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. Studies were done to identify agents which attenuate QUIN production by macrophages. Successful agents were tested in a gerbil ischemia-induced model of CNS inflammation. 4-Chloro-3- hydroxyanthranilate attenuated QUIN production by macrophages and reduced the elevations in brain QUIN levels in the post-ischemic brain. In a guinea pig model of spinal cord contusion injury, 4-chloro-3- hydroxyanthranilate attenuated the elevations in spinal cord QUIN levels and reduced the severity of functional deficits on the third day post injury. Studies will continue to evaluate the long term effects of reducing QUIN accumulations in the spinal cord model of injury and other models of brain inflammation.