Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.19 (GABA transaminase)
 808 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effect of (+/-)-gamma-vinyl GABA (GVG, Vigabatrin), an irreversible inhibitor of the enzyme GABA transaminase, on the acquisition and expression of cocaine-induced sensitization in albino male Sprague-Dawley rats. Animals received a single injection of 1 ml/kg i.p. of 0.9% saline or 15 mg/kg i.p. of (-)-cocaine and locomotor activity was assessed using automated locomotor cages and stereotyped behaviors were scored using a 4-point rating scale (Day 1). Subsequently, animals were given 15 mg/kg i.p. of cocaine every 48 h in their home cage for 1 week (Days 3, 5, and 7) and then given no treatment for 1 week. A challenge injection of 15 mg/kg i.p. of cocaine, but not vehicle, produced a significant increase in locomotor activity and stereotyped behaviors on Day 15 compared to animals that received cocaine on Day 1. Administration of 75 mg/kg i.p. of GVG 2.5 h before the cocaine injections did not significantly alter the acquisition of cocaine-induced locomotor sensitization. However, 150 mg/kg i.p. of GVG significantly attenuated the acquisition of cocaine-induced locomotor sensitization. Administration of 150 mg/kg i.p. of GVG 2.5 h before the cocaine challenge injection on Day 15 significantly attenuated the expression of cocaine-induced locomotor sensitization. Acquisition and expression of cocaine-induced sensitization of stereotypy was also significantly attenuated by 150 mg/kg i.p. of GVG. Since sensitization may be one of the factors involved in relapse to drug use, the present results, in combination with previous findings that GVG blocks the rewarding and incentive motivating effects of cocaine, suggest that GVG might prove useful in the treatment of cocaine addiction.
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PMID:Gamma-vinyl GABA, an irreversible inhibitor of GABA transaminase, alters the acquisition and expression of cocaine-induced sensitization in male rats. 1237 39

Central neurons exposed to several types of sublethal stress, including ischemia, acquire resistance to injury induced by subsequent ischemic insults, a phenomenon called ischemic preconditioning. We modeled this phenomenon in vitro, utilizing exposure to 45 mM KCl to reduce the vulnerability of cultured murine cortical neurons to subsequent oxygen-glucose deprivation. Twenty-four hours after preconditioning, cultures exhibited enhanced depolarization-induced, tetanus toxin-sensitive GABA release and a modest decrease in glutamate release. Total cellular GABA levels were unaltered. Inhibition of GABA degradation with the GABA transaminase inhibitor (+/-)-gamma-vinyl GABA, or addition of low levels of GABA, muscimol, or chlormethiazole to the bathing medium, mimicked the neuroprotective effect of preconditioning against oxygen-glucose deprivation-induced death. However, neuronal death was enhanced by higher levels of these manipulations, as well as by prior selective destruction of GABAergic neurons by kainate. Finally, selective blockade of GABA(A) receptors during oxygen-glucose deprivation or removal of GABAergic neurons eliminated the neuroprotective effects of prior preconditioning. Taken together, these data predict that presynaptic alterations, specifically enhanced GABA release together with reduced glutamate release, may be important mediators of ischemic preconditioning, but suggest caution in regard to interventions aimed at increasing GABA(A) receptor activation.
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PMID:Preconditioned resistance to oxygen-glucose deprivation-induced cortical neuronal death: alterations in vesicular GABA and glutamate release. 1240 32

Heroin has been hypothesized to activate opiate receptors and inhibit gamma-aminobutyric acid (GABA) release from inhibitory GABAergic interneurons which, in turn, activates dopamine projection cells. Since the distal sites and consequences of this disinhibition are not well understood on a systems level, heroin-induced brain activity was measured using functional MRI (fMRI) in rats. A significant blood oxygen level-dependent (BOLD) signal increase was seen in cortical regions, including prefrontal cortex, cingulate, and olfactory cortex following acute heroin administration. In contrast, a significant signal decrease was seen in several subcortical areas, including the caudate and putamen, nucleus accumbens, thalamus, and hypothalamus. Pretreatment of gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, significantly attenuated the heroin-induced BOLD signal changes. Pretreatment of naloxone, an opiate mu receptor antagonist, eliminated the heroin-induced BOLD signal changes and posttreatment of naloxone reversed the heroin-induced BOLD signal changes. It is suggested that the heroin-induced negative and positive BOLD changes are due to direct inhibitory and indirect disinhibitory mechanisms of GABAergic activities. Administration of GVG altered these mechanisms and further suggested that involvement of the opiate's pharmacological actions can, at least in part, be mediated by inhibiting brain GABA release.
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PMID:GABAergic mechanisms of heroin-induced brain activation assessed with functional MRI. 1241 98

