Mechanisms of MPTP toxicity.
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces an experimental model of Parkinson's disease (PD). It replicates most of the clinical features of PD as well as the main biochemical and pathologic hallmarks of the disease. Although the MPTP model departs from PD in several aspects, it is thought that important insights into the neurodegenerative process of PD may be obtained by elucidating the molecular mechanism of MPTP. In this article, we summarize the different steps of the complex metabolic pathway of MPTP and show how they may be implicated in predisposing individuals to PD. We also outline findings pertinent to the mode of action of MPTP including overproduction of free radicals, implication of nitric oxide, nitration of tyrosine, impairment of mitochondrial respiration, and occurrence of apoptosis. All of these factors may participate in the cascade of deleterious events that ultimately lead to the death of dopaminergic neurons after MPTP administration. Because of the similarity between PD and the MPTP model, we are speculating that a similar scenario may underlie the neurodegenerative process in PD.
Przedborski
S
S
Columbia University, Neurology Department, New York, NY 10032, USA.
Jackson-Lewis
V
V
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D005609:Free Radicals; D006801:Humans; D020267:MPTP Poisoning; D008928:Mitochondria / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced; D010302:Parkinson Disease, Secondary / Q000139:chemically induced*; D013378:Substantia Nigra / Q000187:drug effects
D015259:Dopamine Agents; D005609:Free Radicals; D004298:Dopamine