hexokinase isoenzymes from glioma cells: Implications for FDG imaging of human brain tumors

    International Nuclear Information System (INIS)

    Quantitative imaging of glucose metabolism of human brain tumors with PET utilizes 2-[18F]-fluorodeoxy-D-glucose (FDG) and a conversion factor called the lumped constant (LC), which relates the metabolic rate of FDG to glucose. Since tumors have greater uptake of FDG than would be predicted by the metabolism of native glucose, the characteristic of tumors that governs the uptake of FDG must be part of the LC. The LC is chiefly determined by the phosphorylation ratio (PR), which is comprised of the kinetic parameters (Km and Vmax) of hexokinase (HK) for glucose as well as for FDG (LC ∝ (Kmglc · VmaxFDG)/(KmFDG · Vmaxglc). The value of the LC has been estimated from imaging studies, but not validated in vitro from HK kinetic parameters. In this study we measured the kinetic constants of bovine and 36B-10 rat glioma HK I (predominant in normal brain) and 36B-10 glioma HK II (increased in brain tumors) for the hexose substrates glucose, 2-deoxy-D-glucose (2DG) and FDG. Our principal results show that the KmGlc < KmFDG << Km2DG and that PR2DG < PRFDG. The FDG LC calculated from our kinetic parameters for normal brain, possessing predominantly HK I, would be higher than the normal brain LC predicted from animal studies using 2DG or human PET studies using FDG or 2DG. These results also suggest that a shift from HK I to HK II, which has been observed to increase in brain tumors, would have little effect on the value of the tumor LC

  10. Characterization of Task-free and Task-performance Brain States via Functional Connectome Patterns

    OpenAIRE

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

    2013-01-01

    Both resting state fMRI (R-fMRI) and task-based fMRI (T-fMRI) have been widely used to study the functional activities of the human brain during task-free and task-performance periods, respectively. However, due to the difficulty in strictly controlling the participating subject's mental status and their cognitive behaviors during R-fMRI/T-fMRI scans, it has been challenging to ascertain whether or not an R-fMRI/T-fMRI scan truly reflects the participant's functional brain states during task-...

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

    Science.gov (United States)

    Diamond, Adele

    2009-01-01

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

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

    DEFF Research Database (Denmark)

    Haase, Bianca; Humphray, Sean J; Lyer, Stefan; Renner, Marcus; Poustka, Annemarie; Mollenhauer, Jan; Leeb, Tosso

    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...

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  14. Evaluation of sliding window correlation performance for characterizing dynamic functional connectivity and brain states.

    Science.gov (United States)

    Shakil, Sadia; Lee, Chin-Hui; Keilholz, Shella Dawn

    2016-06-01

    A promising recent development in the study of brain function is the dynamic analysis of resting-state functional MRI scans, which can enhance understanding of normal cognition and alterations that result from brain disorders. One widely used method of capturing the dynamics of functional connectivity is sliding window correlation (SWC). However, in the absence of a "gold standard" for comparison, evaluating the performance of the SWC in typical resting-state data is challenging. This study uses simulated networks (SNs) with known transitions to examine the effects of parameters such as window length, window offset, window type, noise, filtering, and sampling rate on the SWC performance. The SWC time course was calculated for all node pairs of each SN and then clustered using the k-means algorithm to determine how resulting brain states match known configurations and transitions in the SNs. The outcomes show that the detection of state transitions and durations in the SWC is most strongly influenced by the window length and offset, followed by noise and filtering parameters. The effect of the image sampling rate was relatively insignificant. Tapered windows provide less sensitivity to state transitions than rectangular windows, which could be the result of the sharp transitions in the SNs. Overall, the SWC gave poor estimates of correlation for each brain state. Clustering based on the SWC time course did not reliably reflect the underlying state transitions unless the window length was comparable to the state duration, highlighting the need for new adaptive window analysis techniques. PMID:26952197

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

    CERN Document Server

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

    2013-01-01

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

  16. Overview of safety pharmacology.

    Science.gov (United States)

    Goineau, Sonia; Lemaire, Martine; Froget, Guillaume

    2013-01-01

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

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

    Science.gov (United States)

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

    2016-05-18

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

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

    Science.gov (United States)

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

    2005-09-12

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

  19. 7.0-T magnetic resonance imaging characterization of acute blood-brain-barrier disruption achieved with intracranial irreversible electroporation.

    Directory of Open Access Journals (Sweden)

    Paulo A Garcia

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

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

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

    International Nuclear Information System (INIS)

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

  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. 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.

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

    International Nuclear Information System (INIS)

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

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

    OpenAIRE

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

    2008-01-01

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

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

    Science.gov (United States)

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

    2016-10-15

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

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

    Directory of Open Access Journals (Sweden)

    Fredholm Merete

    2007-09-01

    Full Text Available Abstract Background The transmembrane presenilin (PSEN proteins, PSEN1 and PSEN2, have been proposed to be the catalytic components of the γ-secretase protein complex, which is an intramembranous multimeric protease involved in development, cell regulatory processes, and neurodegeneration in Alzheimer's disease. Here we describe the sequencing, chromosomal mapping, and polymorphism analysis of PSEN1 and PSEN2 in the domestic pig (Sus scrofa domesticus. Results The porcine presenilin proteins showed a high degree of homology over their entire sequences to the PSENs from mouse, bovine, and human. PSEN1 and PSEN2 transcription was examined during prenatal development of the brain stem, hippocampus, cortex, basal ganglia, and cerebellum at embryonic days 60, 80, 100, and 114, which revealed distinct temporal- and tissue-specific expression profiles. Furthermore, immunohistochemical analysis of PSEN1 and PSEN2 showed similar localization of the proteins predominantly in neuronal cells in all examined brain areas. Conclusion The data provide evidence for structural and functional conservation of PSENs in mammalian lineages, and may suggest that the high sequence similarity and colocalization of PSEN1 and PSEN2 in brain tissue reflect a certain degree of functional redundancy. The data show that pigs may provide a new animal model for detailed analysis of the developmental functions of the PSENs.

  8. 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)

    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

  9. Clinical pharmacology and malaria.

    Science.gov (United States)

    Breckenridge, A M; Winstanley, P A

    1997-10-01

    The role of clinical pharmacology in improving the prevention and treatment of malaria is reviewed. A series of general and specific issues is discussed, concentrating on risk-benefit and cost-effectiveness. The techniques of clinical pharmacokinetics play an important role in the optimal use of drugs and this is illustrated by studies on quinine and proguanil. In discussing amodiaquine toxicity, the role of the pharmacologist and the chemist in designing out drug toxicity lends hope for producing a new generation of antimalarial drugs. PMID:9625927

  10. Pharmacologic treatment of paraphilias.

    Science.gov (United States)

    Assumpção, Alessandra Almeida; Garcia, Frederico Duarte; Garcia, Heloise Delavenne; Bradford, John M W; Thibaut, Florence

    2014-06-01

    The treatment of paraphilias remains a challenge in the mental health field. Combined pharmacologic and psychotherapeutic treatment is associated with better efficacy. The gold standard treatment of severe paraphilias in adult males is antiandrogen treatment with cognitive behavioral therapy. Selective serotonin reuptake inhibitors have been used in mild types of paraphilia and in cases of sexual compulsions and juvenile paraphilias. Antiandrogen treatments seem to be effective in severe paraphilic subjects committing sexual offenses. In particular, gonadotropin-releasing hormone analogs have shown high efficacy working in a similar way to physical castration but being reversible at any time. Treatment recommendations, side effects, and contraindications are discussed. PMID:24877704

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2005-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  13. Non-pharmacological treatments for COPD.

    Science.gov (United States)

    Mulhall, Patrick; Criner, Gerard

    2016-07-01

    Chronic obstructive pulmonary disease (COPD) affects roughly 10% of the global population and is growing in prevalence annually. COPD is characterized by progressive non-reversible narrowing of airways mainly due to cigarette smoking. Therapeutic interventions aimed at altering this progressive disease course can largely be grouped into pharmacological or non-pharmacological therapies. The focus of this paper is on the non-pharmacological aspects of COPD management, reviewing the current literature to provide an evidence-based management approach. Non-pharmacological therapies reviewed in this article include the implementation of comprehensive care models utilizing a coordinated multidisciplinary team, tele-monitoring and patient-centred approach to optimize COPD care and improve compliance. Preventing progression of COPD via smoking cessation remains of paramount importance, and newer therapeutic options including electronic cigarettes show promise in small studies as cessation aids. COPD has systemic manifestations that can be ameliorated with the enrollment in pulmonary rehabilitation programmes, which focus on exercise endurance to improve dyspnoea and quality of life. Advanced therapeutics for COPD includes lung volume reduction surgery for a pre-specified cohort and minimally invasive bronchoscopic valves that in recent reviews show promise. Lastly, patients on maximal COPD therapy with progressive disease can be referred for lung transplantation; however, this often requires a highly selected and motivated patient and care team. Survival rates for lung transplantation are improving; thus, this procedure remains a viable option as more expertise and experience are gained. PMID:27099216

  14. Characterization of specific binding sites for [3H](d)-N-allylnormetazocine in rat brain membranes

    International Nuclear Information System (INIS)

    Binding of [3H](d)-N-allylnormetazocine ([3H](d)-NANM) to rat brain membranes is stereospecific, reversible, and saturable (Bmax . 260 fmol/mg of protein) and manifests moderately high affinity (Kd . 20 nM). The rank order of potency among opioidbenzomorphans and phencyclidine (PCP) analogs for competition for [3H](d)-NANM-binding sites is as follows: (d)-NANM . PCP-3-OH greater than (d)-cyclazocine greater than N-ethylphenylcyclohexylamine greater than PCP greater than (l)-cyclazocine . dextrorphan greater than (d/l)-ethylketocyclazocine greater than (d/l)-bremazocine greater than (1)-NANM greater than 1-phenylcyclohexylamine greater than levorphanol. Other opioid ligands, relatively selective for each of the types of opioid binding sites other than sigma, such as morphine (mu), H-Tyr-D-Ala(Me)Phe-NH-CH2-OH (mu), D-Ala2-D-Leu5-enkephalin (delta), tifluadom (kappa), and U 50488 (kappa) as well as etorphine and naloxone were all unable to compete with [3H](d)-NANM for specific binding even at a concentration of 1 microM. Regional distribution studies of [3H](d)-NANM-binding sites show high density in the hippocampus, thalamus, hypothalamus, and amygdala and low density in cerebellum and nonfrontal neocortex membranes of the rat brain. These binding sites are very sensitive to protein-modifying enzymes and reagents such as trypsin and N-ethylmaleimide and to heat denaturation. These results provide direct biochemical evidence for the existence of distinct (d)-NANM-binding sites in rat brain

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

    OpenAIRE

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

    1991-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  17. 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.

  18. Characterization of Selenoprotein M and Its Response to Selenium Deficiency in Chicken Brain.

    Science.gov (United States)

    Huang, Jia-Qiang; Ren, Fa-Zheng; Jiang, Yun-Yun; Lei, XinGen

    2016-04-01

    Selenoprotein M (SelM) may function as thiol disulfide oxidoreductase that participates in the formation of disulfide bonds and can be implicated in calcium responses. SelM may have a functional role in catalyzing free radicals and has been associated with Alzheimer's disease (AD). However, studies of SelM in chicken remain very limited. In this study, two groups of day-old broiler chicks (n = 40/group) were fed a corn-soy basal diet (BD, 13 μg Se/kg) and BD supplemented with Se (as sodium selenite) at 0.3 mg/kg. The brain was collected at 14, 21, 28, and 42 days of age. We performed a sequence analysis and predicted the structure and function of SelM. We also investigated the effects of Se deficiency on the expression of Selt, Selw, and Selm and the Se status in the chicken brain. The results show that Se deficiency induced the lower (P chicken, which might shed light on the role of SelM in human neurodegenerative disease. More studies are needed to confirm our conclusion. PMID:26315306

  19. 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

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

    Directory of Open Access Journals (Sweden)

    Sergey Shityakov

    2015-06-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  2. Thalamic Kv7 channels: pharmacological properties and activity control during noxious signal processing

    Science.gov (United States)

    Cerina, Manuela; Szkudlarek, Hanna J; Coulon, Philippe; Meuth, Patrick; Kanyshkova, Tatyana; Nguyen, Xuan Vinh; Göbel, Kerstin; Seidenbecher, Thomas; Meuth, Sven G; Pape, Hans-Christian; Budde, Thomas

    2015-01-01

    Background and Purpose The existence of functional Kv7 channels in thalamocortical (TC) relay neurons and the effects of the K+-current termed M-current (IM) on thalamic signal processing have long been debated. Immunocytochemical evidence suggests their presence in this brain region. Therefore, we aimed to verify their existence, pharmacological properties and function in regulating activity in neurons of the ventrobasal thalamus (VB). Experimental Approach Characterization of Kv7 channels was performed by combining in vitro, in vivo and in silico techniques with a pharmacological approach. Retigabine (30 μM) and XE991 (20 μM), a specific Kv7 channel enhancer and blocker, respectively, were applied in acute brain slices during electrophysiological recordings. The effects of intrathalamic injection of retigabine (3 mM, 300 nL) and/or XE991 (2 mM, 300 nL) were investigated in freely moving animals during hot-plate tests by recording behaviour and neuronal activity. Key Results Kv7.2 and Kv7.3 subunits were found to be abundantly expressed in TC neurons of mouse VB. A slow K+-current with properties of IM was activated by retigabine and inhibited by XE991. Kv7 channel activation evoked membrane hyperpolarization, a reduction in tonic action potential firing, and increased burst firing in vitro and in computational models. Single-unit recordings and pharmacological intervention demonstrated a specific burst-firing increase upon IM activation in vivo. A Kv7 channel-mediated increase in pain threshold was associated with fewer VB units responding to noxious stimuli, and increased burst firing in responsive neurons. Conclusions and Implications Kv7 channel enhancement alters somatosensory activity and may reflect an anti-nociceptive mechanism during acute pain processing. PMID:25684311

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

    International Nuclear Information System (INIS)

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

  4. 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

    OpenAIRE

    Rhoo, Kun Hyoe; Granger, Megan; Sur, Joynita; Feng, Changyong; Gelbard, Harris A.; Dewhurst, Stephen; Polesskaya, Oksana

    2014-01-01

    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 thi...

  5. Brain abscess: Current management

    OpenAIRE

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

    2013-01-01

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

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

    DEFF Research Database (Denmark)

    Madsen, Lone B; Thomsen, Bo; Larsen, Knud Erik; Bendixen, Christian; Holm, Ida E; Fredholm, Merete; Jørgensen, Arne L; Nielsen, Anders L; Nielsen, Anders Lade

    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......'s disease. Here we describe the sequencing, chromosomal mapping, and polymorphism analysis of PSEN1 and PSEN2 in the domestic pig (Sus scrofa domesticus). Conclusion: The data provide evidence for structural and functional conservation of PSENs in mammalian lineages, and may suggest that the high sequence...... 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....

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

    Science.gov (United States)

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

    1994-06-15

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

  8. 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.

  9. Pharmacology of antihypertensive drugs.

    Science.gov (United States)

    Pepper, G A

    1999-01-01

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

  10. Pharmacology of Quercus infectoria.

    Science.gov (United States)

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

    1976-12-01

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

  11. PHARMACOLOGICAL IMPORTANCE OF CITRUS FRUITS

    Directory of Open Access Journals (Sweden)

    Amita Tomar *, Mridula Mall and Pragya Rai

    2013-01-01

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

  12. Pharmacological approach to acute pancreatitis

    DEFF Research Database (Denmark)

    Bang, Ulrich-Christian; Semb, Synne; Nojgaard, 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....... Evidence based pharmacological treatment of AP is limited and studies on the effect of potent anti-inflammatory drugs are warranted....

  13. Molecular characterization of Br-cadherin, a developmentally regulated, brain-specific cadherin

    OpenAIRE

    Selig, Sara; Lidov, Hart G. W.; Bruno, Sandra A.; Segal, Michael M.; Kunkel, Louis M

    1997-01-01

    Cadherins are a family of transmembrane proteins that play a crucial role in cell adhesion and in morphogenesis. Several of the cadherins are expressed in the nervous system, but none is neuron-specific. We characterize a new member of the cadherin family, Br-cadherin, which is present exclusively in the central nervous system. Although the Br-cadherin protein is confined to the central nervous system, its mRNA is present in several additional tissues, suggesting that there is posttranscripti...

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

    OpenAIRE

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

    2014-01-01

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

  15. On the Characterization of the Spatio-Temporal Profiles of Brain Activity Associated with Face Naming and the Tip-of-the-Tongue State: A Magnetoencephalographic (MEG) Study

    Science.gov (United States)

    Lindin, Monica; Diaz, Fernando; Capilla, Almudena; Ortiz, Tomas; Maestu, Fernando

    2010-01-01

    The tip-of-the-tongue state (TOT) in face naming is a transient state of difficulty in access to a person's name along with the conviction that the name is known. The aim of the present study was to characterize the spatio-temporal course of brain activation in the successful naming and TOT states, by means of magnetoencephalography, during a…

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1991-06-01

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

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

    International Nuclear Information System (INIS)

    Binding of [3H]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 [3H]cocaine was sensitive to the actions of trypsin and chymotrypsin but not carboxypeptidase, and was eliminated by exposure of the membranes to 950C for 5 min. Specific binding at 2 nM was higher at pH 8.8 than at pH 7.0. Binding of [3H]cocaine (15 nM) was inhibited by increasing concentrations of Na+ ions. Several cocaine analogues, neurotransmitter uptake inhibitors and local anesthetics displaced specific [3H]cocaine binding at 2 nM with various potencies. The cocaine analogue (-)-norcocaine was the most potent (IC50 = 10 nM), while the local anesthetic tetracaine was the least potent in inhibiting [3H]cocaine binding. Several biogenic amine uptake inhibitors, including tricyclic antidepressants and phencyclidine, had IC50 values below μM concentrations

  19. Tissue characterization of brain tumors during and after pion radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Boesiger, P.; Greiner, R.; Schoepflin, R.E.; Kann, R.; Kuenzi, U. (Univ. of Zurich (Switzerland))

    1990-01-01

    Negative Pi-mesons (pions) are applied at the Paul Scherrer Institute in the radiotherapy of highly malignant gliomas using a dose escalation program. The therapy effects of 7 randomly selected patients were followed up by 62 MRI examinations. The quantification of the effects is based on the relaxation times T1 and T2, which are acquired by a new designed multi-echo multiple saturation recovery imaging technique. As a summary of the results, roughly two reaction types are observed. For both types the relaxation times increase up to two to three months after the radiation therapy. Then in one type (two patients) the T1 and T2 values of the tumors, and of the edemas surrounding the tumors, further increase, indicating an unfavorable prognosis. In the other type (five patients) the relaxation times drop down towards, or even below, their initial values, reflecting the onset of the reparation processes in the tissue. This later behavior reflects an at least temporary control of the disease; that is, the short term prognosis for these patients is more favorable. It further can be concluded, with respect to our MR parameters, that the radiotolerance of healthy brain tissue is much higher than that of malignant glioma tissue, despite the fact that these tumors are very seldom definitively radiosensible.

  20. Tissue characterization of brain tumors during and after pion radiation therapy

    International Nuclear Information System (INIS)

    Negative Pi-mesons (pions) are applied at the Paul Scherrer Institute in the radiotherapy of highly malignant gliomas using a dose escalation program. The therapy effects of 7 randomly selected patients were followed up by 62 MRI examinations. The quantification of the effects is based on the relaxation times T1 and T2, which are acquired by a new designed multi-echo multiple saturation recovery imaging technique. As a summary of the results, roughly two reaction types are observed. For both types the relaxation times increase up to two to three months after the radiation therapy. Then in one type (two patients) the T1 and T2 values of the tumors, and of the edemas surrounding the tumors, further increase, indicating an unfavorable prognosis. In the other type (five patients) the relaxation times drop down towards, or even below, their initial values, reflecting the onset of the reparation processes in the tissue. This later behavior reflects an at least temporary control of the disease; that is, the short term prognosis for these patients is more favorable. It further can be concluded, with respect to our MR parameters, that the radiotolerance of healthy brain tissue is much higher than that of malignant glioma tissue, despite the fact that these tumors are very seldom definitively radiosensible

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

    International Nuclear Information System (INIS)

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

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

    International Nuclear Information System (INIS)

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

  3. [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. PMID:15382615

  4. Characterization of Artifacts Produced by Gel Displacement on Non-invasive Brain-Machine Interfaces during Ambulation.

    Science.gov (United States)

    Costa, Álvaro; Salazar-Varas, Rocio; Úbeda, Andrés; Azorín, José M

    2016-01-01

    So far, Brain-Machine Interfaces (BMIs) have been mainly used to study brain potentials during movement-free conditions. Recently, due to the emerging concern of improving rehabilitation therapies, these systems are also being used during gait experiments. Under this new condition, the evaluation of motion artifacts has become a critical point to assure the validity of the results obtained. Due to the high signal to noise ratio provided, the use of wet electrodes is a widely accepted technic to acquire electroencephalographic (EEG signals). To perform these recordings it is necessary to apply a conductive gel between the scalp and the electrodes. This work is focused on the study of gel displacements produced during ambulation and how they affect the amplitude of EEG signals. Data recorded during three ambulation conditions (gait training) and one movement-free condition (BMI motor imagery task) are compared to perform this study. Two phenomenons, manifested as unusual increases of the signals' amplitude, have been identified and characterized during this work. Results suggest that they are caused by abrupt changes on the conductivity between the electrode and the scalp due to gel displacement produced during ambulation and head movements. These artifacts significantly increase the Power Spectral Density (PSD) of EEG recordings at all frequencies from 5 to 90 Hz, corresponding to the main bandwidth of electrocortical potentials. They should be taken into consideration before performing EEG recordings in order to asses the correct gel allocation and to avoid the use of electrodes on certain scalp areas depending on the experimental conditions. PMID:26941601

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

    Science.gov (United States)

    Dahal, Sudhir; Cullum, Brian M.

    2016-04-01

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

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

    OpenAIRE

    Padovani, Eduardo C.

    2016-01-01

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

  7. Quality management of pharmacology and safety pharmacology studies

    DEFF Research Database (Denmark)

    Spindler, Per; Seiler, Jürg P

    2002-01-01

    Pharmacology has traditionally been excluded from the mandatory application of good laboratory practice (GLP) principles. Consensus has been reached through the process of the International Conference on Harmonisation (ICH, Topic S7A) with regard to the definitions of the different types of...... 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...... management should facilitate collaboration across scientific disciplines because a plethora of data, originating from basic pharmacodynamics, toxicology, kinetics, and metabolism, as well as from clinical investigations, are involved in a safety pharmacology assessment. Applying formal GLP standards to...

  8. Cannabinoid receptor localization in brain

    Energy Technology Data Exchange (ETDEWEB)

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

    1990-03-01

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

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

    International Nuclear Information System (INIS)

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

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

    International Nuclear Information System (INIS)

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

  11. Spatiotemporal Expression and Molecular Characterization of miR-344b and miR-344c in the Developing Mouse Brain.

    Science.gov (United States)

    Leong, Jia-Wen; Abdullah, Syahril; Ling, King-Hwa; Cheah, Pike-See

    2016-01-01

    MicroRNAs (miRNAs) are small noncoding RNA known to regulate brain development. The expression of two novel miRNAs, namely, miR-344b and miR-344c, was characterized during mouse brain developmental stages in this study. In situ hybridization analysis showed that miR-344b and miR-344c were expressed in the germinal layer during embryonic brain developmental stages. In contrast, miR-344b was not detectable in the adult brain while miR-344c was expressed exclusively in the adult olfactory bulb and cerebellar granular layer. Stem-loop RT-qPCR analysis of whole brain RNAs showed that expression of the miR-344b and miR-344c was increased as brain developed throughout the embryonic stage and maintained at adulthood. Further investigation showed that these miRNAs were expressed in adult organs, where miR-344b and miR-344c were highly expressed in pancreas and brain, respectively. Bioinformatics analysis suggested miR-344b and miR-344c targeted Olig2 and Otx2 mRNAs, respectively. However, luciferase experiments demonstrated that these miRNAs did not target Olig2 and Otx2 mRNAs. Further investigation on the locality of miR-344b and miR-344c showed that both miRNAs were localized in nuclei of immature neurons. In conclusion, miR-344b and miR-344c were expressed spatiotemporally during mouse brain developmental stages. PMID:27034842

  12. Teaching Pharmacology by Case Study.

    Science.gov (United States)

    Jordan, Sue

    1997-01-01

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

  13. NASA 2010 Pharmacology Evidence Review

    Science.gov (United States)

    Steinberg, Susan

    2011-01-01

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

  14. [Pharmacology of bone resorption inhibitor].

    Science.gov (United States)

    Menuki, Kunitaka; Sakai, Akinori

    2015-10-01

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

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

    OpenAIRE

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

    2011-01-01

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

  16. Glutamate in peripheral organs: Biology and pharmacology.

    Science.gov (United States)

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

    2016-08-01

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

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

    International Nuclear Information System (INIS)

    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 [3H]TZ binding. Saturation studies showed a shift to lower affinity at 370C (K/sub d/ = 0.25 +/- 0.01 nM at O0C; K/sub d/ = 1.46 +/- 0.03 nM at 370C) while the B/sub max/ values remained unchanged (1003 +/- 37 fmoles/mg prot. at 00C and 1001 +/- 43 fmoles/mg prot. at 370C). Inhibition studies showed that [3H]TZ binding displayed no GABA shift at 00C(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 370C (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 370C. In Ro 15-1788/[3H]TZ competition experiments the presence of GABA did not affect the inhibitory potency of Ro 15-1788 on [3H]TZ binding at both temperatures. In conclusion [3H]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

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

    International Nuclear Information System (INIS)

    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 [3H]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 [3H]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 (-)-[3H]nicotine-binding characteristics

  19. Selective kainate receptor (GluK1) ligands structurally based upon1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization

    DEFF Research Database (Denmark)

    Venskutonyte, Raminta; Butini, Stefania; Coccone, Salvatore Sanna; Gemma, Sandra; Brindisi, Margherita; Kumar, Vinod; Guarino, Ergeria; Maramai, Samuele; Valenti, Salvatore; Amir, Ahmad; Valades, Elena Anton; Frydenvang, Karla Andrea; Kastrup, Jette Sandholm Jensen; Novellino, Ettore; Campiani, Giuseppe; Pickering, Darryl S

    2011-01-01

    The physiological function of kainate receptors (GluK1- GluK5) in the central nervous system is not fully understood yet. With the aim of developing potent and selective GluK1 ligands, we have synthesized a series of new thiophene-based GluK1 agonists (6a-c) and antagonists (7a-d). Pharmacological...

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

    OpenAIRE

    Robbins, Trevor W.; Murphy, Emily R.

    2006-01-01

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

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

    OpenAIRE

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

    2016-01-01

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

  2. Pharmacological approaches to the management of binge eating disorder.

    Science.gov (United States)

    Brownley, Kimberly A; Peat, Christine M; La Via, Maria; Bulik, Cynthia M

    2015-01-01

    In the USA, binge eating disorder (BED) is the most common eating disorder, with a lifetime prevalence of ~3.5 % in adult women, 2.0 % in adult men, and 1.6 % in adolescents. BED is characterized by frequent episodes of binge eating that are accompanied by a sense of loss of control over eating and result in marked psychological distress. BED is highly co-morbid with obesity and with depression and other psychiatric conditions, and it is associated with substantial role impairment. Currently, there are no US FDA-approved pharmacological treatments for BED. Animal and human studies implicate underlying dysregulation in dopamine, opioid, acetylcholine, and serotonin neurocircuitry within brain reward regions in the pathogenesis and maintenance of BED. To date, the efficacy of various agents that target these and other neurotransmitter systems involved in motivated feeding behavior, mood regulation, and impulse control have been investigated in the treatment of BED. Several antidepressant and anticonvulsant agents have demonstrated efficacy in reducing binge eating frequency, but only in limited cases have these effects resulted in patients achieving abstinence, which is the primary goal of treatment; they also range from less (fluvoxamine) to more (topiramate) effective in achieving weight loss that is both clinically meaningful and significantly greater than placebo. Collectively, the literature on pharmacological treatment approaches to BED is limited in that very few agents have been studied in multiple, confirmatory trials with adequate follow up, and almost none have been evaluated in large patient samples that are diverse with respect to age, sex, and ethnicity. In addition, prior trials have not adequately addressed, through study design, the high placebo response commonly observed in this patient population. Several novel agents are in various phases of testing, and recent animal studies focusing on glutamate-signaling circuits linking the amygdala to the

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

    NARCIS (Netherlands)

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

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Peiyan Wong

    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

  5. PHARMACOLOGICAL ACTIVITIES OF PROTOCATECHUIC ACID.

    Science.gov (United States)

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

    2015-01-01

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

  6. Nematode cholinergic pharmacology

    International Nuclear Information System (INIS)

    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 [3H]N-methylscopolamine ([3H]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

  7. Nematode cholinergic pharmacology

    Energy Technology Data Exchange (ETDEWEB)

    Segerberg, M.A.

    1989-01-01

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

  8. Behavioral and Cellular Pharmacology Characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) as a Mu Opioid Receptor Selective Ligand

    OpenAIRE

    Zhang, Yan; Braithwaite, Amanda; Yuan, Yunyun; Streicher, John M.; Bilsky, Edward J.

    2014-01-01

    Mu opioid receptor (MOR) selective antagonists and partial agonists have been used for the treatment of opioid abuse and addiction. Our recent efforts on the identification of MOR antagonists have provided several novel leads displaying interesting pharmacological profiles. Among them, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3'-isoquinolyl)acetamido]morphinan (NAQ) showed sub-nanomolar binding affinity to the MOR with significant selectivity over the delta opioid receptor (DOR) a...

  9. Characterization of passive permeability at the blood-tumor barrier in five preclinical models of brain metastases of breast cancer.

    Science.gov (United States)

    Adkins, Chris E; Mohammad, Afroz S; Terrell-Hall, Tori B; Dolan, Emma L; Shah, Neal; Sechrest, Emily; Griffith, Jessica; Lockman, Paul R

    2016-04-01

    The blood-brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers (14)C-aminoisobutyric acid (AIB) and Texas red conjugated dextran prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases. PMID:26944053

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

    Directory of Open Access Journals (Sweden)

    Qi Peng

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1987-02-20

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Wagner, J.A.

    1987-01-01

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

  13. The Pharmacology of Visceral Pain.

    Science.gov (United States)

    Johnson, Anthony C; Greenwood-Van Meerveld, Beverley

    2016-01-01

    Visceral pain describes pain emanating from the internal thoracic, pelvic, or abdominal organs. Unlike somatic pain, visceral pain is generally vague, poorly localized, and characterized by hypersensitivity to a stimulus such as organ distension. While current therapeutics provides some relief from somatic pain, drugs used for treatment of chronic visceral pain are typically less efficacious and limited by multiple adverse side effects. Thus, the treatment of visceral pain represents a major unmet medical need. Further, more basic research into the physiology and pathophysiology of visceral pain is needed to provide novel targets for future drug development. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. However, persistent stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders. We will focus on stress-induced exacerbation of chronic visceral pain and provide supporting evidence that centrally acting drugs targeting the pain and stress-responsive brain regions may represent a valid target for the development of novel and effective therapeutics. PMID:26920016

  14. Tangential symbols: using visual symbolization to teach pharmacological principles of drug addiction to international audiences.

    Science.gov (United States)

    Giannini, A J

    1993-12-01

    Visual art was used to teach the biopsychiatric model of addiction to audiences in the Caribbean, Europe and Mideast. Art slides were tangentially linked to slides of pharmacological data. Stylistically dense art was processed by the intuitive right brain while spare notational pharmacological data was processed by the intellectual (rationalistic) left brain. Simultaneous presentation of these data enhanced attention and retention. This teaching paradigm was based on the nonliterate methods developed by Medieval architects and refined by Italian Renaissance philosopher, Marsilio Ficino. PMID:7510314

  15. Synthesis and characterization of brain penetrant prodrug of neuroprotective D-264: Potential therapeutic application in the treatment of Parkinson's disease.

    Science.gov (United States)

    Dholkawala, Fahd; Voshavar, Chandrashekhar; Dutta, Aloke K

    2016-06-01

    Parkinson's disease (PD) is one of the major debilitating neurodegenerative disorders affecting millions of people worldwide. Progressive loss of dopamine neurons resulting in development of motor dysfunction and other related non-motor symptoms is the hallmark of PD. Previously, we have reported on the neuroprotective property of a potent D3 preferring agonist D-264. In our goal to increase the bioavailability of D-264 in the brain, we have synthesized a modified cysteine based prodrug of D-264 and evaluated its potential in crossing the blood-brain barrier. Herein, we report the synthesis of a novel modified cysteine conjugated prodrug of potent neuroprotective D3 preferring agonist D-264 and systematic evaluation of the hydrolysis pattern of the prodrug to yield D-264 at different time intervals in rat plasma and brain homogenates using HPLC analysis. Furthermore, we have also performed in vivo experiments with the prodrug to evaluate its enhanced brain penetration ability. PMID:26994936

  16. 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…

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

    Science.gov (United States)

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

    2013-01-01

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

  18. Pharmacologic Treatment for Temporomandibular Disorders.

    Science.gov (United States)

    Dym, Harry; Bowler, Dustin; Zeidan, Joseph

    2016-04-01

    Pharmacologic agents play an integral role in the overall management of temporomandibular joint disorder. The general dentist should be familiar with the different classes of drugs currently in use for dealing with this often complex medical/dental problem. PMID:27040290

  19. Systems pharmacology of complex diseases

    OpenAIRE

    Hansen, Jens; Zhao, Shan; Iyengar, Ravi

    2011-01-01

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

  20. 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,…

  1. The Pharmacological Potential of Mushrooms

    Directory of Open Access Journals (Sweden)

    Ulrike Lindequist

    2005-01-01

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

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

    Science.gov (United States)

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

    2010-07-01

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

  3. 7.0-T Magnetic Resonance Imaging Characterization of Acute Blood-Brain-Barrier Disruption Achieved with Intracranial Irreversible Electroporation

    OpenAIRE

    Garcia, Paulo A.; John H. Rossmeisl; Robertson, John L.; Olson, John D.; Johnson, Annette J.; Ellis, Thomas L; Davalos, Rafael V.

    2012-01-01

    The blood-brain-barrier (BBB) presents a significant obstacle to the delivery of systemically administered chemotherapeutics for the treatment of brain cancer. Irreversible electroporation (IRE) is an emerging technology that uses pulsed electric fields for the non-thermal ablation of tumors. We hypothesized that there is a minimal electric field at which BBB disruption occurs surrounding an IRE-induced zone of ablation and that this transient response can be measured using gadolinium (Gd) up...

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

    OpenAIRE

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

    2016-01-01

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

  5. 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.

  6. 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.

  7. Clinical pharmacology and vascular risk.

    Science.gov (United States)

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

    2010-01-01

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

  8. Pharmacology for the treatment of premature ejaculation.

    Science.gov (United States)

    Giuliano, François; Clèment, Pierre

    2012-07-01

    Male sexual response comprises four phases: excitement, including erection; plateau; ejaculation, usually accompanied by orgasm; and resolution. Ejaculation is a complex sexual response involving a sequential process consisting of two phases: emission and expulsion. Ejaculation, which is basically a spinal reflex, requires a tight coordination between sympathetic, parasympathetic, and somatic efferent pathways originating from different segments and area in the spinal cord and innervating pelvi-perineal anatomical structures. A major relaying and synchronizing role is played by a group of lumbar neurons described as the spinal generator of ejaculation. Excitatory and inhibitory influences from sensory genital and cerebral stimuli are integrated and processed in the spinal cord. Premature ejaculation (PE) can be defined by ≤1-min ejaculatory latency, an inability to delay ejaculation, and negative personal consequences. Because there is no physiological impairment in PE, any pharmacological agent with central or peripheral mechanism of action that is delaying the ejaculation is a drug candidate for the treatment of PE. Ejaculation is centrally mediated by a variety of neurotransmitter systems, involving especially serotonin and serotonergic pathways but also dopaminergic and oxytocinergic systems. Pharmacological delay of ejaculation can be achieved either by inhibiting excitatory or reinforcing inhibitory pathways from the brain or the periphery to the spinal cord. PE can be treated with long-term use of selective serotonin-reuptake inhibitors (SSRIs) or tricyclic antidepressants. Dapoxetine, a short-acting SSRI, is the first treatment registered for the on-demand treatment of PE. Anesthetics applied on the glans penis have the ability to lengthen the time to ejaculation. Targeting oxytocinergic, neurokinin-1, dopaminergic, and opioid receptors represent future avenues to delaying ejaculation. PMID:22679220

  9. Phytochemistry and Pharmacology of Berberis Species

    Directory of Open Access Journals (Sweden)

    Najmeh Mokhber-Dezfuli

    2014-01-01

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

  10. 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

  11. Characterization of particulate cyclic nucleotide phosphodiesterases from bovine brain: Purification of a distinct cGMP-stimulated isoenzyme

    International Nuclear Information System (INIS)

    In the absence of detergent, ∼80-85% of the total cGMP-stimulated phosphodiesterase (PDE) activity in bovine brain was associated with washed particulate fractions; ∼85-90% of the calmodulin-sensitive PDE was soluble. Particulate cGMP-stimulated PDE was higher in cerebral cortical gray matter than in other regions. Homogenization of the brain particulate fraction in 1% Lubrol increased cGMP-stimulated activity ∼100% and calmodulin-stimulated ∼400-500%. Although 1% Lubrol readily solubilized these PDE activities, ∼75% of the cAMP PDE activity (0.5 μM [3H]cAMP) that was not affected by cGMP was not solubilized. This cAMP PDE activity was very sensitive to inhibition by Rolipram but not cilostamide. Thus, three different PDE types, i.e., cGMP stimulated, calmodulin sensitive, and Rolipram inhibited, are associated in different ways with crude bovine brain particulate fractions. The brain enzyme exhibited a slightly greater subunit Mr than did soluble forms from calf liver or bovine brain, as evidenced by protein staining or immunoblotting after polyacrylamide gel electrophoresis under denaturing conditions. Incubation of brain particulate and liver soluble cGMP-stimulated PDEs with V8 protease produced several peptides of similar size, as well as at least two distinct fragments of ∼27 kDa from the brain and ∼23 kDa from the liver enzyme. After photolabeling in the presence of [32P]cGMP and digestion with V8 protease, [32P]cGMP in each PDE was predominantly recovered with a peptide of ∼14 kDa. All of these observations are consistent with the existence of at least two discrete forms (isoenzymes) of cGMP-stimulated PDE

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

    Science.gov (United States)

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

    2016-08-01

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

  13. Paradoxical pharmacology: turning our pharmacological models upside down.

    Science.gov (United States)

    Page, Clive

    2011-04-01

    Paradoxical pharmacology is a term first suggested by Richard Bond to refer to intriguing observations that chronic use of some drug types can have the opposite biological effect(s) to those seen following acute administration of the same drug. A good example of 'paradoxical pharmacology' is the research Richard has pioneered showing that whereas acute administration of β-blockers is contraindicated in the treatment of asthma, chronic use of certain β-blockers can have therapeutic benefit. It would appear that those β-blockers that can act as inverse agonists at the β2 receptor particularly show this paradoxical effect and the findings of Richard's research not only challenge the dogma of the treatment of asthma but also challenge many of the pharmacological principles of ligand/receptor interactions established by Sir James Black and others. In this paper, I discuss Richard's efforts to evaluate the chronic effects of β-blockers in the airways and how this research caught the imagination of Sir James Black. PMID:21458081

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

    Directory of Open Access Journals (Sweden)

    Robert J Lipinski

    Full Text Available 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.

  15. Pharmacology teaching and its reform in China

    Institute of Scientific and Technical Information of China (English)

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

    2004-01-01

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

  16. Brain Basics

    Medline Plus

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

  17. Brain Basics

    Science.gov (United States)

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

  18. Brain Basics

    Medline Plus

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

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

    Directory of Open Access Journals (Sweden)

    Tine eVerreet

    2016-05-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  1. Pharmacological effects of Sapindus mukorossi.

    Science.gov (United States)

    Upadhyay, Aparna; Singh, D K

    2012-01-01

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

  2. Pharmacological effects of Sapindus mukorossi

    Directory of Open Access Journals (Sweden)

    Aparna Upadhyay

    2012-10-01

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

  3. Pharmacological potential of cerium oxidenanoparticles

    Science.gov (United States)

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

    2011-04-01

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

  4. Pharmacologic interventions in aging hair

    OpenAIRE

    Trüeb, Ralph M

    2006-01-01

    The appearance of hair plays an important role in people’s overall physical appearance and self-perception. With today’s increasing life-expectations, the desire to look youthful plays a bigger role than ever. The hair care industry has become aware of this and is delivering active products directed towards meeting this consumer demand. The discovery of pharmacological targets and the development of safe and effective drugs also indicate strategies of the drug industry for maintenance of heal...

  5. Pharmacological effects of Sapindus mukorossi

    OpenAIRE

    Aparna Upadhyay; D K Singh

    2012-01-01

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

  6. The clinical pharmacology of ageing

    OpenAIRE

    Swift, C G

    2003-01-01

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

  7. Pharmacologic management of eating disorders.

    Science.gov (United States)

    Price, W A

    1988-05-01

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

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

    NARCIS (Netherlands)

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

    1988-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2011-01-01

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

  10. Understanding brain networks and brain organization

    Science.gov (United States)

    Pessoa, Luiz

    2014-09-01

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

  11. Learning abilities, NGF and BDNF brain levels in two lines of TNF-alpha transgenic mice, one characterized by neurological disorders, the other phenotypically normal.

    Science.gov (United States)

    Aloe, L; Properzi, F; Probert, L; Akassoglou, K; Kassiotis, G; Micera, A; Fiore, M

    1999-09-01

    In this study we used two lines of transgenic mice overexpressing tumor necrosis factor alpha (TNF-alpha) in the central nervous system (CNS), one characterized by reactive gliosis, inflammatory demyelination and neurological deficits (Tg6074) the other showing no neurological or phenotypical alterations (TgK3) to investigate the effect of TNF-alpha on brain nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels and learning abilities. The results showed that the amount of NGF in the brain of Tg6074 and TgK3 transgenic mice is low in the hippocampus and in the spinal cord, increases in the hypothalamus of Tg6074 and showed no significant changes in the cortex. BDNF levels were low in the hippocampus and spinal cord of TgK3. BDNF increased in the hypothalamus of TgK3 and Tg6074 while in the cortex, BDNF increased only in Tg6074 mice. Transgenic mice also had memory impairments as revealed by the Morris Water Maze test. These findings indicate that TNF-alpha significantly influences BDNF and NGF synthesis, most probably in a dose-dependent manner. Learning abilities were also differently affected by overexpression of TNF-alpha, but were not associated with inflammatory activity. The possible functional implications of our findings are discussed. PMID:10517960

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

    International Nuclear Information System (INIS)

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

  13. 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

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

    Science.gov (United States)

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

    2015-12-01

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

  15. Characterization of Neurophysiological and Behavioral Changes, MRI Brain Volumetry and 1H MRS in zQ175 Knock-In Mouse Model of Huntington's Disease

    Science.gov (United States)

    Heikkinen, Taneli; Lehtimäki, Kimmo; Vartiainen, Nina; Puoliväli, Jukka; Hendricks, Susan J.; Glaser, Jack R.; Bradaia, Amyaouch; Wadel, Kristian; Touller, Chrystelle; Kontkanen, Outi; Yrjänheikki, Juha M.; Buisson, Bruno; Howland, David; Beaumont, Vahri; Munoz-Sanjuan, Ignacio; Park, Larry C.

    2012-01-01

    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 strategies to

  16. 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

  17. Brain herniation

    Science.gov (United States)

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

  18. Brain abscess: Current management

    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.

  19. Brain abscess: Current management.

    Science.gov (United States)

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

    2013-08-01

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

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

    International Nuclear Information System (INIS)

    The binding of radiolabelled norzimeldine, a potent selective 5-HT reuptake inhibitor, to rat brain homogenates is described. 3H-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 3H-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)

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

    OpenAIRE

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

    2015-01-01

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

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

    International Nuclear Information System (INIS)

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

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

    Directory of Open Access Journals (Sweden)

    Catherine Fassbender

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

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

    Science.gov (United States)

    Lv, Xue-Man; Liu, Yan; Wu, Fei; Yuan, Yi; Luo, Min

    2016-04-01

    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 × 10(6) 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. PMID:27212930

  5. 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.

  6. Pharmacologic considerations for Shuttle astronauts

    Science.gov (United States)

    Santy, Patricia A.; Bungo, Michael W.

    1991-01-01

    Medication usage by crewmembers in the preflight and inflight mission periods is common in the Shuttle Program. The most common medical reports for which medication is used are: space motion sickness (SMS), sleeplessness, headache, and backache. A number of medications are available in the Shuttle Medical Kit to treat these problems. Currently, astronauts test all frequently used medications before mission assignment to identify potential side-effects, problems related to performance, personal likes/dislikes, and individual therapeutic effect. However, microgravity-induced changes in drug pharmacokinetics, in combination with multiple operational factors, may significantly alter crewmember responses inflight. This article discusses those factors that may impact pharmacologic efficacy during Shuttle missions.

  7. Gaultheria: Phytochemical and pharmacological characteristics.

    Science.gov (United States)

    Liu, Wei-Rui; Qiao, Wen-Lin; Liu, Zi-Zhen; Wang, Xiao-Hong; Jiang, Rui; Li, Shu-Yi; Shi, Ren-Bing; She, Gai-Mei

    2013-01-01

    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. PMID:24084015

  8. 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.

  9. Non pharmacological treatments in fibromyalgia

    Directory of Open Access Journals (Sweden)

    M. Spath

    2011-09-01

    Full Text Available To fully answer the complex question of what modes of non pharmacological treatments are useful for fibromyalgia (FM one should ask different layers of questions, and as with peeling layers of onions, be prepared to shed some tears. The first painful question, or layer of the onion, is related to understanding patients’ complaints. Patients who experience recurrent as well as persistent physical symptoms without any objective evidence are too often classified as “psychosomatic disorders” or worse as “non disease” (see Sarzi this issue...

  10. Pharmacologic Therapies in Musculoskeletal Conditions.

    Science.gov (United States)

    Loveless, Melinda S; Fry, Adrielle L

    2016-07-01

    Musculoskeletal conditions are common, and there are many options for pharmacologic therapy. Unfortunately, there is not strong evidence for the use of many of these medications. Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are generally first-line medications for most musculoskeletal pain, but there is more evidence these medications are not as safe as once thought. Other analgesic and antispasmodic medications can be effective for acute pain but generally are not as effective for chronic pain. Antidepressants and anticonvulsants can be more effective for chronic or neuropathic pain. Topical formulations of NSAIDs can be effective for pain with fewer side effects. PMID:27235619

  11. 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

  12. Non-pharmacological intervention for posterior cortical atrophy.

    Science.gov (United States)

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

    2016-08-16

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

  13. 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

  14. A review on protocatechuic Acid and its pharmacological potential.

    Science.gov (United States)

    Kakkar, Sahil; Bais, Souravh

    2014-01-01

    Flavonoids and polyphenols are heterocyclic molecules that have been associated with beneficial effects on human health, such as reducing the risk of various diseases like cancer, diabetes, and cardiovascular and brain diseases. Protocatechuic acid (PCA) is a type of widely distributed naturally occurring phenolic acid. PCA has structural similarity with gallic acid, caffeic acid, vanillic acid, and syringic acid which are well-known antioxidant compounds. More than 500 plants contain PCA as active constituents imparting various pharmacological activity and these effects are due to their antioxidant activities, along with other possible mechanisms, such as anti-inflammatory properties and interaction with several enzymes. Over the past two decades, there have been an increasing number of publications on polyphenols and flavonoids, which demonstrate the importance of understanding the chemistry behind the antioxidant activities of both natural and synthesized compounds, considering the benefits from their dietary ingestion as well as pharmacological use. This work aims to review the pharmacological effects of PCA molecules in humans and the structural aspects that contribute to these effects. PMID:25006494

  15. Brain Basics

    Medline Plus

    Full Text Available ... Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of the brain's structure, studies show that brain growth in children with autism ...

  16. Pharmacological approach to acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

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

    2008-01-01

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

  17. A Pharmacological Primer of Biased Agonism

    OpenAIRE

    Andresen1, Bradley T.

    2011-01-01

    Biased agonism is one of the fastest growing topics in G protein-coupled receptor pharmacology; moreover, biased agonists are used in the clinic today: carvedilol (Coreg®) is a biased agonist of beta-adrenergic receptors. However, there is a general lack of understanding of biased agonism when compared to traditional pharmacological terminology. Therefore, this review is designed to provide a basic introduction to classical pharmacology as well as G protein-coupled receptor signal transductio...

  18. 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.

  19. Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold

    DEFF Research Database (Denmark)

    Nørholm, Ann-Beth; Francotte, Pierre; Olsen, Lars;

    2013-01-01

    Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing...... receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X......-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a Kd of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive...

  20. Identification and pharmacological characterization of 3,6-diazabicyclo[3.1.1]heptane-3-carboxamides as novel ligands for the α4β2 and α6/α3β2β3 nicotinic acetylcholine receptors (nAChRs).

    Science.gov (United States)

    Strachan, Jon-Paul; Kombo, David C; Mazurov, Anatoly; Heemstra, Ronald; Bhatti, Balwinder S; Akireddy, Rao; Murthy, Srinivasa; Miao, Lan; Jett, John E; Speake, Jason; Bencherif, Merouane

    2014-10-30

    We have synthesized a novel series of compounds, 3,6-diazabicyclo[3.1.1]heptane-3-carboxamides, targeting both the α4β2 and α6/α3β2β3 nAChRs. Members of the obtained chemical library are partial or full agonists at both the high sensitivity (α4)2(β2)3 and α6/α3β2β3 nAChRs. 3-(Cyclopropylcarbonyl)-3,6-diazabicyclo[3.1.1]heptane (TC-8831 or compound 7 herein) demonstrated a safe in vitro pharmacological profile and the potential for reducing or preventing L-dopa-induced dyskinesias (LID) in several in vivo animal models [1-4]. In vivo metabolism studies in rat and in vitro metabolism studies in liver microsomes from human, rat, dog and monkey showed TC-8831 to be relatively stable. In vivo pharmacokinetic analysis in the rat confirmed brain penetration, with an average brain:plasma ratio of approximately 0.3 across time points from 0.5 to 4 h. Docking into homology models predicted alternative binding modes for TC-8831 and highlighted the importance of the cationic center, hydrogen-bond acceptor, and hydrophobic aliphatic features in promoting binding affinity to both nAChRs. Pharmacophore elucidation confirmed the importance of these key interactions. QSAR modeling suggested that binding affinity is primarily driven by ligand shape, relative positive charge distribution onto the molecular surface, and molecular flexibility. Of the two subtypes, ligand binding to α6β2β3 appears to be more sensitive to bulkiness and flexibility. PMID:25147147

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

    Science.gov (United States)

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

    2016-05-01

    The microtubule (MT)-stabilizing protein tau disengages from MTs and forms intracellular inclusions known as neurofibrillary tangles in Alzheimer's disease and related tauopathies. Reduced tau binding to MTs in tauopathies may contribute to neuronal dysfunction through decreased MT stabilization and disrupted axonal transport. Thus, the introduction of brain-penetrant MT-stabilizing compounds might normalize MT dynamics and axonal deficits in these disorders. We previously described a number of phenylpyrimidines and triazolopyrimidines (TPDs) that induce tubulin post-translational modifications indicative of MT stabilization. We now further characterize the biologic properties of these small molecules, and our results reveal that these compounds can be divided into two general classes based on the cellular response they evoke. One group composed of the phenylpyrimidines and several TPD examples showed a bell-shaped concentration-response effect on markers of MT stabilization in cellular assays. Moreover, these compounds induced proteasome-dependent degradation of α- and β-tubulin and caused altered MT morphology in both dividing cells and neuron cultures. In contrast, a second group comprising a subset of TPD molecules (TPD+) increased markers of stable MTs in a concentration-dependent manner in dividing cells and in neurons without affecting total tubulin levels or disrupting MT architecture. Moreover, an example TPD+ compound was shown to increase MTs in a neuron culture model with induced tau hyperphosphorylation and associated MT deficits. Several TPD+ compounds were shown to be both brain penetrant and orally bioavailable, and a TPD+ example increased MT stabilization in the mouse brain, making these compounds potential candidate therapeutics for neurodegenerative tauopathies such as Alzheimer's disease. PMID:26980057

  2. 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

  3. Characterization of acetylcholinesterase from the brain of the Amazonian tambaqui (Colossoma macropomum) and in vitro effect of organophosphorus and carbamate pesticides.

    Science.gov (United States)

    Assis, Caio Rodrigo Dias; Castro, Patrícia Fernandes; Amaral, Ian Porto Gurgel; Carvalho, Elba Verônica Matoso Maciel; Carvalho, Luiz Bezerra; Bezerra, Ranilson Souza

    2010-10-01

    In the present study, acetylcholinesterase (AChE) from the brain of the Amazonian fish tambaqui (Colossoma macropomum) was partially characterized and its activity was assayed in the presence of five organophosphates (dichlorvos, diazinon, chlorpyrifos, and tetraethyl pyrophosphate [TEPP]) and two carbamates (carbaryl and carbofuran) insecticides. Optimal pH and temperature were 7.0 to 8.0 and 45°C, respectively. The enzyme retained approximately 70% of activity after incubation at 50°C for 30 min. The insecticide concentration capable of inhibiting half of the enzyme activity (IC50) for dichlorvos, chlorpyrifos, and TEPP were calculated as 0.04 µmol/L, 7.6 µmol/L, and 3.7 µmol/L, respectively. Diazinon and temephos did not inhibit the enzyme. The IC50 values for carbaryl and carbofuran were estimated as 33.8 µmol/L and 0.92 µmol/L, respectively. These results suggest that AChE from the juvenile C. macropomum brain could be used as an alternative biocomponent of organophosphorus and carbamate biosensors in routine pesticide screening in the environment. PMID:20872688

  4. [Pharmacological treatment of acute cough].

    Science.gov (United States)

    Småbrekke, Lars; Melbye, Hasse

    2009-05-14

    Acute cough may cause considerable distress for patients with upper airway infections, and is a symptom commonly presented to doctors. We wanted to assess the evidence basis for pharmacological treatment of this condition. Predefined terms (MeSH and Emtree) and free text were used to search PubMed and Embase for double-blind randomized trials, reviews and guidelines. Little evidence supports the use of guaifenesine, bromhexine and acetylcysteine for acute cough associated with upper airway infections. Likewise, there is insufficient evidence to decide whether noscapine, codeine and ehylmorphine are beneficial for acute cough on this indication. Well-designed randomized controlled trials with valid outcomes are needed to document possible benefits of treatment. Treatment with codeine or ethylmorphine may be at the expense of adverse effects, abuse or dependence. PMID:19448753

  5. Rocuronium bromide: a pharmacological study

    Directory of Open Access Journals (Sweden)

    Maaly M.H Gaafary, **Essam F. Al. Alkami

    2001-06-01

    Full Text Available This work was designed to assess the pharmacological effects of rocuronium. In either isolated preparation or intact animals. Rocuronium (6-96 g/ml caused a significant dose related reduction in the amplitude of rat phrenic nerve diaphragm contraction in response to indirect stimulation, the mean percentage reduction were statistically significant. The addition of neostgmine (0.25 g/ml caused complete reversal of the relaxant effect of rocuronium . In intact cat gastrocnemius sciatic nerve preparation rocuronium (25 - 200 g/kg caused dose dependent statiscally significant reduction. In comparing the drug with succinyl choline by the head drop method the mean time in second was 15.34 ±1.57 and 10.44 ±0.91 respectively.

  6. Pharmacological activities of Curcuma caesia

    Directory of Open Access Journals (Sweden)

    Satyendra Singh Baghel

    2013-01-01

    Full Text Available Curcuma caesia Roxb. is a perennial, erect rhizomatous herb with large leaves. Fresh rhizomes are aromatic with intense camphoraceous odour, cultivated for its rhizomes, which are used in traditional medicine. The plant is reported to contain camphor, ar-turmerone, (Z-ocimene, ar-curcumene, 1, 8-cineole, elemene, borneol, bornyl acetate and curcumene as the major constituents. The plant has been reported to have antifungal activity, anti-asthmatic, smooth muscle relaxant, antimicrobial activity, antioxidant activity, analgesic, locomotor depressant, anticonvulsant and muscle relaxant effects, anti-inflammatory properties. It is now considered as a valuable source of unique natural products for development of medicines against various diseases. This review gives a view mainly on the meditional uses, phytochemistry and pharmacological actions of the plant.

  7. Pharmacological challenges in chronic pancreatitis

    DEFF Research Database (Denmark)

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

    2014-01-01

    . 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...... 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...

  8. A new positron emission tomography imaging agent for the serotonin transporter: synthesis, pharmacological characterization, and kinetic analysis of [{sup 11}C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine ([{sup 11}C]AFM)

    Energy Technology Data Exchange (ETDEWEB)

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

    2004-07-01

    The synthesis, radiolabeling, and in vitro and in vivo evaluation of a new positron emission tomography (PET) radioligand for the serotonin transporter (SERT), [{sup 11}C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine ([{sup 11}C]AFM) is reported. AFM was prepared from 4-chloro-3-nitrobenzyl acetate and thiosalicylic acid in a five-step synthetic sequence. In binding studies in vitro with cloned human transporters, AFM displayed high binding affinity (Ki 1.04 nmol/L for hSERT) and good selectivity (Ki 664 nmol/L for hNET and >10,000 nmol/L for hDAT) for SERT. The radiolabled compound [{sup 11}C]AFM was prepared in 30-37 minutes from its monomethylamine precursor by reaction with high specific activity [{sup 11}C]iodomethane. Radiochemical yield was 12.3 {+-} 8.1% based on [{sup 11}C]iodomethane and specific activity was 1733 {+-} 428 Ci/mmol at end of synthesis (EOS, n = 14). Radiochemical and chemical purity of the final product was >97%. Biodistribution studies in rats indicated that [{sup 11}C]AFM entered the brain readily and localized in regions known to contain high concentrations of SERT, with high specific to nonspecific binding ratios. Furthermore, binding of [{sup 11}C]AFM in SERT-rich regions was blocked by the cold compound AFM and the selective serotonin reuptake inhibitor citalopram but not by the selective norepinephrine reuptake inhibitor nisoxetine or the selective dopamine reuptake inhibitor GBR 12935. At 30 minutes after injection, >95% of the brain activity corresponded to the parent compound, indicating the absence of radiolabeled metabolites in the rat brain. PET imaging experiments in baboons showed a brain distribution pattern of [{sup 11}C]AFM consistent with the regional concentrations of SERT, with the highest levels of radioactivity detected in the midbrain and thalamus, moderate levels in the hippocampus and striatum, and the low levels in the cortical regions. Pretreatment of the baboons with citalopram (4 and 6 mg

  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. Comparison of Fluid Attenuated Inversion Recovery Sequence with Spin Echo T2-Weighted MRI for Characterization of Brain Pathology

    CERN Document Server

    Sahu, Indra Dev; Shrestha, Shanta Lal; Ghimire, Ram Kumar

    2009-01-01

    Twenty cases of different brain pathology have been studied via MRI using an open resistive magnet with magnetic field strength of 0.2 Tesla. The relative signal intensity with respect to the repetition time (TR) at fixed echo time (TE) 0.117 sec. has been studied. It was found that the signal intensity saturates for most lesions beyond a certain TR~6 sec in the T2 - weighted image. The signal intensity differs with respect to the inversion time (TI) for fat and cerebrospinal fluid (CSF). It was found that the intensity is nulled for CSF at TI ~1.5 sec. and for Fat at TI~0.10 sec in the FLAIR imaging sequence. Thus the intensity of the lesions is qualitatively different for the two sequences. From the radiological diagnostic point of view, it was concluded that the FLAIR sequence is more useful for the detection of lesions compared to T2 sequences.

  11. 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 for...

  12. A symptom-based approach to pharmacologic management of fibromyalgia.

    Science.gov (United States)

    Boomershine, Chad S; Crofford, Leslie J

    2009-04-01

    Fibromyalgia is a prevalent disorder that is characterized by widespread pain along with numerous other symptoms, including fatigue, poor sleep, mood disorders, and stiffness. Previous guidelines for the management of fibromyalgia recommended an approach that integrates pharmacologic and nonpharmacologic therapies selected according to the symptoms experienced by individual patients. However, they offered no recommendations for a system of patient assessment that would provide a basis for individualized treatment selection. We present a simple, rapid and easily remembered system for symptom quantitation and pharmacologic management of fibromyalgia that combines visual analogue scale symptom scores from a modified form of the disease-neutral Fibromyalgia Impact Questionnaire, with a review of medications that can be used to treat the individual symptoms. This symptom-based approach is amenable to caring for patients with fibromyalgia in a busy clinical practice. PMID:19337283

  13. Genomic architecture of pharmacological efficacy and adverse events.

    Science.gov (United States)

    Chhibber, Aparna; Kroetz, Deanna L; Tantisira, Kelan G; McGeachie, Michael; Cheng, Cheng; Plenge, Robert; Stahl, Eli; Sadee, Wolfgang; Ritchie, Marylyn D; Pendergrass, Sarah A

    2014-12-01

    The pharmacokinetic and pharmacodynamic disciplines address pharmacological traits, including efficacy and adverse events. Pharmacogenomics studies have identified pervasive genetic effects on treatment outcomes, resulting in the development of genetic biomarkers for optimization of drug therapy. Pharmacogenomics-based tests are already being applied in clinical decision making. However, despite substantial progress in identifying the genetic etiology of pharmacological response, current biomarker panels still largely rely on single gene tests with a large portion of the genetic effects remaining to be discovered. Future research must account for the combined effects of multiple genetic variants, incorporate pathway-based approaches, explore gene-gene interactions and nonprotein coding functional genetic variants, extend studies across ancestral populations, and prioritize laboratory characterization of molecular mechanisms. Because genetic factors can play a key role in drug response, accurate biomarker tests capturing the main genetic factors determining treatment outcomes have substantial potential for improving individual clinical care. PMID:25521360

  14. Evaluation of the antagonism of nicotine by mecamylamine and pempidine in the brain

    International Nuclear Information System (INIS)

    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 [3H]-pempidine was studied in vitro to mouse brain homogentate and in situ to rat brain slices. The in situ binding of [3H]-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 [3H]-L-nicotine binding

  15. Complex Pharmacology of Free Fatty Acid Receptors

    DEFF Research Database (Denmark)

    Milligan, Graeme; Shimpukade, Bharat; Ulven, Trond;

    2016-01-01

    G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond...... pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or "free" fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets for...... the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential....

  16. Dynamic neuroimaging of brain function.

    Science.gov (United States)

    Simpson, G V; Pflieger, M E; Foxe, J J; Ahlfors, S P; Vaughan, H G; Hrabe, J; Ilmoniemi, R J; Lantos, G

    1995-09-01

    To fully characterize the brain processes underlying sensorimotor and cognitive function, the spatial distribution of active regions, their interconnected regions must be measured. We describe methods for imaging brain sources from surface-recorded EEG and magnetoencephalographic data, called electromagnetic source imaging (EMSI). EMSI provides brain source locations within the common framework of magnetic resonance (MR) images of brain anatomy. This allows integration of data from other functional brain imaging methods, like positron emission tomography and functional MR imaging, which can improve the accuracy of EMSI localization. EMSI also provides submillisecond temporal resolution of the dynamic processes within brain systems. Examples are given of applications to visual perceptual and attentional studies. PMID:8576389

  17. Chemistry, Pharmacology and Health Benefits of Anthocyanins.

    Science.gov (United States)

    Smeriglio, Antonella; Barreca, Davide; Bellocco, Ersilia; Trombetta, Domenico

    2016-08-01

    Anthocyanins are naturally occurring molecules belonging to the flavonoid class characterized by the presence of chromophores. Apart from their well-known antioxidant activity, they show a wide variety of health-promoting properties for human health, ranging from cytoprotective, antimicrobial and antitumour activities to neuroprotective, anti-obesity and lipidomic potential, properties for which anthocyanins have been prescribed as medicines in several countries for thousands of years. Despite this, these phytochemicals have received less attention than other flavonoids, and there is still a gap in the literature, particularly regarding pharmacological and toxicological aspects. Moreover, epidemiological evidence suggests a direct correlation between anthocyanin intake and a lower incidence of chronic and degenerative diseases. In light of this, the aim of this review is to cover the current literature on anthocyanins, their biological in vitro and in vivo effects and their potential therapeutic applications, as well as their bioavailability and pharmacokinetics, all of which are essential to gain a better understanding of their biological effectiveness and potential toxicity. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27221033

  18. 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, or ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are metastatic, ...

  19. Brain Basics

    Medline Plus

    Full Text Available ... Basics will introduce you to some of this science, such as: How the brain develops How genes and the environment affect the brain The basic structure of the brain How different parts of the brain communicate and work with each other How changes in the brain ...

  20. 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 ...

  1. Brain Fingerprinting

    Directory of Open Access Journals (Sweden)

    ravi kumar

    2012-12-01

    Full Text Available Brain Fingerprinting is a scientific technique to determine whether or not specific information is stored in an individual's brain by measuring a electrical brain wave response to Word, phrases, or picture that are presented on computer screen. Brain Fingerprinting is a controversial forensic science technique that uses electroencephalograph y (EEG to determine whether specific information is stored in a subject's brain

  2. Characterization of recombinant RI beta and evaluation of the presence of RI beta protein in rat brain and testicular extracts.

