The kynurenine catabolic pathway for tryptophan degradation in humans produces metabolites that are neurologically active and affect neurotransmission and neuronal integrity. Quinolinic acid (QUIN) is a product of the pathway which has been implicated in numerous neuropsychiatric disorders and has been correlated with depression in patients administered the inflammatory cytokine, interferon (IFN)-?. Besides, activation of the kynurenine pathway by inflammation leads to elevated levels of QUIN, which have been shown to cause depressive-like behavior in mice. The mechanism by which QUIN acts in the brain is to activate excitotoxic neurotransmitter pathways involving the amino acid glutamate and by leading to lipid peroxidation. Following metabolism by indoleamine 2,3-dioxygenase and subsequent steps, three consecutive enzymes of the kynurenine pathway determine the metabolic partitioning of tryptophan metabolites to QUIN, picolinic acid (PIC), or further metabolism. We hypothesize that the shift of QUIN and PIC levels is linked to chronic inflammation and major depression. To test this hypothesis, we will, in the first aim, study the structure and action of the enzymes and the mechanisms controlling QUIN and PIC production. In the second aim, a new, rapid and efficient analytical method will be developed for in vitro and ex vivo quantitation of QUIN and PIC levels and will be applied to samples obtained from patient populations expected to exhibit high levels of QUIN as a result of increased inflammation and from assays using purified protein to simulate similar distributions. Through these studies, the correlation between kynurenine metabolites and major depression will be investigated, and small molecule inhibitors will be used as probes for modulating the production of QUIN and PIC levels.
