ROLE OF BRANCHED-CHAIN AMINOTRANSFERASE ISOENZYMES AND GABAPENTIN IN NEUROTRANSMITTER METABOLISM

Because it is well known that excess branched-chain amino acids (BCAAs ) have a profound influence on neurological function, studies were con ducted to determine the impact of BCAAs on neuronal and astrocytic met abolism and on trafficking between neurons and astrocytes. The first s tep in the metabolism of BCAAs is transamination with alpha-ketoglutar ate to form the branched-chain alpha-keto acids (BCKAs). The brain is unique in that it expresses two separate branched-chain aminotransfera se (BCAT) isoenzymes, One is the common peripheral form [mitochondrial (BCATm)], and the other [cytosolic (BCATc)] is unique to cerebral tis sue, placenta, and ovaries. Therefore, attempts were made to define th e isoenzymes' spatial distribution and whether they might play separat e metabolic roles. Studies were conducted on primary rat brain cell cu ltures enriched in either astroglia or neurons. The data show that ove r time BCATm becomes the predominant isoenzyme in astrocyte cultures a nd that BCATc is prominent in early neuronal cultures. The data also s how that gabapentin, a structural analogue of leucine with anticonvuls ant properties, is a competitive inhibitor of BCATc but that it does n ot inhibit BCATm. Metabolic studies indicated that BCAAs promote the e fflux of glutamine from astrocytes and that gabapentin can replace leu cine as an exchange substrate. Studying astrocyte-enriched cultures in the presence of [U-C-14]glutamate we found that BCKAs, but not BCAAs, stimulate glutamate transamination to alpha-ketoglutarate and thus ir reversible decarboxylation of glutamate to pyruvate and lactate, there by promoting glutamate oxidative breakdown. Oxidation of glutamate app eared to be largely dependent on the presence of an alpha-keto acid ac ceptor for transamination in astrocyte cultures and independent of ast rocytic glutamate dehydrogenase activity. The data are discussed in te rms of a putative BCAA/BCKA shuttle, where BCATs and BCAAs provide the amino group for glutamate synthesis from alpha-ketoglutarate via BCAT m in astrocytes and thereby promote glutamine transfer to neurons, whe reas BCATc reaminates the amino acids in neurons for another cycle.