    Science.gov (United States)

    DeManno, D A; Jackiw, V; Brooks, E; Hunzicker-Dunn, M

    1994-07-21

    Based upon recent reports that the mRNA from the regulatory (R) RI beta subunit of cAMP-dependent protein kinase (PKA) was expressed in testicular extracts, we determined whether testicular extracts exhibited RI beta protein. To accomplish this goal, we initially determined the fundamental labeling and ionic characteristics of recombinant RI beta. Recombinant RI beta eluted from DEAE-cellulose with a salt concentration (of 0.075 M) equivalent to its elution position from soluble mouse brain extracts with catalytic subunit-free RI alpha. As predicted by its amino acid sequence homology to RI alpha, recombinant RI beta was not phosphorylated by PKA but was labeled specifically with 8-azido-adenosine 3':5'-[32P]monophosphate (8-N3[32P]cAMP). Additionally, RI antisera reacted equally with RI alpha (47 kDa) and recombinant RI beta (53 kDa). However, recombinant RI beta exhibited an unexpectedly basic pI of 6.65-6.85. By using a pH gradient for isoelectric focussing that allowed for clear focussing of 8-N3[32P]cAMP-labeled recombinant RI beta, 8-N3[32P]cAMP-labeled RI beta was readily detected by two-dimensional gel electrophoresis in rat brain particulate extracts and exhibited a pI equivalent to that of recombinant RI beta. The 53-kDa RI beta was undetectable either by its immunoreactivity or upon photoaffinity labeling with 8-N3[32P]cAMP by one or two-dimensional gel electrophoresis in soluble or particulate extracts of testes of 14-day-old, 45-day-old, or adult rats or in epididymal sperm. However, 8-N3[32P]cAMP-labeled RI beta was detected, albeit in very small levels, by two-dimensional electrophoresis upon separation of PKAs in testes of 14-day-old rats by DEAE-cellulose chromatography but was absent in equivalent extracts from adult rat testes. These results demonstrate that the unexpectedly basic pI of RI beta allows for its clear separation by two-dimensional electrophoresis from the RII proteins and therefore allows for its unambiguous identification. Further

  3. 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

  4. Molecular cloning and characterization of a novel sequence, vof-16, with enhanced expression in permanent ischemic rat brain.

    Science.gov (United States)

    Tohda, Michihisa; Watanabe, Hiroshi

    2004-08-01

    We reported previously that chronic hypoperfusion induced by permanent occlusion of the bilateral common carotid arteries (2VO) in rats caused progressive cognitive deficits and neuronal damage in the hippocampus and the white matter. These changes are similar to those observed in human dementia. Reverse transcription-polymerase chain reaction (RT-PCR) differential display was carried out to identify mRNAs encoding the intrinsic factors involved in permanent ischemia from the 2VO rat brain. Over 20 clones which showed different expression levels in 2VO and sham-operated rats were isolated. One of these, named vof-16, was markedly enhanced the expression by 2VO. The whole sequence of vof-16 mRNA was 2098 nt. The distribution of vof-16 transcripts was examined by RT-PCR and in situ hybridization. The results revealed that vof-16 was abundant in the hippocampus, the tenia tecta, the piriform cortex and the area around the aorta. The expression levels of vof-16 in 2VO and sham-operated rat hippocampus were determined by a quantitative PCR method. The expression was abundant in the hippocampus of rats with cognitive impairment induced by 2VO. In contrast, the expression levels of vof-16 were lower in the 2VO rats with no impairment and in sham-operated rats. These results suggest that the expression levels of vof-16 may be related to the cognitive impairment induced by chronic ischemia after 2VO. PMID:15305027

  5. Characterization of nicotine binding in mouse brain and comparison with the binding of alpha-bungarotoxin and quinuclidinyl benzilate

    International Nuclear Information System (INIS)

    The binding of [3H]nicotine to mouse brain has been measured and subsequently compared with the binding of [125I]alpha-bungarotoxin (alpha-BTX) and L-[3H]quinuclidinyl benzilate (QNB). The binding of nicotine was saturable, reversible, and stereospecific. The average KD and Bmax were 59 nM and 88 fmoles/mg of protein, respectively. Although the rates of association and dissociation of nicotine were temperature-dependent, the incubation temperature had no effect on either KD or Bmax. When measured at 20 degrees or 37 degrees, nicotine appeared to bind to a single class of binding sites, but a second, very low-affinity, binding site was observed at 4 degrees. Nicotine binding was unaffected by the addition of NaCl, KCl, CaCl2, or MgSO4 to the incubation medium. Nicotinic cholinergic agonists were potent inhibitors of nicotine binding; however, nicotinic antagonists were poor inhibitors. The regional distribution of binding was not uniform: midbrain and striatum contained the highest number of receptors, whereas cerebellum had the fewest. Differences in site densities, regional distribution, inhibitor potencies, and thermal denaturation indicated that nicotine binding was not the same as either QNB or alpha-BTX binding, and therefore that receptors for nicotine may represent a unique population of cholinergic receptors

  6. Imaging and histological characterization of a human brain xenograft in pig: the first induced glioma model in a large animal.

    Science.gov (United States)

    Selek, Laurent; Seigneuret, Eric; Nugue, Guillaume; Wion, Didier; Nissou, Marie France; Salon, Caroline; Seurin, Marie José; Carozzo, Claude; Ponce, Frédérique; Roger, Thierry; Berger, François

    2014-01-15

    The prognosis of glioblastoma remains poor despite significant improvement in cytoreductive surgery, external irradiation and new approach of systemic treatment as antiangiogenic therapy. One of the issues is the low concentration in the infiltrated parenchyma of therapeutic agent administered intravenously mainly due to the blood-brain barrier. An intracerebral injection is advocated to overpass this barrier, this kind of administration need a low flow and continuous injection. The development of sophisticated implanted devices for convection-enhanced delivery is a mandatory step to have a controlled released of a therapeutic agent in glioblastoma treatment. Before testing such a device in a clinical trial a serious preclinical studies are required, in order to test it in realistic conditions we have develop the first induced high grade glioma model in a non-rodent animal: the pig. 21 pigs have been implanted in the parietal lobe with human glioblastoma cell lineage under a chemical immunosuppression by ciclosporine. A MRI follow up was then realized. 15 pigs have been implanted with U87MG, 14 have presented a macroscopic significant tumor, with radiological and anatomapathological characteristics of high grade glioma. 6 pigs were implanted with G6, stem-like cells tumors of glioblastoma, 1 pig develops a macroscopic tumor. This is the first reproducible glioma model in a large animal described, it open the way to preclinical studies to test implanted devices in anatomic realistic conditions, without the ethical issues of a primate use. PMID:24126047

  7. 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.

  8. Biochemical and pharmacological studies of native and irradiated crotamine with gamma radiation of Co60

    International Nuclear Information System (INIS)

    Ionizing radiation can change the molecular structure and affect the biological properties of biomolecules. This has been employed to attenuate animal toxins. Crotamine is a strongly basic polypeptide from South American rattlesnake venom, composed of 42 amino acid residues. It induces skeletal muscle spasms, leading to a spastic paralysis of hind limbs in mice. The objective was to carry out biochemical and pharmacological studies of native and irradiated crotamine with Co. Crotamine was purified from Crotalus durissus terrificus venom by Sephadex G-100 gel filtration followed by ion exchange chromatography, using a Fast performance Liquid Chromatography (FPLC) system. It was irradiated at 2 mg/ml in 0.15 m NaCl with 2.0 kGy gamma radiation emitted by a Co source. Native and irradiated crotamine were evaluated by biochemical characterization, toxic activity (LD50), and biodistribution. The native and irradiated crotamine were labeled with 29.6 MBq of I using chloramine T method and separated in a Sephadex G-50 column. Male Swiss mice (35 @ 5 g) were injected IP with 0.1 mL (2.4x10 cpm/mouse) of I native crotamine or with 0.4 mL (1.3 x 10 cpm/mouse) of I irradiated crotamine. The animals were sacrificed by ether inhalation at 0.08, 0.25, 0.5,1, 2, 3, 4, 8, 12, and 24 hours. Blood, spleen, liver, kidneys, brain, lungs, heart, and skeletal muscle were collected in order to determine radioactivity content. The results showed that gamma radiation did not change protein concentration, electrophoretic profile, or protein primary structure, although differences could be seen by spectroscopic techniques. Gamma radiation reduced crotamine toxicity, but did not eliminate bioactivity. Biodistribution studies showed that native and irradiated crotamine have hepatic metabolism and renal elimination. Native and irradiated crotamine have an affinity to skeletal muscle and did not cross the blood-brain barrier. (author)

  9. Expression patterns of nicotinic subunits α2, α7, α8, and β1 affect the kinetics and pharmacology of ACh-induced currents in adult bee olfactory neuropiles.

    Science.gov (United States)

    Dupuis, Julien Pierre; Gauthier, Monique; Raymond-Delpech, Valérie

    2011-10-01

    Acetylcholine (ACh) is the main excitatory neurotransmitter of the insect brain, where nicotinic acetylcholine receptors (nAChRs) mediate fast cholinergic synaptic transmission. In the honeybee Apis mellifera, nAChRs are expressed in diverse structures including the primary olfactory centers of the brain, the antennal lobes (ALs) and the mushroom bodies (MBs), where they participate in olfactory information processing. To understand the nature and properties of the nAChRs involved in these processes, we performed a pharmacological and molecular characterization of nAChRs on cultured Kenyon cells of the MBs, using whole cell patch-clamp recordings combined with single-cell RT-PCR. In all cells, applications of ACh as well as nicotinic agonists such as nicotine and imidacloprid induced inward currents with fast desensitization. These currents were fully blocked by saturating doses of the antagonists α-bungarotoxin (α-BGT), dihydroxy-β-erythroidine (DHE), and methyllycaconitine (MLA) (MLA ≥ α-BGT ≥ DHE). Molecular analysis of ACh-responding cells revealed that of the 11 nicotinic receptor subunits encoded within the honeybee genome, α2, α8, and β1 subunits were expressed in adult Kenyon cells. Comparison with the expression pattern of adult AL cells revealed the supplementary presence of subunit α7, which could be responsible for the kinetic and pharmacological differences observed when comparing ACh-induced currents from AL and Kenyon cells. Together, our data demonstrate the existence of functional nAChRs on adult MB Kenyon cells that differ from nAChRs on AL cells in both their molecular composition and pharmacological properties, suggesting that changing receptor subsets could mediate different processing functions depending on the brain structure within the olfactory pathway. PMID:21734106

  10. Pharmacologic Agents for Chronic Diarrhea.

    Science.gov (United States)

    Lee, Kwang Jae

    2015-10-01

    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly. PMID:26576135

  11. Prostaglandins: pharmacology and clinical application.

    Science.gov (United States)

    Karim, S M; Hillier, K

    1974-01-01

    Prostaglandin research has been 1 of the most stimulating features of biomedical investigation in the past decade. Interest developed at a time of expanding knowledge of hormonal and neurohormonal behavior and research work received a tremendous impetus in the early 1960s with the elucidation in Sweden of the chemical structures of prostaglandins, followed by the discovery of their biosynthetic pathways. The original findings of large amounts of prostaglandin in the male accessory genital glands and their secretions, and subsequent discovery in the menstrual and amniotic fluids linked these substances with human production. As a result of further investigation, clinical applications of prostaglandins for the induction of labor and termination of early unwanted pregnancies have been developed. Apart from the functions of the prostaglandins in the reproductive area, they have been shown to have a widespread distribution in the body and produce many different pharmacological effects. Prostaglandins are thought to be involved in the regulation of blood pressure and through their vascular effects have therapeutic potential in the treatment of hypertension and peripheral vascular disease. Through their bronchodilator effect, some prostaglandins may become useful in the treatment of asthma. PMID:4611742

  12. Pharmacological challenges in chronic pancreatitis

    Directory of Open Access Journals (Sweden)

    Anne Estrup Olesen

    2013-01-01

    Full Text Available 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.

  13. Bromodomains and their pharmacological inhibitors.

    Science.gov (United States)

    Gallenkamp, Daniel; Gelato, Kathy A; Haendler, Bernard; Weinmann, Hilmar

    2014-03-01

    Over 60 bromodomains belonging to proteins with very different functions have been identified in humans. Several of them interact with acetylated lysine residues, leading to the recruitment and stabilization of protein complexes. The bromodomain and extra-terminal domain (BET) proteins contain tandem bromodomains which bind to acetylated histones and are thereby implicated in a number of DNA-centered processes, including the regulation of gene expression. The recent identification of inhibitors of BET and non-BET bromodomains is one of the few examples in which effective blockade of a protein-protein interaction can be achieved with a small molecule. This has led to major strides in the understanding of the function of bromodomain-containing proteins and their involvement in diseases such as cancer and inflammation. Indeed, BET bromodomain inhibitors are now being clinically evaluated for the treatment of hematological tumors and have also been tested in clinical trials for the relatively rare BRD-NUT midline carcinoma. This review gives an overview of the newest developments in the field, with a focus on the biology of selected bromodomain proteins on the one hand, and on reported pharmacological inhibitors on the other, including recent examples from the patent literature. PMID:24497428

  14. Brain Basics

    Medline Plus

    Full Text Available ... The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are the basic working unit of the ... distant nerve cells (via axons) to form brain circuits. These circuits control specific body functions such as ...

  15. Brain Basics

    Medline Plus

    Full Text Available ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of the brain's structure, studies ...

  16. Brain Basics

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    Full Text Available ... Brain Basics provides information on how the brain works, how mental illnesses are disorders of the brain, ... others live with symptoms of mental illness every day. They can be moderate, or serious and cause ...

  17. Brain Basics

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    Full Text Available ... helps Sarah to better cope with her feelings. Brain Research Modern research tools and techniques are giving scientists ... the treatment for a person's specific conditions. Such brain research help increase the understanding of how the brain ...

  18. Brain Basics

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    Full Text Available ... little dopamine or problems using dopamine in the thinking and feeling regions of the brain may play ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses ...

  19. Brain Basics

    Medline Plus

    Full Text Available ... as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are the basic working unit of the brain ... specialized for the function of conducting messages. A neuron has three basic parts: Cell body which includes ...

  20. Brain Malformations

    Science.gov (United States)

    Most brain malformations begin long before a baby is born. Something damages the developing nervous system or causes it ... medicines, infections, or radiation during pregnancy interferes with brain development. Parts of the brain may be missing, ...

  1. Brain Basics

    Medline Plus

    Full Text Available ... brain's structure, studies show that brain growth in children with autism appears to peak early. And as ... grow there are differences in brain development in children who develop bipolar disorder than children who do ...

  2. Brain Basics

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    Full Text Available ... Basics will introduce you to some of this science, such as: How the brain develops How genes and the environment affect the brain The basic structure of the brain How different parts of ...

  3. Brain Basics

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    Full Text Available ... understanding of the brain than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures ...

  4. Brain Basics

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    Full Text Available ... science, such as: How the brain develops How genes and the environment affect the brain The basic ... that with brain development in people mental disorders. Genes and environmental cues both help to direct this ...

  5. Brain surgery

    Science.gov (United States)

    Craniotomy; Surgery - brain; Neurosurgery; Craniectomy; Stereotactic craniotomy; Stereotactic brain biopsy; Endoscopic craniotomy ... cut depends on where the problem in the brain is located. The surgeon creates a hole in ...

  6. Brain mapping

    OpenAIRE

    Blaž Koritnik

    2004-01-01

    Cartography of the brain ("brain mapping") aims to represent the complexities of the working brain in an understandable and usable way. There are four crucial steps in brain mapping: (1) acquiring data about brain structure and function, (2) transformation of data into a common reference, (3) visualization and interpretation of results, and (4) databasing and archiving. Electrophysiological and functional imaging methods provide information about function of the human brain. A prere...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1987-09-07

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

  8. High Affinity Binding of 3[H]-Cimetidine to a Heme-Containing Protein in Rat Brain

    OpenAIRE

    Stadel, Rebecca; Yang, Jun; Nalwalk, Julia W.; Phillips, James G.; Hough, Lindsay B.

    2007-01-01

    [3H]-Cimetidine (3HCIM) specifically binds to an unidentified site in the rat brain. Because recently-described ligands for this site have pharmacological activity, 3HCIM binding was presently characterized. 3HCIM binding was saturable, heat-labile, and distinct from the histamine H2 receptor. To test the hypothesis that 3HCIM binds to a cytochrome P450 (CYP), the effects of non-selective and isoform-selective CYP inhibitors were studied. The heme inhibitor KCN and the non-selective CYP inhib...

