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)

The slow onset and carry-over effect of valproic acid (VPA) therapy observed in some clinical as well as experimental animal studies have been examined by parallel pharmacokinetic and pharmacological investigations in a mouse model. VPA was rapidly transferred into brain and was cleared from that tissue with rates which exceeded plasma clearance rates. Of several VPA metabolites present in plasma, only one could be found in the brain: 2-propyl-2-pentenoic acid. This metabolite was cleared from plasma and from brain slower than the parent drug. gamma-Aminobutyric acid (GABA) concentrations were increased within 15 min after VPA injection and remained significantly elevated for at least 8 h. A similar time course was found in regard to the increase of the electroconvulsive threshold (maximal seizures) induced by VPA administration. The activity of glutamic acid decarboxylase rose parallel to the elevation of brain GABA levels, whereas the activity of GABA aminotransferase was not affected. Whereas the rapid onset of the effect on electroconvulsive threshold and on GABA metabolism can be explained by the rapid entrance of VPA into brain, the carry-over effects observed correlated with the kinetics of the metabolite 2-propyl-2-pentenoic acid better than with those of VPA due to the persistence of this metabolite in brain.
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PMID:Valproic acid: brain and plasma levels of the drug and its metabolites, anticonvulsant effects and gamma-aminobutyric acid (GABA) metabolism in the mouse. 680 Dec 54

Mice were treated with different doses of the GABA aminotransferase (GABA-T) inhibitors aminooxyacetic acid, gamma-acetylenic acid, gamma-vinyl GABA and ethanolamine-O-sulphate via the drinking water for periods of 1-12. All drugs caused marked elevations of whole brain GABA concentrations within 4 days of treatment which were associated with increases in the electroconvulsive threshold. However, the effect on seizure threshold could not be enhanced by an increase in the daily dosage of the GABA-T inhibitors and, especially with higher doses, tolerance to the anticonvulsant effect developed. At least in part, this finding may be attributed to a decrease in the activity of glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis. On the other hand, with valproic acid (VPA) no tendency towards a reduced anticonvulsant effectiveness during medication was observed. VPA caused only non-significant increases in cerebral GABA levels but elevated brain GAD activity significantly. No behavioral changes were seen following subchronic administration of GABA-T inhibitors and VPA except in cases where the daily fluid intake was markedly reduced. Our data suggest that the anticonvulsant efficacy of long term treatment with GABA-T inhibitors is limited by the development of compensatory mechanisms, such as reduction of GAD activity, which in turn reduce the amount of GABA available for synaptic transmission, though overall GABA concentrations in the brain are highly elevated. Drug such as VPA which cause only moderate effects on GABA metabolism seem superior in this respect.
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PMID:Anticonvulsant and biochemical effects of inhibitors of GABA aminotransferase and valproic acid during subchronic treatment in mice. 680 73

Mice were continuously treated with valproic acid (VPA) via the drinking water for period from 1 to 12 days. The daily drug intake varied between 500 and 580 mg/kg. However, due to the rapid elimination of VPA in this species average plasma concentrations of only 3-4 micrograms/ml VPA were present at 8:30 a.m., the time chosen for determinations. In the brain, VPA levels were about 10% of those in plasma. In regard to VPA metabolism the products of beta-oxidation 2-en-VPA 2-propyl-2-pentenoic acid) and 3-keto-VPA (2-propyl-3-oxopentanoic acid) proved to be the main metabolites in plasma although other (minor) metabolites of VPA were also present. The only metabolite of VPA detected in the brain was 2-en-VPA. VPA medication caused a significant increase in the threshold for electroconvulsions which was associated with a slight increment of brain GABA levels. The activity of glutamic acid decarboxylase was significantly elevated whereas GABA aminotransferase was not affected. After withdrawal of VPA, a delayed effect on seizure threshold was observed which extended to time periods where VPA could no longer be detected in the brain, but 2-en-VPA was still present.
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PMID:Valproic acid: metabolite concentrations in plasma and brain, anticonvulsant activity, and effects on GABA metabolism during subacute treatment in mice. 681 Jul 78