Vigabatrin (VGB, gamma-vinyl-gamma-aminobutyric acid (GABA)), an irreversible inhibitor of GABA transaminase, increases regional inhibitory effects by elevating GABA concentration and reducing glutamate synthesis. In the present study, changes in glutamate dehydrogenase (GDH) activity and its immunoreactivity in the seizure prone gerbil hippocampus after treating VGB were investigated to identify the effect of VGB on energy and/or glutamate metabolism via GDH. In the VGB treated group, GDH immunoreactivity and its activity in the hippocampus were significantly decreased, as compared with those of controls. These findings suggest that VGB administration may suppress the development and spread of seizures not only by elevating the level of GABA, but also by affecting the glutamate signaling and energy metabolism in neurons.
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PMID:Effect of vigabatrin on glutamate dehydrogenase in the hippocampus of seizure prone gerbils. 1266 50

Gamma-aminobutyric acid transaminase (GABA-T, EC 2.6.1.19) is a pyridoxal phosphate (PLP) dependent enzyme that catalyzes the degradation of gamma-aminobutyric acid. The kinetics of this reaction are studied in vitro, both in the absence, and in the presence of two inhibitors: gamma-vinyl GABA (4-aminohex-5-enoic acid), and a natural product, taurine (ethylamine-2-sulfonic acid). A kinetic model that describes the transamination process is proposed. GABA-T from Pseudomonas fluorescens is inhibited by gamma-vinyl GABA and taurine at concentrations of 51.0 and 78.5 mM. Both inhibitors show competitive inhibition behavior when GABA is the substrate and the inhibition constant (Ki) values for gamma-vinyl GABA and taurine were found to be 26 +/- 3 mM and 68 +/- 7 mM respectively. The transamination process of alpha-ketoglutarate was not affected by the presence of gamma-vinyl GABA, whereas, taurine was a noncompetitive inhibitor of GABA-T when alpha-ketoglutarate was the substrate. The inhibition dissociation constant (Kii) for this system was found to be 96 +/- 10 mM. The Michaelis-Menten constant (Km) in the absence of inhibition, was found to be 0.79 +/- 0.11 mM, and 0.47 +/- 0.10 mM for GABA and alpha-ketoglutarate respectively.
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PMID:Kinetic studies on the inhibition of GABA-T by gamma-vinyl GABA and taurine. 1456 43

We have developed defective herpes simplex virus 1 (HSV-1) vectors, based on amplicon plasmids with a replication-deficient mutant, as helper for the transfer of the glutamic acid decarboxylase (GAD67) or beta-galactosidase (beta-gal) gene as control directed by HCMV promoter into neuronal-like cells (PC12) and primary neurons. GAD67 protein was detected immunochemically, while GAD67 activity in virus-producing and nonproducing cell lines was detected enzymatically or by GABA release. Infection with GAD67-expressing amplicon vectors enhanced the resistance of PC12 cells to H(2)O(2). This protection was related to increased energy metabolism, as shown by MTT reduction and ATP level, and involved the GABA shunt, as shown by the reduction in ATP level seen in the presence of gamma-vinyl GABA (GVG), a specific GABA transaminase inhibitor. Level of glutathione (GSH), which requires ATP for its synthesis, was increased by the GAD67 transgene. The activity of glucose-6-phosphate dehydrogenase involved in the maintenance of the NADPH that can be used for the regeneration of the GSH pool, was increased by infection with amplicon vectors. Thus, replication-deficient HSV-1 and the GAD67 transgene have complementary neuroprotective effects and infection with GAD67-expressing amplicon vectors was able to protect nondifferentiated cortical neurons from glutamate toxicity mediated by oxidative stress. Such defective GAD67-expressing HSV-1, as neurotropic vector, should be helpful in neurodegenerative diseases implicating alterations of energy metabolism and oxidative stress in neuronal cells expressing GABA transaminase.
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PMID:Enhancement of neuronal protection from oxidative stress by glutamic acid decarboxylase delivery with a defective herpes simplex virus vector. 1463 8

Epileptic patients experienced an irreversible loss of their peripheral visual field upon treatment with vigabatrin (gamma-vinyl GABA), an inhibitor of the GABA degrading enzyme, GABA transaminase. Subsequently, central visual function was reported to also be irreversibly altered. This visual loss is associated with a decrease in the electroretinogram measurement localizing the deficit to the retina. To investigate its cellular origin, we treated rats daily with vigabatrin for 45 days. Two days after arresting this treatment, rats exhibited an irreversible decrease in the photopic electroretinogram, the flicker response, and the oscillatory potentials. These functional alterations were associated with a peripheral disorganization of the outer retina. However, photoreceptor damage was not limited to these disorganized areas, but cone inner and outer segments were severely injured in more central areas and their numbers were irreversibly decreased by 17 to 20%. Ultrastructural examination of the retina confirmed the presence of major photoreceptor damages, which were further supported by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 activation both indicative of photoreceptor apoptosis. This study suggests that the visual field loss in vigabatrin-treated epileptic patients may result from a sequence of events starting from cone cell injury to a more severe disorganization of the photoreceptor layer.
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PMID:Vigabatrin, the GABA-transaminase inhibitor, damages cone photoreceptors in rats. 1512 10