  9. Characterization of Aromatase Expression in the Adult Male and Female Mouse Brain. I. Coexistence with Oestrogen Receptors α and β, and Androgen Receptors

    OpenAIRE

    Davor Stanić; Sydney Dubois; Hui Kheng Chua; Bruce Tonge; Nicole Rinehart; Malcolm K Horne; Wah Chin Boon

    2014-01-01

    Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, in...

  10. The pharmacology of nomegestrol acetate.

    Science.gov (United States)

    Ruan, Xiangyan; Seeger, Harald; Mueck, Alfred O

    2012-04-01

    Nomegestrol acetate (NOMAC) is a 19-norprogesterone derivative with high biological activity at the progesterone receptor, a weak anti-androgenic effect, but with no binding to estrogen, glucocorticoid or mineralocorticoid receptors. At dosages of 1.5mg/day or more, NOMAC effectively suppresses gonadotropic activity and ovulation in women of reproductive age. Hemostasis, lipids and carbohydrate metabolism remain largely unchanged. In normal and cancerous human breast cells, NOMAC has shown favorable effects on estrogen metabolism. Like natural progesterone (but in contrast to some other synthetic progestogens), it does not appear stimulate the proliferation of cancerous breast cells. While there has been some experience of the use of NOMAC in combination with estrogens as a hormone replacement therapy, most of the data on the compound are reported in the context of its inclusion as a component of a new contraceptive pill comprising 2.5mg NOMAC combined with 1.5mg estradiol. Because of its strong endometrial efficacy, and due to its high antigonadotropic activity and long elimination half-life (about 50h), the contraceptive efficacy of the new pill is maintained even when dosages are missed. Furthermore, for the first time with a monophasic 24/4 regimen containing estradiol, cyclical stability can be achieved comparable with that obtained using pills containing ethinyl estradiol and progestogens like levonorgestrel or drospirenone. The addition of NOMAC to estradiol means that the beneficial effects of estrogen are not lost, which is of especial importance in relation to the cardiovascular system. On the basis both of its pharmacology and of studies performed during the development of the NOMAC/estradiol pill, involving some 4000 women in total, good long-term tolerability can be expected for NOMAC, although its safety profile is still to be fully ascertained, as the clinical endpoint studies are yet to be completed. PMID:22364709

  11. Pharmacologic treatment of migraine. Comparison of guidelines.

    NARCIS (Netherlands)

    Schuurmans, A.; Weel, C. van

    2005-01-01

    OBJECTIVE: To compare guidelines (not the primary studies) for pharmacologic treatment of migraine as to methods of guideline development; recommendations, particularly on triptans; and quality of supporting evidence (with emphasis on comparative studies of triptans versus ergot alkaloids and nonste

  12. Occurrence of two somatostatin variants in the frog brain: characterization of the cDNAs, distribution of the mRNAs, and receptor-binding affinities of the peptides.

    OpenAIRE

    Tostivint, H; Lihrmann, I; Bucharles, C; Vieau, D; Coulouarn, Y; A. Fournier; Conlon, J M; Vaudry, H.

    1996-01-01

    In tetrapods, only one gene encoding a somatostatin precursor has been identified so far. The present study reports the characterization of the cDNA clones that encode two distinct somatostatin precursors in the brain of the frog Rana ridibunda. The cDNAs were isolated by using degenerate oligonucleotides based on the sequence of the central region of somatostatin to screen a frog brain cDNA library. One of the cDNAs encodes a 115-amino acid protein (prepro-somatostatin-14; PSS1) that exhibit...

  13. CASSIA TORA: A PHYTO-PHARMACOLOGICAL OVERVIEW

    OpenAIRE

    Das Chandan; Dash Sujit; Sahoo Durga Charan; Mohanty Arnabaditya; Rout Dolley

    2011-01-01

    Cassia tora, a popular Indian medicinal plant, has long been used in Ayurvedic system of medicine. The plant has been found to possess diverse number of pharmacological activities. The present paper gives an account of updated information on its phytochemical and pharmacological activities. The review reveals that wide range of phytochemical constituents have been isolated from the plant and it possess important activities like laxative, skin diseases, ringworm, eye diseases, liver complaint,...

  14. Methods in pharmacology: measurement of cardiac output

    OpenAIRE

    Geerts, Bart F; Aarts, Leon P; Jansen, Jos R.

    2011-01-01

    Many methods of cardiac output measurement have been developed, but the number of methods useful for human pharmacological studies is limited. The ‘holy grail’ for the measurement of cardiac output would be a method that is accurate, precise, operator independent, fast responding, non-invasive, continuous, easy to use, cheap and safe. This method does not exist today. In this review on cardiac output methods used in pharmacology, the Fick principle, indicator dilution techniques, arterial pul...

  15. Pharmacological treatment of depression in older people

    OpenAIRE

    Curran, Stephen; Byrne, Andrew; Wattis, John

    2006-01-01

    In the light of recent National Institute for Clinical Excellence (NICE) and Committee for the Safety of Medicines (CSM) guidance we discuss the importance of the diagnosis of depression in old age and review pharmacological interventions. An introductory section is followed by sections on each of the main antidepressant groups. This briefly describes their pharmacology and reviews research done specifically relevant to older people. Finally practical clinical applications are discussed.

  16. Methodological innovations expand the safety pharmacology horizon.

    Science.gov (United States)

    Pugsley, M K; Curtis, M J

    2012-09-01

    Almost uniquely in pharmacology, drug safety assessment is driven by the need for elaboration and validation of methods for detecting drug actions. This is the 9th consecutive year that the Journal of Pharmacological and Toxicological Methods (JPTM) has published themed issues arising from the annual meeting of the Safety Pharmacology Society (SPS). The SPS is now past its 10th year as a distinct (from pharmacology to toxicology) discipline that integrates safety pharmacologists from industry with those in academia and the various global regulatory authorities. The themes of the 2011 meeting were (i) the bridging of safety assessment of a new chemical entity (NCE) between all the parties involved, (ii) applied technologies and (iii) translation. This issue of JPTM reflects these themes. The content is informed by the regulatory guidance documents (S7A and S7B) that apply prior to first in human (FIH) studies, which emphasize the importance of seeking model validation. The manuscripts encompass a broad spectrum of safety pharmacology topics including application of state-of-the-art techniques for study conduct and data processing and evaluation. This includes some exciting novel integrated core battery study designs, refinements in hemodynamic assessment, arrhythmia analysis algorithms, and additionally an overview of safety immunopharmacology, and a brief survey discussing similarities and differences in business models that pharmaceutical companies employ in safety pharmacology, together with SPS recommendations on 'best practice' for the conduct of a non-clinical cardiovascular assessment of a NCE. PMID:22617368

  17. Brain Basics

    Medline Plus

    Full Text Available ... in Real Life Brain Research Glossary Brain Basics (PDF, 10 pages) Introduction Watch the Brain Basics video ... early brain development, and may also assist in learning and memory. ... rise to disabilities or diseases. neural circuit —A network of neurons ...

  18. Brain Basics

    Medline Plus

    Full Text Available ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of the brain's structure, studies show that brain growth in children with autism appears to peak early. And as ...

  19. Brain Basics

    Medline Plus

    Full Text Available ... Research Modern research tools and techniques are giving scientists a more detailed understanding of the brain than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of the brain's structure, studies ...

  20. Brain Basics

    Medline Plus

    Full Text Available ... Welcome. Brain Basics provides information on how the brain works, how mental illnesses are disorders of the brain, ... highly developed area at the front of the brain that, in humans, plays a role in executive functions such as ...

  1. Pharmacological properties of homomeric and heteromeric GluR1o and GluR3o receptors

    DEFF Research Database (Denmark)

    Nielsen, B S; Banke, T G; Schousboe, A; Pickering, Darryl

    .1+/-2.9. The pharmacological profiles of these receptors resembled that of native rat brain AMPA receptors: AMPA analogues > L-glutamate > quinoxaline-2,3-diones > kainate. In the Xenopus oocyte expression system we had previously shown that the agonist (R,S)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl...

  2. Synthesis and preliminary pharmacological evaluation of a new putative radioiodinated AMPA receptor ligand for molecular imaging

    International Nuclear Information System (INIS)

    A new (radio)iodinated AMPA receptor ligand has been developed and pharmacologically evaluated in vitro and ex vivo using rodents. The new radioligand was directly labeled by electrophilic radioiodo-destannylation with iodine-131 in high radiochemical yields of 97% within 2 min. The new radioligand showed an excellent initial brain uptake of 2.1%ID/g at 10 min post injection, but a fast wash-out reduced the uptake by about 10-fold at 60 min post injection. Due to high nonspecific binding accompanied with a uniform distribution in brain tissue, however, the new radiotracer appears not suitable for AMPA receptor imaging in vivo.

  3. Cytokines and brain excitability

    OpenAIRE

    Galic, Michael A.; Riazi, Kiarash; Pittman, Quentin J.

    2011-01-01

    Cytokines are molecules secreted by peripheral immune cells, microglia, astrocytes and neurons in the central nervous system. Peripheral or central inflammation is characterized by an upregulation of cytokines and their receptors in the brain. Emerging evidence indicates that pro-inflammatory cytokines modulate brain excitability. Findings from both the clinical literature and from in vivo and in vitro laboratory studies suggest that cytokines can increase seizure susceptibility and may be in...

  4. Brain mapping

    Directory of Open Access Journals (Sweden)

    Blaž Koritnik

    2004-08-01

    Full Text Available Cartography of the brain ("brain mapping" aims to represent the complexities of the working brain in an understandable and usable way. There are four crucial steps in brain mapping: (1 acquiring data about brain structure and function, (2 transformation of data into a common reference, (3 visualization and interpretation of results, and (4 databasing and archiving. Electrophysiological and functional imaging methods provide information about function of the human brain. A prerequisite for multisubject, multidimensional and multimodal mapping is transformation of individual images to match a standard brain template. To produce brain maps, color, contours, and other visual cues are used to differentiate metabolic rates, electrical field potentials, receptor densities, and other attributes of structure or function. Databases are used to organize and archive data records. By relating the maps to cognitive functions and psychological models, brain mapping offers a prerequisite for the understanding of organizational principles of the human brain.

  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

    2014-09-01

    Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU. PMID:24487571

  6. Quantitative autoradiography of ligands for dopamine receptors and transporters in brain of Göttingen minipig: comparison with results in vivo

    DEFF Research Database (Denmark)

    Minuzzi, Luciano; Alstrup, Aage Kristian Olsen; 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......, the saturation binding parameters of [3H]SCH 23390 for DA D1 receptors and [3H]raclopride for DA D2/3 receptors were measured by quantitative autoradiography in cryostat sections from brain of groups of 8 week old and adult female Göttingen minipigs. The magnitudes of Bmax and Kd for these ligands...... were similar 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...

  7. Drug targeting to the brain.

    Science.gov (United States)

    Pardridge, William M

    2007-09-01

    The goal of brain drug targeting technology is the delivery of therapeutics across the blood-brain barrier (BBB), including the human BBB. This is accomplished by re-engineering pharmaceuticals to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium. Certain endogenous peptides, such as insulin or transferrin, undergo receptor-mediated transport (RMT) across the BBB in vivo. In addition, peptidomimetic monoclonal antibodies (MAb) may also cross the BBB via RMT on the endogenous transporters. The MAb may be used as a molecular Trojan horse to ferry across the BBB large molecule pharmaceuticals, including recombinant proteins, antibodies, RNA interference drugs, or non-viral gene medicines. Fusion proteins of the molecular Trojan horse and either neurotrophins or single chain Fv antibodies have been genetically engineered. The fusion proteins retain bi-functional properties, and both bind the BBB receptor, to trigger transport into brain, and bind the cognate receptor inside brain to induce the pharmacologic effect. Trojan horse liposome technology enables the brain targeting of non-viral plasmid DNA. Molecular Trojan horses may be formulated with fusion protein technology, avidin-biotin technology, or Trojan horse liposomes to target to brain virtually any large molecule pharmaceutical. PMID:17554607

  8. SECONDARY BRAIN INJURY

    Directory of Open Access Journals (Sweden)

    Ida Ayu Basmatika

    2013-03-01

    Full Text Available Secondary brain injury is a condision that occurs at some times after the primary impact and can be largely prevented and treated. Most brain injury ends with deadly consequences which is caused by secondary damage to the brain. Traumatic brain injured still represents the leading cause of morbidity and mortality in individuals under the age of 45 years in the world. The classification of secondary brain injured is divided into extracranial and intracranial causes. The cause of extracranial such as hipoxia, hypotensi, hyponatremia, hypertermia, hypoglycemia or hyperglycemia. The cause of intracranial such as extradural, subdural, intraserebral, intraventrikular, dan subarachnoid hemorrhage. Beside that secondary injury can also be caused by edema and infection. Post-traumatic cerebral injured is characterized by direct tissue damage, impaired regulation of cerebral blood flow (cerebral blood flow / CBF, and disruption of metabolism. Manifestations of secondary brain injured include increased intracranial pressure, ischemic brain damage, cerebral hypoxia and hypercarbi, as well as disruption of cerebral autoregulation. The first priority is to stabilize the patient's cervical spine injury, relieve and maintain airway, ensure adequate ventilation (breathing, and making venous access for fluid resuscitation pathways (circulation and assessing the level of awareness and disability. This steps is crucial in patients with head injured to prevent hypoxia and hypotension, which is the main cause of secondary brain injury.

  9. Valproic acid modulates brain plasticity through epigenetic chromatin remodeling in the blind rat: implications for human sight recovery.

    Science.gov (United States)

    Fetter-Pruneda, I; Martínez-Méndez, R; Olivos-Cisneros, L; Diaz, D; Padilla-Cortés, P; Báez-Saldaña, A; Gutiérrez-Ospina, G

    2011-01-01

    Blindness is a pervasive sensory condition that imposes diverse difficulties to carry on with activities of daily living. In blind individuals, the brain is subjected to a large scale reorganization characterized by expanded cortical territories associated with somatosensory and auditory functions and the recruitment of the former visual areas to perform bimodal somatosensory and auditory integration. This poses obstacles to efforts aimed at reassigning visual functions to the recruited visual cortex in the blind, especially after the end of the ontogentic sensitive period. Devising pharmacological measures to modulate the magnitude of brain plasticity could improve our chances of recovering visual functions in the blind. Here, by using the primary somatosensory cortex (S1) in the rat as a working model, we showed that valproic acid administered through the mother's milk prevents cortical reorganization in blinded rats by delaying neuronal histone de-acetylation. These results suggest that in the future, we might be able to devise epigenetic pharmacological measures that could improve our chances of reassigning visual functions to the once deprived former visual cortex in the blind, by modulating the magnitude of brain plasticity during critical times of development. PMID:22423589

  10. 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...

  11. Gabapentin in the management of dysautonomia following severe traumatic brain injury: a case series

    DEFF Research Database (Denmark)

    Baguley, Ian J; Heriseanu, Roxana E; Gurka, Joseph A;

    2007-01-01

    The pharmacological management of dysautonomia, otherwise known as autonomic storms, following acute neurological insults, is problematic and remains poorly researched. This paper presents six subjects with dysautonomia following extremely severe traumatic brain injury where gabapentin controlled...

  12. Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid

    DEFF Research Database (Denmark)

    Frydenvang, Karla Andrea; Pickering, Darryl S; Greenwood, Jeremy R;

    2010-01-01

    We describe an improved synthesis and detailed pharmacological characterization of the conformationally restricted analogue of the naturally occurring nonselective glutamate receptor agonist ibotenic acid (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA, 5) at A...

  13. Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist.

