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)

The homospecific activity of GABA-transaminase (EC 2.6.1.19; GABA-T) in brain or neurons was determined as a function of development in vivo or in culture by measuring the enzyme activity together with the relative amount of GABA-T apoenzyme by the aid of a monospecific anti-GABA-T antibody. It was observed that both in cerebral cortex and cerebellum in vivo and in neurons cultured from these brain regions the homospecific activity of GABA-T changed during development. By incubation of tissue extracts with similar extracts in which GABA-T activity had been selectively and irreversibly destroyed with gamma-vinyl GABA (Vigabatrin) it was established that this change in homospecific activity was at least partly due to the presence of an endogenous activator of GABA-T. The results point towards a rather complex endogenous regulation of GABA-T during development in vivo and in vitro.
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PMID:Development of homospecific activity of GABA-transaminase in the mouse cerebral cortex and cerebellum and in neurons cultured from these brain areas. 271 65

1. The interactions of three GABAergic compounds, gamma-acetylenic GABA, gamma-vinyl GABA and ethylenediamine with the analgesic effects of morphine and pentazocine were examined in mice using the hot plate and tail immersion tests. 2. A significant increase in reaction time induced by morphine was noted in the tail immersion test after pretreatment with the drugs acting through GABA functions. 3. The inhibitors of GABA transaminase, gamma-acetylenic GABA and gamma-vinyl GABA, and the GABAmimetic ethylenediamine did not significantly change the analgesic action induced by pentazocine. 4. In the hot plate test the three GABAergic compounds antagonized the analgesic effects of pentazocine in contraposition with previous results indicating that morphine-induced analgesia is increased by pretreatment with those agents. 5. These findings suggest that GABAergic and opiopeptidergic systems are interconnected through mu receptors, whereas the kappa opiate systems seem to be unrelated to GABA functions.
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PMID:A comparison of GABAergic influences on the analgesic responses to morphine and pentazocine. 271 13

The effects of three drugs, namely gamma-vinyl GABA (vigabatrin), gamma-acetylenic GABA, and aminooxyacetic acid, which increase brain GABA concentrations by irreversible inhibition of GABA degradation, were studied in amygdala-kindled rats. Vigabatrin 800 or 1,200 mg/kg i.p. 4 h after its administration, caused prolongation of behavioural seizures and electrographic afterdischarges recorded from the stimulated amygdala. One to three days after administration it dose dependently reduced seizure severity, seizure duration and afterdischarge duration in most animals. Determination of GABA levels in synaptosomes isolated from 12 brain regions of kindled rats 4 or 48 h after injection of 1,200 mg/kg vigabatrin indicated that the variable effects of this drug at different times after its administration could be related to differences in the time course of nerve terminal GABA increases in selective brain regions such as amygdala and corpus striatum. In contrast to vigabatrin, gamma-acetylenic GABA, 100 mg/kg i.p., reduced seizure severity in kindled rats as early as 4 h after its administration but afterdischarge duration increased significantly on subsequent days. Similar late increases in afterdischarge duration (and limbic seizure activity) after the time of maximum anticonvulsant effect had elapsed were also observed with vigabatrin, which could suggest that the anticonvulsant effect of such drugs is followed by withdrawal hyperexcitability. Aminooxyacetic acid, 20 mg/kg i.p., exerted no significant anticonvulsant effect in kindled rats but prolonged afterdischarge duration in several of the animals studied. The data suggest that GABA-T inhibitors, such as vigabatrin, differ from most antiepileptic drugs previously tested in the kindling model in that they may produce both anticonvulsant and proconvulsant effects at the same dose in the same animal as a function of time after administration.
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PMID:Anticonvulsant and proconvulsant effects of inhibitors of GABA degradation in the amygdala-kindling model. 274 84

This study better defines the way in which the thalamus controls expression of experimental generalized seizures. The effects of small intrathalamic injections of the direct GABA agonist muscimol on the thresholds of pentylenetetrazol (PTZ)-induced seizures and on spontaneous behavior were determined in the rat and compared with the effects of injections of gamma-vinyl-GABA (GVG), an irreversible inhibitor of GABA transaminase. Muscimol injections produced neuronal inhibition in a relatively small area of thalamus, whereas GVG injections produced inhibition in a much larger area. Muscimol injections in the midline thalamus in the vicinity of the paraventricular, paratenial, interanteromedial, intermediodorsal, and central medial nuclei facilitated PTZ myoclonic and clonic seizures and also produced sedation. These effects on seizure thresholds were attributable both to a lower PTZ threshold dose for initiation of electroencephalographic (EEG) seizure activity and to an increased probability of this EEG activity being expressed as behavioral seizures. Midline injections located more posteriorly in the thalamus also inhibited tonic seizures. Muscimol injections placed laterally, dorsally, or ventrally to this midline thalamic region had much less effect on behavior or seizures. In contrast, GVG injections in the anterior medial thalamus elevated the threshold for all PTZ seizure types and for associated EEG seizure activity but had little effect on spontaneous behavior. These findings demonstrate the existence of an important seizure regulatory system in the midline of the thalamus and a direct anatomic link between the mechanisms for regulating arousal and seizure production which may help explain the association between sleep and seizure facilitation in humans.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of a median thalamic system regulating seizures and arousal. 275 1

By using a radioreceptor assay GABA was detectable in rat interscapular brown adipose tissue (IBAT), the levels being 1% those of CNS and 10-fold those of peripheral plasma. Injection of the glutamic acid decarboxylase (GAD) inhibitor 3-mercaptopropionic acid lowered IBAT GABA levels by about half while injection of the GABA transaminase inhibitor gamma-acetylenic GABA increased them by 230%. Rats kept at 4 degrees C for 14 days exhibited IBAT GABA levels that were about half those found at 22 degrees C. Accumulation of IBAT GABA after gamma-acetylenic GABA increased by 2-fold in cold-exposed rats. Sympathetic denervation of IBAT prevented the effect of the cold environment on GABA content and impaired that on GABA accumulation. GAD activity was detectable in IBAT homogenates and isolated brown adipocytes. Exposure of rats to cold increased Vmax of GAD without modifying its Km, regardless of intactness of innervation. In binding studies with 3H-GABA as a ligand, two types of sites were uncovered of KD = 14 and 146 nM, respectively. In the presence of 2.5 mM Ca2+ bicuculline and baclofen were 57 and 46% as effective as GABA to displace 3H-GABA from IBAT binding sites. The results indicate existence, possible synthesis and type A and B receptors of GABA in rat IBAT.
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PMID:GABA and its neural regulation in rat brown adipose tissue. 275 28

Vigabatrin (gamma vinyl GABA, GVG), an enzyme-activated, irreversible inhibitor of GABA transaminase, was administered orally to rats, dogs, and monkeys to observe toxicologic reactions. Myelin vacuolation of the brain was observed. The vacuolation was limited to myelinated tracts and resulted from separation of the myelin sheath at the interperiod line. There was no evidence of demyelination, axonal degeneration, or damage uolation was histologically similar to that observed in association with other drugs such as triethyltin, isoniazid, or hexachlorophene. However, the distribution is limited to the brain and is reversible upon discontinuation of therapy. Two postmortem and three operative specimens from humans have revealed no evidence of vacuolation of myelin.
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PMID:The neuropathology of vigabatrin. 276 14

The binding of 4-amino-n-[2,3-3H]butyric acid (GABA) to receptor sites in the supraoesophageal ganglia of the locust Schistocerca gregaria is reported. Binding is saturable with a Kd of 30 nM and a Bmax of 150 fmol/mg protein. Binding is sodium-independent with a pH optimum of 6.8 and the pharmacological properties of the site suggest a receptor rather than an uptake or transport protein. The assay is being utilised in a comparative study of the binding sites of the GABA receptor and the enzyme 4-aminobutyrate: 2-oxoglutarate amino-transferase (EC 2.6.1.19, GABA-T). GABA binds to at least 4 proteins in the nervous system of vertebrates: the GABAA and GABAB receptors, GABA-T the enzyme involved in the GABA shunt, and the GABA transport system. In the invertebrates the status of these GABA-binding proteins is less well established. There are reports of a GABA receptor complex resembling the GABAA receptor; GABA-T activity has been reported and we have recently purified the enzyme from locust ganglia; it is assumed that GABA uptake systems are present in invertebrates. Proteins with different functions which specifically bind the same ligand are interesting from an evolutionary point of view. Are they distinct gene products or is the sub-unit of the receptor which binds GABA an enzyme which has lost the ability to bind pyroxidal phosphate? Do either receptor or enzyme differ significantly from their mammalian counterparts?
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PMID:GABA binding to receptor sites in locust supraoesophageal ganglia. 282 55

Studies have shown that benzodiazepines (BZs) both disrupt discrimination and increase resistance to punishment. Using a delayed response task, we provide evidence that effects of BZs on discrimination cannot be fully explained by deficits in either short or long term memory, or by intolerance for delay of reward. A schedule with rewarded, nonrewarded (Time out: TO) and conflict components was used to investigate effects in rats of compounds active at the BZ receptor on successive discrimination and punished responding in parallel. The GABA transaminase inhibitor ethanolamine-O-sulphate exerted additive effects with chlordiazepoxide (CDP) on punished but not TO responding. Both GABA and CDP injected into the amygdala selectively increased conflict rates, but with peripheral treatment CDP also increased TO rates. Two inverse BZ agonists, CGS 8216 and FG 7142 antagonzied the anti-conflict effects of GABA and CDP, given within the amygdala or peripherally, but the increase in TO rates induced by systemic CDP was counteracted only by peripheral treatments. These compounds also reduced rates of conflict responding below baseline, consistent with anxiogenic activity. Effects of the BZ antagonist Ro 15-1788 were broadly similar to those of the inverse agonists, except that it did not antagonise the anti-conflict action of intra-amygdaloid GABA, nor significantly reduce punished responding at the single dose used. We conclude from these results that the anti-conflict effects of BZs are mediated by a GABAergic amygdaloid mechanism, but that the same mechanism is not involved in BZ effects on discrimination.
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PMID:Are the effects of benzodiazepines on discrimination and punishment dissociable? 282 45

Vigabatrin (gamma-vinyl GABA) is a new anticonvulsive drug that irreversibly inhibits the activity of GABA transaminase. The effect of vigabatrin on neurotransmission-related amino acids in CSF of 28 epileptic patients was studied and the relationship between the amino acid pattern and clinical response during 7 months of administration of vigabatrin. Of this study population, 46% had more than 50% decrease in seizure frequency (responders). In 54% the seizures decreased less than 50% (nonresponders). In the whole study group, the levels of total GABA during vigabatrin treatment were 283%, free GABA 197%, homocarnosine 310% and glycine 128% that of the levels at baseline in the same patients. Glutamate, glutamine, aspartate, asparagine, and taurine concentrations did not change. The amino acid pattern in CSF during administration of vigabatrin did not differ significantly in responders and nonresponders. The study suggests that both GABAergic and glycinergic neurotransmission are affected by vigabatrin. The changes in CSF levels of neurotransmitter amino acids are, however, not necessarily related to the clinical response.
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PMID:Effect of vigabatrin (gamma-vinyl GABA) on amino acid levels in CSF of epileptic patients. 285 6

Kindling is an animal model of epilepsy produced by focal electrical stimulation of the brain. This chapter: describes the kindling phenomenon; considers the validity of kindling as an animal model and proposes a hypothesis as to how kindling might contribute to human epileptogenesis; presents a critical review of current insights into the underlying mechanisms; and emphasizes that, if progress is to be made in understanding the mechanisms, the network of brain structures underlying kindling must be elucidated. Recent investigations directly related to the network issue are considered, namely studies demonstrating that a brainstem structure, the substantia nigra (SN), can regulate the kindled seizure threshold. Thus, either microinjection of a GABA receptor agonist or a GABA transaminase inhibitor into SN, but not into nearby sites, elevates kindled-seizure threshold. Likewise, destruction of SN, but not of adjacent structures, is associated with an increase of kindled-seizure threshold. These treatments suppress not only clonic motor seizures, but also complex partial seizures and afterdischarge at the site of stimulation. These findings demonstrate that the SN can regulate the intrinsic neuronal excitability of forebrain structures. A hypothesis is advanced that generation of a complex partial seizure requires activation of neurons in the SN which in turn feed back through polysynaptic connections to influence neurons at the site of seizure origin. This nigral influence on neurons at the site of seizure origin is either a direct excitation or a disinhibition. Thus, the seizure represents reverberatory activity within a network of brain structures which includes the SN. Other investigators have proposed that the centrencephalic system subserved seizure propagation; the relationship of the hypothesis proposed here to these earlier ideas is discussed.
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PMID:Kindling model of epilepsy. 287 21


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