BRAIN QUINOLINIC ACID METABOLISM--ROLE IN NEUROPATHOLOGY

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Quinolinic acid (QUIN) is an neurotoxic tryptophan and kynurenine pathway metabolite that has been implicated in the etiology of many neurologic diseases. We have discovered that pronounced increases in brain tissue and cerebrospinal fluid QUIN levels occur in patients and experimental animals with inflammatory neurologic diseases, including microbiological infections, physical trauma and autoimmune conditions. These increases are related to increased activity of indoleamine-2,3-dioxygenase and kynurenine-3-hydroxylase. Macrophages are an important source of QUIN in the central nervous system of patients with inflammatory neurologic diseases. Cytokines, including interferon-gamma, tumor necrosis factor- alpha and interleukin-6 promote QUIN synthesis, particularly in combination. Drugs such as 4-chloro-3-hydroxyanthranilate can attenuate QUIN production by macrophages. Strategies to attenuate the synthesis of QUIN or attenuate its stimulatory effects on the N-methyl-D-aspartate receptors which mediate its neurologic effects are potentially new approaches to the therapy of inflammatory neurologic diseases.