title: Differential effect of gamma-vinyl GABA and valproate on GABA-transaminase from cultured neurones and astrocytes.
abstract: A preferential effect of valproate on gamma-aminobutyric acid (GABA) in the nerve terminal compartment has been proposed. Gamma-vinyl GABA, an irreversible inhibitor of GABA-transaminase (GABA-T) causes a preferential increase in the GABA compartment of the non-nerve terminal. The aim of the present study was to investigate further this apparent differential effect on GABA-T of these compounds in neurones and glia. The investigations were undertaken in neurones and astrocytes, cultured separately. After incubation with valproate, the IC50 value for astrocytes was found to be 1202 microM of valproate and for neurones 634 microM. Assuming regional differences of concentrations of valproate in the brain, the observed IC50 values might be clinically relevant. Culturing the cells in the presence of gamma-vinyl GABA demonstrated IC50 values for astrocytes and neurones of 89 and 24 microM, respectively. The (S)isomer of gamma-vinyl GABA was the most active inhibitor of GABA-T in both glia and neurones. After withdrawal of gamma-vinyl GABA from the culture media of the cells, in neurones 50% of the activity of GABA-T was regained within 2-4 days. In astrocytes a similar time course was observed. These findings are in agreement with clinical data: the IC50 values correspond to clinically-relevant serum levels of gamma-vinyl GABA in humans only the (S)isomer showed an antiepileptic effect in animal models of epilepsy a delayed antiepileptic effect, after withdrawal of gamma-vinyl GABA, has been established in clinical studies.
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000378:metabolism*; D000614:Aminocaproates / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000201:enzymology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology*; D005260:Female; D007123:Immunoelectrophoresis, Two-Dimensional; D007395:Interneurons / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D011247:Pregnancy; D014635:Valproic Acid / Q000494:pharmacology*; D020888:Vigabatrin
chemical_list: D000614:Aminocaproates; D014635:Valproic Acid; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin