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 technique of estimating gamma-aminobutyric acid (GABA) turnover by inhibiting its major degrading enzyme GABA-T (4-aminobutyrate:2-oxoglutarate aminotransferase; EC 2.6.1.19) and measuring GABA accumulation has been used repeatedly, but, at least in rats, its usefulness has been limited by several difficulties, including marked differences in the degree of GABA-T inhibition in different brain regions after systemic injection of GABA-T inhibitors. In an attempt to improve this type of approach for measuring GABA turnover, the time course of GABA-T inhibition and accumulation of GABA in 12 regions of rat brain has been studied after systemic administration of aminooxyacetic acid (AOAA), injected at various doses and with different routes of administration. A total and rapidly occurring inhibition of GABA-T in all regions was obtained with intraperitoneal injection of 100 mg/kg AOAA, whereas after lower doses, marked regional differences in the degree of GABA-T inhibition were found, thus leading to underestimation of GABA synthesis rates, e.g., in substantia nigra. The activity of the GABA-synthesizing enzyme GAD (L-glutamate-1-decarboxylase; EC 4.1.1.15) was not reduced significantly at any time after intraperitoneal injection of AOAA, except for a small decrease in olfactory bulbs. Even the highest dose of AOAA tested (100 mg/kg) was not associated with toxicity in rats, but induced motor impairment, which was obviously related to the marked GABA accumulation found with this dose. The increase in GABA concentrations induced with intraperitoneal injection of 100 mg/kg AOAA was rapid in onset, allowing one to estimate GABA turnover rates from the initial rate of GABA accumulation, i.e., during the first 30 min after AOAA injection. GABA turnover rates thus determined were correlated in a highly significant fashion with the GAD activities determined in brain regions, with highest turnover rates measured in substantia nigra, hypothalamus, olfactory bulb, and tectum. Pretreatment of rats with diazepam, 5 mg/kg i.p., 5-30 min prior to AOAA, reduced the AOAA-induced GABA accumulation in all 12 regions examined, most probably as a result of potentiation of postsynaptic GABA function. The data indicate that AOAA is a valuable tool for regional GABA turnover studies in rats, provided the GABA-T inhibitor is administered in sufficiently high doses to obtain complete inhibition of GABA degradation.
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PMID:Use of inhibitors of gamma-aminobutyric acid (GABA) transaminase for the estimation of GABA turnover in various brain regions of rats: a reevaluation of aminooxyacetic acid. 280 89

Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra.
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PMID:Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. 370 28

Lipid peroxide levels, were found to be significantly higher in brains of 18 month old as compared to 4 month old rats, with particularly large increases occurring in the olfactory bulb, globus pallidus, cerebral cortex and caudate-putamen (CP). Eighteen month old rats fed a vitamin E deficient diet for 9 months before sacrifice had lipid peroxide levels significantly higher than age-matched controls in the cerebral cortex, hippocampus and hypothalamus. Age-related decreases were seen in choline acetyltransferase, acetylcholinesterase and 3H-QNB binding in some but not all brain regions, while GABA transaminase and MAO showed age-related increases. No age-related change was seen in tyrosine hydroxylase in the CP or in 3H-dihydroalprenolol (DHA) or 3H-spiroperidol binding in the cortex. As compared with controls, vitamin E deficient rats showed decreases of 38% in cortical 3H-DHA binding, of 33% in 3H-QNB binding in the CP and of 23% and 12% in choline acetyltransferase in the CP and cerebellum, respectively. There were no completely consistent regional correlations between significant changes in lipid peroxidase levels and any neurotransmitter indices studied except for MAO which was only measured in the caudate-putamen.
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PMID:Lipid peroxides in brain during aging and vitamin E deficiency: possible relations to changes in neurotransmitter indices. 613 87

Bilateral ablation of the olfactory bulbs caused marked changes in the 'turnover' of several neurotransmitters in the amygdaloid cortex and the mid-brain areas of the rat brain. Following tyrosine and tryptophan hydroxylase inhibition, the decrease in the concentration of noradrenaline and serotonin respectively in the amygdaloid cortex was not so marked in the bulbectomized rats as in their controls. This suggests that the 'turnover' of these biogenic amines is reduced following bulbectomy. Following GABA transaminase inhibition, the increase in the concentration of GABA in this region was increased compared to the controls thereby suggesting that the 'turnover' of the inhibitory neurotransmitter was enhanced, glutamate decarboxylase activity was also increased in the amygdaloid cortex. No changes were found in the 'turnover' of noradrenaline or serotonin in the mid-brain but that of dopamine was decreased as was the activity of glutamate decarboxylase. It is concluded that changes in neurotransmitter 'turnover' in these brain regions are attributable to the destruction of the olfactory bulbs and may contribute to the behavioural deficits which we, and others, have reported elsewhere.
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PMID:Changes in neurotransmitter metabolism following olfactory bulbectomy in the rat. 620 59

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 distributions of gamma-aminobutyric acid (GABA), glutamate decarboxylase (GAD), and gamma-aminobutyrate transaminase (GABA-T) have been studied in various brain areas of mice. These neurochemical markers, which are related to inhibitory neurotransmission, were investigated in different inbred strains of mice (C3H/He, C57/BR, and their F1 hybrids). The regional distributions of GABA, GAD activity, and GABA-T activity in adult mice of these three strains were quite similar. No significant differences were found in any brain area for GAD or GABA-T activity. However, significant differences in GABA level were found in several brain areas among these strains of mice, especially in hypothalamus, hippocampus, olfactory bulb, and occipital cortex. These results provide further information to the possible influence of the GABAergic system in these brain areas.
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PMID:Regional distributions of gamma-aminobutyric acid (GABA), glutamate decarboxylase (GAD), and gamma-aminobutyrate transaminase (GABA-T) in the central nervous brains of C57/BR, C3H/He, and F1 hybrid mice. 737 85

Previous studies have demonstrated that the expression of one of the isoforms of glutamate decarboxylase, GAD67, is selectively reduced in cultured cortical neurons and in rat cerebral cortex when the concentration of GABA is elevated. We asked whether the expression of GAD67 was similarly affected by elevated GABA throughout the brain. The concentration of GABA in rat brain was increased by inhibiting GABA transaminase (GABA-T) with vigabatrin (gamma-vinylGABA, GVG), an antiepileptic drug and selective inhibitor of GABA-T. Rats were injected with saline or vigabatrin (150 mg/kg) daily for 5 days, and the effects of accumulated GABA on total GAD activity and the expression of GAD65 and GAD67 proteins were determined in twelve brain regions. The GABA concentration was significantly elevated in all regions except amygdala and olfactory bulb after vigabatrin treatment. Total GAD activity was significantly lower than controls in six regions: cerebellum, frontal cortex, thalamus, substantia nigra, ventral tegmentum, and the remaining midbrain. The decrease in GAD activity was largest in cerebellum and thalamus (33% and 29%), while the changes in the other four areas were 15-18%. Vigabatrin treatment significantly reduced GAD67 protein in all regions except olfactory bulb, whereas GAD65 protein decreased significantly only in cerebellum. The failure to detect significant changes in GAD activity in regions having a significant change in GAD67 levels is attributable to the small contribution of GAD67 to total GAD in those regions. It is evident that there are marked regional differences in the effects of tissue GABA levels on the expression of GAD67.
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PMID:Elevation of brain GABA levels with vigabatrin (gamma-vinylGABA) differentially affects GAD65 and GAD67 expression in various regions of rat brain. 966 22

Kindling is a chronic model of epilepsy characterized by a progressive increase in response to the same regularly applied electrical stimulus. The biological basis of the kindling phenomenon requires to be determined, but several studies indicate that impairment of GABAergic inhibition may be involved. In the present experiments, GABA turnover was determined in vivo by the GABA aminotransferase (GABA-T) inhibition method in 13 brain regions in three groups of rats: (1) a group which was kindled via electrical stimulation of intra-amygdala electrodes and was sacrificed 36 days after the last fully kindled seizure for neurochemical determinations; (2) a group of implanted but non-stimulated rats (sham control group) in which neurochemical measurements were done at the same time after electrode implantation as in the kindled group; and (3) a group of non-implanted, naive control rats. Regional GABA levels were determined after vehicle injection as well as 30 and 90 min after administration of aminooxyacetic acid (AOAA) at a dose which completely inhibits GABA-T. Compared to naive controls, prolonged electrode implantation in the amygdala induced a significant reduction of AOAA-induced GABA accumulation in amygdala, hippocampus, piriform cortex, olfactory bulb, frontal cortex, striatum, hypothalamus, tectum, and cerebellar cortex. In view of the GABA hypothesis of kindling, reduced GABA turnover in response to electrode implantation would suggest that the implantation per se exerts a pro-kindling effect, which was recently demonstrated in rats with intraamygdala electrodes. However, amygdala kindling itself appeared to antagonize the effect of electrode implantation in most regions. Thus, although, compared to naive controls, the predominant change in kindled rats was a decrease in GABA turnover, this decrease was less marked than in sham controls. In thalamus and brainstem kindling markedly increased GABA turnover above the levels determined in both naive and sham controls, possibly in response to impaired postsynaptic GABAergic function. The data indicate that both electrode implantation and kindling significantly alter regional GABA turnover, which might contribute to the pathophysiology of the kindling phenomenon. Furthermore, the data substantiate that the choice of adequate controls is critical in neurochemical and functional studies on the kindling phenomenon.
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PMID:Effect of depth electrode implantation with or without subsequent kindling on GABA turnover in various rat brain regions. 1051 Sep 76

Heroin has been hypothesized to activate opiate receptors and inhibit gamma-aminobutyric acid (GABA) release from inhibitory GABAergic interneurons which, in turn, activates dopamine projection cells. Since the distal sites and consequences of this disinhibition are not well understood on a systems level, heroin-induced brain activity was measured using functional MRI (fMRI) in rats. A significant blood oxygen level-dependent (BOLD) signal increase was seen in cortical regions, including prefrontal cortex, cingulate, and olfactory cortex following acute heroin administration. In contrast, a significant signal decrease was seen in several subcortical areas, including the caudate and putamen, nucleus accumbens, thalamus, and hypothalamus. Pretreatment of gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, significantly attenuated the heroin-induced BOLD signal changes. Pretreatment of naloxone, an opiate mu receptor antagonist, eliminated the heroin-induced BOLD signal changes and posttreatment of naloxone reversed the heroin-induced BOLD signal changes. It is suggested that the heroin-induced negative and positive BOLD changes are due to direct inhibitory and indirect disinhibitory mechanisms of GABAergic activities. Administration of GVG altered these mechanisms and further suggested that involvement of the opiate's pharmacological actions can, at least in part, be mediated by inhibiting brain GABA release.
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PMID:GABAergic mechanisms of heroin-induced brain activation assessed with functional MRI. 1241 98