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)

Vigabatrin is a selective, irreversible suicide inhibitor of GABA transaminase and thus increases brain and CSF GABA. In 33 adult patients with long standing refractory epilepsy on treatment with one or two standard anti-convulsant drugs, the addition of vigabatrin up to 3g daily for eight weeks was associated with a 48.2% reduction in seizure frequency. Twenty patients who had exhibited a 50% or more reduction in frequency of one or more seizure types entered an eight week double-blind placebo controlled phase. Patients on vigabatrin maintained a 54.7% reduction of seizure frequency, whereas those on placebo showed an 18.6% increase in seizure frequency, a highly significant difference between the two groups. In the open phase, seven patients were withdrawn due to unacceptable and reversible adverse events. The commonest side effects were drowsiness, depression and mood instability, and headaches. Vigabatrin is a potentially valuable new treatment for chronic epilepsy, especially partial seizures with or without secondary generalisation.
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PMID:Vigabatrin: rational treatment for chronic epilepsy. 229 96

1-O-Linolenoyl-2-O-(4-aminobutyryl)-3-O-(4-vinyl-4-aminobutyryl)glycerol (LGV) was synthesized as an example of a prodrug which readily penetrates the blood-brain barrier (brain penetration index 97% +/- 15%) and releases two active substances in the central nervous system (CNS): GABA (4-aminobutanoic acid) and the GABA transaminase inhibitor (GABA-T) of GABA breakdown. In vitro studies showed that the compound can inhibit GABA-T after hydrolysis by CNS esterases and that it enhanced GABAergic inhibition when applied to rat hippocampus slices. In vivo studies indicate that LGV depresses the spontaneous locomotor activity of mice. Its activity on a molar basis was some 300 times greater than that of gamma-vinyl-GABA.
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PMID:Synthesis, brain uptake, and pharmacological properties of a glyceryl lipid containing GABA and the GABA-T inhibitor gamma-vinyl-GABA. 229 39

The tetrazolium salt procedure of van Gelder (1965) for the demonstration of GABA transaminase (GABAT; the most important GABA degrading enzyme) was adapted for microphotometric measurements of GABAT activities in brain sections using the hippocampus of rats as selected brain region. The final incubation medium consisted of 50 mM GABA, 5 mM alpha-ketoglutarate, 7 mM NAD, 10 mM sodium azide, 6 mM nitroblue tetrazolium chloride, 20 mM malonate and 15% polyvinyl alcohol in 0.05 M Hepes buffer; the final pH was 8.0. There was a linear relationship between GABAT activity and section thickness up to 14 microns and between GABAT activity and reaction time at least up to 20 min (kinetic and end-point measurements). Phenazine methosulfate as an exogenous electron carrier and pyridoxal-5-phosphate as coenzyme of GABAT did not enhance the demonstrable GABAT activities, whereas sodium azide as a blocker of the respiratory chain resulted in an increase of demonstrable enzyme activities. A coreaction of succinate dehydrogenase was excluded by the use of malonate (competitive inhibitor). Using the incubation medium described GABAT activities were demonstrated via the endogenous enzymes succinic semialdehyde dehydrogenase and NADH tetrazolium reductase which were shown to be not rate limiting and seems to be similarly localized as GABAT.
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PMID:Microphotometric determination of enzymes in brain sections. II. GABA transaminase. 233 51

The effects of aminooxyacetic acid (AOAA), an aspartate aminotransferase (AAT) inhibitor, L-canaline, an ornithine aminotransferase inhibitor, and gamma-acetylenic GABA and gabaculine, both gamma-aminobutyric acid transaminase (GABA-T) inhibitors, on the release of aspartate from slices of rat medulla oblongata and hippocampus were studied. The slices were superfused and electrically stimulated. There was a Ca2(+)-dependent stimulus-evoked release of endogenous aspartate. AOAA (10(-4) and 10(-3) M) decreased the evoked release of aspartate in the medulla oblongata but not in the hippocampus. In addition, AOAA produced a decrease in the spontaneous efflux and tissue content of aspartate in the medulla oblongata. L-Canaline (5 x 10(-5) M), gamma-acetylenic GABA (10(-4) M) and gabaculine (10(-5) M) did not affect the evoked release of aspartate in the medulla oblongata, while these agents produced a decrease in spontaneous efflux and tissue content of aspartate. These findings suggest that AAT participates in the synthesis of transmitter aspartate in the medulla oblongata of the rat. It appears that there are the pools of transmitter aspartate and non-transmitter aspartate in the rat medulla oblongata.
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PMID:Electrical stimulation-evoked release of endogenous aspartate from rat medulla oblongata slices. Effects of inhibitors of aspartate aminotransferase and GABA transaminase. 234 2

