This proposal deals with the question to what extent the endogenous excitotoxin quinolinic acid (QUIN) may be involved in the pathogenesis of temporal lobe epilepsy. The hypothesis is based on the realization that QUIN, a potent convulsant, causes a specific pattern of hippocampal neurodegeneration upon intracerebral application in rats and that the QUIN-induced lesion is virtually indistinguishable from that seen in the human disorder. The idea has been further substantiated recently by the observation that hippocampal neurons containing quinolinic acid phosphoribosyltransferase (QPRT), QUIN's selective catabolic enzyme, are singularly resistant to neurodegenerative processes both in human specimens and in the QUIN-treated rat hippocampus. These findings strongly suggest a role of QUIN, a selective agonist at cerebral N-methyl-D-aspartate (NMDA) receptors, in the course of epilepsy. The proposed studies are designed to further evaluate details of this role in human brain material and in animal experiments. To this end, the following studies will be performed: 1) Continued immunohistochemical and biochemical analysis of temporal lobe tissue samples obtained during epilepsy surgery. Particular emphasis will be placed on a possible relationship between QUIN and the neurotransmitters GABA and norepinephrine; 2) Detailed immunohistochemical and biochemical analysis of the events taking place in the rat hippocampus at various timepoints following a local QUIN injection. Again, care will be taken to assess possible links between the metabolic machineries for QUIN, GABA and norepinephrine; 3) Evaluation of the detoxifying role of QPRT in vivo. Specific inhibitors of QUIN biosynthesis and degradation will be synthesized and used as pharmacological probes in vivo. Drug effects will be monitored by microdialysis, electrophysiological and morphological techniques; 4) Examination of the properties of QPRT in vitro . Using purified protein, the precise mechanisms of action of new QPRT-inhibitors will be determined. Taken together, the resulting data will permit a realistic evaluation of the QUIN-hypothesis of temporal lobe epilepsy. In addition, this work may pinpoint novel avenues for the treatment of the disease.
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