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Helen A Baghdoyan - One of the best experts on this subject based on the ideXlab platform.
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GABAergic transmission in rat pontine reticular formation regulates the induction phase of anesthesia and modulates hyperalgesia caused by sleep deprivation
European Journal of Neuroscience, 2014Co-Authors: Giancarlo Vanini, Helen A Baghdoyan, Kriste Nemanis, Ralph LydicAbstract:The oral part of the pontine reticular formation (PnO) contributes to the regulation of sleep, anesthesia and pain. The role of PnO c-aminobutyric acid (GABA) in modulating these states remains incompletely understood. The present study used time to loss and time to resumption of righting response (LoRR and RoRR) as surrogate measures of loss and resumption of consciousness. This study tested three hypotheses: (i) pharmacologically manipulating GABA levels in rat PnO alters LoRR, RoRR and nociception; (ii) propofol decreases GABA levels in the PnO; and (iii) inhibiting GABA synthesis in the PnO blocks hyperalgesia caused by sleep deprivation. Administering a GABA synthesis Inhibitor [3-mercaptopropionic acid (3-MPA)] or a GABA Uptake Inhibitor [nipecotic acid (NPA)] into rat PnO significantly altered LoRR caused by propofol. 3-MPA significantly decreased LoRR for propofol (18%). NPA significantly increased LoRR during administration of propofol (36%). Neither 3-MPA nor NPA altered RoRR following cessation of propofol or isoflurane delivery. The finding that LoRR was decreased by 3-MPA and increased by NPA is consistent with measures showing that extracellular GABA levels in the PnO were decreased (41%) by propofol. Thermal nociception was significantly decreased by 3-MPA and increased by NPA, and 3-MPA blocked the hyperalgesia caused by sleep deprivation. The results demonstrate that GABA levels in the PnO regulate the time for loss of consciousness caused by propofol, extend the concept that anesthetic induction and emergence are not inverse processes, and suggest that GABAergic transmission in the PnO mediates hyperalgesia caused by sleep loss.
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γ aminobutyric acid mediated neurotransmission in the pontine reticular formation modulates hypnosis immobility and breathing during isoflurane anesthesia
Anesthesiology, 2008Co-Authors: Giancarlo Vanini, Ralph Lydic, Chris J Watson, Helen A BaghdoyanAbstract:BACKGROUND: Many general anesthetics are thought to produce a loss of wakefulness, in part, by enhancing gamma-aminobutyric acid (GABA) neurotransmission. However, GABAergic neurotransmission in the pontine reticular formation promotes wakefulness. This study tested the hypotheses that (1) relative to wakefulness, isoflurane decreases GABA levels in the pontine reticular formation; and (2) pontine reticular formation administration of drugs that increase or decrease GABA levels increases or decreases, respectively, isoflurane induction time. METHODS: To test hypothesis 1, cats (n = 5) received a craniotomy and permanent electrodes for recording the electroencephalogram and electromyogram. Dialysis samples were collected from the pontine reticular formation during isoflurane anesthesia and wakefulness. GABA levels were quantified using high-performance liquid chromatography. For hypothesis 2, rats (n = 10) were implanted with a guide cannula aimed for the pontine reticular formation. Each rat received microinjections of Ringer's (vehicle control), the GABA Uptake Inhibitor nipecotic acid, and the GABA synthesis Inhibitor 3-mercaptopropionic acid. Rats were then anesthetized with isoflurane, and induction time was quantified as loss of righting reflex. Breathing rate was also measured. RESULTS: Relative to wakefulness, GABA levels were significantly decreased by isoflurane. Increased power in the electroencephalogram and decreased activity in the electromyogram caused by isoflurane covaried with pontine reticular formation GABA levels. Nipecotic acid and 3-mercaptopropionic acid significantly increased and decreased, respectively, isoflurane induction time. Nipecotic acid also increased breathing rate. CONCLUSION: Decreasing pontine reticular formation GABA levels comprises one mechanism by which isoflurane causes loss of consciousness, altered cortical excitability, muscular hypotonia, and decreased respiratory rate.
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pontine reticular formation pno administration of hypocretin 1 increases pno GABA levels and wakefulness
Sleep, 2008Co-Authors: Chris J Watson, Ralph Lydic, Haideliza Sotocalderon, Helen A BaghdoyanAbstract:Γ-AMINOBUTYRIC ACID (GABA) IS THE MAJOR InhibitorY NEUROTRANSMITTER IN BRAIN, AND MOST CLINICALLY USED DRUGS THAT POTENTIATE GABAergic transmission produce a loss of normal wakefulness.1–4 Chronic insomnia, which occurs in about 10% of the US population,5 is frequently treated by drugs that act as agonists at the benzodiazepine binding site on the GABAA receptor complex.1 However, microinjection of the GABAA receptor agonist muscimol into the oral part of the pontine reticular formation (PnO) increases wakefulness and decreases sleep.6–9 Consistent with these findings are data showing that PnO microinjection of the GABAA receptor antagonist bicuculline decreases wakefulness and increases rapid eye movement (REM) sleep.8–10 Taken together, these data support the interpretation that within the PnO, GABAergic transmission promotes wakefulness and inhibits sleep. Hypocretin-1 (orexin A) is an endogenous hypothalamic peptide that contributes to the regulation of behavioral and electroencephalographic (EEG) arousal.11 Defects in hypocretinergic signaling underlie the human sleep disorder narcolepsy12 and cause a narcoleptic-like phenotype in dog13 and mouse.14 Hypocretinergic neurons project to every major arousal-promoting nucleus in the brain, including the PnO.15–17 Hypocretin receptors are present18 and functionally active19 in rat PnO. Hypocretin-1 directly excites PnO neurons in cat, and microinjection of hypocretin-1 into cat PnO during non-REM (NREM) sleep increases REM sleep.20 No previous studies have investigated the effects on sleep and wakefulness of microinjecting hypocretin-1 into rat PnO. The present study tested the hypothesis that PnO administration of hypocretin-1 increases PnO GABA levels and increases wakefulness. This hypothesis was examined with 2 approaches. First, in vivo microdialysis in anesthetized rat and high performance liquid chromatography (HPLC) were used to quantify the effects of hypocretin-1 on PnO GABA levels. Second, PnO microinjection in unanesthetized rat was used to assess the effects of hypocretin-1 on sleep and wakefulness. This study also tested the hypothesis that PnO administration of drugs known to selectively increase or decrease GABA levels causes an increase or decrease, respectively, in wakefulness. PnO microinjection of nipecotic acid, a GABA Uptake Inhibitor known to increase extracellular GABA levels in vivo,21,22 was predicted to increase wakefulness. PnO microinjection of 3-mercaptopropionic acid (3-MPA), a glutamic acid decarboxylase Inhibitor that decreases extracellular GABA levels in vivo,22 was predicted to decrease wakefulness. Preliminary portions of this report have been presented as abstracts.23–25
Ralph Lydic - One of the best experts on this subject based on the ideXlab platform.
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GABAergic transmission in rat pontine reticular formation regulates the induction phase of anesthesia and modulates hyperalgesia caused by sleep deprivation
European Journal of Neuroscience, 2014Co-Authors: Giancarlo Vanini, Helen A Baghdoyan, Kriste Nemanis, Ralph LydicAbstract:The oral part of the pontine reticular formation (PnO) contributes to the regulation of sleep, anesthesia and pain. The role of PnO c-aminobutyric acid (GABA) in modulating these states remains incompletely understood. The present study used time to loss and time to resumption of righting response (LoRR and RoRR) as surrogate measures of loss and resumption of consciousness. This study tested three hypotheses: (i) pharmacologically manipulating GABA levels in rat PnO alters LoRR, RoRR and nociception; (ii) propofol decreases GABA levels in the PnO; and (iii) inhibiting GABA synthesis in the PnO blocks hyperalgesia caused by sleep deprivation. Administering a GABA synthesis Inhibitor [3-mercaptopropionic acid (3-MPA)] or a GABA Uptake Inhibitor [nipecotic acid (NPA)] into rat PnO significantly altered LoRR caused by propofol. 3-MPA significantly decreased LoRR for propofol (18%). NPA significantly increased LoRR during administration of propofol (36%). Neither 3-MPA nor NPA altered RoRR following cessation of propofol or isoflurane delivery. The finding that LoRR was decreased by 3-MPA and increased by NPA is consistent with measures showing that extracellular GABA levels in the PnO were decreased (41%) by propofol. Thermal nociception was significantly decreased by 3-MPA and increased by NPA, and 3-MPA blocked the hyperalgesia caused by sleep deprivation. The results demonstrate that GABA levels in the PnO regulate the time for loss of consciousness caused by propofol, extend the concept that anesthetic induction and emergence are not inverse processes, and suggest that GABAergic transmission in the PnO mediates hyperalgesia caused by sleep loss.
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γ aminobutyric acid mediated neurotransmission in the pontine reticular formation modulates hypnosis immobility and breathing during isoflurane anesthesia
Anesthesiology, 2008Co-Authors: Giancarlo Vanini, Ralph Lydic, Chris J Watson, Helen A BaghdoyanAbstract:BACKGROUND: Many general anesthetics are thought to produce a loss of wakefulness, in part, by enhancing gamma-aminobutyric acid (GABA) neurotransmission. However, GABAergic neurotransmission in the pontine reticular formation promotes wakefulness. This study tested the hypotheses that (1) relative to wakefulness, isoflurane decreases GABA levels in the pontine reticular formation; and (2) pontine reticular formation administration of drugs that increase or decrease GABA levels increases or decreases, respectively, isoflurane induction time. METHODS: To test hypothesis 1, cats (n = 5) received a craniotomy and permanent electrodes for recording the electroencephalogram and electromyogram. Dialysis samples were collected from the pontine reticular formation during isoflurane anesthesia and wakefulness. GABA levels were quantified using high-performance liquid chromatography. For hypothesis 2, rats (n = 10) were implanted with a guide cannula aimed for the pontine reticular formation. Each rat received microinjections of Ringer's (vehicle control), the GABA Uptake Inhibitor nipecotic acid, and the GABA synthesis Inhibitor 3-mercaptopropionic acid. Rats were then anesthetized with isoflurane, and induction time was quantified as loss of righting reflex. Breathing rate was also measured. RESULTS: Relative to wakefulness, GABA levels were significantly decreased by isoflurane. Increased power in the electroencephalogram and decreased activity in the electromyogram caused by isoflurane covaried with pontine reticular formation GABA levels. Nipecotic acid and 3-mercaptopropionic acid significantly increased and decreased, respectively, isoflurane induction time. Nipecotic acid also increased breathing rate. CONCLUSION: Decreasing pontine reticular formation GABA levels comprises one mechanism by which isoflurane causes loss of consciousness, altered cortical excitability, muscular hypotonia, and decreased respiratory rate.
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pontine reticular formation pno administration of hypocretin 1 increases pno GABA levels and wakefulness
Sleep, 2008Co-Authors: Chris J Watson, Ralph Lydic, Haideliza Sotocalderon, Helen A BaghdoyanAbstract:Γ-AMINOBUTYRIC ACID (GABA) IS THE MAJOR InhibitorY NEUROTRANSMITTER IN BRAIN, AND MOST CLINICALLY USED DRUGS THAT POTENTIATE GABAergic transmission produce a loss of normal wakefulness.1–4 Chronic insomnia, which occurs in about 10% of the US population,5 is frequently treated by drugs that act as agonists at the benzodiazepine binding site on the GABAA receptor complex.1 However, microinjection of the GABAA receptor agonist muscimol into the oral part of the pontine reticular formation (PnO) increases wakefulness and decreases sleep.6–9 Consistent with these findings are data showing that PnO microinjection of the GABAA receptor antagonist bicuculline decreases wakefulness and increases rapid eye movement (REM) sleep.8–10 Taken together, these data support the interpretation that within the PnO, GABAergic transmission promotes wakefulness and inhibits sleep. Hypocretin-1 (orexin A) is an endogenous hypothalamic peptide that contributes to the regulation of behavioral and electroencephalographic (EEG) arousal.11 Defects in hypocretinergic signaling underlie the human sleep disorder narcolepsy12 and cause a narcoleptic-like phenotype in dog13 and mouse.14 Hypocretinergic neurons project to every major arousal-promoting nucleus in the brain, including the PnO.15–17 Hypocretin receptors are present18 and functionally active19 in rat PnO. Hypocretin-1 directly excites PnO neurons in cat, and microinjection of hypocretin-1 into cat PnO during non-REM (NREM) sleep increases REM sleep.20 No previous studies have investigated the effects on sleep and wakefulness of microinjecting hypocretin-1 into rat PnO. The present study tested the hypothesis that PnO administration of hypocretin-1 increases PnO GABA levels and increases wakefulness. This hypothesis was examined with 2 approaches. First, in vivo microdialysis in anesthetized rat and high performance liquid chromatography (HPLC) were used to quantify the effects of hypocretin-1 on PnO GABA levels. Second, PnO microinjection in unanesthetized rat was used to assess the effects of hypocretin-1 on sleep and wakefulness. This study also tested the hypothesis that PnO administration of drugs known to selectively increase or decrease GABA levels causes an increase or decrease, respectively, in wakefulness. PnO microinjection of nipecotic acid, a GABA Uptake Inhibitor known to increase extracellular GABA levels in vivo,21,22 was predicted to increase wakefulness. PnO microinjection of 3-mercaptopropionic acid (3-MPA), a glutamic acid decarboxylase Inhibitor that decreases extracellular GABA levels in vivo,22 was predicted to decrease wakefulness. Preliminary portions of this report have been presented as abstracts.23–25
Wagner Ferreira Dos Santos - One of the best experts on this subject based on the ideXlab platform.
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parawixin2 a novel non selective GABA Uptake Inhibitor from parawixia bistriata spider venom inhibits pentylenetetrazole induced chemical kindling in rats
Neuroscience Letters, 2013Co-Authors: Erica Aparecida Gelfuso, Alexandra Olimpio Siqueira Cunha, Marcia Renata Mortari, Jose Luiz Liberato, Rene Oliveira Beleboni, Norberto Peporine Lopes, Wagner Ferreira Dos SantosAbstract:Abstract The aims of the present work were to investigate the effects of the repeated administration of Parawixin2 (2-amino-5-ureidopentanamide; formerly FrPbAII), a novel GABA and glycine Uptake Inhibitor, in rats submitted to PTZ-induced kindling. Wistar rats were randomly divided in groups ( n = 6–8) for different treatments. Systemic injections of PTZ were administered every 48 h in the dose of 33 mg/kg; i.p., that is sufficient to induce fully kindled seizures in saline i.c.v. treated rats in a short period of time (28 days). Treatments in two types of positive controls (diazepam – DZP and nipecotic acid – NA groups) consisted in daily systemic injections of DZP (2 mg/kg; i.p.) or i.c.v. injections of NA (12 μg/μL), while in experimental groups in daily i.c.v. injections of different doses of Parawixin2 (0.15; 0.075; 0.015 μg/μL). Seizures were analyzed using the Lamberty & Klitgaard score and kindling was considered as established after at least three consecutive seizures of score 4 or 5. Cumulative seizure scores for each group were analyzed using repeated measures of ANOVA followed by Tukey test. PTZ induced 4 and 5-score seizures after 12 injections in saline treated rats, whereas daily injection of Parawixin2 inhibited the onset of seizures in a dose dependent manner. Also, the challenging administration of PTZ did not raise seizure score in animals treated with the highest dose of Parawixin2 or those treated with DZP or NA. These findings together with previous data from our laboratory show that Parawixin2 could be a useful probe to design new antiepileptic drugs.
