Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P80404 (GABA transaminase)
 786 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diazepam-induced GH secretion was tested on 28 male volunteers before and after a 3-day treatment with methysergide, pimozide, or sodium valproate. Serum GH, diazepam, and blood glucose levels were determined. Without prior medication, the mean serum GH level increased 336% 1 h after diazepam administration. Treatment with the serotonin antagonist, methysergide, had no effect on the diazepam-stimulated GH secretion, whereas pimozide, the selective dopamine receptor-blocking agent, reduced the GH response to diazepam by 50% (P less than 0.05). Sodium valproate, a gamma-aminobutyric acid transaminase inhibitor, also inhibited diazepam-induced GH secretion; stimulated GH levels were 51% at 30 min (P less than 0.025), 39% at 60 min (P less than 0.025), and 46% at 90 min (P less than 0.025) relative to the stimulated levels without medication. No difference was found in blood glucose or serum diazepam levels after the drug treatments relative to the values obtained under basal conditions. It is suggested that diazepam-induced GH secretion is at least partly mediated via dopaminergic mechanisms. Serotonin does not seem to be involved. It is further proposed that gamma-aminobutyric acid plays an inhibitory role in GH secretion.
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PMID:The effect of methysergide, pimozide, and sodium valproate on the diazepam-stimulated growth hormone secretion in man. 37 Jan 37

Bilateral ischemia has been shown to alter the net brain levels of energy metabolites such as ATP, phosphocreatine, glucose, and glycogen. The amino acid neurotransmitter gamma-aminobutyric acid (GABA) exerts a tonic inhibitory influence on neural activity. The present studies were designed to evaluate the influence of elevated GABA levels on the metabolic sequelae of ischemia. The GABA transaminase inhibitor gamma-vinyl-GABA (GVG; vigabatrin) was administered to Mongolian gerbils before the production of a bilateral ischemic incident. GABA levels were elevated in all regions assayed. Levels of energy metabolites were also increased, an indication of reduced energy utilization. In control animals, in the absence of GVG, 1 min of bilateral ischemia produced decreases in the levels of all metabolites. In animals pretreated with GVG, the effects of 1 min of bilateral ischemia were attenuated. These data suggest that the level of ongoing activity may affect the response to an ischemic insult. Furthermore, GVG may have a clinical indication in reducing the effect of minor ischemic incidents.
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PMID:Elevated gamma-aminobutyric acid levels attenuate the metabolic response to bilateral ischemia. 149 8

The effect of acute and chronic ethanol administration on the level of gamma-aminobutyric acid (GABA), glutamate, aspartate, and glutamine was investigated. The level of GABA rose both after acute and chronic ethanol administration. In chronic experiments also the level of glutamate, aspartate and glutamine were increased. In acute experiments the incorporation from glucose into the studied amino acids (neuronal compartment) increased, while in chronic experiments a decreasing trend was observed. In the glial compartment the incorporation increased only into glutamate and glutamine in acute experiments, while in chronic experiments a decreased incorporation into glutamine was recorded. The activities of three enzymes were studied in seven parts of the brain after acute ethanol administration. The activity of glutamic acid decarboxylase increased in the hypothalamus and brain cortex and decreased in the medulla oblongata. The activity of GABA transaminase did not change and the activity of glutamine synthetase decreased only in the hippocampus. In accordance with several other studies, the presented results show that ethanol interferes with the GABA system in the brain. It is suggested that the primary effect of ethanol is exerted on the cell membranes with preference for the regions connected with the GABA system.
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PMID:[The effect of ethanol on gamma-aminobutyric acid in the brain]. 257 92

