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)

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

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

The objective of the present study was to compare the effects of elevation of GABA concentration and those of inactivation of L-ornithine: 2-oxoacid aminotransferase (OAT) on the in vivo metabolism of L-ornithine (Orn) in brain. Vigabatrin (4-aminohex-5-enoic acid) and gabaculine (5-amino-1,3-cyclohexadienyl carboxylic acid), two well known inactivators of GABA-T, were used to elevate brain GABA concentrations. The latter inactivates OAT also. Transamination of Orn is, from a quantitative point of view, a significant reaction in mouse brain. GABA is a feed-back regulator of OAT. Within GABAergic neurons Orn concentration may be regulated by endogenous GABA. Extensive inactivation of OAT causes a considerable increase of Orn concentration, both in synaptosomes and in non-synaptosomal compartments. The results are compatible with a role of Orn as precursor of glutamate and/or GABA in certain neurons.
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PMID:Interrelationships between ornithine, glutamate, and GABA. II. Consequences of inhibition of GABA-T and ornithine aminotransferase in brain. 289 88

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

Vigabatrin (gamma-vinyl GABA), an enzyme-activated, irreversible inhibitor of GABA transaminase, was administered orally to albino Sprague Dawley and pigmented Lister-Hooded rats. A dose-dependent retinal lesion characterized histologically by disruption of the outer nuclear layer was observed in the Sprague Dawley rat but not in Lister-Hooded rats, indicating that this alteration is related to the absence of pigment. The lesion is similar to that induced in albino rats by light and certain drugs. In addition, myelin vacuolation of the brain was observed in both rat strains, consistent with the findings of other toxicity studies with vigabatrin. In all cases, the vacuolation was limited to myelinated tracts and resulted from separation of the myelin sheath at the intraperiod line. There was no evidence of demyelination, axonal degeneration or damage to contiguous structures in the affected areas. The vacuolation is histologically similar to that induced in rats by certain other compounds such as isoniazid, hexachlorophene, and triethyltin, but differs in that it is focal in distribution, it is limited to the brain, and is reversible upon cessation of treatment.
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PMID:A study of the effects of vigabatrin on the central nervous system and retina of Sprague Dawley and Lister-Hooded rats. 361 99

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

Vigabatrin (VGB) is an antiepileptic drug (AED) that acts by irreversibly inhibiting gamma-aminobutyric acid transaminase (GABA-T). To evaluate immune responses to GVG, we studied 29 idiopathic or symptomatic epileptic children and also examined a control group (n = 15). Epileptic children were tested before and after 1 and 3 months of VGB treatment. Whole blood was used to connect subsets with commercial monoclonal antibodies. Peripheral blood mononuclear cells (PBMC) were used to assess natural killer (NK) cell activity and lymphocyte response to phytohemagglutinin (PHA) and concavalin A (Con A). Immunoglobulin (Ig) levels were tested in serum. At baseline, no immunologic abnormalities were observed in either control or treated patients. During treatment, the percentage and absolute number of B lymphocytes, serum concentration of Ig, number of T total mature lymphocytes (CD3), T-rosetting lymphocytes (CD11), T-helper cells (CD4), and mitogenic response of lymphocytes remained unchanged. Several other immunologic responses showed a statistically significant increase after 1 and 3 months of VGB treatment, however, including the percentage and absolute number of T-suppressor cells (CD8) and NK cells and NK cell activity. The correlation between number of NK cells and NK cell activity was significant. Data obtained demonstrated that VGB may interfere with the modulation of the immune system, especially cytotoxic cell populations.
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PMID:Immunologic aspects of vigabatrin treatment in epileptic children. 760 23

Vigabatrin (gamma-vinyl-GABA or GVG) is an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), which is an enzyme responsible for gamma-aminobutyric acid (GABA) catabolism. Inhibition of GABA catabolism increases brain concentration of GABA, a neural inhibitor. GVG has been found to be a potent new anti-epileptic drug, especially in the treatment of refractory epilepsy, in particular of complex partial seizures. Three patients who developed a severe status epilepitus while on GVG treatment are reported. A possible proconvulsive effect of GVG is hypothesized, which might result from disinhibition in the nigro-collicular pathway due to increased GABA-levels.
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PMID:Status epilepticus during vigabatrin treatment: a report of three cases. 767 Jul 70

The CNS neurotransmitter GABA is distributed extensively throughout the suprachiasmatic nucleus, the site of circadian pacemaker cells in mammals. Pharmacological agents that act at GABAA receptors alter specific circadian responses to light and may induce phase shifts of circadian rhythms. In the present study, the role of endogenously released GABA in rhythm regulation was investigated using vigabatrin (gamma-vinyl GABA), an agent that has been shown to increase chronically or acutely the CNS levels of this neurotransmitter by inhibiting GABA transaminase. In Experiment 1, hamsters in constant darkness (DD) received a saline or a vigabatrin injection 1 hr before a 15-min, 700-lux light pulse. Vigabatrin increased photic phase delays but did not affect advances. In Experiment 2, vigabatrin delivered chronically via osmotic minipump treatment did not affect locomotor activity period in DD. However, after 14 days of infusion, photic phase delays (but not advances) were greatly increased in the vigabatrin group. In Experiment 3, in constant light (LL), chronic vigabatrin-treated animals showed an increased period that returned to pretreatment values after the 14-day drug infusion. The results are consistent with the phase-dependent effects of other agents that alter GABA neurotransmission. The data support the general hypothesis that GABA modulates the circadian responses to light in a phase-dependent manner, and may participate in entrainment to light-dark cycles by influencing the relative responsiveness to light in the early and late subjective night.
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PMID:Inhibition of GABA transaminase enhances light-induced circadian phase delays but not advances. 777 93

The discriminative stimulus effects of indirect-acting GABAergic drugs were compared to those of pentobarbital (PB) and midazolam in rats trained to discriminate 5 mg/kg PB from saline under a two-lever fixed-ratio 32 schedule of food reinforcement. PB and midazolam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Valproic acid, an antiepileptic drug and GABA transaminase inhibitor, substituted for PB but only at a dose that produced response rate suppression. Vigabatrin, an irreversible GABA transaminase inhibitor, failed to substitute for PB, but did produce a dose-dependent decrease in response rates. The GABA uptake inhibitors, 1-[2-[bis[4-(trifluoromethyl)phenyl]-methoxy]ethyl]-1,2,5,6- tetrahydro-3-pyridinecarboxylic acid (CI-966) and (R(-)-N-[4,4-bis(3-methylthien-2-yl)but-3-enyl] nipecotic acid HCl (tiagabine), produced no greater than 40% PB-lever responding. Aminooxyacetic acid (AOAA), which is described as a nonselective presynaptic GABA agonist, yielded a maximum of 43% PB-lever responding. These results indicate that the discriminative stimulus effects of the indirect GABAA agonists, PB and midazolam, although similar to one another, differ from those of presynaptic GABAergic drugs. Differences in the discriminative stimulus properties of GABA transaminase inhibitors and uptake inhibitors also exist, indicating that not all presynaptic GABA agonists have similar behavioral profiles. These results contribute to a further understanding of the similarities and differences in the behavioral effects of drugs that enhance GABAergic neurotransmission.
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PMID:Discriminative stimulus effects of presynaptic GABA agonists in pentobarbital-trained rats. 811 28


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