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)

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

This study is concerned with the alterations in central and peripheral psychophysiological measures and psychometric variables after experimental manipulation of the most important inhibitory transmitter system of the CNS, the gamma-aminobutyric acid (GABA) system. Vigabatrin (GVG), a new enzyme-activated, irreversible inhibitor of GABA transaminase, which increases cerebrospinal fluid concentrations of GABA and other substrates of GABA transaminase, was given in single oral doses of 1 g, 2 g and 3 g to 10 normal healthy volunteers. In this double-blind, placebo-controlled crossover study, 3 mg lorazepam was given as reference compound. Blood sampling for vigabatrin kinetics, EEG recordings and evaluation of pulse, blood pressure and side effects were carried out at the hours 0, 1, 2, 4, 6, 8 and 24, and psychometric tests at the same times (except the first hour). Pharmacokinetic analyses demonstrated good absorption of GVG with peak plasma concentrations found within the first two hours, dose-dependent areas under the plasma concentration-time curves and about 65% recovery in the 24-h urine. Computer-assisted spectral analysis of the EEG suggested that GVG produces only small changes in the normal CNS, characterized by an augmentation of total power, absolute and relative power of the beta activity and acceleration of the centroid of the total activity. There was also a trend towards an increase of alpha activity and of the absolute and relative power of the dominant frequency, decrease in the alpha centroid and increase of the centroid of the combined delta and theta activity. Lorazepam 3 mg, in contrast, produced highly significant changes characterized by a decrease of total power, alpha activity, absolute and relative power of the dominant frequency and centroid of the combined delta and theta activity, while beta activity as well as the centroid of the alpha, beta and total activity increased. In the resting condition an additional augmentation of slow activity suggested hypnotic properties of 3 mg lorazepam. The latter changes are typical for anxiolytic sedatives and were also reflected at the behavioral level where psychometric data demonstrated a deterioration in the noo- and thymopsychic parameters and sedative effects in psychophysiological variables. GVG, on the other hand, produced only subtle changes characterized by an improvement of noo- and thymopsychic variables and vegetative activation.
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PMID:Psychophysiological and psychometric studies after manipulating the GABA system by vigabatrin, a GABA-transaminase inhibitor. 372 43

The effects of low s.c. doses of gamma-acetylenic gamma-aminobutyric acid (GAG) on glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid transaminase (GABA-T) activities, as well as of gamma-vinyl GABA (GVG) and gabaculine on GABA-T activities, were examined using preparations from retina and several other regions of rat central nervous system (CNS). GAG, in doses of 5 to 50 mg/kg, inactivated retinal GAD to a significantly greater degree than GAD from any other CNS region studied. Retinal GABA-T activities were also differentially inactivated by 1 to 50 mg/kg of GAG, 50 mg/kg of GVG, or 1 and 5 mg/kg of gabaculine. GAG, in doses of 25 and 50 mg/kg, more completely inactivated GAD and GABA-T in frontal cortex than in other brain regions. Frontal cortical GABA-T was not differentially inactivated by 10 and 50 mg/kg of GVG or 1 and 5 mg/kg of gabaculine. The effects of GAG on retinal GABA enzymes were long-lasting and not reversed by dialysis. The GAD and GABA-T activities from 1:1 mixes of control and GAG-treated retinal preparations were comparable to the means of the GAG-treated and control activities. The effects documented in this study, therefore, probably reflect irreversible in vivo changes. After peripheral administration, GAG, GVG and gabaculine might reach higher levels in the retina than in the brain. Alternatively, the differential effects of these compounds might be due to the relative proportions of catalytically active GABA enzymes in different CNS regions. On the basis of the foregoing results, the retina might be a particularly suitable region of the CNS for enzyme-activated irreversible inhibitors to label catalytically active enzymes of GABA metabolism.
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PMID:In vivo action of enzyme-activated irreversible inhibitors of glutamic acid decarboxylase and gamma-aminobutyric acid transaminase in retina vs. brain. 373 30

The inhibitory action of gamma-aminobutyric acid (GABA) on prolactin (PRL) messenger ribonucleic acid (mRNA) levels was studied in vitro in rat anterior pituitary cells in culture and in intact rats in vivo. PRL mRNA levels were determined by hybridization of cytoplasmic RNA with a radiolabelled deoxyribonucleic acid probe complementary to rat PRL mRNA. Incubation of anterior pituitary cultures with GABA (10-100 microM) produced a dose-dependent decrease in PRL mRNA levels with half-maximal inhibition near 1 microM. The effect was time dependent and reversible after drug withdrawal. Inhibition by GABA was antagonized by bicuculline (10 microM) and mimicked by the GABAA receptor agonists muscimol and isoguvacine, but not with the GABAB agonist baclofen, indicating the involvement of GABAA receptors in the accumulation of PRL mRNA. To investigate the role of endogenous GABA on PRL biosynthesis in vivo, GABA levels were raised by using the GABA transaminase blockers vinyl GABA and ethanolamine-O-sulfate. Injection of vinyl GABA into rats (100 or 800 mg/kg every 2nd day) resulted in a dose- and time-dependent decrease in PRL mRNA levels in rat adenohypophysis. Similar results were obtained by addition of ethanolamine-O-sulfate to the drinking water (5 mg/ml, 250 mg/day). This treatment resulted in a rapid decrease of circulating PRL levels. This was followed by a delayed decrease in PRL mRNA concentrations in the adenohypophysis leading to a transient increase in hormone levels in the anterior pituitary. The results indicate that GABA has an inhibitory role on PRL secretion and PRL gene expression by a direct action at GABAA receptors on pituitary lactotrophs.
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PMID:In vivo and in vitro studies of GABAergic inhibition of prolactin biosynthesis. 374 9

The occurrence and distribution of 4-aminobutyrate:2-oxoglutarate transaminase (GABA-T) activity were examined in the guinea pig lung using biochemical and enzymehistochemical methods. Specific GABA-T reactivity was confined primarily to the arteries and to a lesser extent to the veins. No activity could be observed in association with bronchi, alveoli and nerve fibers. Our findings indicate that the GABA-T activity in the lung is specifically located in blood vessels. This study is the first to demonstrate GABA-T activity in peripheral blood vessels.
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PMID:Specific, vascular localization of GABA-transaminase in the guinea pig lung. 374 51

The presence of gamma-hydroxybutyric acid (GHB) in synaptosome-enriched fractions of rat brain was ascertained using a GLC technique. The stability of GHB in synaptosomes was evaluated by addition of various gamma-aminobutyric acid (GABA) transaminase (GABA-T) inhibitors, GHB, or ethosuximide to the homogenizing medium. Furthermore, changes in whole brain GHB levels were compared with those in the synaptosomal fraction in animals treated with GABA-T inhibitors, GABA, or ethosuximide. GHB was present in synaptosome-enriched fractions in concentrations ranging from 40 to 70 pmol/mg of protein. There was no evidence for redistribution, leakage, or metabolism of GHB during the preparation of synaptosomes. The elevations of whole brain GHB level associated with GABA-T or ethosuximide treatment were reflected by a parallel increase in synaptosomal GHB content. These data add to the growing evidence that GHB may have neurotransmitter or neuromodulator function.
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PMID:gamma-Hydroxybutyric acid in subcellular fractions of rat brain. 379

The effect of melatonin on in vivo gamma-aminobutyric acid (GABA) accumulation in several brain regions was determined by measuring the increase of GABA levels following inhibition of GABA transaminase. A single melatonin injection (25-300 micrograms/kg) augmented significantly, by 17-20%, GABA accumulation in the hypothalamus and caused a dose-dependent increase of this parameter in the pineal gland. Significant rises of GABA accumulation were found in the cerebellum and cerebral cortex after administering 100-300 and 300 micrograms/kg of melatonin, respectively.
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PMID:Melatonin increases in vivo GABA accumulation in rat hypothalamus, cerebellum, cerebral cortex and pineal gland. 380 13

The presence and distribution of gamma-aminobutyric acid (GABA) degradative enzyme (GABA transaminase-succinic semialdehyde dehydrogenase) activity in the rat myenteric plexus was determined histochemically using laminar preparations of the small intestine. Blue-diformazan staining resulting from reduction of the tetrazolium salt, Nitro-BT, during GABA catabolism was present in a scattered population of ileal and jejunal myenteric ganglion cells, including those resembling multipolar type II and unipolar nerve cells. Such staining was almost completely prevented under conditions of GABA-T inhibition. These results indicate that GABA is enzymically degraded at specific sites in the rat enteric nervous system where it is proposed to have a neurotransmitter function.
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PMID:The distribution of GABA-transaminase-dehydrogenase activity in the myenteric plexus of rat small intestine: a histochemical analysis. 396 Mar 92

The effect of gamma-aminobutyric acid (GABA) on levels of messenger ribonucleic acid (mRNA) encoding prolactin (PRL) was studied in cultured anterior pituitary cells, in vitro and in intact rats, in vivo. As quantitated by hybridization to a 32P-labeled rat PRL complementary deoxyribonucleic acid (cDNA) probe, levels of PRL mRNA in cultured pituitary cells were decreased by about 50% following 3 days exposure to 10(-5) M GABA. This effect was mimicked by muscimol (10(-6) M) and antagonized by bicuculline (10(-5) M). An increase of endogenous GABA levels in vivo effected by injection of GABA transaminase blockers (aminooxyacetic acid, 20 mg/kg, twice daily; vinyl GABA, 800 mg/kg) into rats resulted in a similar decrease in rat PRL mRNA levels in the adenohypophysis 3-4 days following commencement of the drug treatment. These findings suggest that GABA might inhibit PRL gene expression by a direct action on lactotrophs of the adenohypophysis.
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PMID:gamma-Aminobutyric acid decreases levels of messenger ribonucleic acid encoding prolactin in the rat pituitary. 399 Oct 46

The high seizure susceptibility in epileptic chickens is due to an autosomal recessive mutation. In 3-day-old chicks homozygous for the epilepsy gene (epileptics), elevation of body temperature using microwave diathermy evoked an initial febrile seizure resembling the clonic seizures evoked in epileptic chicks by photic stimulation. After complete recovery, this was followed by a clonic-tonic seizure. In nonepileptic heterozygote hatchmates (carriers) of the same age, only the latter seizure pattern was observed. In 16- to 17-day-old chicks of either phenotype, both seizure patterns were observed during hyperthermia. In all cases, the temperature at which seizures occurred was significantly lower in epileptic than in nonepileptic chicks, indicating a lower threshold for febrile seizures when there is an inherited predisposition to convulse. The occurrence of seizures was dependent on the body temperature and not on the rate of rise of temperature. Elevation of the brain gamma-aminobutyric acid (GABA) concentrations by administration of the GABA transaminase inhibitor gamma-vinyl GABA reduced the incidence of the initial febrile seizures and increased the latency in those birds that were not fully protected.
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PMID:Experimental febrile convulsions in epileptic chickens: the anticonvulsant effect of elevated gamma-aminobutyric acid concentrations. 404 16


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