Mytilineou C, Leonardi E K, Radcliffe P, Heinonen E H, Han S K, Werner P, Cohen G, Olanow C W
Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
J Pharmacol Exp Ther. 1998 Feb;284(2):700-6.
Oxidative stress is thought to play an important role in the pathogenesis of Parkinson's disease (PD). Glutathione (GSH), a major cellular antioxidant, is decreased in the substantia nigra pars compacta of PD patients. The aim of the present study was to investigate whether deprenyl and its desmethyl metabolite, putative neuroprotective agents in the treatment of PD, could protect cultured rat mesencephalic neurons from cell death caused by GSH depletion due to treatment with L-buthionine-(S,R)-sulfoximine (BSO). BSO (10 microM) caused extensive cell death after 48 hr, as demonstrated by disruption of cellular integrity and release of lactate dehydrogenase into the culture medium. Both deprenyl and desmethylselegiline, at concentrations of 5 and 50 microM, significantly protected dopaminergic neurons from toxicity without preventing the BSO-induced loss in GSH. Protection was not associated with monoamine oxidase type B inhibition in that pargyline, a potent MAO inhibitor, was ineffective and pretreatment with pargyline did not prevent the protective effects of deprenyl. Protection was not associated with inhibition of dopamine uptake by deprenyl because the dopamine uptake inhibitor mazindol did not diminish BSO toxicity. The antioxidant ascorbic acid (200 microM) also protected against BSO-induced cell death, suggesting that oxidative events were involved. This study demonstrates that deprenyl and its desmethyl metabolite can diminish cell death associated with GSH depletion.
氧化应激被认为在帕金森病（PD）的发病机制中起重要作用。谷胱甘肽（GSH）是一种主要的细胞抗氧化剂，在PD患者的黑质致密部中含量降低。本研究的目的是调查丙炔苯丙胺及其去甲基代谢产物（PD治疗中的假定神经保护剂）是否能保护培养的大鼠中脑神经元免受因L-丁硫氨酸-（S，R）-亚砜亚胺（BSO）处理导致的GSH耗竭所引起的细胞死亡。48小时后，10微摩尔的BSO导致广泛的细胞死亡，这可通过细胞完整性的破坏以及乳酸脱氢酶释放到培养基中得到证明。丙炔苯丙胺和去甲基司来吉兰在浓度为5和50微摩尔时，均能显著保护多巴胺能神经元免受毒性，且不会阻止BSO诱导的GSH损失。这种保护作用与B型单胺氧化酶抑制无关，因为有效的MAO抑制剂帕吉林无效，且用帕吉林预处理并不能阻止丙炔苯丙胺的保护作用。这种保护作用也与丙炔苯丙胺对多巴胺摄取的抑制无关，因为多巴胺摄取抑制剂吗吲哚并不能减轻BSO的毒性。抗氧化剂抗坏血酸（200微摩尔）也能保护细胞免受BSO诱导的细胞死亡，这表明氧化事件参与其中。本研究表明，丙炔苯丙胺及其去甲基代谢产物可减少与GSH耗竭相关的细胞死亡。
