BRAIN QUINOLINIC ACID METABOLISM--ROLE IN NEUROPATHOLOGY

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The accumulation of toxins within the brain has been implicated in the pathogenesis of neurologic diseases. Quinolinic acid (QUIN) is a neurotoxic tryptophan and kynurenine pathway metabolite which accumulates within the brain of patients and experimental animals with inflammatory neurologic diseases, including microbiological infections, physical trauma and autoimmune conditions. Activated macrophages are an important source of QUIN. We have found that 4-Chloro-3-hydroxyanthranilate attenuates QUIN production by macrophages and reduces the elevations in brain QUIN levels in a guinea pig model of spinal cord contusion injury. 4-Chloro-3-hydroxyanthranilate reduced the severity of functional deficits on the third day post injury. We are continuing to investigate the effects of 4-chloro-3-hydroxyanthranilate and other kynurenine pathway inhibitors on kynurenine pathway metabolism. Their effects on neurologic disease progression in animal models of inflammatory neurologic conditions is also being investigated.