Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.19 (GABA transaminase)
808 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ventral hippocampi of male, Fischer-344 rats were implanted with microdialysis probes and the effects of systemically administered kainic acid (KA) (8 mg/kg, s.c.) on the in vivo release of amino acids were measured for four hours after administration. In order to measure GABA release in vivo, gamma-vinyl-GABA (GVG), an irreversible inhibitor of GABA transaminase, was injected intrahippocampally prior to perfusion. GVG pretreatment resulted in measurable levels of GABA in the perfusate without significant effects on the release of aspartate, glutamate, glutamine, glycine or taurine. Following GVG pretreatment systemic administration of KA produced a time-dependent increase in GABA, as well as all other amino acids except glutamine, which was initially decreased. These results show for the first time that systemically administered KA increases extracellular GABA levels, an effect previously reported only in vitro. These data suggest that prior to destruction of GABA-containing interneurons in the hippocampus, there is an increased activity of those GABA interneurons reflected as an increase in extracellular GABA levels.
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PMID:Systemic administration of kainic acid increases GABA levels in perfusate from the hippocampus of rats in vivo. 208 85

gamma-Aminobutyric acid (GABA) neurones are present in the zona incerta (ZI) where other systems have been shown to influence gonadotrophin release. This report investigates the effect of GABA agents in the ZI on ovulation and luteinizing hormone (LH) release. In intact females under Saffan anaesthesia, bilateral stereotactic injections into the ZI of two GABA transaminase inhibitors [amino(oxy)acetic acid and gamma-acetylene GABA] on the morning of pro-estrus or two GABA agonists on the afternoon of pro-estrus inhibited ovulation. The selective GABA B agonist baclofen was effective at 0.05 nM; muscimol, a mixed GABA A and B agonist, was 50-fold less potent, while the selective GABA A agonist isoguvacine had no effect at 500 nM. Administration of baclofen at 0.05 and 5 nM into the ZI significantly reduced plasma LH concentration in untreated ovariectomized rats and also prevented the rise in LH normally induced in ovariectomised rats primed with 5 micrograms oestradiol benzoate (OB) plus 0.5 mg progesterone. In ovariectomised rats primed with 5 micrograms OB alone, administration of the selective GABA A antagonist bicuculline (200 and 260 pg/side) had no effect on plasma LH, while the GABA B antagonist phaclofen (10 pg/side) stimulated a rise in plasma LH, 40 and 60 min after injection. These results indicate that GABA activity in the ZI exerts an inhibitory effect on LH release and ovulation and this is preferentially exerted via GABA B receptors.
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PMID:Role of gamma-aminobutyric acid in the zona incerta in the control of luteinizing hormone release and ovulation. 212 61

Gabaculine, 5-amino-1,3-cyclohexadienylcarboxylate, is an analogue of GABA and a potent irreversible inhibitor of GABA aminotransferase. However, D-3-aminoisobutyrate-pyruvate aminotransferase for which GABA was neither a substrate nor an inhibitor was also inactivated by gabaculine. The Ki for D-3-aminoisobutyrate-pyruvate aminotransferase was 8.3 x 10(-6) M, and the Kcat for its turnover was 0.31 min-1 at 25 degrees C. beta-Alanine protected the enzyme from inactivation by gabaculine, but GABA did so to much a lesser extent.
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PMID:Irreversible inhibition of D-3-aminoisobutyrate-pyruvate aminotransferase by gabaculine. 212 4

Pretreatment with 5-hydroxytryptophan (5-HTP), a precursor of 5-HT, antagonised while pretreatment with p-chlorophenylalanine (PCPA), a 5-HT depletor, potentiated the myoclonus induced by picrotoxin, a GABA antagonist. Pretreatment with aminooxyacetic acid (AOAA), a GABA transaminase inhibitor, antagonised picrotoxin-induced myoclonus. The combined effect of the least protective doses of AOAA and 5-HTP was greater than the sum of their individual inhibitory effects on picrotoxin-induced myoclonus. Further, AOAA failed to inhibit picrotoxin-induced myoclonus in PCPA pretreated rats. These findings suggest that the central 5-HT-ergic system exerts a facilitatory influence on the GABA-ergic system and thus it is involved in the antimyoclonic action of GABA.
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PMID:A functional interaction between GABA and 5-HT in inhibiting picrotoxin-induced myoclonus in rats. 214 69

