The explicit overall goal of the studies described in this proposal is to examine a possible role of the tryptophan metabolite quinolinic acid (QUIN) in the pathogenesis of seizure disorders. QUIN is present in both rat and human brains and has been shown to possess convulsive and neurodegenerative properties following intracerebral application. Electroencephalographical, neurochemical and morphological changes will be assessed simultaneously in unanesthetized rats after intrahippocampal QUIN injections. All analyses will be performed continuously and bilaterally, taking advantage of novel techniques developed in our laboratory. Correlations between the various parameters tested will be attempted and the data compared to relevant findings in human seizure disorders. Other experiments will examine basic questions which are germane to our central hypothesis, i.e. are QUIN levels altered in experimental seizure models? can QUIN be released from brain tissue? and can peripheral administration of kynurenine, a metabolic QUIN-precursor, influence central QUIN-functions? Kindled- and kainic acid-induced seizures will constitute our experimental paradigms for these investigations. QUIN levels (and the activity of the specific QUIN-catabolizing enzyme QUIN-phosphoribosyltransferase) will be determined by recently developed methodologies. Taken together, the projects outlined here should enable us to realistically evaluate whether or not an integral involvement of QUIN in epileptic phenomena should be considered.
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