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neuropharmacological profile of frpbaii purified from the venom of the social spider parawixia bistriata araneae araneidae in wistar rats
Life Sciences, 2007Co-Authors: Erica Aparecida Gelfuso, Alexandra Olimpio Siqueira Cunha, Marcia Renata Mortari, Jose Luiz Liberato, Karina Haddad Paraventi, Rene Oliveira Beleboni, Joaquim Coutinhonetto, Norberto Peporine Lopes, Wagner Ferreira Dos SantosAbstract:Abstract The aims of the present study were to investigate the anticonvulsant activity and behavioral toxicity of FrPbAII using freely moving Wistar rats. Moreover, the effectiveness of this compound against chemical convulsants was compared to that of the Inhibitor of the GABAergic Uptake, nipecotic acid. Our results show that FrPbAII was effective against seizures induced by the i.c.v. injection of pilocarpine (ED 50 = 0.05 μg/animal), picrotoxin (ED 50 = 0.02 μg/animal), kainic acid (ED 50 = 0.2 μg/animal) and the systemic administration of PTZ (ED 50 = 0.03 μg/animal). The anticonvulsant effect of FrPbAII differed from that of nipecotic acid in potency, as the doses needed to block the seizures were more than 10 folds lower. Toxicity assays revealed that in the rotarod, the toxic dose of the FrPbAII is 1.33 μg/animal, and the therapeutic indexes were calculated for each convulsant. Furthermore, the spontaneous locomotor activity of treated animals was not altered when compared to control animals but differed from the animals treated with nipecotic acid. Still, FrPbAII did not induce changes in any of the behavioral parameters analyzed. Finally, when tested for cognitive impairments in the Morris water maze, the i.c.v. injection of FrPbAII did not alter escape latencies of treated animals. These findings indicate that the novel GABA Uptake Inhibitor is a potent anticonvulsant with mild side-effects when administered to Wistar rats.
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anticonvulsant and anxiolytic activity of frpbaii a novel GABA Uptake Inhibitor isolated from the venom of the social spider parawixia bistriata araneidae araneae
Brain Research, 2006Co-Authors: Jose Luiz Liberato, Erica Aparecida Gelfuso, Alexandra Olimpio Siqueira Cunha, Marcia Renata Mortari, Rene Oliveira Beleboni, Joaquim Coutinhonetto, Wagner Ferreira Dos SantosAbstract:Abstract This study was aimed at determining the effects of FrPbAII (174 Da), a novel isolated component from Parawixia bistriata spider venom, in the CNS of Wistar rats. Considering that FrPbAII inhibits the high affinity GABAergic Uptake in a dose-dependent manner, its anxiolytic and anticonvulsant effects were analyzed in well-established animal models. Injection of FrPbAII in the rat hippocampus induced a marked anxiolytic effect, increasing the occupancy in the open arms of the elevated plus maze (EC 50 = 0.09 μg/μl) and increasing the time spent in the lit area of the light–dark apparatus (EC 50 = 0.03 μg/μl). Anxiolytic effects were also observed considering the number of entries in the open arms of the EPM and in the lit compartment of the light–dark box. Interestingly, when microinjected bilaterally in the SNPr of freely moving rats, FrPbAII (0.6 μg/μl) effectively prevented seizures induced by the unilateral GABAergic blockade of Area tempestas (bicuculline, 0.75 μg/μl). This anticonvulsant effect was similar to that evoked by muscimol (0.1 μg/μl) and baclofen (0.6 μg/μl), but differed from that of the specific GAT1 Inhibitor, nipecotic acid (0.7 μg/μl). This difference could be accounted either for the parallel action of FrPbAII over glycinergic transporters or to an inspecific activity on GABAergic transporters. Data from the present investigation might be pointing to a novel compound with interesting and yet unexplored pharmacological potential.
