Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.6.1.19 (GABA transaminase)
 808 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The turnover of GABA (estimated from the post-mortem accumulation of GABA), and the activity of glutamic acid decarboxylase and GABA transaminase, along with the saturation of both enzymes by cofactor pyridoxal phosphate, were studied in the substantia nigra of rats of both sexes. Although no sex differences were found in the in vitro measured characteristics of both enzymes involved in GABA metabolism, the turnover of GABA was greater in males. This finding is consistent with our previous reports showing the greater resistance of male rats to GABA-related convulsions.
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PMID:Sex difference in the turnover of GABA in the rat substantia nigra. 368 Dec 88

4-Amino-2-(substituted methyl)-2-butenoic acids, where X (the substituted group) = F, Cl, OH, are synthesized from Cbz-protected tert-butyl 4-aminobutanoate. Successive substitutions at the alpha-carbon by phenylseleno and hydroxymethyl groups, followed by elimination of the selenoxide and halide substitution at the hydroxymethyl group, afford the compounds in good yields. An unexpected degree of stereoselectivity is observed in the selenoxide elimination step, which yields the desired E isomer as the sole product. These compounds complement two previously reported series of compounds (Silverman, R. B.; Levy, M. A. Biochem. Biophys. Res. Commun. 1980, 95, 250-255; J. Biol. Chem. 1981, 256, 11 565-11 568) and are used in an approach to map a section of the active site of gamma-aminobutyric acid aminotransferase (GABA-T). None of these compounds is a time-dependent inactivator of GABA-T, but all are potent competitive reversible inhibitors; the hydroxy compound has a Ki value of 5 microM. That these compounds are not inactivators suggests that either elimination of X does not occur or that there is no active site nucleophile in the appropriate position for reaction following elimination. With use of the fluoro analogue, enzyme-catalyzed fluoride ion release is demonstrated, indicating that elimination does occur. Unlike the previous two series of compounds (op. cit.) in which exclusive elimination occurs when the substituent is a halogen but exclusive transamination prevails for the hydroxyl-substituted analogues, in the series described here, the fluoro analogue gives a 4:1 ratio of elimination to transamination. This suggests that the 2,3-double bond stabilizes the product of azallylic isomerization of the Schiff base between the fluoro compound and pyridoxal phosphate. The results described here indicate that the design of a mechanism-based inactivator for GABA-T should not be based on electrophile generation near the 2-position of enzyme-bound GABA. Furthermore, substitution of an inhibitor with a 2-hydroxymethyl group (or other hydrogen-bonding substituent) and a 2,3-double bond may lend auspicious binding properties to the molecule for GABA-T.
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PMID:4-Amino-2-(substituted methyl)-2-butenoic acids: substrates and potent inhibitors of gamma-aminobutyric acid aminotransferase. 370 87

The effects of 2-Chloroadenosine (CADO), a stable analog of adenosine, on GABA turnover rate and GABA content in the rat hippocampus in vivo have been studied. The intracerebroventricular injection of CADO reduced the GABA turnover rate in the hippocampus, as estimated from the rate of GABA accumulation after inhibition of GABA transaminase (GABA-T) by aminooxyacetic acid (AOAA). The effect of CADO on AOAA-induced accumulation of GABA in the hippocampus was blocked by the intraperitoneal injection of the adenosine receptor antagonist caffeine. Furthermore, CADO at the dose of 5 micrograms per ventricle produced a significant decrease in GABA content in the hippocampus. Our results support the hypothesis that adenosine exerts inhibitory effects on GABAergic circuits in the hippocampus.
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PMID:Effects of 2-chloroadenosine on hippocampal GABA content and turnover. 371 82

The effects of gamma-aminobutyric acid transaminase (GABA-T) inhibitors on rat endothelial GABA-T activity has been studied utilizing a modified tetrazolium salt histochemical technique. Blue-diformazan staining of cerebrovascular and parenchymal sites of GABA catabolism in normal brain was almost completely prevented in unfixed frozen brain sections from rats subjected to 'in vivo' GABA-T inhibition using aminooxyacetic acid or gabaculine. These results provide histochemical evidence for the efficacy of using systemically administered GABA-T inhibitors to inhibit endothelial GABA-T activity.
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PMID:Cerebral endothelial GABA-T activity: effects of in vivo GABA-T inhibition. 372 99

