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)

tau-Vinyl GABA (vigabatrin, GVG) is a novel antiepileptic drug that irreversibly inhibits GABA transaminase and elevates GABA levels in all parts of the brain. In the present study, we investigated the anxiolytic and behavioral effects of GVG in the elevated plus-maze and the hole board compared to diazepam. Doses of 500 and 1,000 mg/kg GVG were injected IP to different groups of male Wistar rats and animals were tested either 4 or 24 h after injection. Animals administered diazepam (1.5 mg/kg, IP) and saline (1 ml) were tested 20 min after injection. GVG and diazepam were found to decrease significantly the number of squares visited and rearing; both had a suppressant effect on locomotor activity. Neither drug had an effect on exploration (head dipping). GVG at a dose of 1,000 mg/kg was shown to have a similar anxiolytic activity either after 4 or 24 h as diazepam, while GVG at 500 mg/kg did not show any significant anxiolytic effect.
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PMID:Vigabatrin has an anxiolytic effect in the elevated plus-maze test of anxiety. 135 80

Multiple administrations of the psychotomimetic drug, phencyclidine-HCI (PCP), decreased striatal neuropeptide Y-like immunoreactivity (NPY-LI) levels in a dose-dependent manner. Single or multiple PCP administrations decreased striatal NPY levels after 10-12 h; levels returned to control 24 h after a single dose or 58 h after multiple doses. In contrast, no significant changes were seen in nigral NPY levels with either acute or multiple-dose PCP treatments. The role of monoamine, sigma or opioid receptors in PCP-induced striatal NPY changes was evaluated. When administered alone, the alpha 1-adrenergic antagonist, prazosin, the sigma antagonist, BMY 14802, and the dopamine D2 antagonist, sulpiride decreased striatal NPY levels; however, only prazosin and the dopamine D1 antagonist, SCH 23390, significantly attenuated PCP-induced changes. Administration of the gamma-aminobutyric acid transaminase (GABA-T) inhibitors, amino-oxyacetic acid (AOAA) or gamma-vinyl-GABA (GVG, vigabatrin, MDL 71,754) alone had no effect on striatal NPY-LI levels while administration of these indirect GABA agonists prior to or concurrently with PCP treatment completely blocked PCP-induced changes in striatal NPY-LI levels. The effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, on striatal NPY-LI content resembled that of PCP and was also blocked by the two indirect GABA agonists. These data suggest that NPY systems are modulated by glutamatergic activity (specifically by the NMDA receptor) and that the interaction between these two transmitter systems is mediated by GABAergic mechanisms.
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PMID:Characterization of phencyclidine-induced effects on neuropeptide Y systems in the rat caudate-putamen. 136 Aug 68

gamma-Vinyl GABA (GVG, vigabatrin) is a GABA transaminase-inhibiting antiepileptic agent. In dogs, chronic GVG administration produces reversible microvacuolation (intramyelinic edema) in discrete brain regions and slowing in central afferent transmission as measured by somatosensory evoked potentials (SEPs). Because this microvacuolation is especially prominent in the optic tract, this study tested the sensitivity of visual evoked potentials (VEPs) to GVG-induced changes in conduction. We also replicated the earlier SEP findings. Eight beagles received daily oral vigabatrin at the maximum tolerated dose (300 mg/kg/day); four were placebo controls. Cortical VEPs and SEPs were recorded using scalp needle electrodes at baseline and every 2 weeks throughout treatment. One treatment dog died at 2 weeks. The remainder showed an increase in central latencies beginning at 6 weeks, attaining significance (p < 0.05) at 8 and 10 weeks for SEPs and VEPs, respectively. No changes occurred in peripheral or spinal conduction in treated dogs, or in any measure in control dogs. Three GVG and two control dogs were followed after drug was withdrawn; both VEP and SEP measures returned to baseline values within 5 weeks. These findings support the use of VEPs and SEPs to monitor patients receiving vigabatrin therapy.
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PMID:Effects of high-dose gamma-vinyl GABA (vigabatrin) administration on visual and somatosensory evoked potentials in dogs. 142 96

The effects of adding vigabatrin (GVG) to the antiepileptic regimens of 16 children with refractory epilepsy have been studied. One-half of the regimens included sodium valproate (VPA). Parameters studied were seizure reduction, platelet GABA-T activity, and steady-state plasma concentrations (CSS) of GVG and VPA. Add-on GVG reduced the seizure frequency both in patients receiving VPA (from 42.9 to 4.5 seizures/month, p < 0.01) and in those without VPA (from 60.0 to 31.7 seizures/month, p < 0.05). GVG also reduced GABA-T activity in both groups (from 19.4 to 5.4, p < 0.001 and from 8.3 to 4.5 pmol/min/mg of protein, p < 0.05, respectively). Seizure reduction and GABA-T inhibition were greater in patients taking VPA than in those who were not. In patients receiving VPA, no significant changes were observed in VPA CSS values before and after the addition of GVG. On the other hand, no differences were found in GVG CSS values between patients with and without VPA. It is concluded that the coadministration of GVG to valproate reduces the frequency of seizures in refractory epileptic children and does not affect the steady-state plasma concentrations of either drug. Therefore, their association could be useful in clinical practice.
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PMID:Coadministration of vigabatrin and valproate in children with refractory epilepsy. 147 47

