BRAIN QUINOLINIC ACID METABOLISM--BASIC AND CLINICAL STUDIES

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L-tryptophan (L-TRP) is an essential amino acid that is metabolized in the brain to serotonin (5-HT) and through the kynurenine pathway to quinolinic acid (QUIN). Studies in experimental animals have established QUIN as a potent neurotoxin and convulsant and potentially QUIN may have a role in human neurodegenerative and convulsant disorders. Furthermore, the rate of metabolism of L- TRP through the kynurenine pathway may influence L-TRP concentrations in brain and therefore the availability of L-TRP for conversion to 5-HT. To investigate the role of QUIN in human neuropathology and study L-TRP metabolism through the kynurenine pathway, we have perfected methods to quantify QUIN, 3- hydroxykynurenine (3-HKYN) and L-TRP in brain. Completed studies to date demonstrate that during systemic L-TRP loads, changes in the concentrations of QUIN and 3-HKYN far exceed the magnitude of changes in 5-HT and 5-HIAA. Severe insulin-induced hypoglycemia increases brain QUIN and it remains to be determined whether QUIN contributes to neuropathology associated with hypoglycemia. 4- chloro-3-hydroxyanthranilic acid inhibited brain 3- hydroxyanthranilic acid both in vivo and in vitro.