The effects of systemically injected caerulein, a cholecystokinin octapeptide analogue, on GABA content and turnover have been studied in various regions of rat brain. Caerulein decreased GABA levels in the nucleus accumbens, tuberculum olfactorium and substantia nigra and diminished GABA turnover rates in the striatum, nucleus accumbens and substantia nigra, as estimated from the rate of GABA accumulation after inhibition of GABA transaminase by aminooxyacetic acid (AOAA). These results indicate the effect of caerulein on the utilization of GABA in specific cerebral regions and suggest that the GABAergic system is involved in the mechanism of action of peripherally administered caerulein.
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PMID:Changes in GABA content and turnover in discrete regions of rat brain after systemic administration of caerulein. 234 75

Vigabatrin (gamma-vinyl-GABA), an irreversible inhibitor of gamma-aminobutyric acid transaminase, has been reported to be effective in the treatment of refractory epilepsies. Animal toxicology studies have shown that long-term application of vigabatrin induces intramyelinic edema and microvacuolation of the white matter in non-primate species. However, clinical and neuropathological studies of patients exposed to long-term vigabatrin treatment have, so far, provided no evidence for microvacuolation in the human brain. We report on the histopathological findings of selective amygdalohippocampectomy specimens from a 36-year-old female patient treated with vigabatrin for a period of 11.5 months, and from 2 control patients with chronic refractory temporal lobe seizures. All specimens showed changes associated with chronic epileptic seizures including focal neuronal loss and hippocampal gliosis. Microvacuoles, intramyelinic edema or other manifestations of neurotoxic damage were not observed in vigabatrin exposed tissue, supporting the view that this compound may not exert hippocampal neurotoxicity in humans.
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PMID:Neuropathology of a human hippocampus following long-term treatment with vigabatrin: lack of microvacuoles. 238 87

1. Gamma-vinyl GABA (GVG) is a new anticonvulsant drug that enhances levels of GABA in the brain by irreversibly inhibiting GABA transaminase. 2. To further evaluate the effects and mechanism of action of GVG in the human brain, we measured acetylcholinesterase (AChE) activity and levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), cyclic nucleotides (cAMP, cGMP), total GABA (TGABA), and GVG in CSF of 78 patients with complex partial epilepsy. The CSF samples were taken at baseline and after 3 months of GVG administration (3 g GVG per day). Thereafter, the responders (= 50% decrease in number of seizures) were divided (double-blind) into two groups that received either 1.5 g or 3 g of GVG per day for the next 3 months. The third CSF sample was taken after this double-blind period. 3. TGABA levels were increased during the GVG treatment (p less than 0.001). In the whole group of patients AChE, HVA, 5-HIAA, and cAMP did not differ from baseline values, cGMP levels were slightly elevated after 3 months of GVG administration (p = 0.019), but were no longer elevated after 6 months. Responders had slightly lower AChE activity than nonresponders (p = 0.041). After 6 months of drug treatment the cGMP levels of patients receiving 1.5 g of GVG did not differ from those receiving 3 g. 4. In conclusion, GVG administration elevates levels of TGABA in the CSF without any clear of constant change to cholinergic and aminergic transmission or effect on cyclic nucleotides. Our study further emphasizes the specific mechanism of action of GVG via GABAergic transmission.
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PMID:Effect of gamma-vinyl GABA treatment on cholinergic and aminergic neurotransmission and on cyclic nucleotides in human complex partial epilepsy--a CSF study. 245 56

1. 3H-gamma-Aminobutyric acid (GABA) release elicited by a depolarizing K+ stimulus or by noradrenergic transmitter was examined in rat pineals in vitro. 2. The release of 3H-GABA was detectable at a 20 mM K+ concentration in medium and increased steadily up to 80 mM K+. 3. In a Ca2+-free medium 3H-GABA release elicited by 30 mM K+, but not that elicited by 50 mM K+, became blunted. 4. Norepinephrine (NE; 10(-6)-10(-4) M) stimulated 3H-GABA release from rat pineal explants in a dose-dependent manner. 5. The activity of 10(-5) M NE on pineal GABA release was suppressed by equimolecular amounts of prazosin or phentolamine (alpha 1- and alpha 1/alpha 2-adrenoceptor blockers, respectively) and was unaffected by propranolol (beta-adrenoceptor blocker). 6. The alpha 1-adrenoceptor agonist phenylephrine (10(-7)-10(-5) M) and the beta-adrenoceptor agonist isoproterenol (10(-5) M) mimicked the GABA releasing activity of NE, while 10(-7) M isoproterenol failed to affect it; the alpha 2-adrenoceptor agonist clonidine (10(-7)-10(-5) M) did not modify 3H-GABA release. 7. The addition of 10(-4) M GABA or of the GABA transaminase inhibitor gamma-acetylenic GABA or aminooxyacetic acid inhibited the melatonin content and/or release to the medium in rat pineal organotypic cultures. 8. GABA at concentrations of 10(-5) M or greater partially inhibited the NE-induced increase in melatonin production by pineal explants. 9. The depressant effect of GABA on melatonin production was inhibited by the GABA type A receptor antagonist bicuculline; bicuculline alone increased the pineal melatonin content. Baclofen, a GABA type B receptor agonist, did not affect the pineal melatonin content or release. 10. The decrease in serotonin (5-HT) content of rat pineal explants brought about by NE was not modified by GABA; GABA by itself increased 5-HT levels. 11. These results indicate that (a) GABA is released from rat pineals by a depolarizing stimulus of K+ through a mechanism which is partially Ca2+ dependent; (b) NE releases rat pineal GABA via interaction with alpha 1-adrenoceptors; (c) GABA inhibits melatonin production in vitro via interaction with GABA type A receptor sites; and (d) GABA's effect on NE-induced melatonin release does not correlate with the lack of effect on the NE-induced decrease in pineal 5-HT content.
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PMID:Release and effect of gamma-aminobutyric acid (GABA) on rat pineal melatonin production in vitro. 247 90

The main objective of this work was to study the role of the GABAergic system on the convulsions elicited by the organochlorine insecticide lindane. The concentration of lindane in rat brain at the onset of the first tonic convulsion was taken as the endpoint for the neurotoxic action of the insecticide administered by intravenous infusion. Pretreatment with the GABA agonists muscimol and progabide, the GABA uptake blocker SK&F 89976-A, the GABA transaminase inhibitor gamma-acetylenic GABA, and the GABA indirect agonist phenobarbital significantly increased the threshold concentration of lindane in brain required to induce convulsions. The GABA agonist THIP, the GABA competitive antagonist bicuculline, and the prodrug cetyl-GABA had no effect on the brain level of lindane required to induce seizures. The noncompetitive GABA antagonists, picrotoxinin and pentylenetetrazol, significantly decreased the brain concentration of lindane needed to elicit convulsions. The concentration of GABA in the brain of lindane-treated rats was only modified by the significant increase produced after gamma-acetylenic GABA pretreatment. These results show that the convulsions elicited by lindane can be facilitated by some GABA antagonists and antagonized by GABA mimetics, especially those that enhance GABA functionality. The present data are consistent with the proposed in vitro competition of lindane for the picrotoxinin binding site associated with the Cl- ionophore of the GABAA receptor, and suggest that lindane may also interact in vivo with this site.
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PMID:GABAergic modulation of lindane (gamma-hexachlorocyclohexane)-induced seizures. 247 71

Slices of rat temporo-parietal cortex were prelabeled with gamma-[3H]aminobutyric acid ([3H]GABA), in the presence of the glial GABA uptake inhibitor beta-alanine. The slices were then superfused with a medium containing the GABA transaminase inhibitor aminooxyacetic acid and stimulated electrically (5 min, 2 msec, 36 mA at 5 or 10 Hz), in the presence of the neuronal GABA reuptake inhibitor SK&F 89976A [N-(4,4-diphenyl-3-butenyl)-nipecotic acid] and of beta-alanine. Representative experiments showed that the tritium released could be accounted for almost entirely by authentic [3H]GABA. The electrically evoked overflow of [3H]GABA was tetrodotoxin sensitive and largely calcium-dependent. Exogenous GABA, added to the superfusion medium at 3 to 30 microM, reduced in a concentration-dependent manner the electrically evoked (5 Hz) release of [3H]GABA. The GABAB receptor agonist (-)-baclofen, but not the GABAA receptor agonist muscimol, mimicked GABA and produced a concentration-inhibition curve almost superimposable to that of the natural transmitter. The effects of GABA and of (-)-baclofen were much more pronounced at 5 than at 10 Hz. The GABA-induced inhibition of [3H]GABA release was sensitive to the novel GABAB receptor antagonist beta-(p-chlorophenyl)-3-amino propyl phosphonic acid which, by itself, increased the [3H]GABA overflow. The inhibitory effect of GABA was not counteracted by the GABAA receptor antagonists bicuculline or SR 95531 [2-(3'-carbethoxy-2'-propenyl)-3-amino-6-paramethoxy-phenyl-pyr idazinium bromide]. The results are compatible with the presence in the rat cerebral cortex of autoreceptors mediating inhibition of GABA release and belonging to the GABAB type. These autoreceptors may be activated tonically under physiological conditions.
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PMID:Release of gamma-[3H]aminobutyric acid (GABA) from electrically stimulated rat cortical slices and its modulation by GABAB autoreceptors. 254 42


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