Bilateral ischemia has been shown to alter the net brain levels of energy metabolites such as ATP, phosphocreatine, glucose, and glycogen. The amino acid neurotransmitter gamma-aminobutyric acid (GABA) exerts a tonic inhibitory influence on neural activity. The present studies were designed to evaluate the influence of elevated GABA levels on the metabolic sequelae of ischemia. The GABA transaminase inhibitor gamma-vinyl-GABA (GVG; vigabatrin) was administered to Mongolian gerbils before the production of a bilateral ischemic incident. GABA levels were elevated in all regions assayed. Levels of energy metabolites were also increased, an indication of reduced energy utilization. In control animals, in the absence of GVG, 1 min of bilateral ischemia produced decreases in the levels of all metabolites. In animals pretreated with GVG, the effects of 1 min of bilateral ischemia were attenuated. These data suggest that the level of ongoing activity may affect the response to an ischemic insult. Furthermore, GVG may have a clinical indication in reducing the effect of minor ischemic incidents.
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PMID:Elevated gamma-aminobutyric acid levels attenuate the metabolic response to bilateral ischemia. 149 8

Seizure susceptibility and GABA metabolism were altered in the substantia nigra [SN] of adult male Sprague Dawley rats when these animals were acclimating to an altered plasma osmolality. Changes in GABA metabolism were measured in vivo in SN of the freely moving rat. Suitable precautions were taken to avoid any post-mortem flux of glutamate to GABA and to correct for the underestimation of GABA build up in SN due to the finite diffusion rate of gamma-vinyl GABA [GVG] after stereotaxic injection of small amounts into one side of the brain. Control experiments provided evidence that changes in osmolality, within a normal physiological range, did not affect significantly gamma-aminobutyric acid transaminase [GABA-T]. Also kindling via the medial septum [MS], in the absence of electrical stimulation did not alter GABA metabolism in SN, thus providing a stable baseline for studies of osmotic effects. Hyperosmolality was associated with a rise in seizure thresholds, with a marked reduction of the rate of GABA synthesis in SN, and with a substantial increase in turnover time of the GABA pool. Hypoosmolality, of a degree known to be associated with mild cerebral edema and swelling localized to astrocytes, markedly reduced seizure threshold, and reduced GABA pool size in SN, but did not alter the rate of GABA synthesis significantly. These results demonstrate by new and independent means the relationship between GABA metabolism in the SN and seizure susceptibility in vivo.
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PMID:Alterations of GABA metabolism and seizure susceptibility in the substantia nigra of the kindled rat acclimating to changes in osmotic state. 178 28

Vigabatrin (gamma-vinyl-GABA, GVG) is an inhibitor of brain GABA transaminase (GABA-T) that also inhibits platelet GABA-T in rats and humans. We have compared the effects of single and multiple doses of GVG on both enzymes in 19 groups of 10 adult male Wistar rats, treated with increasing GVG doses (0-1,600 mg/kg/day) for 1, 8, and 28 days. The platelet GABA-T was more sensitive to the inhibitory effects of GVG than the brain enzyme was especially with low dosages of GVG. After 8 days of treatment, higher GVG plasma levels and a higher inhibition of both enzymes were shown. However, after 28 days, lower GVG plasma levels and similar inhibition of both enzymes compared to the eighth day were found. Correlations between platelet and brain GABA-T for individual rats were statistically significant after 1 day (r = 0.40, p less than 0.01) but not after 8 and 28 days of treatment because of the total inhibition of platelet GABA-T and only partial inhibition of brain GABA-T. We concluded the following: (a) platelet GABA-T is more inhibited than brain GABA-T when low doses of GVG are used and (b) multiple doses reach a higher inhibition of both enzymes than single doses, which could be explained by an increase in GVG concentrations.
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PMID:Relationship between platelet and brain GABA transaminase inhibition by single and multiple doses of vigabatrin in rats. 191 85

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

Biochemical and pharmacological effects of gamma-vinyl GABA (Vigabatrin, GVG), and irreversible enzyme-activated inhibitor of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T), were measured in mice. This anticonvulsant produced a time- and dose-dependent elevation of the GABA, phenylalanine and lysine contents of cortical tissue and simultaneously decreased glutamate, aspartate and alanine levels. In addition, GVG caused a biphasic change in glutamine concentrations (a decline 1-4 hours after administration, followed 20 hours later by an increase). Moreover, we found a new, as yet unidentified amino acid in the brain eluting with the same retention time as alpha-aminoadipic acid from an HPLC cation-exchange column. The level of this novel chemical entity was greatly increased by GVG 20 hours after injection of the drug. At all tested intervals between 1 and 60 hours after injection, GVG was ineffective against maximal electroshock. The GABA-T inhibitor dose-dependently protected mice against isoniazid-induced seizures, simultaneously causing an increase in brain GABA concentrations. However, this apparent correlation applied only until 4 hours after treatment. To better define the anticonvulsant profile of GVG, groups of mice were treated, 1, 2, 4, and 24 hours prior to challenge with convulsant doses of strychnine, pentetrazole (PTZ), and picrotoxin, and brain amino acid levels, including brain concentrations of GVG, were measured. In all instances, the time dependency of the anticonvulsant effects of GVG and of increases in brain GABA levels differed. Amino acid concentrations in animals treated only with GVG were similar to those in animals given GVG and a chemical convulsant. GVG showed no selectivity for seizures produced by impairment of GABA-ergic neurotransmission. Although GVG is an effective GABA-T inhibitor, it apparently affects several other pyridoxal-phosphate-dependent cerebral enzymes and/or interacts with other neurotransmitter systems as well.
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PMID:Gamma-vinyl GABA: comparison of neurochemical and anticonvulsant effects in mice. 341 34

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


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