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)

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

Valproate exhibits potent antiepileptic and antimyoclonic activity in a number of clinical and experimental syndromes. The mechanism of action of valproate remains unknown, but several neurotransmitter systems are affected directly or indirectly by valproate administration. The levels of the serotonin precursor and the principal serotonin metabolite, tryptophan and 5-hydroxyindoleacetic acid, respectively, are elevated in rodent brain following the administration of anticonvulsant doses of valproate. However, the anticonvulsant action of valproate is preserved in mice pretreated with p-chlorophenylalanine, which depletes the brain levels of serotonin and serotonin metabolites. Valproate administration elevates the level of the inhibitory transmitter glycine in the urine and plasma of patients and experimental animals, and the hepatic glycine cleavage enzyme is inhibited by valproate. The cerebral glycine levels in rodents are not affected by valproate administration, and the inhibitory action of glycine on reticular neuron firing is not affected by iontophoretically applied valproate. Valproate exerts multiple effects on the inhibitory GABA transmitter system. Elevation in brain GABA level occurs in parallel with the anticonvulsant activity observed following valproate administration, and high levels of valproate inhibit the GABA-metabolizing enzymes GABA-T and SSADH and cause a reduction in the rate of GABA turnover. Valproate has no effect on GABA uptake, release, or binding to the GABA receptor complex. Iontophoretically applied valproate augments the inhibitory action of GABA on neuronal firing in a number of brain regions including the reticular formation. Excitatory amino acid antagonists have recently been shown to possess anticonvulsant and antimyoclonic activity in a number of animal models. The ability of these compounds to decrease the brain level of the excitatory transmitter aspartate is shared by valproate. The valproate-induced decrease in aspartate level is dose dependent and coincides with the period of anticonvulsant protection. There is also a strong correlation between the anticonvulsant potency of a number of valproate analogs and their ability to reduce cerebral aspartate levels.
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PMID:Valproate and myoclonus. 308 Aug 55

The distribution of VPA has been investigated in several brain areas of the rat, and GABA increases were measured. A biphasic exponential decay was observed for VPA; the slowest decrease was noted in the olfactory bulbs and in the hypothalamus where GAD and GABA-T activities were the highest. The data may be correlated with the prolonged effect of VPA in these areas.
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PMID:Distribution of sodium valproate and GABA metabolism in CNS of the rat. 644 8

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


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