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)

In mice, the influence of valproic acid (di-n-propylacetate, DPA) on central level of gamma-aminobutyric acid (GABA) as well as the activity of the enzymes regulating GABA metabolism, glutamate decarboxylase (GAD) and GABA-alpha-oxoglutarate aminotransferase (GABA-T) were studied. It was shown that the elevation of GABA by DPA was accompanied by an activation of GAD. GABA-T was inhibited only by toxic doses or high concentrations of DPA in vivo and in vitro, and so was GAD. DPA proved able to antagonize the biochemical alterations induced by convulsant doses of isoniazid, i.e., decreases in the level of GABA and the activity of GAD. These results point to a role of the transmitter pool of GABA regulated by GAD in the anticonvulsant effect of DPA.
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PMID:[On the mechanism of action of valproid acid]. 32 17

A detailed presentation of 15 case-histories of subjects of both sexes, drawn from all decennies of life from the first to the eight, suggesting a syndrome originated from a possible GABA deficiency, is carefully made. Such syndrome is believed to be characterized by basic depressive state, loss of the habit of stretching oneself, sleep disorders, mostly with early morning awakening, constipation and nuchal headache. The above symptoms have been associated to a deficiency of GABA after noting the very speed recovery after administration of N-dipropylacetic acid, an inhibitor of GABA transaminase.
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PMID:A syndrome from a possible GABA deficiency. Clinical-therapeutic report on 15 cases. 35 28

The aims of the present studies were (a) to determine the effects of pharmacological elevation of GABA by treatment with DPA (competitive inhibitor of GABA transaminase) on a form of aggression displayed by grouped female mice towards lactating and non-lactating intruders; (b) to estimate GABA levels in six different brain areas of intact and gonadectomized male and female mice. The results revealed that DPA treatment considerably reduced this form of aggression. Increased GABA levels, modulated by the hormonal state of the animals, were observed in most brain areas studied.
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PMID:Studies on the involvement of GABA in the aggression directed by groups of intact or gonadectomized male and female mice towards lactating intruders. 676 32

The effect of di-n-propylacetic acid (valproic acid), a gamma-aminobutyric acid transaminase inhibitor, on the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) response to gonadotropin-releasing hormone (LHRH) was studied in five normal women during the proliferative and luteal phases of the menstrual cycle. Valproic acid produced no significant change in the basal serum concentrations of LH, FSH, estradiol, and progesterone in either the proliferative or the luteal phase of the study. In the proliferative phase the delta LH (maximum increment above baseline) following LHRH stimulation rose from 32.8 +/- 21.2 (mean +/- SD) to 52.2 +/- 28.7 mlU/ml (not significant) after valproic acid, while the delta FSH rose from 2.2 +/- 1.1 to 5.0 +/- 3.6 mlU/ml (not significant). Four of the five volunteers showed an augmentation of the delta LH response to LHRH after valproic acid while the fifth subject showed no change. In three subjects the augmented delta LH response after valproic acid was highly significant. By contrast, the delta LH in the luteal phase following LHRH stimulation fell from 65.3 +/- 20.1 to 43.1 +/- 12.9 mlU/ml after valproic acid (p less than 0.03). Corresponding delta FSH values were 2.5 +/- 1.1 and 2.1 +/- 0.8 mlU/ml (not significant). It is speculated that gamma-aminobutyric acid may exert a modulatory role on gonadotropin secretion following LHRH stimulation and that this effect is influenced by the phase of the menstrual cycle.
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PMID:A presumptive role for gamma-aminobutyric acid in the regulation of gonadotropin secretion in man. 681 Jun 97

The effect of the GABA transaminase inhibitor valproic acid (DPA) on serotonin (5HT) metabolism of different brain regions were studied in both grouped and isolated rats. One hour after DPA injection 5HT levels in the amygdala were increased in grouped and isolated rats. In the hypothalamus of grouped rats, changes in 5HT metabolism were also found. The alteration in 5HT metabolism in grouped rats was reversed 150 min after injection of DPA. At this same time, a large and significant increase in 5HT turnover was observed in all brain areas examined in isolated rats. It can be concluded that prolonged isolation induces a differential sensitivity to the effects of DPA leading to differences in 5HT metabolism: the drug effect being more intense in isolated rats.
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PMID:Effect of valproic acid on brain serotonin metabolism in isolated and grouped rats. 681 96

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 discriminative stimulus effects of indirect-acting GABAergic drugs were compared to those of pentobarbital (PB) and midazolam in rats trained to discriminate 5 mg/kg PB from saline under a two-lever fixed-ratio 32 schedule of food reinforcement. PB and midazolam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Valproic acid, an antiepileptic drug and GABA transaminase inhibitor, substituted for PB but only at a dose that produced response rate suppression. Vigabatrin, an irreversible GABA transaminase inhibitor, failed to substitute for PB, but did produce a dose-dependent decrease in response rates. The GABA uptake inhibitors, 1-[2-[bis[4-(trifluoromethyl)phenyl]-methoxy]ethyl]-1,2,5,6- tetrahydro-3-pyridinecarboxylic acid (CI-966) and (R(-)-N-[4,4-bis(3-methylthien-2-yl)but-3-enyl] nipecotic acid HCl (tiagabine), produced no greater than 40% PB-lever responding. Aminooxyacetic acid (AOAA), which is described as a nonselective presynaptic GABA agonist, yielded a maximum of 43% PB-lever responding. These results indicate that the discriminative stimulus effects of the indirect GABAA agonists, PB and midazolam, although similar to one another, differ from those of presynaptic GABAergic drugs. Differences in the discriminative stimulus properties of GABA transaminase inhibitors and uptake inhibitors also exist, indicating that not all presynaptic GABA agonists have similar behavioral profiles. These results contribute to a further understanding of the similarities and differences in the behavioral effects of drugs that enhance GABAergic neurotransmission.
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PMID:Discriminative stimulus effects of presynaptic GABA agonists in pentobarbital-trained rats. 811 28

1. The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine. Its mechanism of action is unknown. We tested the effects of sodium valproate and GABAA-agonist muscimol on dural plasma protein ([125I]-bovine serum albumin) extravasation evoked by either unilateral trigeminal ganglion stimulation (0.6 mA, 5 ms, 5 Hz, 5 min) or substance P (SP) administration (1 nmol kg-1,i.v.) in anaesthetized Sprague-Dawley rats. 2. Intraperitoneal (i.p.) injection of sodium valproate or muscimol, but not baclofen (< or = 10 mg kg-1, i.p.) dose-dependently reduced dural plasma protein extravasation caused either by electrical trigeminal stimulation (ED50: 6.6 +/- 1.4 mg kg-1, i.p., and 58 +/- 18 micrograms kg-1, i.p. for valproate or muscimol, respectively) or by intravenous substance P administration (ED50: 3.2 +/- 1.4 mg kg-1, i.p. and 385 +/- 190 micrograms kg-1, i.p. for valproate or muscimol, respectively). 3. Valproate (6.6 mg kg-1, i.p.) or muscimol (58 micrograms kg-1, i.p.) had no effect on mean arterial blood pressure or heart rate when measured for 30 min after i.p. administration. 4. The GABAA-antagonist bicuculline (0.01 mg kg-1, i.p.) completely reversed the effect of valproate and muscimol on plasma extravasation following electrical stimulation or substance P administration, whereas the GABAB-receptor antagonist, phaclofen (0.01-1 mg kg-1, i.p.) did not. Bicuculline or phaclofen, given alone, did not alter the plasma extravasation response after either electrical stimulation or SP administration. 5. Valproate decreased plasma extravasation following substance P administration in adult animals, neonatally treated with capsaicin by a bicuculline-reversible mechanism. This suggests that GABAA receptors are not found primarily on those afferent neurones or fibres which are sensitive to capsaicin treatment in neonatal rats.6. We conclude that sodium valproate blocks plasma extravasation in the meninges through GABAA mediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinically. Agonists and modulators at the GABAA receptor may become useful for the development of selective therapeutic agents for migraine and cluster headache.
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PMID:Peripheral GABAA receptor-mediated effects of sodium valproate on dural plasma protein extravasation to substance P and trigeminal stimulation. 856 34

Valproic acid has been shown to be effective in migraine prophylaxis. Its method of action is believed to be the inhibition of gamma-aminobutyric acid transaminase. The therapeutic dose needed to prevent migraine headaches has been examined in several studies, yet the optimum dose has not been found. In this case report, valproic acid was given to a 24-year-old woman with chronic headaches at 1000 mg per day. Her headaches resolved for 2 months. She tapered herself off of the medication, and her headaches returned. She was restarted at 500 mg per day of valproic acid and again, her headaches resolved. She preferred being on the lower dose which she found as effective as the higher dose. Her case makes two interesting points. The first is that lower dosages of valproic acid may be as effective as higher ones in headache prophylaxis. The second is that more studies looking at dose ranges are needed to correlate effectiveness with daily requirements.
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PMID:High-dose versus low-dose valproic acid as a prophylactic medication. 882 9

The discriminative stimulus effects of GABAergic drugs were evaluated in rats trained to discriminate the direct GABA(A) agonist, muscimol (1.0 mg/kg I.P.), from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. Another direct GABA(A) agonist, THIP, produced full substitution for muscimol, however, at doses producing response rate decreasing effects. Diazepam, an allosteric modulator of GABA-mediated postsynaptic inhibition, yielded a maximum of 50% muscimol-lever responding at a dose that also decreased rates of responding. Partial substitution for muscimol (maximal levels of 71% muscimol-lever responding) was also produced by the GABA agonist progabide. Propofol, an anesthetic that potentiates GABA(A) receptor function, and the GABA uptake inhibitor, tiagabine, produced no greater than 53 and 48% muscimol-lever responding, respectively. Valproic acid, a reversible GABA transaminase inhibitor, failed to substitute for muscimol, and vigabatrin, an irreversible GABA transaminase inhibitor, yielded a maximal 46% muscimol-lever responding. These results demonstrate the pharmacological specificity of muscimol discrimination by showing that only direct agonists for the GABA site on the GABA(A) receptor complex produce full substitution. GABA agonists acting by other mechanisms can be distinguished from muscimol and THIP in this procedure.
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PMID:Muscimol-like discriminative stimulus effects of GABA agonists in rats. 947 76


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