BRAIN QUINOLINIC ACID METABOLISM--ROLE IN NEUROPATHOLOGY

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Quinolinic acid (QUIN) is an excitotoxic metabolite of tryptophan metabolized via the kynurenine pathway. QUIN activates N-methyl-D-aspartate excitatory amino acid receptors and can cause convulsions and neurodegeneration. These effects are attenuated by the related metabolite kynurenic acid (KYNA). The activity of indoleamine-2,3 dioxygenase (IDO), the first enzyme of the kynurenine pathway in extrahepatic tissues, is increased during activation of the immune system. Therefore, QUIN and KYNA may contribute to neuronal dysfunction and neurodegeneration that accompany certain infectious diseases. Substantial increases in the concentrations of QUIN and KYNA occur in the cerebrospinal fluid (CSF) of patients with the acquired immune deficiency syndrome (AIDS) as well as other infectious disease in macaques and humans, particularly diseases associated with neurologic and neuropathologic changes. Brain QUIN levels are increased following both ischemia and insulin-induced hypoglycemia. Our future studies are focused on whether the increases in QUIN and KYNA have a neuropathogenic role in infectious diseases and whether strategies to attenuate the magnitude of their increase are of clinical benefit.