The neurotoxin MPTP is known to induce parkinsonian syndromes in man, monkeys, dogs and mice. This proposal seeks to investigate the mechanism by which MPTP produces the mouse parkinsonian syndrome. The overall goal is not to establish the MPTP treated mouse as a model for human Parkinsonism, but to investigate the mechanism by which MPTP kills cells in the mouse substantia nigra. It is known that MPTP and its metabolite, MPP+, are capable of inducing systemic oxidative stress. This is discussed in the preliminary evidence section. It seems appropriate, therefore, to demonstrate whether or not MPTP induces oxidative stress in the brain as well. This will be done by compromising the cellular defense mechanisms against oxidative stress of mice and looking for an increased susceptibility to the neurotoxicity of MPTP. These defense mechanisms will be compromised by depleting brain GSH, making mice vitamin E deficient, or by inhibition of GSSG reductase with BCNU. These manipulations will provide very specific information that will elucidate the mechanism of toxicity of MPTP in the mouse brain. In addition, the importance of the deactivation of MPTP by cytochrome P450 will be examined. This enzyme is primarily responsible for the deactivation of many xenobiotics. Its actions with MPTP are therefore important. Finally, various ultimate mechanisms of cell killing will be examined such as oxidation of protein sulfhydryls, lipid peroxidation and vitamin E depletion. This mechanistic approach may provide some insight into the possible factors leading to Parkinsonism in humans.
