Endogenous neurotoxic amino acids (EAA) functioning as excitotoxins are believed to play a causative role in progressive neurodegenerative diseases such as Huntington's Disease (HD). Traditionally, it was assumed that hyperphysiological concentrations of endogenous EAA receptor ligands such as glutamate or quinolinic acid (QUIN) are necessary for nerve cell death to occur (""""""""direct excitotoxicity""""""""). Recently, it has become clear that an alternative mechanism termed """"""""weak"""""""" or """"""""indirect"""""""" excitotoxicity may constitute an equally plausible pathogenic mechanism. Based on several lines of experimental evidence, this hypothesis holds that neurons which are ill- protected by defective cellular energy metabolism and/or a deficiency in the function of the endogenous neuroprotective agent kynurenic aid (KYNA) become vulnerable to normally innocuous concentrations of endogenous excitotoxins. Notably, KYNA concentrations and the enzymes responsible for its production are substantially decreased in the basal ganglia of late stage HD patients. The present proposal was designed to examine in detail the neurobiology of KYNA as it pertains to both direct and indirect excitotoxic neurodegeneration. Thus using post- mortem brain tissue, KYNA content and biosynthesis will be studied in early HD victims (Specific Aim 1).
In Specific Aim 2, the regulation of KYNA production will be examined in the rat striatum in vitro and in vivo, using excitotoxins and pharmacological interventions experimental as tools. Results from these studies will then be applied to the design of toxicity studies which will be performed in rat cortico-striatal organotypic cultures (Specific Aim 3) and in the rat striatum in vivo (Specific Aim 4). Here, we shall examine if manipulations of the brain's KYNA system can increase or decrease neuronal vulnerability to direct or indirect excitotoxins. In summary, the proposed studies will provide critical test for the hypothesis that brain kynurenines, and the neuroprotective EAA receptor antagonist KYNA in particular, are causally involved in excitotoxic neurodegeneration in animals and humans.
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