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)

Ethylenediamine, a GABA receptor agonist induced a small hyperalgesic state in mice, but increased morphine analgesia. The interaction with this morphine effect was not dose-dependent. Ethylenediamine significantly antagonized tolerance development at relatively low doses (5-10 mg/kg). The GABA mimetic agent increased the frequency of abstinence signs in the naloxone-precipitated morphine withdrawal in mice. The effect of ethylenediamine on morphine withdrawal was suppressed by the irreversible GABA transaminase inhibitor, gamma-vinyl GABA.
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PMID:Effects of ethylenediamine on morphine analgesia and tolerance-dependence in mice. 405 78

Rat brain GABA levels were elevated chronically by daily administration of gamma-vinyl GABA, an enzyme-activated, irreversible inhibitor of GABA:2-oxo-glutarate aminotransferase (GABA-T; EC2.6.1.19). Following various periods of drug treatment and withdrawal, the sensitivity of dopamine and GABA receptors in the CNS was determined by biochemical and behavioral evaluations. In contrast to chronic haloperidol treatment, none of the treatment schedules with gamma-vinyl GABA had any significant effect on parameters such as apomorphine induced locomotor activity, [3H] spiperone binding or dopamine-stimulated adenylate cyclase in the corpus striatum; nor did gamma-vinyl GABA treatment affect [3H] GABA binding or GABA-activated [3H] diazepam binding in the cerebral cortex. Moreover, co-administration of gamma-vinyl GABA and haloperidol did not alter the ability of the neuroleptic to induce supersensitivity in the striatal dopaminergic system. Thus, it appears that, in contrast to reported studies using chronic administration of other less specific GABA-T inhibitors such as gamma-acetylenic GABA, amino-oxyacetic acid and isonicotinic acid hydrazide or direct GABA agonists such as THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c-)-pyridin-3-ol) or kojic amine, gamma-vinyl GABA does not alter the sensitivity of the striatal dopaminergic system.
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PMID:Chronic elevation of brain GABA by gamma-vinyl GABA treatment does not alter the sensitivity of GABAergic or dopaminergic receptors in rat CNS. 630 25

Intraperitoneal injection of ethanol (1-2 g/kg) and chlordiazepoxide (2-16 mg/kg) suppressed susceptibility to audiogenically induced, clonic-tonic seizures and antagonized forelimb tremor in rats undergoing ethanol withdrawal, 30 min after treatment. However, a smaller dose of ethanol (0.5 g/kg) actually increased clonic seizure frequency, suggesting that ethanol exerts a biphasic proconvulsant/anticonvulsant action. Direct activation of gamma-aminobutyric acid (GABA) receptors by intracisternal administration of GABA (100-1000 micrograms), muscimol (0.3-1.0 micrograms) or 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) (0.3-3.0 micrograms) 5 to 10 min before testing also reduced susceptibility to audiogenic clonic-tonic seizures. In sharp contrast to these anticonvulsant actions, GABA, muscimol and THIP had no effect on withdrawal-induced forelimb tremors. Blockade of GABA uptake with 1-2,4-diaminobutyric acid (300 and 600 mg/kg i.p.) and inhibition of GABA transaminase with aminooxyacetic acid (12.5 and 25.0 mg/kg i.p.) both reduced susceptibility to seizures. However, anticonvulsant doses of these two drugs, unlike GABA, muscimol and THIP, also reduced forelimb tremor. Three other GABA transaminase inhibitors, gamma-vinyl GABA (450 and 900 mg/kg i.p.), gamma-acetylenic GABA (50-150 mg/kg i.p.) and ethanolamine-O-sulfate (250-750 mg/kg i.p.), were inactive against ethanol withdrawal audiogenic seizures and forelimb tremors. These results indicate that direct GABA receptor activation can selectively suppress one type of ethanol withdrawal response (i.e., audiogenic seizure susceptibility) while failing to influence another (forelimb tremors).
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PMID:Differential sensitivity of ethanol withdrawal signs in the rat to gamma-aminobutyric acid (GABA)mimetics: blockade of audiogenic seizures but not forelimb tremors. 631 80

The anticonvulsant effect of inhibitors of GABA-T (R/S-gamma-vinyl-GABA, ethanolamine-O-sulfate, gabaculine, aminooxyacetic acid) was enhanced by 10 mmol/kg glycine in animal seizure models which are based on a functional GABA deficit. Similar to glycine in their action, although less effective, were its close structural analogues (sarcosine, N,N-dimethylglycine) and homologous omega-aminoacids (beta-alanine, taurine, gamma-aminobutyric acid, delta-aminovaleric acid). It is assumed that glycine and its structural analogues act on supraspinal glycine receptors as glycine agonists. Our observation is the first example of the synergistic interaction of two inhibitory neuronal systems resulting in the amplification of the anticonvulsant effect. Combined treatment with GABA-T inhibitors and glycine may turn out to be of practical importance in the therapy of seizure disorders and other diseases, for which treatment with GABA-T inhibitors is considered a potentially useful therapeutic approach.
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PMID:Synergistic anticonvulsant effects of GABA-T inhibitors and glycine. 647 85