The presence of gamma-hydroxybutyric acid (GHB) in synaptosome-enriched fractions of rat brain was ascertained using a GLC technique. The stability of GHB in synaptosomes was evaluated by addition of various gamma-aminobutyric acid (GABA) transaminase (GABA-T) inhibitors, GHB, or ethosuximide to the homogenizing medium. Furthermore, changes in whole brain GHB levels were compared with those in the synaptosomal fraction in animals treated with GABA-T inhibitors, GABA, or ethosuximide. GHB was present in synaptosome-enriched fractions in concentrations ranging from 40 to 70 pmol/mg of protein. There was no evidence for redistribution, leakage, or metabolism of GHB during the preparation of synaptosomes. The elevations of whole brain GHB level associated with GABA-T or ethosuximide treatment were reflected by a parallel increase in synaptosomal GHB content. These data add to the growing evidence that GHB may have neurotransmitter or neuromodulator function.
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PMID:gamma-Hydroxybutyric acid in subcellular fractions of rat brain. 379

Inhibition of GABA transaminase which led to a several-fold increase of GABA levels in the goldfish optic tectum or diazepam pre-treatment, were unable to protect tectal neurons from kainic acid neurotoxicity, as judged by light and electron microscopic observations and by the drop of marker enzymes for neurotransmitters. In an in vitro preparation of tectal slices GABA, added to the incubation medium, had no effect on a metabolic parameter (CO2 production from exogenous glucose) related to the excitatory action of kainic acid. It is concluded that, in the goldfish optic tectum, pharmacological manipulation cannot enhance the activity of GABAergic circuits to the extent necessary to block the neuroexcitatory and neurotoxic action of kainic acid.
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PMID:Pharmacological manipulation of GABA system does not protect the goldfish optic tectum from the neuroexcitatory and neurotoxic action of kainic acid. 630 39

Stimulation of the gamma-aminobutyric acid (GABA) shunt by valproate and its major metabolite, E-delta 2-valproate, has been proposed to decrease brain energy metabolism. In order to elucidate this hypothesis, the effect of these drugs on substrate utilization in neonatal rat brain slices was studied. The overall rate of lactate utilization was dose-dependently inhibited by both drugs. Valproate and E-delta 2-valproate inhibited both sterol and fatty acid syntheses from 3-hydroxybutyrate. The rate of glucose utilization was not affected by valproate nor E-delta 2-valproate. The inhibition of the GABA aminotransferase by aminooxyacetate decreased lipogenesis from lactate, 3-hydroxybutyrate and glucose. The inhibitor of the mitochondrial pyruvate carrier, alpha-cyano-4-hydroxycinnamate, strongly decreased the rate of lactate, 3-hydroxybutyrate and glucose utilization, suggesting that the inhibition of pyruvate mitochondrial carrier is not the mode of action of these drugs. It is suggested that inhibition of plasma membrane monocarboxylate carrier by valproate and E-delta 2-valproate, but not the activation of the GABA shunt, is responsible for the inhibition of the brain fuel utilization.
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PMID:Inhibition of neonatal brain fuel utilization by valproate and E-delta 2-valproate is not a consequence of the stimulation of the gamma-aminobutyric acid shunt. 796 21

The metabolic precursors and cerebral compartmentation of the augmented GABA pool induced by vigabatrin, an irreversible inhibitor of GABA transaminase, have been investigated by 13C NMR. Adult rats receiving rat chow ad libitum were given either drinking water only or drinking water containing 2.5 g/L vigabatrin for 7 days. Both groups of animals were infused either with [1,2(-13)C2]acetate (15 mumol/min/100 g body weight), an exclusive precursor of GABA formation through the glial glutamine pathway, or with [1,2(-13)C2]glucose (15 mumol/min/100 g body weight), a substrate that can produce GABA through the glial glutamine pathway or by direct metabolism in the neurons. The brains were frozen in situ, extracted with perchloric acid, and analyzed by 13C NMR. In vigabatrin-treated animals [13C]glutamine, a common intermediate for [13C]GABA synthesis from glucose or acetate, was accumulated to similar amounts during infusions with [1,2(-13)C2]glucose or [1,2(-13)C2]acetate. However, [13C]GABA accumulation was sevenfold higher during [1,2(-13)C2]glucose infusions or twofold higher during [1,2(-13)C2]acetate infusions. These results show that the direct pathway of GABA formation by neuronal metabolism of glucose predominates over the alternative pathway through glial glutamine. Near-equilibrium relationships of the aminotransferases of GABA and aspartate imply that the observed [13C]GABA accumulation occurs initially in the neuronal compartment.
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PMID:Metabolic precursors and compartmentation of cerebral GABA in vigabatrin-treated rats. 885 58

