Obata T, Yamanaka Y
Department of Pharmacology, Oita Medical University, 1-1, Hasama-machi, Oita 879-5593, Japan.
Nihon Yakurigaku Zasshi. 2001 Feb;117(2):105-10. doi: 10.1254/fpj.117.105.
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.
氧自由基的形成与1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）和铁所导致的多巴胺能毒性有关。尽管MPTP在脑内被B型单胺氧化酶（MAO-B）转化为1-甲基-4-苯基吡啶（MPP+）后会引发帕金森综合征，但该疾病的病因仍不明确。MPP+是最有效的多巴胺（DA）释放剂之一。铁催化的DA自氧化和氧化应激可能参与帕金森病的发病机制。如果MPP+对羟自由基（·OH）形成的影响确实是由于DA释放所致，那么利血平诱导的DA耗竭可能会减少MPP+诱导的·OH形成。咪达普利是一种血管紧张素转换酶（ACE）抑制剂，它可以通过抑制血管紧张素释放DA来抵抗MPP+诱导的·OH形成。组氨酸是一种单线态氧（1O2）清除剂，可保护细胞免受MPP+诱导的·OH形成。氟伐他汀是一种低密度脂蛋白（LDL）氧化抑制剂，能够抵抗MPP+诱导的·OH形成。对LDL氧化敏感性的抑制作用可以减少·OH的产生。这些药物可能被用作抗帕金森病药物。未来有必要进行进一步的临床研究。
