A major objective of this proposal is to determine the molecular mechanisms underlying the enhanced neurotoxicity of MPTP in aged rodents (C57B1/6 mice). This objective is directly related to our long-term goal of using neurotoxins to determine the molecular mechanisms underlying the process of neuronal degeneration in Parkinson's disease. A second objective is to determine if the neuropathological changes in the nervous system of the old mouse more closely resemble those seen in Parkinson's disease than those observed in younger animals given MPTP. Success in these studies could lead to a greater understanding of the disease and why it affects the aging nervous system. In turn, new treatment and possibly even preventative strategies, as well as a much more accessible animal model for the disease might be realized. Specifically, we will study the various factors which might influence the biodisposition of MPTP and its major metabolite, MPP+, in animals of different ages to see which of these are responsible for the enhanced effects of MPTP in aged animals. Secondly, we plan to delineate the morphological features of MPTP-induced neurotoxicity in old mice, and compare them with those seen in Parkinson's disease, and in MPTP-induced parkinsonism in primates. Methodology to be used will involve the introduction of MPTP, MPP+ and other neurotoxins in animals of different ages. These compounds will be administered both systemically and directly to the CNS, either alone or in combination with pharmacological agents which block or exacerbate toxicity. Similar in-vitro studies with these agents will also be performed. Analytical techniques to be used for the identification and quantitation of neurotransmitters, MPTP, MPP+, other toxins, drugs and metabolites will include high pressure liquid chromatography (with spectrophotometric and electrochemical detection); gas chromatography/mass spectroscopy; radiometric techniques (liquid scintillation counting); and spectrophotometric techniques. In addition, standard histological techniques will be employed to assess the morphological features of MPTP in aged rodents.