Regional distribution of endogenous gamma-aminobutyric acid (GABA), its synthesizing enzyme, glutamic acid decarboxylase (GAD), and metabolic enzyme, GABA transaminase (GABA-T), were determined in the intestinal tract of guinea pigs and cats and the findings compared with the number of ganglion cells in Auerbach's plexus. There were positive correlations among the GABA contents and the numbers of neural cells of the plexus. The precise localization of GABA and GAD in individual layers (mucosa, circular and longitudinal muscles, and Auerbach's plexus) in the human and cat colon was also determined. The endogenous GABA contents and GAD activity were the highest in Auerbach's plexus in tissues of both species. These results indicate that GABA is synthesized and localized in Auerbach's plexus and probably plays a significant role in the enteric nervous system.
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PMID:GABA, glutamic acid decarboxylase, and GABA transaminase levels in the myenteric plexus in the intestine of humans and other mammals. 682 80

The effects of local anesthetics on the synthesis, release, and degradation of gamma-aminobutyric acid (GABA) in rat brains were investigated. The addition of procaine, lidocaine, cocaine, or tetracaine did not alter either glutamic acid decarboxylase (GAD) activity or GABA transaminase (GABA-T) activity in vitro. Neither did the enzyme activities in rats with local anesthetic-induced convulsions differ from control values. Tetracaine inhibited high K+-evoked [2,3-3H]GABA release from synaptosomes of rat brain in a dose-dependent manner with a minimal effective concentration of 10(-4) M. Cocaine, lidocaine, and procaine also reduced the release, although they were less potent than tetracaine. The GABA release inhibitors in order of potency are tetracaine, cocaine, lidocaine, and procaine which correlates well with their relative toxicity as convulsants. These results suggest that local anesthetics reduce GABAergic activities by inhibiting the release of the neurotransmitter from the nerve terminals, and that inhibition of the GABA system may be involved in the mechanism of local anesthetic-induced convulsions.
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PMID:Inhibition of gamma-aminobutyric acid release from synaptosomes by local anesthetics. 685 79

The influence of GABA and of drugs, known to alter GABA-metabolism, on the hypovolaemia-provoked vasopressin release was investigated in rats. Blood volume was decreased without altering plasma osmolality or arterial blood pressure by i.p. injection of polyethylene glycol and the resulting plasma vasopressin concentration was measured using a radioimmunoassay. I.c.v. injections of GABA (0.4-2 mg) markedly suppressed the hypovolaemia-induced vasopressin release. The central inhibitory effect of GABA could not be related to appropriate changes in peripheral parameters believed to regulate vasopressin release (arterial blood pressure, renin-angiotensin system). Aminooxyacetic acid (9-81 mg kg-1, i.m.) and gamma-vinyl-GABA (1.5 g kg-1, i.p.), two potent inhibitors of GABA aminotransferase and known to increase brain GABA content, reduced vasopressin release to a comparable degree as did GABA (i.c.v.). On the other hand, 3-mercaptopropionic acid (10-90 mg kg-1, i.p.), an inhibitor of the GABA synthetizing enzyme glutamic acid decarboxylase, promoted the release of vasopressin when the rats were killed prior to the onset of convulsions. These results, on the whole, intimate the existence of a GABA-mediated inhibition in the central control of vasopressin release.
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PMID:Evidence for the involvement of a GABA-mediated inhibition in the hypovolaemia-induced vasopressin release. 719 56

When gamma-aminobutyric acid aminotransferase (GABA-T) activity was measured in vitro in rat brain, neither isoniazid (INH) nor for of its known metabolites (isonicotinic acid, acetylisoniazid, acetylhydrazine, diacetylhydrazine) inhibited the enzyme in concentrations (5 mM) far higher than those likely to be achieved when INH is administered to man. In contrast, hydrazine (5 micrometers) caused a 50% inhibition of GABA-T without inhibiting glutamic acid decarboxylase (GAD). Rats were injected daily for 109 days with hydrazine (0.08 or 0.16 mmol/kg/day), after which amino acid contents and enzyme activities were measured in their brains. Both hydrazine doses caused significant elevations of whole brain GABA content and reductions of GABA-T activity, but did not affect GAD activity. Chronic administration of hydrazine at these doses did not reduce weight gain or alter rat behavior, nor did it produce any irreversible pathologic changes in liver or alterations in hepatic aryl hydrocarbon hydroxylase activity. However, hydrazine treatment caused changes in the contents of many brain amino acids besides GABA, and markedly increased concentrations of ornithine, tyrosine, and alpha-aminoadipic acid in rat plasma. Inhibition of GABA-T activity and the other biochemical alterations observed in patients given high doses of INH probably result from hydrazine formed in the metabolic degradation of INH. Thus administration of hydrazine might be a more direct means of elevating brain GABA content in patients where this seems indicated, and might not entail a greater risk of adverse effects.
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PMID:Elevation of brain GABA content by chronic low-dosage administration of hydrazine, a metabolite of isoniazid. 725 11

The effect of several antivitamin B6 on gamma-aminobutyric acid (GABA) metabolism was studied in the rat retina. The rat electroretinogram (ERG) was also recorded after administration of these drugs. Aminooxyacetic acid (AOAA) and hydrazine administration increased the GABA content and inhibited the GABA degrading enzyme, GABA transaminase in retina. In addition, there drugs elongated the peak latency of the oscillatory potential in the rat ERG. In contrast, 4-deoxypyridoxine (DOP) or isonicotinic acid hydrazide (INAH) administration decreased the GABA content and inhibited the GABA synthesizing enzyme, glutamic acid decarboxylase in retina, and administration of these drugs together with AOAA lessened the degrees of elevation of GABA content and of the elongation of the peak latency produced as compared with AOAA alone, though neither of the former drugs had a significant effect on ERG. The retinal GABA seems to play an important role in relation to the oscillatory potential of ERG.
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PMID:The effect of antivitamin B6 administration on gamma-aminobutyric acid metabolism in retina and electroretinogram. 741 Dec 49

GABAergic modulation of enkephalin, substance P and glutamic acid decarboxylase (GAD67) gene expression and the alterations induced by dopamine receptor blockade were studied in the rat striatum. Following subchronic treatment with the GABA-A agonist muscimol, the GABA-B agonist baclofen or the GABA transaminase inhibitor gamma-vinyl GABA there were no significant changes in striatal peptide and GAD67 gene expression. Following repeated administration of the D-2 antagonists, eticlopride and haloperidol, there was an increase in enkephalin and GAD67 mRNA levels and parallel decrease in that of substance P. These were unaffected by co-administration of gamma-vinyl GABA. The D-1 antagonist, SCH 23390 administered alone or together with gamma-vinyl GABA did not alter peptide or GAD67 mRNA levels. It seems that pharmacological stimulation of GABA receptors has little effect on enkephalin, substance P or GAD67 mRNA expression in striatal output neurons.
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PMID:GABAergic modulation of striatal peptide expression in rats and the alterations induced by dopamine antagonist treatment. 753 10

The MAO inhibitor phenelzine (2-phenylethylhydrazine; PLZ) is used widely in psychiatry for the treatment of depression and panic disorder. Its N-acetyl metabolite, N2-acetylphenelzine (N2AcPLZ) is a reasonably potent nonselective inhibitor of monoamine oxidase (MAO) that causes elevation in brain levels of the biogenic amines. In the studies reported here, PLZ (0.05 mmol/kg/day), N2AcPLZ (0.10 mmol/kg/day) or vehicle were administered to male rats for 28 days s.c. with Alzet minipumps, and their effects on GABAergic function were examined. Whole brain concentrations of gamma-aminobutyric acid (GABA) were significantly elevated in the PLZ but not in the N2AcPLZ-treated group. PLZ was found to inhibit the anabolic enzyme glutamic acid decarboxylase (GAD) and, to a greater extent, the catabolic enzyme GABA transaminase (GABA-T). The results of these investigations suggest that the free hydrazine moiety in PLZ is crucial to producing the elevated levels of GABA, probably through inhibition of GABA-T. Despite the considerable increase in whole brain GABA levels in the PLZ-treated rats, there were no significant differences in GABAA or benzodiazepine receptor binding parameters (KD or Bmax) between the groups as measured using 3H-muscimol and 3H-flunitrazepam in radioligand binding assays.
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PMID:Chronic administration of the antidepressant phenelzine and its N-acetyl analogue: effects on GABAergic function. 793 Dec 16


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