This proposal deals with the examination of two compounds, quinolinic acid (QUIN) and kynurenic acid (KYNA), in brain tissue. Interest in QUIN, an excitotoxin present in mammalian brain, is based on its potential involvement in the precipitation of nerve cell death in neurodegenerative disorders such as Huntington's disease. KYNA, a brain constituent metabolically related to QUIN, is a neuroprotectant in animal paradigms and may participate in the prevention of neurodegenerative processes in man. The proposed studies are designed to examine these concepts from several perspectives, employing in vitro studies in brain slices and in an established model of the rat corticostriatal system, in vivo animal experimentation, and studies in post-mortem human brain tissue. The work will include biochemical, immunohistochemical, histological and ultrastructural evaluation. To accomplish these goals, the following projects will be included. 1) In rat brain slices, the biochemical machinery responsible for the neosynthesis of QUIN and KYNA from their respective bioprecursors will be investigated. Attempts will be made to characterize and purify enzymes involved in QUIN and KYNA production; 2) In organotypic tissue cultures of the rat corticostriatal system, the toxic effects of QUIN and its bioprecursor 3-hydroxyanthranilic acid will be studied, and three avenues of pharmacological intervention to achieve neuroprotection will be assessed. The effects of neuronal damage on QUIN's immediate biosynthetic enzyme, 3-hydroxyanthranilic acid oxygenase will be investigated by ultrastructural immunocytochemistry; 3) Using brain microdialysis and osmotic minipumps, selected issues related to kynurenine metabolism, excitotoxicity and neuroprotection will be investigated in the in vivo situation. Experimental protocols will be in part dictated by the outcome of studies 1 and 2; 4) In human control and Huntington's disease post-mortem brain tissue, the presence and characteristics of four enzymes involved in the biosynthesis of QUIN and KYNA, respectively, will be investigated. In these studies, expertise from pre-clinical work e=will be used for a direct assessment of brain kynurenines in a human neurodegenerative disorder.

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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University of Maryland Baltimore
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