We studied the effects of microinjected drugs and brainstem lesions on motor and limbic seizures in the kindling model of epilepsy. The duration of motor seizures was determined by timing the colonic and tonic movements of the extremities. The duration of limbic seizures was determined by measuring afterdischarge recorded on the electroencephalogram. Bilateral microinjection of a gamma-aminobutyric acid (GABA) agonist, muscimol, into the area of the substantia nigra (SN) markedly suppressed both motor and limbic seizures induced by stimulation of amygdala, olfactory structures, or lateral entorhinal cortex. Microinjection of saline did not suppress seizures. The suppressive effect of muscimol: (i) dissipated after several hours and was dependent on dose; (ii) was due to an elevation of the seizure threshold, since typical seizures could be elicited with electrical current far exceeding the threshold; and (iii) exhibited spatial specificity since muscimol injections 1 to 2 mm dorsal to the SN or into neocortex did not suppress the seizures. The actions of muscimol were probably mediated by its GABA agonist properties, since microinjection of an irreversible inhibitor of GABA transaminase (gamma-vinyl GABA) into the area of the SN also suppressed kindled seizures. Destruction of brainstem structures was produced by microinjection of the neurotoxin, N-methyl-D,L-aspartate. Seizures were markedly suppressed in animals with bilateral destruction of the SN but not in animals in which the SN was spared bilaterally. We interpret the data to indicate that the SN is the site at which the GABA agonists and lesions act to raise the threshold for kindled seizures. The suppression of limbic seizures indicates that this brainstem nucleus can regulate the intrinsic neuronal excitability of hemispheric sites.
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PMID:Evidence implicating substantia nigra in regulation of kindled seizure threshold. 648 54

The effects of bilateral microinjection of gamma-vinyl GABA (GVG, an irreversible inhibitor of GABA-T) were tested during the development of seizures induced by i.p. administration of 10 mg/kg of kainic acid. Intrahippocampal injection of GVG prevents the development of the seizures at an early stage in about half of the cases. In the remaining animals status epilepticus comparable to that of controls develops. Intra-amygdaloid injection reduces the severity of the seizures from the first motor limbic signs. Finally, intranigral injection prevents the appearance of convulsive status epilepticus or, when it develops, reduces its duration. The role that these three structures could play in the electro-clinical development of kainic acid-induced seizures is discussed.
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PMID:[Role of the hippocampus, amygdala and the substantia nigra in the evolution of status epilepticus induced by systemic injection of kainic acid in the rat]. 652 78

The synergistic amplification of the anticonvulsant effects of direct and indirect GABA agonists by glycine has previously been demonstrated. We show in the present report that the anticonvulsant effect of vinyl GABA, a GABA-T (4-aminobutyrate: 2-oxoglutarate aminotransferase) inhibitor with antiepileptic efficacy, can be amplified by esters of glycine. Among the compounds studied glycine tert. butylester was the most promising. It was effective at a lower dose and had a considerably longer duration of action than glycine. From the observed glycine and glycine tert. butylester levels it is evident that glycine tert. butylester is rapidly hydrolysed within brain and other tissues. It is therefore a pro-drug of glycine, capable of enhancing central glycinergic activity.
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PMID:The amplification of the anticonvulsant effect of vinyl GABA (4-aminohexenoic acid) by esters of glycine. 654 89

Changes in gamma-aminobutyric acid (GABA) occurring in the presence and in the absence of GABA-containing nerve terminals were estimated in rats in which the dense GABA projection to the substantia nigra was surgically destroyed on one side of the brain. The net increase in GABA of the denervated nigra was compared with that of the intact nigra at various times after a single injection of gama-vinyl-GABA, which irreversibly inhibits GABA transaminase. Total GABA reached a maximum within 12 hours, but the GABA pool associated with nerve terminals did not increase until 36 hours and peaked at 60 hours. The onset and peak of anticonvulsant activity against maximal electroshock seizures directly paralleled the time course for the increase in GABA in nerve terminals, but was not positively correlated with that independent of the terminals. This result supports the concept that elevating GABA in nerve terminals facilitates GABA-mediated synaptic transmission and predicts anticonvulsant activity.
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PMID:Seizure protection and increased nerve-terminal GABA: delayed effects of GABA transaminase inhibition. 676 30

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

The rate of cortical gamma-aminobutyric acid (GABA) turnover was estimated by determining the rate of GABA accumulation following inhibition of GABA transaminase by gamma-vinyl-GABA (1.5 g/kg, i.v.) in paralysed, ventilated rats. During 1 h of bicuculline-induced seizures (1.2 mg/kg, i.v.) the rate of accumulation of cortical GABA level is approximately threefold greater than in the control group receiving gamma-vinyl-GABA alone, suggesting that the GABA shunt activity increases in parallel with the increase in overall cortical metabolic rate observed during bicuculline seizures. Pretreatment with gamma-vinyl-GABA did not affect the bicuculline-induced changes in other major cortical amino acids.
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PMID:Cortical GABA turnover during bicuculline seizures in rats. 687 71


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