    Science.gov (United States)

    Zhang, Minli; Zhou, Diansong; Wang, Yi; Maier, Donna L; Widzowski, Daniel V; Sobotka-Briner, Cynthia D; Brockel, Becky J; Potts, William M; Shenvi, Ashok B; Bernstein, Peter R; Pierson, M Edward

    2011-11-01

    The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT(1B) receptor (K(i), 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC(50) values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients. PMID:21825000

  14. Conotoxins: Structure, Therapeutic Potential and Pharmacological Applications.

    Science.gov (United States)

    Mir, Rafia; Karim, Sajjad; Kamal, Mohammad Amjad; Wilson, Cornelia M; Mirza, Zeenat

    2016-01-01

    Cone snails, also known as marine gastropods, from Conus genus produce in their venom a diverse range of small pharmacologically active structured peptides called conotoxins. The cone snail venoms are widely unexplored arsenal of toxins with therapeutic and pharmacological potential, making them a treasure trove of ligands and peptidic drug leads. Conotoxins are small disulfide bonded peptides, which act as remarkable selective inhibitors and modulators of ion channels (calcium, sodium, potassium), nicotinic acetylcholine receptors, noradrenaline transporters, N-methyl-D-aspartate receptors, and neurotensin receptors. They are highly potent and specific against several neuronal targets making them valuable as research tools, drug leads and even therapeutics. In this review, we discuss their gene superfamily classification, nomenclature, post-translational modification, structural framework, pharmacology and medical applications of the active conopeptides. We aim to give an overview of their structure and therapeutic potential. Understanding these aspects of conopeptides will help in designing more specific peptidic analogues. PMID:26601961

  15. Towards a genealogy of pharmacological practice.

    Science.gov (United States)

    Camargo, Ricardo; Ried, Nicolás

    2016-03-01

    Following Foucault's work on disciplinary power and biopolitics, this article maps an initial cartography of the research areas to be traced by a genealogy of pharmacological practice. Pharmacology, as a practical activity, refers to the creation, production and sale of drugs/medication. This work identifies five lines of research that, although often disconnected from each other, may be observed in the specialized literature: (1) pharmaceuticalization; (2) regulation of the pharmaceutical industry; (3) the political-economic structure of the pharmaceutical industry; (4) consumption/consumerism of medications; (5) and bio-knowledge. The article suggests that a systematic analysis of these areas leads one to consider pharmacological practice a sui generis apparatus of power, which reaches beyond the purely disciplinary and biopolitical levels to encompass molecular configurations, thereby giving rise not only to new types of government over life, but also to new struggles for life, extending from molecular to population-wide levels. PMID:25956710

  16. Pharmacological action and mechanisms of ginkgolide B

    Institute of Scientific and Technical Information of China (English)

    XIA Shi-hai; FANG Dian-chun

    2007-01-01

    Objective To review the recent research progress in pharmacological actions and mechanisms of ginkgolide B.Data sources Information included in this article was identified by searching of PUBMED (1987-2006) online resources using the key terms "ginkgolide B", "platelet activating factor", and "pharmacological".Study selection Mainly original milestone articles and critical reviews written by major pioneer investigators of the field were selected.Results The key issues related to the pharmacological actions and mechanisms of ginkgolide B were summarized. The ginkgolide B possesses a number of beneficial effects such as anti-inflammatory, anti-allergic, antioxidant, and neuroprotective effects. Meantime, their mechaniams were discussed.Conclusions The Ginkgolide B is the most potent antagonist of platelet activating factor (PAF) and exhibits therapeutic action in a variety of diseases mainly by the PAF receptor.

  17. Brain Basics

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    Full Text Available ... the anatomy, physiology, and chemistry of the nervous system. When the brain cannot effectively coordinate the billions ... basic working unit of the brain and nervous system. These cells are highly specialized for the function ...

  18. Brain Basics

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    Full Text Available ... the brain cannot effectively coordinate the billions of cells in the body, the results can affect many ... unit of the brain and nervous system. These cells are highly specialized for the function of conducting ...

  19. Brain Basics

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    Full Text Available ... Neurons & Neural Circuits Neurons are the basic working unit of the brain and nervous system. These cells ... A nerve cell that is the basic, working unit of the brain and nervous system, which processes ...

  20. Brain Basics

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    Full Text Available ... Trials — Participants Statistics Help for Mental Illnesses Outreach Research Priorities Funding Labs at NIMH News About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The ...

  1. Brain Basics

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    Full Text Available ... brain may play a role in disorders like schizophrenia or attention deficit hyperactivity disorder (ADHD) . Glutamate —the ... mental disorders, including autism , obsessive compulsive disorder (OCD) , schizophrenia , and depression . Brain Regions Just as many neurons ...

  2. Brain Basics

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    Full Text Available ... medical professionals who can diagnose mental disorders are psychologists or clinical social workers. The psychiatrist asked Sarah ... important research tool in understanding how the brain functions. Another type of brain scan called magnetoencephalography, or ...

  3. Brain Basics

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    Full Text Available ... normal brain development and function can go awry, leading to mental illnesses. Brain Basics will introduce you ... of DNA. Sometimes this copying process is imperfect, leading to a gene mutation that causes the gene ...

  4. Brain Basics

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    Full Text Available ... and epigenetic changes can be passed on to future generations. Further understanding of genes and epigenetics may ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses ...

  5. Brain Basics

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    Full Text Available ... works in healthy people, and how normal brain development and function can go awry, leading to mental ... and are working to compare that with brain development in people mental disorders. Genes and environmental cues ...

  6. Brain Basics

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    Full Text Available ... body, the results can affect many aspects of life. Scientists are continually learning more about how the brain grows and works in healthy people, and how normal brain development and function ...

  7. Brain Basics

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    Full Text Available ... problems using dopamine in the thinking and feeling regions of the brain may play a role in ... obsessive compulsive disorder (OCD) , schizophrenia , and depression . Brain Regions Just as many neurons working together form a ...

  8. Brain Basics

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    Full Text Available ... medications could reduce the amount of trial and error and frustration that many people with depression experience ... early brain development, and may also assist in learning and memory. hippocampus —A portion of the brain ...

  9. Brain Basics

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    Full Text Available ... Brain Basics will introduce you to some of this science, such as: How the brain develops How ... cell, and responds to signals from the environment; this all helps the cell maintain its balance with ...

  10. Brain Basics

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    Full Text Available ... Life Brain Basics in Real Life—How Depression affects the Brain Meet Sarah Sarah is a middle- ... However, recent research points to a possible new class of antidepressants that can relieve symptoms of the ...

  11. Brain Basics

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    Full Text Available ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses ... depression experience when starting treatment. Gene Studies Advanced technologies are also making it faster, easier, and more ...

  12. Brain Basics

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    Full Text Available ... have been linked to many mental disorders, including autism , obsessive compulsive disorder (OCD) , schizophrenia , and depression . Brain ... studies show that brain growth in children with autism appears to peak early. And as they grow ...

  13. Brain Basics

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    Full Text Available ... body, the results can affect many aspects of life. Scientists are continually learning more about how the brain grows and works in healthy people, and how normal brain development ...

  14. Brain Diseases

    Science.gov (United States)

    The brain is the control center of the body. It controls thoughts, memory, speech, and movement. It regulates the function of many organs. When the brain is healthy, it works quickly and automatically. However, ...

  15. Brain Basics

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    Full Text Available ... working unit of the brain and nervous system. These cells are highly specialized for the function of ... nerve cells (via axons) to form brain circuits. These circuits control specific body functions such as sleep ...

  16. Brain Basics

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    Full Text Available ... mainly involved in controlling movement and aiding the flow of information to the front of the brain, ... the neuron will fire. This enhances the electrical flow among brain cells required for normal function and ...

  17. Brain Basics

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    Full Text Available ... speech. The brain continues maturing well into a person's early 20s. Knowing how the brain is wired ... in Parkinson's disease, a disorder that affects a person's ability to move as they want to, resulting ...

  18. Brain Basics

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    Full Text Available ... of brain scan called magnetoencephalography, or MEG, can capture split-second changes in the brain. Using MEG, ... The study of how environmental factors like diet, stress and post-natal care can change gene expression ( ...

  19. Brain Basics

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    Full Text Available ... neurons, the most highly specialized cells of all, conduct messages. Every cell in our bodies contains a ... brain's structure, studies show that brain growth in children with autism appears to peak early. And as ...

  20. Brain Basics

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    Full Text Available ... can be related to changes in the anatomy, physiology, and chemistry of the nervous system. When the ... healthy people, and how normal brain development and function can go awry, leading to mental illnesses. Brain ...

  1. Brain Basics

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    Full Text Available ... Real Life Brain Basics in Real Life—How Depression affects the Brain Meet Sarah Sarah is a ... volunteers PubMed Central: An archive of life sciences journals NIH Research Fact Sheets NIH Office of Science ...

  2. Brain Basics

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    Full Text Available ... How the brain develops How genes and the environment affect the brain The basic structure of the ... inside contents of the cell from its surrounding environment and controls what enters and leaves the cell, ...

  3. Brain Basics

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    Full Text Available ... how the brain works, how mental illnesses are disorders of the brain, and ongoing research that helps us better understand and treat disorders. Mental disorders are common. You may have a ...

  4. Brain Basics

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    Full Text Available ... affect many aspects of life. Scientists are continually learning more about how the brain grows and works ... early brain development. It may also assist in learning and memory. Problems in making or using glutamate ...

  5. Brain Basics

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    Full Text Available ... all. She was happily married and successful in business. Then, after a serious setback at work, she ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses ...

  6. Brain Basics

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    Full Text Available ... and the environment affect the brain The basic structure of the brain How different parts of the ... for the cell to work properly including small structures called cell organelles. Dendrites branch off from the ...

  7. Brain Basics

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    Full Text Available ... may help improve treatments for anxiety disorders like phobias or post-traumatic stress disorder (PTSD) . Prefrontal cortex ( ... brain's structure, studies show that brain growth in children with autism appears to peak early. And as ...

  8. Brain Basics

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    Full Text Available ... Real Life Brain Basics in Real Life—How Depression affects the Brain Meet Sarah Sarah is a ... blues" from time to time. In contrast, major depression is a serious disorder that lasts for weeks. ...

  9. Pharmacological evaluation of bee venom and melittin

    OpenAIRE

    Camila G. Dantas; Tássia L.G.M. Nunes; Tâmara L.G.M. Nunes; Ailma O. da Paixão; Francisco P. Reis; Waldecy de L. Júnior; Juliana C. Cardoso; Kátia P. Gramacho; Gomes, Margarete Z

    2014-01-01

    The objective of this study was to identify the pharmacological effects of bee venom and its major component, melittin, on the nervous system of mice. For the pharmacological analysis, mice were treated once with saline, 0.1 or 1.2 mg/kg of bee venom and 0.1 mg/kg of melittin, subcutaneously, 30 min before being submitted to behavioral tests: locomotor activity and grooming (open-field), catalepsy, anxiety (elevated plus-maze), depression (forced swimming test) and apomorphine-induced stereot...

  10. CASSIA TORA: A PHYTO-PHARMACOLOGICAL OVERVIEW

    Directory of Open Access Journals (Sweden)

    Das Chandan

    2011-04-01

    Full Text Available Cassia tora, a popular Indian medicinal plant, has long been used in Ayurvedic system of medicine. The plant has been found to possess diverse number of pharmacological activities. The present paper gives an account of updated information on its phytochemical and pharmacological activities. The review reveals that wide range of phytochemical constituents have been isolated from the plant and it possess important activities like laxative, skin diseases, ringworm, eye diseases, liver complaint, dysentery and anthelmentic. Various other activities like antioxidant, hypoglycemic, hypolipidemic, antinociceptive, antiplasmodial, antifungal & antimicrobial, hyperlipemia & hypotensive have also been reported. These reports are very encouraging and indicate that herb should be studied more extensively for its therapeutic benefits.

  11. PHYTO-PHARMACOLOGICAL REVIEW OF ARGYREIA NERVOSA

    Directory of Open Access Journals (Sweden)

    A. Krishnaveni

    2011-02-01

    Full Text Available Herbal medicines are the significant and reliable sources for treating various diseases. Argyreia nervosa is traditionally used in wound healing, syphilius,diuretics,rheumatic affections, leucohorrhoea.,cerebral disorders, ulcers, as anti-tumour and to prevent contraception.Phytoconstituents such as flavanoids, steroids, ergoline alkaloids and triterpenoids were identified. Pharmacological studies proved its anticonvulsant, immunomodulatory, hypotensive, anti- inflammatory and nootropic effect.The present form of article highlights the phytochemical and pharmacological studies including traditional practice of Argyreia nervosa have been carried out so far.

  12. Characterization of the Roman lines/strains of rats as a genetic model of psychiatric disorders: a behavioral and brain dialysis study

    OpenAIRE

    Piludu, Maria Antonietta

    2016-01-01

    State of the art Depressive disorders are fairly prevalent in the general population, with a higher rate in women compared to men, are disabling, since they can significantly impair psychosocial functioning, and are typically associated with high mortality due mainly to the high rate of suicides but also to the negative impact that depression has on the course of co-occurring illnesses. In addition, pharmacological and psychological antidepressant therapies in use have a limited efficacy and/...

  13. Brain Basics

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    Full Text Available ... pituitary-adrenal (HPA) axis. Brain Basics in Real Life Brain Basics in Real Life—How Depression affects the Brain Meet Sarah Sarah ... having trouble coping with the stresses in her life. She began to think of suicide because she ...

  14. Brain Basics

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    Full Text Available ... Life Brain Basics in Real Life—How Depression affects the Brain Meet Sarah Sarah is a middle-aged woman ... new memories. hypothalmic-pituitary-adrenal (HPA) axis —A brain-body ... stress. impulse —An electrical communication signal sent between neurons ...

  15. Brain Aneurysm

    Science.gov (United States)

    A brain aneurysm is an abnormal bulge or "ballooning" in the wall of an artery in the brain. They are sometimes called berry aneurysms because they ... often the size of a small berry. Most brain aneurysms produce no symptoms until they become large, ...

  16. Brain Basics

    Medline Plus

    Full Text Available ... other cells guide neurons in forming various brain structures. Neighboring neurons make connections with each other and with distant nerve cells (via axons) to form brain circuits. These circuits control specific body functions such as sleep and speech. The brain continues ...

  17. Left Brain. Right Brain. Whole Brain

    Science.gov (United States)

    Farmer, Lesley S. J.

    2004-01-01

    As the United States student population is becoming more diverse, library media specialists need to find ways to address these distinctive needs. However, some of these differences transcend culture, touching on variations in the brain itself. Most people have a dominant side of the brain, which can affect their personality and learning style.…

  18. Physician attitudes towards pharmacological cognitive enhancement: safety concerns are paramount.

    Science.gov (United States)

    Banjo, Opeyemi C; Nadler, Roland; Reiner, Peter B

    2010-01-01

    The ethical dimensions of pharmacological cognitive enhancement have been widely discussed in academic circles and the popular media, but missing from the conversation have been the perspectives of physicians - key decision makers in the adoption of new technologies into medical practice. We queried primary care physicians in major urban centers in Canada and the United States with the aim of understanding their attitudes towards cognitive enhancement. Our primary hypothesis was that physicians would be more comfortable prescribing cognitive enhancers to older patients than to young adults. Physicians were presented with a hypothetical pharmaceutical cognitive enhancer that had been approved by the regulatory authorities for use in healthy adults, and was characterized as being safe, effective, and without significant adverse side effects. Respondents overwhelmingly reported increasing comfort with prescribing cognitive enhancers as the patient age increased from 25 to 65. When asked about their comfort with prescribing extant drugs that might be considered enhancements (sildenafil, modafinil, and methylphenidate) or our hypothetical cognitive enhancer to a normal, healthy 40 year old, physicians were more comfortable prescribing sildenafil than any of the other three agents. When queried as to the reasons they answered as they did, the most prominent concerns physicians expressed were issues of safety that were not offset by the benefit afforded the individual, even in the face of explicit safety claims. Moreover, many physicians indicated that they viewed safety claims with considerable skepticism. It has become routine for safety to be raised and summarily dismissed as an issue in the debate over pharmacological cognitive enhancement; the observation that physicians were so skeptical in the face of explicit safety claims suggests that such a conclusion may be premature. Thus, physician attitudes suggest that greater weight be placed upon the balance between

  19. Physician attitudes towards pharmacological cognitive enhancement: safety concerns are paramount.

    Directory of Open Access Journals (Sweden)

    Opeyemi C Banjo

    Full Text Available The ethical dimensions of pharmacological cognitive enhancement have been widely discussed in academic circles and the popular media, but missing from the conversation have been the perspectives of physicians - key decision makers in the adoption of new technologies into medical practice. We queried primary care physicians in major urban centers in Canada and the United States with the aim of understanding their attitudes towards cognitive enhancement. Our primary hypothesis was that physicians would be more comfortable prescribing cognitive enhancers to older patients than to young adults. Physicians were presented with a hypothetical pharmaceutical cognitive enhancer that had been approved by the regulatory authorities for use in healthy adults, and was characterized as being safe, effective, and without significant adverse side effects. Respondents overwhelmingly reported increasing comfort with prescribing cognitive enhancers as the patient age increased from 25 to 65. When asked about their comfort with prescribing extant drugs that might be considered enhancements (sildenafil, modafinil, and methylphenidate or our hypothetical cognitive enhancer to a normal, healthy 40 year old, physicians were more comfortable prescribing sildenafil than any of the other three agents. When queried as to the reasons they answered as they did, the most prominent concerns physicians expressed were issues of safety that were not offset by the benefit afforded the individual, even in the face of explicit safety claims. Moreover, many physicians indicated that they viewed safety claims with considerable skepticism. It has become routine for safety to be raised and summarily dismissed as an issue in the debate over pharmacological cognitive enhancement; the observation that physicians were so skeptical in the face of explicit safety claims suggests that such a conclusion may be premature. Thus, physician attitudes suggest that greater weight be placed upon the