The role of catecholamine neuronal input on GABAergic activity in the hypothalamus, telencephalon, optic tectum, and cerebellum was investigated in early recrudescent female goldfish (Carassius auratus). A new quantitative technique was developed and validated, permitting concomitant quantification and correlational analysis of glutamic acid decarboxylase 65 (GAD65), GAD67, and GAD3 mRNA levels and in vivo GABA synthesis. Catecholamine depletion was achieved by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 50 microg/g body weight) and dopamine (DA) depletion verified by HPLC. Endogenous GABA levels were increased by intraperitoneal administration of gamma-vinyl GABA (GVG; 300 microg/g body weight), an inhibitor of the GABA catabolic enzyme GABA transaminase. Treatment with MPTP resulted in a greater than twofold increase in GABA synthesis rate in the optic tectum and telencephalon. The increase in GABA synthesis rate was highly correlated with an increase in GAD67, but not GAD65 or GAD3 mRNA levels. These results suggest that catecholaminergic input exerts inhibitory effects on GABA synthesis rates through the modulation of GAD67 in the optic tectum and telencephalon. Together with previously published observations in rodents and primates, it is suggested that catecholaminergic control of GABA synthesis must have evolved more than 200 million years ago, before the emergence of the teleost fishes.
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PMID:Increased GAD67 mRNA levels are correlated with in vivo GABA synthesis in the MPTP-treated catecholamine-depleted goldfish brain. 1536 87

Previous work indicated a role for GABA and glutamate in the reinforcing effects of drugs of abuse. The present studies assessed the effects of GABAergic and glutamatergic manipulations on the reinforcing effects of nicotine as assessed by intravenous nicotine self-administration. Male Wistar rats were allowed to self-administer either of two nicotine doses under a fixed ratio or a progressive ratio schedule of reinforcement. The effects of a glutamatergic compound on nicotine self-administration in male DBA/2J mice were also explored. Finally, to assess for nonspecific effects of the drug manipulations, the effects of all test compounds on responding maintained by a food reinforcer were investigated. The pharmacological manipulations used were: gamma-vinyl-GABA (vigabatrin or GVG), an irreversible inhibitor of GABA transaminase, the GABAB receptor agonists (-)baclofen and CGP44532, and the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP. GVG, CGP44532, and (-)baclofen dose-dependently decreased nicotine self-administration on the fixed-ratio schedule, but also decreased food-maintained responding. Furthermore, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive-ratio schedule. MPEP dose-dependently decreased nicotine self-administration with no effect on food-maintained responding in rats. MPEP also decreased nicotine self-administration in the mice. These results demonstrate that activation of GABAB receptors or blockade of mGluR5 decreased nicotine self-administration. Although there was some selectivity for the effects of the GABAergic manipulations, there was clear selectivity of the effects of MPEP on nicotine- versus food-maintained responding. Thus, compounds that increase GABAergic neurotransmission and antagonists at mGluR5 have potential as anti-smoking medications for humans.
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PMID:Role of gamma-aminobutyric acid (GABA) and metabotropic glutamate receptors in nicotine reinforcement: potential pharmacotherapies for smoking cessation. 1554 54

The antiepilepsy drug vigabatrin (1; 4-aminohex-5-enoic acid; gamma-vinyl GABA) is a mechanism-based inactivator of the pyridoxal 5'-phosphate (PLP)-dependent enzyme gamma-aminobutyric acid aminotransferase (GABA-AT). Inactivation has been shown to proceed by two divergent mechanisms (Nanavati, S. M. and Silverman, R. B. (1991) J. Am. Chem. Soc. 113, 9341-9349), a Michael addition pathway (Scheme 2, pathway a) and an enamine pathway (Scheme 2, pathway b). Analogs of vigabatrin with a cyclopropyl or cyanocyclopropyl functionality in place of the vinyl group (2-5) were synthesized as potential inactivators of GABA-AT that can inactivate the enzyme only through a Michael addition pathway, but they were found to be only weak inhibitors of the enzyme.
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PMID:Synthesis of cyclopropane isosteres of the antiepilepsy drug vigabatrin and evaluation of their inhibition of GABA aminotransferase. 1555 44


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