Giancarlo Vanini - One of the best experts on this subject based on the ideXlab platform.
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GABAergic transmission in rat pontine reticular formation regulates the induction phase of anesthesia and modulates hyperalgesia caused by sleep deprivation
European Journal of Neuroscience, 2014Co-Authors: Giancarlo Vanini, Helen A Baghdoyan, Kriste Nemanis, Ralph LydicAbstract:The oral part of the pontine reticular formation (PnO) contributes to the regulation of sleep, anesthesia and pain. The role of PnO c-aminobutyric acid (GABA) in modulating these states remains incompletely understood. The present study used time to loss and time to resumption of righting response (LoRR and RoRR) as surrogate measures of loss and resumption of consciousness. This study tested three hypotheses: (i) pharmacologically manipulating GABA levels in rat PnO alters LoRR, RoRR and nociception; (ii) propofol decreases GABA levels in the PnO; and (iii) inhibiting GABA synthesis in the PnO blocks hyperalgesia caused by sleep deprivation. Administering a GABA synthesis Inhibitor [3-mercaptopropionic acid (3-MPA)] or a GABA Uptake Inhibitor [nipecotic acid (NPA)] into rat PnO significantly altered LoRR caused by propofol. 3-MPA significantly decreased LoRR for propofol (18%). NPA significantly increased LoRR during administration of propofol (36%). Neither 3-MPA nor NPA altered RoRR following cessation of propofol or isoflurane delivery. The finding that LoRR was decreased by 3-MPA and increased by NPA is consistent with measures showing that extracellular GABA levels in the PnO were decreased (41%) by propofol. Thermal nociception was significantly decreased by 3-MPA and increased by NPA, and 3-MPA blocked the hyperalgesia caused by sleep deprivation. The results demonstrate that GABA levels in the PnO regulate the time for loss of consciousness caused by propofol, extend the concept that anesthetic induction and emergence are not inverse processes, and suggest that GABAergic transmission in the PnO mediates hyperalgesia caused by sleep loss.
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γ aminobutyric acid mediated neurotransmission in the pontine reticular formation modulates hypnosis immobility and breathing during isoflurane anesthesia
Anesthesiology, 2008Co-Authors: Giancarlo Vanini, Ralph Lydic, Chris J Watson, Helen A BaghdoyanAbstract:BACKGROUND: Many general anesthetics are thought to produce a loss of wakefulness, in part, by enhancing gamma-aminobutyric acid (GABA) neurotransmission. However, GABAergic neurotransmission in the pontine reticular formation promotes wakefulness. This study tested the hypotheses that (1) relative to wakefulness, isoflurane decreases GABA levels in the pontine reticular formation; and (2) pontine reticular formation administration of drugs that increase or decrease GABA levels increases or decreases, respectively, isoflurane induction time. METHODS: To test hypothesis 1, cats (n = 5) received a craniotomy and permanent electrodes for recording the electroencephalogram and electromyogram. Dialysis samples were collected from the pontine reticular formation during isoflurane anesthesia and wakefulness. GABA levels were quantified using high-performance liquid chromatography. For hypothesis 2, rats (n = 10) were implanted with a guide cannula aimed for the pontine reticular formation. Each rat received microinjections of Ringer's (vehicle control), the GABA Uptake Inhibitor nipecotic acid, and the GABA synthesis Inhibitor 3-mercaptopropionic acid. Rats were then anesthetized with isoflurane, and induction time was quantified as loss of righting reflex. Breathing rate was also measured. RESULTS: Relative to wakefulness, GABA levels were significantly decreased by isoflurane. Increased power in the electroencephalogram and decreased activity in the electromyogram caused by isoflurane covaried with pontine reticular formation GABA levels. Nipecotic acid and 3-mercaptopropionic acid significantly increased and decreased, respectively, isoflurane induction time. Nipecotic acid also increased breathing rate. CONCLUSION: Decreasing pontine reticular formation GABA levels comprises one mechanism by which isoflurane causes loss of consciousness, altered cortical excitability, muscular hypotonia, and decreased respiratory rate.