We have documented the presence of five mitochondrial enzymes in samples of chorionic villus tissue and measured the levels of activity. Three of the enzymes catalyse biotin-dependent reactions. These are propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase and pyruvate carboxylase. The other enzymes, 4-aminobutyric acid aminotransferase and succinic semialdehyde dehydrogenase, are involved in the degradation of the central inhibitory neurotransmitter GABA. Distinct diseases in which there is deficiency of each of these enzymes have been documented in man. Significant levels of activity were observed for all five enzymes in chorionic villus tissue. This methodology should permit early prenatal diagnosis of deficiencies of these enzymes by chorionic villus biopsy in the first trimester.
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PMID:Activity of biotin-dependent and GABA metabolizing enzymes in chorionic villus samples: potential for 1st trimester prenatal diagnosis. 372 38

Uptake of labelled dopamine and GABA and activities of GABA transaminase, dehydrogenase and reductase of succinic semialdehyde were studied in brain of rats with different duration of ethanol narcosis. The data obtained showed the differences in activities of the dopamine and GABA systems, which were not similar in different brain regions. These differences were manifested by both initial activities (hemispheres, brain stem) and different changes of these systems after the ethanol injection (basal ganglia, hemispheres).
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PMID:[Characteristics of dopamine and GABA system functions in the brain of animals with different durations of ethanol sleep]. 372 69

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

Four inhibitors of gamma-aminobutyric acid transaminase (GABA-T) were investigated together with respect to their effects on hole-board exploration and temperature and the relation with effects on quasi-morphine-abstinence behaviour induced by dipropylacetate (DPA) in rats. Amino-oxyacetic acid (AOAA), gamma-acetylenic-GABA (GAG), gamma-vinyl-GABA (GVC) and ethanolamine-O-sulfate (EOS) were found to reduce hole-board exploration especially in the higher doses used, although the time-course of the effect was different for the compounds. For EOS and GVG the decrease in hole-board exploration paralleled a strong hypothermic effect. The compounds AOAA and GAG exerted a less and more transient hypothermic effect. However, the decrease in hole-board exploration did not fall in with this decrease in temperature. AOAA and GAG were found to decrease DPA-induced body shakes and locomotor activity, while GVG and EOS had no effect on body shakes and transient effects but opposite to each other, on locomotor activity. The efficacy of the GABA-T-inhibitors was measured biochemically, and the influence on the activity of glutamate decarboxylase (GAD) was also determined. AOAA and GAG were found to be strong inhibitors of GABA-T whereas the other two compounds were less efficient in the used doses. In addition AOAA and GAG influenced the activity of GAD strongly, while using GVG only a small decrease was found. The results suggest that the anti-quasi-withdrawal, the sedative and the hypothermic effects are not related to each other nor related to an effect on GABA-T. The suppressive effects on quasi-withdrawal body shakes, however, could be related to the inhibition of GAD and a hypothesis involving a compartmentalized action of DPA on GABA-metabolism has been proposed.
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PMID:Effects of inhibitors of GABA-transaminase on hole-board exploration and on temperature. Relation with effects on quasi-morphine abstinence behaviour induced by sodium dipropylacetate. 393 14

The pharmacohistochemical method previously used to identify the distribution in rat brain of gamma-aminobutyric acid transaminase (GABA-T)-intensive neurons has been applied to the rat pons and medulla. The method involves systemic administration of the irreversible GABA-T inhibitor Gabaculine and the detection, 12 to 15 hours after the injection of the newly synthesized GABA-T by histochemical means. GABA-T-intensive neurons were found to be rich in the following hindbrain structures: inferior colliculus, nuclei of the raphe system, nuclei parabrachialis dorsalis and ventralis, nucleus cuneiformis, nucleus vestibularis medialis, nucleus tractus spinalis nervi trigemini, nucleus vagus, nucleus cochlearis, nucleus reticularis lateralis, nucleus ambiguus, nucleus cuneatus lateralis, inferior olive, and reticular formation of the pons and medulla. Neurons of the deep cerebellar nuclei and the rostral portion of the lateral vestibular nucleus were negative for GABA-T but were surrounded by granular staining indicative of impinging GABA-T-rich nerve endings. These results provide further support for the hypothesis that GABA neurons are far more GABA-T-intensive than other neurons in the central nervous system.
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PMID:Distribution of GABA-T-intensive neurons in the rat hindbrain. 396 38


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