Brain GABA levels rise and plateau following prolonged administration of the irreversible GABA-transaminase inhibitor vigabatrin (gamma-vinylGABA). Recently it has been shown that increased GABA levels reduces GAD67 protein, one of two major isoforms of glutamic acid decarboxylase (GAD). The effects of GABA elevation on GABA synthesis were assessed in vivo using 1H and 13C-edited NMR spectroscopy. Rates of turnover of cortical glutamate and GABA from intravenously administered [1-13C]glucose were measured in alpha-chloralose anesthetized rats 24 hours after receiving vigabatrin (500 mg/kg, i.p.) and in non-treated controls. GABA concentration was increased 2-fold at 24 hours (from 1.3 +/- 0.4 to 2.7 +/- 0.9 mumol/g) and GABA-T activity was inhibited by 60%. Tricarboxylic acid cycle flux was not affected by vigabatrin treatment compared to non-treated rats (0.47 +/- 0.19 versus 0.52 +/- 0.18 mumol/g, respectively). GABA-C2 fractional enrichment (FE) measured in acid extracts rose more slowly in vigabatrin-treated compared to non-treated rats, reaching > 90% of the glutamate FE after 3 hours. In contrast, GABA FE > or = glutamate FE in non-treated rats. A metabolic model consisting of a single glutamate pool failed to account for the rapid labeling of GABA from glutamate. Metabolic modelling analysis based on two (non-communicating) glutamate pools revealed a approximately 70% decrease in the rate of GABA synthesis following vigabatrin-treatment, from 0.14 (non-treated) to 0.04 mumol/g/min (vigabatrin-treated). These findings, in conjunction with the previously reported differential effects of elevated GABA on the GAD isoforms, suggests that GAD67 may account for a major fraction of cortical GABA synthesis in the alpha-chloralose anesthetized rat brain in vivo.
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PMID:The rate of turnover of cortical GABA from [1-13C]glucose is reduced in rats treated with the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA). 889 66

The objective of the present study was to assess the degree to which astrocytic glutamine provides carbon for net synthesis of GABA in the rat neocortex in vivo. Isotopic labeling of GABA and glutamate from astrocytic glutamine was followed in halothane anesthetized and ventilated rats during an intravenous infusion of [2-(13)C]glucose. A net increase in GABA was achieved by administration of the GABA-transaminase inhibitor, gabaculine to suppress catabolism of GABA and recycling of (13)C label. (13)C Percentage enrichments of GABA, glutamate and glutamine were assessed in tissue extracts using (13)C-edited (1)H nuclear magnetic resonance at 8.4 T. GABA levels increased 2.6 micromol/g at 2 h and 6.1 micromol/g at 5 h after gabaculine, whereas glutamate and glutamine decreased in toto by 5.6 micromol/g at 2 h and 3.1 micromol/g at 5 h. Selective enrichment of glutamine, glutamate, and GABA C3's over other carbon positions was observed consistent with a precursor role for astrocytic glutamine. Between 1 h (control) and 3 h (gabaculine-treated) of [2-(13)C]glucose infusion, (13)C percentage enrichment increased in glutamine C3 (from 3.2+/-0.5 to 7.0+/-0.9%), glutamate C3 (from 1.8+/-0.5 to 3.4+/-0.9%), and GABA C3 (from 2.7+/-1.6 to 4.8+/-0.4%). The measured incremental [3-(13)C]GABA concentration (0.15 micromol/g) was close to the predicted value (0.13 micromol/g) that would be expected if the increase in GABA were produced entirely from glutamine compared to glutamate (0.07 micromol/g) based on the average precursor enrichments between 1 and 3 h. We conclude that glutamine is the major source of GABA carbon in the rat neocortex produced acutely following GABA-T inhibition by gabaculine in vivo.
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PMID:Glutamine is the major precursor for GABA synthesis in rat neocortex in vivo following acute GABA-transaminase inhibition. 1170 Nov 33

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


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