Dopamine efflux by MPTP and hydroxyl radical generation.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP(+)) by B-form monoamine oxidase (MAO) in the brain, which is one of the most potent dopamine (DA)-releasing agents. MPP(+) perfusion into the striatum increases extracellular DA levels and this increase may concomitantly induce the formation of reactive free oxygen radicals, such as hydroxyl radical (.OH). These elevations seem to induce lipid peroxidation of striatum membranes, as detected by increases non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) levels. Sustained increase in striatal DA efflux by MAO inhibition produce.OH generation by products of monoamine. Therefore, reserpine-induced DA depletion clearly decreased MPP(+)-induced.OH formation. Neuromelanine synthesis from DA produce highly reactive free radicals. Nitric oxide (NO) contributes to produce MPP(+)-induced.OH generation via NO synthase (NOS) activation by depolarization. The antioxidation effect of angiotensin converting enzyme (ACE) inhibitor protects against MPP(+)-induced.OH generation due to the suppression of the Ca(2+)-dependent release of DA. These findings may be useful in elucidating the actual mechanism of free radical formation in the pathogenesis of neurodegenerative brain disorders, including Parkinson's disease and traumatic brain injuries. This review describes the free radicals mechanisms involved in MPTP toxicity and their possible involvement in the the pathogenesis of Parkinson's disease.
Department of Pharmacology, Oita Medical University, Oita, Japan. tobata@oita-med.ac.jp
T
T
Obata
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism*; D020267:MPTP Poisoning / Q000378:metabolism* / Q000503:physiopathology; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine