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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023515-03
Application #
3407105
Study Section
Toxicology Study Section (TOX)
Project Start
1987-11-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Schools of Pharmacy
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
Klaidman, L K; Adams Jr, J D; Leung, A C et al. (1993) Redox cycling of MPP+: evidence for a new mechanism involving hydride transfer with xanthine oxidase, aldehyde dehydrogenase, and lipoamide dehydrogenase. Free Radic Biol Med 15:169-79
Adams, J D; Pickford, M S; Wong, C G (1992) The acute retinal histopathology of MPTP. Neurotoxicology 13:541-49
Adams Jr, J D; Odunze, I N (1991) Oxygen free radicals and Parkinson's disease. Free Radic Biol Med 10:161-9
Adams Jr, J D; Klaidman, L K; Odunze, I N et al. (1991) Effects of MPTP on the cerebrovasculature. Int J Dev Neurosci 9:155-9
Adams Jr, J D; Klaidman, L K; Odunze, I N et al. (1991) Alzheimer's and Parkinson's disease. Brain levels of glutathione, glutathione disulfide, and vitamin E. Mol Chem Neuropathol 14:213-26
Adams Jr, J D; Odunze, I N; Sevanian, A (1990) Induction by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine of lipid peroxidation in vivo in vitamin E deficient mice. Biochem Pharmacol 39:R5-8
LeBel, C P; Odunze, I N; Adams Jr, J D et al. (1989) Perturbations in cerebral oxygen radical formation and membrane order following vitamin E deficiency. Biochem Biophys Res Commun 163:860-6
Adams Jr, J D; Kalivas, P W; Miller, C A (1989) The acute histopathology of MPTP in the mouse CNS. Brain Res Bull 23:1-17