Steve H White - One of the best experts on this subject based on the ideXlab platform.
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first demonstration of a functional role for central nervous system betaine γ aminobutyric acid transporter mgat2 based on synergistic anticonvulsant action among Inhibitors of mgat1 and mgat2
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Steve H White, Alan Sarup, Tina Bolvig, Gitte Petersen, Orla M Larsson, William P. Watson, Suzanne L. Hansen, Scott Slough, Jens Kristian Perregaard, Rasmus P. ClausenAbstract:In a recent study, EF1502 [ N -[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo [ d ]isoxazol-3-ol], which is an N -substituted analog of the GAT1-selective GABA Uptake Inhibitor exo -THPO (4-amino-4,5,6,7-tetrahydrobenzo[ d ]isoxazol-3-ol), was found to inhibit GABA transport mediated by both GAT1 and GAT2 in human embryonic kidney (HEK) cells expressing the mouse GABA transporters GAT1 to 4 (mGAT1–4). In the present study, EF1502 was found to possess a broad-spectrum anticonvulsant profile in animal models of generalized and partial epilepsy. When EF1502 was tested in combination with the clinically effective GAT1-selective Inhibitor tiagabine [( R )- N -[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid] or LU-32-176B [ N -[4,4-bis(4-fluorophenyl)-butyl]-3-hydroxy-4-amino-4,5,6,7-tetrahydrobenzo[ d ]isoxazol-3-ol], another GAT1-selective N -substituted analog of exo -THPO, a synergistic rather than additive anticonvulsant interaction was observed in the Frings audiogenic seizure-susceptible mouse and the pentylenetetrazol seizure threshold test. In contrast, combination of the two mGAT1-selective Inhibitors, tiagabine and LU-32-176B, resulted in only an additive anticonvulsant effect. Importantly, the combination of EF1502 and tiagabine did not result in a greater than additive effect in the rotarod behavioral impairment test. In subsequent in vitro studies conducted in HEK-293 cells expressing the cloned mouse GAT transporters mGAT1 and mGAT2, EF1502 was found to noncompetitively inhibit both mGAT1 and the betaine/GABA transporter mGAT2 ( K i of 4 and 5 μM, respectively). Furthermore, in a GABA release study conducted in neocortical neurons, EF1502 did not act as a substrate for the GABA carrier. Collectively, these findings support a functional role for mGAT2 in the control of neuronal excitability and suggest a possible utility for mGAT2-selective Inhibitors in the treatment of epilepsy.