  20. Alternative Radioligands for Investigating the Molecular Pharmacology of Melatonin Receptors.

    Science.gov (United States)

    Legros, Céline; Brasseur, Chantal; Delagrange, Philippe; Ducrot, Pierre; Nosjean, Olivier; Boutin, Jean A

    2016-03-01

    Melatonin exerts a variety of physiologic activities that are mainly relayed through the melatonin receptors MT1 and MT2 Low expressions of these receptors in tissues have led to widespread experimental use of the agonist 2-[(125)I]-iodomelatonin as a substitute for melatonin. We describe three iodinated ligands: 2-(2-[(2-iodo-4,5-dimethoxyphenyl)methyl]-4,5-dimethoxy phenyl) (DIV880) and (2-iodo-N-2-[5-methoxy-2-(naphthalen-1-yl)-1H-pyrrolo[3,2-b]pyridine-3-yl])acetamide (S70254), which are specific ligands at MT2 receptors, and N-[2-(5-methoxy-1H-indol-3-yl)ethyl]iodoacetamide (SD6), an analog of 2-[(125)I]-iodomelatonin with slightly different characteristics. Here, we further characterized these new ligands with regards to their molecular pharmacology. We performed binding experiments, saturation assays, association/dissociation rate measurements, and autoradiography using sheep and rat tissues and recombinant cell lines. Our results showed that [(125)I]-S70254 is receptor, and can be used with both cells and tissue. This radioligand can be used in autoradiography. Similarly, DIV880, a partial agonist [43% of melatonin on guanosine 5'-3-O-(thio)triphosphate binding assay], selective for MT2, can be used as a tool to selectively describe the pharmacology of this receptor in tissue samples. The molecular pharmacology of both human melatonin receptors MT1 and MT2, using a series of 24 ligands at these receptors and the new radioligands, did not lead to noticeable variations in the profiles. For the first time, we described radiolabeled tools that are specific for one of the melatonin receptors (MT2). These tools are amenable to binding experiments and to autoradiography using sheep or rat tissues. These specific tools will permit better understanding of the role and implication in physiopathologic processes of the melatonin receptors. PMID:26759496

  1. Secondary metabolites from natural sources: chemical and pharmacological characterization

    OpenAIRE

    Festa, Carmen

    2010-01-01

    Natural products have long been a source of bioactive metabolites utilized for the treatment of human disease. In spite the impressive progress of new competing methodologies, as for example, combinatorial chemistry and high-throughput screening or genetic engineering, natural products remain a valuable source of bioactive compounds with therapeutic potential. In recent years, the marine environment has been seen as a vast resource for the discovery of structurally unique bioactive secon...

  2. PHARMACOLOGICAL CHARACTERIZATION OF TERPENIC SECONDARY METABOLITES ISOLATED FROM SALVIA SPECIES

    OpenAIRE

    Bonito, Maria Carmela

    2009-01-01

    Recently most interest has been focused on active compounds extracted from natural sources. This is due to the fact that many of these natural products in plants of medicinal value can offer new sources of drugs. The genus Salvia from the Lamiaceae family has numerous different species - about 900 species- which are extensively distributed in various regions of the world. Many Salvia species are well-studied and widely used in traditional medicine. Plants belonging to the genus Salvia are ...

  3. Design, synthesis, and pharmacological characterization of polyamine toxin derivatives

    DEFF Research Database (Denmark)

    Jensen, Lars S; Bølcho, Ulrik; Egebjerg, Jan; Strømgaard, Kristian

    2006-01-01

    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 for...

  4. Pharmacological characterization of the sulphonylurea receptor in rat isolated aorta

    OpenAIRE

    Löffler, Cornelia; Quast, Ulrich

    1997-01-01

    The binding of the sulphonylurea [3H]-glibenclamide, a blocker of adenosine 5′-triphosphate (ATP)-sensitive K+ channels (KATP channels), was studied in endothelium-denuded rings from rat aorta.[3H]-glibenclamide labelled two classes of binding sites with KD values of 20±5 nM and 32±1 μM. The high affinity component, which comprised 17% of total binding at 1 nM [3H]-glibenclamide, had an estimated binding capacity of 150 fmol mg−1 wet weight.Other sulphonylureas such as glipizide and glibornur...

  5. The Pharmacological Activities of (−-Anonaine

    Directory of Open Access Journals (Sweden)

    Chung-Yi Chen

    2013-07-01

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

  6. Plant cannabinoids: a neglected pharmacological treasure trove

    OpenAIRE

    Mechoulam, Raphael

    2005-01-01

    Most of the cannabinoids in Cannabis sativa L. have not been fully evaluated for their pharmacological activity. A publication in this issue presents evidence that a plant cannabinoid, Δ9-tetrahydrocannabivarin is a potent antagonist of anandamide, a major endogenous cannabinoid. It seems possible that many of the non-psychoactive constituents of this plant will be of biological interest.

  7. Pharmacological Interventions for Students with ADD.

    Science.gov (United States)

    Austin, Vance L.

    2003-01-01

    A review of the research on pharmacological interventions for students with attention deficit disorder finds that psychostimulants such as methylphenidate (Ritalin) are effective in improving focus and impulse control, but should be used in conjunction with psychosocial and behavioral interventions. Comprehensive medical screenings and guidelines…

  8. Radioreceptor assay: theory and applications to pharmacology

    International Nuclear Information System (INIS)

    The aim of the first part of this work is to present the theory of the radioreceptor assay and to compare it to the other techniques of radioanalysis (radioimmunoassay, competitive protein binding assays). The technology of the radioreceptor assay is then presented and its components (preparation of the receptors, radioligand, incubation medium) are described. The analytical characteristics of the radioreceptor assay (specificity, sensitivity, reproductibility, accuracy) and the pharmacological significance of the results are discussed. The second part is devoted to the description of the radioreceptor assays of some pharmacological classes (neuroleptics, tricyclic antidepressants, benzodiazepines, β-blockers, anticholinergic drugs) and to their use in therapeutic drug monitoring. In conclusion, by their nature, radioreceptor assays are highly sensitive, reliable, precise, accurate and simple to perform. Their chief disadvantage relates to specificity, since any substance having an appreciable affinity to the receptor site will displace the specifically bound radioligand. Paradoxically in some cases, this lack of specificity may be advantageous in that it allows for the detection of not only the apparent compound but of active metabolites and endogenous receptor agonists as well and in that radioreceptors assays can be devised for a whole pharmacological class and not only for one drug as it is the case for classical physico-chemical techniques. For all these reasons future of radioreceptor assay in pharmacology appears promising

  9. Investigational pharmacology for low back pain

    Directory of Open Access Journals (Sweden)

    Avinash K Bhandary

    2010-09-01

    Full Text Available Avinash K Bhandary1 , Gary P Chimes2, Gerard A Malanga3 1Department of Physical Medicine and Rehabilitation, 2Department of Physical Medicine and Rehabilitation, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 3New Jersey Sports Medicine Institute; Overlook Hospital; Mountainside Hospital; Rehabilitation Medicine and Electrodiagnosis, St Michael’s Medical Center; Horizon Healthcare Worker’s Compensation Services, Blue Cross and Blue Shield Worker’s Compensation, Summit, NJ, USAStudy design: Review and reinterpretation of existing literature.Objective: This review article summarizes the anatomy and pathogenesis of disease processes that contribute to low back pain, and discusses key issues in existing therapies for chronic low back pain. The article also explains the scientific rationale for investigational pharmacology and highlights emerging compounds in late development.Results/conclusion: While the diverse and complex nature of chronic low back pain continues to challenge clinicians, a growing understanding of chronic low back pain on a cellular level has refined our approach to managing chronic low back pain with pharmacology. Many emerging therapies with improved safety profiles are currently in the research pipeline and will contribute to a multimodal therapeutic algorithm in the near future. With the heterogeneity of the patient population suffering from chronic low back pain, the clinical challenge will be accurately stratifying the optimal pharmacologic approach for each patient.Keywords: low back pain, investigational, pharmacology, drugs

  10. Systems Pharmacology in Small Molecular Drug Discovery

    Directory of Open Access Journals (Sweden)

    Wei Zhou

    2016-02-01

    Full Text Available Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity, target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

  11. PHYTO-PHARMACOLOGICAL REVIEW OF ARGYREIA NERVOSA

    OpenAIRE

    Krishnaveni, A; T. Sant Rani

    2011-01-01

    Herbal medicines are the significant and reliable sources for treating various diseases. Argyreia nervosa is traditionally used in wound healing, syphilius,diuretics,rheumatic affections, leucohorrhoea.,cerebral disorders, ulcers, as anti-tumour and to prevent contraception.Phytoconstituents such as flavanoids, steroids, ergoline alkaloids and triterpenoids were identified. Pharmacological studies proved its anticonvulsant, immunomodulatory, hypotensive, anti- inflammatory and no...

  12. Pharmacological interventions for phantom limb pain

    Institute of Scientific and Technical Information of China (English)

    FANG Jun; LIAN Yan-hong; XIE Kang-jie; CAI Shu-nü

    2013-01-01

    Objective To review the mechanisms and current clinical application of pharmacological interventions for phantom limb pain.Data sources Both Chinese and English language literatures were searched using MEDLINE (1982-2011),Pubmed (1982-2011) and the Index of Chinese Language Literature (1982-2011).Study selection Data from published articles about pharmacological management of phantom limb pain in recent domestic and foreign literature were selected.Data extraction Data were mainly extracted from 96 articles which are listed in the reference section of this review.Results By reviewing the mechanisms and current clinical application of pharmacological interventions for phantom limb pain,including anticonvulsants,antidepressants,local anaesthetics,N-methyl-D-aspartate receptor antagonists,non-steroidal anti-inflammatory drugs,tramadol,opioids,calcitonin,capsaicin,beta-adrenergic blockers,clonidine,muscle relaxants,and emerging drugs,we examined the efficacy and safety of these medications,outlined the limitations and future directions.Conclusions Although there is lack of evidence-based consensus guidelines for the pharmacological management of phantom limb pain,we recommend tricyclic antidepressants,gabapentin,tramadol,opioids,local anaesthetics and N-methyl-D-aspartate receptor antagonists as the rational options for the treatment of phantom limb pain.

  13. Clinical pharmacology of novel anticancer drug formulations

    NARCIS (Netherlands)

    Stuurman, F.E.

    2013-01-01

    Studies outlined in this thesis describe the impact of drug formulations on pharmacology of anticancer drugs. It consists of four parts and starts with a review describing the mechanisms of low oral bioavailability of anti-cancer drugs and strategies for improvement of the bioavailability. The major

  14. Pharmacologic desensitization for dental phobias: clinical observations.

    OpenAIRE

    Moore, P. A.; Peskin, R. M.; Pierce, C. J.

    1990-01-01

    The elimination of the extreme fear reported by dental phobic patients traditionally involves psychologic interventions such as systematic desensitization. Observations resulting from a conscious sedation approach, as outlined in two case histories, suggest that a desensitization phenomena is occurring. This pharmacologic desensitization appears to mimic elements of systematic desensitization. Optimal management of fearful patients may sometimes require conjunctive support from both dental be...

  15. Non Pharmacological Cognitive Enhancers – Current Perspectives

    OpenAIRE

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

    2015-01-01

    Cognition refers to the mental processes involved in thinking, knowing, remembering, judging, and problem solving. Cognitive dysfunctions are an integral part of neuropsychiatric disorders as well as in healthy ageing. Cognitive Enhancers are molecules that help improve aspects of cognition like memory, intelligence, motivation, attention and concentration. Recently, Non Pharmacological Cognitive Enhancers have gained popularity as effective and safe alternative to various established drugs. ...

  16. Mitochondria: pharmacological manipulation of cell death

    OpenAIRE

    Bouchier-Hayes, Lisa; Lartigue, Lydia; Newmeyer, Donald D.

    2005-01-01

    Cell death by apoptosis or necrosis is often important in the etiology and treatment of disease. Since mitochondria play important roles in cell death pathways, these organelles are potentially prime targets for therapeutic intervention. Here we discuss the mechanisms through which mitochondria participate in the cell death process and also survey some of the pharmacological approaches that target mitochondria in various ways.

  17. Systems Pharmacology in Small Molecular Drug Discovery.

    Science.gov (United States)

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-01-01

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level. PMID:26901192

  18. In vitro pharmacological profiling of R406 identifies molecular targets underlying the clinical effects of fostamatinib.

    Science.gov (United States)

    Rolf, Michael G; Curwen, Jon O; Veldman-Jones, Margaret; Eberlein, Cath; Wang, Jianyan; Harmer, Alex; Hellawell, Caroline J; Braddock, Martin

    2015-10-01

    Off-target pharmacology may contribute to both adverse and beneficial effects of a new drug. In vitro pharmacological profiling is often applied early in drug discovery; there are fewer reports addressing the relevance of broad profiles to clinical adverse effects. Here, we have characterized the pharmacological profile of the active metabolite of fostamatinib, R406, linking an understanding of drug selectivity to the increase in blood pressure observed in clinical studies. R406 was profiled in a broad range of in vitro assays to generate a comprehensive pharmacological profile and key targets were further investigated using functional and cellular assay systems. A combination of traditional literature searches and text-mining approaches established potential mechanistic links between the profile of R406 and clinical side effects. R406 was selective outside the kinase domain, with only antagonist activity at the adenosine A3 receptor in the range relevant to clinical effects. R406 was less selective in the kinase domain, having activity at many protein kinases at therapeutically relevant concentrations when tested in multiple in vitro systems. Systematic literature analyses identified KDR as the probable target underlying the blood pressure increase observed in patients. While the in vitro pharmacological profile of R406 suggests a lack of selectivity among kinases, a combination of classical searching and text-mining approaches rationalized the complex profile establishing linkage between off-target pharmacology and clinically observed effects. These results demonstrate the utility of in vitro pharmacological profiling for a compound in late-stage clinical development. PMID:26516587

  19. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use.

    Science.gov (United States)

    Taylor, Charles P; Traynelis, Stephen F; Siffert, Joao; Pope, Laura E; Matsumoto, Rae R

    2016-08-01

    Dextromethorphan (DM) has been used for more than 50years as an over-the-counter antitussive. Studies have revealed a complex pharmacology of DM with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential. DM is rapidly metabolized to dextrorphan, which has hampered the exploration of DM therapy separate from its metabolites. Coadministration of DM with a low dose of quinidine inhibits DM metabolism, yields greater bioavailability and enables more specific testing of the therapeutic properties of DM apart from its metabolites. The development of the drug combination DM hydrobromide and quinidine sulfate (DM/Q), with subsequent approval by the US Food and Drug Administration for pseudobulbar affect, led to renewed interest in understanding DM pharmacology. This review summarizes the interactions of DM with brain receptors and transporters and also considers its metabolic and pharmacokinetic properties. To assess the potential clinical relevance of these interactions, we provide an analysis comparing DM activity from in vitro functional assays with the estimated free drug DM concentrations in the brain following oral DM/Q administration. The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α3β4 subunits, and cause agonist activity at sigma-1 receptors. PMID:27139517

  20. Pharmacological management of anticholinergic delirium - theory, evidence and practice.

    Science.gov (United States)

    Dawson, Andrew H; Buckley, Nicholas A

    2016-03-01

    The spectrum of anticholinergic delirium is a common complication following drug overdose. Patients with severe toxicity can have significant distress and behavioural problems that often require pharmacological management. Cholinesterase inhibitors, such as physostigmine, are effective but widespread use has been limited by concerns about safety, optimal dosing and variable supply. Case series support efficacy in reversal of anticholinergic delirium. However doses vary widely and higher doses commonly lead to cholinergic toxicity. Seizures are reported in up to 2.5% of patients and occasional cardiotoxic effects are also recorded. This article reviews the serendipitous path whereby physostigmine evolved into the preferred anticholinesterase antidote largely without any research to indicate the optimal dosing strategy. Adverse events observed in case series should be considered in the context of pharmacokinetic/pharmacodynamic studies of physostigmine which suggest a much longer latency before the maximal increase in brain acetylcholine than had been previously assumed. This would favour protocols that use lower doses and longer re-dosing intervals. We propose based on the evidence reviewed that the use of cholinesterase inhibitors should be considered in anticholinergic delirium that has not responded to non-pharmacological delirium management. The optimal risk/benefit would be with a titrated dose of 0.5 to 1 mg physostigmine (0.01-0.02 mg kg(-1) in children) with a minimum delay of 10-15 min before re-dosing. Slower onset and longer acting agents such as rivastigmine would also be logical but more research is needed to guide the appropriate dose in this setting. PMID:26589572