It has previously been found that the GABA transaminase inhibitors gamma-acetylen GABA (GAG) and sodium valproate reduced intromission behavior in male rats without affecting mounting behavior. These effects were obtained, however, only in doses that also impaired motor execution. The purpose of the present study was to establish whether copulatory thrusting patterns were affected by these GABA transaminase inhibitors. Sodium valproate, 200 mg/kg, reduced the number of intromissions and the intromission rate without affecting mounting behavior. GAG, 100 mg/kg, had similar effects on sexual behavior. The only effect obtained on copulatory thrusting patterns was a small reduction in mount and intromission thrust frequency after GAG 100 mg/kg. It is unlikely that this effect is responsible for the inhibitory actions of GAG on sexual behavior, especially since sodium valproate did not modify copulatory thrusting patterns, but inhibited sexual behavior in a manner similar to that of GAG.
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PMID:Copulatory thrusting pattern in the male rat after acute treatment with GABA transaminase inhibitors. 215 60

Morphine (15 mg/kg i.p.) produces a biphasic action on motility: hypokinesia and muscular rigidity ("catatonia"), followed by a hyperkinesia in association with some stereotyped behaviour. In the present studies, alterations in GABA (gamma-aminobutyric acid) turnover were studied in possible correlation with changes in motility. As a criterion of GABA turnover its accumulation after inhibition of GABA transaminase by gamma-acetylene GABA (GAG) was measured. During the first, depressory phase only, GABA turnover was increased in the substantia nigra. In contrast, GABA turnover was continuously enhanced during both phases of morphine's action in the nucleus accumbens. No significant alterations were observed in striatum or globus pallidus. These findings seem to be consistent with the assumption of at least a short- and a long-lasting action of morphine on the basal ganglia.
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PMID:Effects of morphine on gamma-aminobutyric acid turnover in the basal ganglia. Possible correlation with its biphasic action on motility. 217 42

Previous studies found that injection of the GABA uptake inhibitor nipecotic acid into the nucleus tractus solitarius (NTS) increases arterial pressure. This effect of nipecotic acid was not antagonized by the selective GABAA receptor blocking agent bicuculline, suggesting that the action of nipecotic acid was mediated through an action of GABA on GABAB receptors in the NTS. The present studies examined this issue using a newly described GABAB antagonist, phaclofen. Injection of phaclofen (4 nmol in 100 nl artificial CSF) into the NTS of chloralose-anesthetized rats produced a slight decrease in arterial pressure (-8 +/- 2 mmHg) lasting less than 1 min. Smaller doses had no effect. Phaclofen antagonized in a dose-dependent (0.5-4 nmol) manner the increase in arterial pressure produced by injection into the NTS of the GABAB agonist baclofen (5-100 pmol). In contrast, phaclofen had no effect on the pressor response elicited by injection into the NTS of the GABAA agonist muscimol. Phaclofen (4 nmol) injected into the NTS totally reversed the increase in blood pressure elicited by injection into the NTS of a maximally effective dose of nipecotic acid (10 nmol). Phaclofen also inhibited the pressor response elicited by injection into the NTS of another indirectly acting GABA agonist, gamma-vinylGABA (GVG). Although GVG is an effective inhibitor of GABA transaminase, the enzyme involved in the metabolism of GABA, the time course of inhibition of GABA transaminase evoked by GVG was not consistent with the pressor response being produced by this mechanism. However, the pressor response elicited by GVG is consistent with its reported ability to inhibit GABA uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endogenous GABA acts on GABAB receptors in nucleus tractus solitarius to increase blood pressure. 217 40

A variety of alkyl-substituted 4-aminobutanoic acid derivatives, including a homologous series of 3-alkyl-4-aminobutanoic acid analogues, 4-methyl isomer analogues, the 3,3-dimethyl analogue, and (E)-4-amino-3-methyl-2-butenoic acid, were synthesized and tested as alternate substrates for purified gamma-aminobutyric acid aminotransferase from pig brain. All of the compounds were substrates, but their activities diminished as the size and bulk of the 3-alkyl substituent increased. Several differences were observed between the alkyl-substituted analogues and the corresponding aryl-substituted compounds previously reported (Silverman, R. B., Invergo, B. J., and Levy, M. A. (1987) J. Biol. Chem. 262, 3192-3195). These findings will be important in future designs of inhibitors of gamma-aminobutyric acid aminotransferase.
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PMID:4-Amino-3-alkylbutanoic acids as substrates for gamma-aminobutyric acid aminotransferase. 226 25

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


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