This project was designed to assess in detail the structural and biochemical correlates and prerequisites of nerve cell degeneration caused by quinolinic acid (QUIN). This compound, an endogenous tryptophan metabolite, has been shown to occur in brain tissue. Lesions resulting from an exposure of striatal tissue to QUIN are reminiscent of those observed in the human neurodegenerative disorder, Huntington's disease. In parallel experiments in the whole animal (in vivo) and in organotypic tissue cultures (in vitro), four issues will be examined: the ontogeny of QUIN-neurotoxicity; the characteristics of receptors for QUIN and its specific antagonist, 2-amino-7-phosphono heptanoic acid; the modulation of QUIN-neurotoxicity by surgical and pharmacological means; and the metabolism and localization of QUIN in brain tissue. Analyses will be biochemical and light microscopical in the in vivo paradigms and light and electron microscopical in the culture studies. The proposed comprehensive approach using complementary methodologies can be anticipated to yield baseline data concerning various important aspects of QUIN neurobiology with particular relevance for QUIN-neurotoxicity (and its prevention by selective blocking agents). The data accumulated in the course of the grainting period will allow a realistic evaluation of a possible role in QUIN in Huntington's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology A Study Section (NEUA)
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Vanderbilt University Medical Center
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United States
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