The etiology of nerve cell death in Huntington's disease (HD) and Parkinson's disease (PD) is unknown. The fundamental hypothesis in the present proposal is that a defect in energy metabolism may lead to slow excitotoxic neuronal death in these diseases. A defect in energy metabolism may lead to partial neuronal depolarization enabling voltage- dependent excitatory amino acid receptors to be activated by endogenous levels of glutamate. In the present proposal we wish to test this hypothesis and to develop toxins 3-nitropropionic acid and sodium azide procedures lesions which show specific striatal neurotoxicity. In the case of 3-nitropropionic acid the toxicity is age-dependent. We found that chronic systemic administration of low doses of 3-nitropropionic acid to middle-aged rats result in subtle lesions that share several anatomical and neurochemical features with HD. These include relative vulnerability of the striatum, increased vulnerability in older animals, sparing of aspiny neurons, and characteristic dendritic changes. The goal of this proposal is to further characterize the mechanism and specificity of striatal lesions produced by inhibitors of oxidative phosphorylation. We will study specific inhibitors of complex I (MPP+), complex II (3-nitropropionic acid and malonate) and complex IV (sodium azide), using neurochemical, neuroanatomical, and molecular biologic tools. We will examine whether the striatal degree of energy depletion using direct measurements of ATP and lactate. We will test the idea that toxicity occurs due to a secondary excitotoxic mechanism by examining the effects of excitatory amino acid antagonists, and by removing glutamatergic afferents to the striatum. We will determine whether chronic administration of 3-nitropropionic acid leads to oxidative damage to DNA and proteins, which could contribute to an ongoing degenerative process. We will carry out further studies of the age-dependence of preliminary findings indicate that intrastriatal injections of malonate, which is a competitive inhibitor of complex II, produces a different pattern of cell damage that produced by 3-nitroproprionic acid, which is an irreversible inhibitor of complex II. We will determine whether these differences are related to the degree of metabolic compromise produced by the 2 compounds. Lastly we will determine whether several agents which either increase ATP production or bypass mitochondrial defects can prevent lesions produced by these mitochondrial toxins. We will examine the effects of coenzyme Q, riboflavin with nicotinamide, 1,3, butanediol, succinate and carnitine. If these strategies are effective, they may be directly applicable to the development of new treatments for HD and PD
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