EFFECTS OF ANTICONVULSANT DRUG GABAPENTIN ON THE ENZYMES IN METABOLICPATHWAYS OF GLUTAMATE AND GABA

Gabapentin is a novel anticonvulsant drug. The anticonvulsant mechanis m of gabapentin is not known. Based on the amino acid structure of gab apentin we explored its possible effects on glutamate and gamma-aminob utyric acid (GABA) metabolism in brain as they may relate to its antic onvulsant mechanisms of action. Gabapentin was tested for its effects on seven enzymes in the metabolic pathways of these two neurotransmitt ers: alanine aminotransferase (AL-T), aspartate aminotransferase (AS-T ), GABA aminotransferase (GABA-T), branched-chain amino acid aminotran sferase (BCAA-T), glutamine synthetase (Gln-S), glutaminase (GLNase), and glutamate dehydrogenase (GDH). In the presence of 10 mM gabapentin , only GABA-T, BCAA-T, and GDH activities were affected by this drug. Inhibition of GABA-T by gabapentin was weak (33%). The K-i values for inhibition of cytosolic and mitochondrial forms of GABA-T (17-20 mM) w ere much higher than the K-m values for GABA (1.5-1.9 mM). It is, ther efore, unlikely that inhibition of GABA-T by gabapentin is clinically relevant. As with leucine, gabapentin stimulated GDH activity. The GDH activity in rat brain synaptosomes was activated 6-fold and 3.4-fold, respectively, at saturating concentrations (10 mM) of leucine and gab apentin. The half-maximal stimulation by gabapentin was observed at ap proximately 1.5 mM. Gabapentin is not a substrate of BCAA-T, but it ex hibited a potent competitive inhibition of both cytosolic and mitochon drial forms of brain BCAA-T. Inhibition of BCAA-T by this drug was rev ersible. The K-i values (0.8-1.4 mM) for inhibition of transamination by gabapentin were close to the apparent K-m values for the branched-c hain amino acids (BCAA) L-leucine, L-isoleucine, and L-valine (0.6-1.2 mM), suggesting that gabapentin may significantly reduce synthesis of glutamate from BCAA in brain by acting on BCAA-T.