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Chapter: Basic & Clinical Pharmacology : Pharmacologic Management of Parkinsonism & Other Movement Disorders

MPTP & Parkinsonism

MPTP is a protoxin that is converted by monoamine oxidase B to N-methyl-4-phenylpyridinium (MPP+).

MPTP & Parkinsonism

Reports in the early 1980s of a rapidly progressive form of parkinsonism in young persons opened a new area of research in the etiology and treatment of parkinsonism. The initial report described apparently healthy young people who attempted to support their opioid habit with a meperidine analog synthesized by an amateur chemist. They unwittingly self-administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and subsequently developed a very severe form of par-kinsonism.

MPTP is a protoxin that is converted by monoamine oxidase B to N-methyl-4-phenylpyridinium (MPP+). MPP+ is selectively taken up by cells in the substantia nigra through an active mechanism normally responsible for dopamine reuptake. MPP+ inhibits mitochondrial complex I, thereby inhibiting oxidative phosphorylation. The interaction of MPP+ with complexI probably leads to cell death and thus to striatal dopamine depletion and parkinsonism.

Recognition of the effects of MPTP suggested that spontane-ously occurring Parkinson’s disease may result from exposure to an environmental toxin that is similarly selective in its target. However, no such toxin has yet been identified. It also suggested a successful means of producing an experimental model of Parkinson’s disease in animals, especially nonhuman primates. This model is assisting in the development of new antiparkin-sonism drugs. Pretreatment of exposed animals with a monoam-ine oxidase B inhibitor such as selegiline prevents the conversion of MPTP to MPP+ and thus protects against the occurrence of parkinsonism. This observation has provided one reason to believe that selegiline or rasagiline may retard the progression of Parkinson’s disease in humans

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Basic & Clinical Pharmacology : Pharmacologic Management of Parkinsonism & Other Movement Disorders : MPTP & Parkinsonism |


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