[Parkinsonism induced by MPTP and free radical generation].
Oxygen free radical formation has been implicated in dopaminergic toxicity caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and iron. Although MPTP produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP+) by type B monoamine oxidase (MAO-B) in the brain, the etiology of this disease remains obscure. MPP+ is one of the most potent dopamine (DA)-releasing agents. Iron-catalyzed DA autoxidation and oxidative stress may be involved in the pathogenesis of Parkinson's disease. If indeed the effect of MPP+ on hydroxyl radical (.OH) formation is due to DA release, reserpine-induced DA depletion may reduce MPP(+)-induced .OH formation. Imidapril, an angiotensin converting enzyme (ACE) inhibitor, can resist MPP(+)-induced .OH formation via suppression of release of DA by angiotensin. Histidine, a singlet oxygen (1O2) scavenger, protects MPP(+)-induced .OH formation. Fluvastatin, an inhibitor of low-density lipoprotein (LDL) oxidation, can resist MPP(+)-induced .OH formation. The inhibitory effect on the susceptibility of LDL oxidation can reduce .OH generation. These drugs may be applied as antiparkinsonian agents. Further clinical investigation is necessary in the future.
Department of Pharmacology, Oita Medical University, 1-1, Hasama-machi, Oita 879-5593, Japan. tobata@oita-med.ac.jp
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D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism*; D007501:Iron; D020267:MPTP Poisoning / Q000188:drug therapy / Q000209:etiology; D008995:Monoamine Oxidase; D018384:Oxidative Stress
D000978:Antiparkinson Agents; D017665:Hydroxyl Radical; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007501:Iron; D008995:Monoamine Oxidase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine