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 metabolic 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 have been measured in the cerebrospinal fluid (CSF) of patients with acquired immune deficiency syndrome (AIDS) as well as other infectious diseases (bacterial, viral, fungal and parasitic) in humans (Lyme disease) and macaques, particularly diseases associated with neurologic and neuropathologic changes. Brain QUIN levels are increased following both ischemia and insulin-induced hypoglycemia. There is no evidence for elevated QUIN in non-inflammatory neurologic diseases such as Huntington's and Alzheimer's. Type-D retrovirus infected macaques exhibit elevated IDO and QUIN levels in cerebral cortex correlated with the severity of neuropathology. Rodent models of immune stimulation are being investigated with regard to alternatives to primate studies. 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.