BRAIN-SPECIFIC MODULATION OF KYNURENIC ACID SYNTHESIS IN THE RAT

This study was designed to investigate modulatory mechanisms that cont rol the synthesis of the neuroprotective endogenous excitatory amino a cid receptor antagonist kynurenate. De novo kynurenate formation was e xamined in vitro using tissue slices from rat brain, liver, and kidney , In slices from adult cerebral cortex, veratridine, quisqualate, and L-alpha-aminoadipate decreased kynurenate synthesis substantially. Glu cose removal or changes in the ionic milieu, too, influenced kynurenat e formation significantly, suggesting that demands on cellular energy interfere with kynurenate production in the adult rat brain. The effec ts of quisqualate and L-alpha-aminoadipate were also observed in the i mmature brain, in the quinolinate-lesioned adult striatum, and, to a l esser extent, in peripheral organs. In contrast, the effect of veratri dine was not seen in the lesioned brain or in kidney and liver tissue, indicating its dependency on intact neuron-glia interactions, Compare d with the normal adult brain, ionic manipulations yielded qualitative ly distinct results in the developing brain and in the periphery, but their effects remained unchanged in the lesioned striatum. Glucose dep rivation was less consequential in the immature than in the adult brai n and was entirely ineffective in the lesioned striatum and in the per iphery, These results further link cellular, especially astrocytic, en ergy metabolism to kynurenate formation in the brain, More generally, the existence of brain-specific mechanisms for the regulation of kynur enate production is suggestive of a modulatory role of this metabolite in excitatory amino acid receptor function and dysfunction.