PubMed · 2564063
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1989-03-11. Vigabatrin.. https://pubmed.ncbi.nlm.nih.gov/2564063/
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The acute effects of the irreversible gamma-aminobutyric acid (GABA) transaminase inhibitor, gamma-vinyl GABA (Vigabatrin), were studied in the central nervous system of the rat. GABA concentrations were monitored in the hippocampus by implantation of microdialysis probes. Two doses of gamma-vinyl GABA (1.6 and 8.0 mM) were administered via the probes and were found to cause a transient increase in the basal GABA outflow (10-fold) during the period of drug administration. In addition, gamma-vinyl GABA pretreatment (1.6 mM) seemed to decrease K(+)-evoked GABA release (P < 0.05). The immediate increase of GABA outflow after gamma-vinyl GABA administration may be the result of direct blockade of GABA uptake sites, a finding which further indicates that the action of GABA transaminase inhibitors may be mediated partly through GABA uptake inhibition.
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.
Pig brain 4-aminobutyrate aminotransferase is inactivated by pre-incubation with pyrroloquinoline quinone (2,7,9-tricarboxy-1H-pyrrolo[2,3,f]quinoline- 4,5-dione; PQQ) at pH 7. The reaction of approximately 2 SH residues/dimer is sufficient to inactivate the enzyme. Reoxidized aminotransferase is reactivated by E. coli thioredoxin. Similar results were obtained with E. coli 4-aminobutyrate aminotransferase. The spectroscopic properties of thioredoxin, tagged with the fluorescence probe, anthraniloyl, were used to monitor its interaction with re-oxidized 4-aminobutyrate aminotransferase. During the regeneration of native aminotransferase by thioredoxin, the substrate forms a covalent intermediate with the oxidoreductase, as revealed by gel filtration chromatography. It is postulated that the substrate (oxidized aminotransferase) forms a covalent intermediate with thioredoxin through disulfide linkages.