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First Demonstration of a Functional Role for Central Nervous System Betaine/-Aminobutyric Acid Transporter (mGAT2) Based on Synergistic Anticonvulsant Action among Inhibitors of mGAT1 and mGAT2
2004Co-Authors: Steve H White, Alan Sarup, Tina Bolvig, Gitte Petersen, Orla M Larsson, William P. Watson, Suzanne L. Hansen, Scott Slough, Jens Perregaard, Rasmus P. ClausenAbstract:In a recent study, EF1502 [N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo [d]isoxazol-3-ol], which is an N-substituted analog of the GAT1-selective GABA Uptake Inhibitor exo-THPO (4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol), was found to inhibit GABA transport mediated by both GAT1 and GAT2 in human embryonic kidney (HEK) cells expressing the mouse GABA transporters GAT1 to 4 (mGAT1–4). In the present study, EF1502 was found to possess a broad-spectrum anticonvulsant profile in animal mod-els of generalized and partial epilepsy. When EF1502 was tested in combination with the clinically effective GAT1-selective Inhibitor tiagabine [(R)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid] or LU-32-176B [N-[4,4-bis(4-fluorophenyl)-butyl]-3-hydroxy-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol], another GAT1
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correlation between anticonvulsant activity and Inhibitory action on glial γ aminobutyric acid Uptake of the highly selective mouse γ aminobutyric acid transporter 1 Inhibitor 3 hydroxy 4 amino 4 5 6 7 tetrahydro 1 2 benzisoxazole and itsn alkylated
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Steve H White, Alan Sarup, Tina Bolvig, Anders S Kristensen, Gitte Petersen, Nathan Nelson, Darryl S Pickering, Orla M Larsson, Bente Frolund, Povl KrogsgaardlarsenAbstract:The Inhibitory effect of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole ( exo -THPO) and its N -methylated ( N -methyl- exo -THPO) and N -ethylated ( N -ethyl- exo -THPO) analogs, derived from γ-aminobutyric acid (GABA) and 4,5,6,7-tetrahydroisoxazolo[4,5- c ]pyridin-3-ol (THPO) on GABA transport was investigated using cultured neocortical neurons (GABA-ergic) and astrocytes and cloned mouse GABA transporters GAT1–4 expressed in human embryonic kidney (HEK) 293 cells. Anticonvulsant activity was assessed after i.c.v. administration to Frings audiogenic seizure-susceptible mice. Anticonvulsant activity of the O -pivaloyloxymethyl prodrug of N -methyl- exo -THPO was assessed after i.p. administration. Results from these studies were compared with those obtained from similar studies with the novel anticonvulsant drug tiagabine, which acts via inhibition of GABA transport. exo -THPO and its N -alkyl analogs inhibited neuronal, astrocytic, and GAT1-mediated GABA transport but not GABA Uptake mediated by GAT2–4. N -Methyl- exo -THPO was 8-fold more potent as an Inhibitor of astrocytic versus neuronal GABA Uptake. The IC50 value for inhibition of GABA Uptake by GAT1 closely reflected its IC50 value for inhibition of neuronal Uptake. Tiagabine was approximately 1000-fold more potent than exo -THPO and its alkyl derivatives as an Inhibitor of GABA Uptake in cultured neural cells and GAT1-expressing HEK 293 cells. exo -THPO, its alkylated analogs, and tiagabine displayed a time- and dose-dependent inhibition of audiogenic seizures after i.c.v. administration. N -Methyl- exo -THPO was the most potent anticonvulsant among the exo -THPO compounds tested and only slightly less potent than tiagabine. The findings suggest a correlation between anticonvulsant efficacy and selective inhibition of astroglial GABA Uptake. Furthermore, results obtained with the N -methyl- exo -THPO prodrug demonstrate the feasibility of developing a glial-selective GABA Uptake Inhibitor with systemic bioavailability.
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anticonvulsant activity of the γ aminobutyric acid Uptake Inhibitor n 4 4 diphenyl 3 butenyl 4 5 6 7 tetrahydroisoxazolo 4 5 c pyridin 3 ol
European Journal of Pharmacology, 1993Co-Authors: Steve H White, Povl Krogsgaardlarsen, Jason P Hunt, Harold H Wolf, Ewart A Swinyard, Erik Falch, Arne SchousboeAbstract:The N-4,4-diphenyl-3-butenyl derivative of the glial selective gamma-aminobutyric acid (GABA) Uptake Inhibitor 4,5,6,7-tetrahydroisoxazolo [4,5-c]pyridin-3-ol (N-DPB-THPO), was tested for its ability to block sound-induced seizures in the audiogenic seizure-susceptible Frings mouse model of epilepsy. Following intracerebroventricular (i.c.v.) administration, N-DPB-THPO blocked tonic hindlimb extension in a dose- and time-dependent manner. At the doses tested no gross behavioral effects were noted.