Wang Hongmin, Shimoji Mika, Yu Seong-Woon, Dawson Ted M, Dawson Valina L
Department of Neurology, Neuroscience, and Physiology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Ann N Y Acad Sci. 2003 Jun;991:132-9. doi: 10.1111/j.1749-6632.2003.tb07471.x.
Experimental intoxication models are used to study the more common sporadic form of Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) animal models of PD provide a valuable and predictive tool to probe the molecular mechanisms of dopamine neuronal cell death in PD. MPTP is a powerful neurotoxin that induces neuronal degeneration in the substantia nigra pars compacta and produces PD-like symptoms in several mammalian species tested, a feat not yet accomplished in genetically engineered mice expressing human genetic mutations. The mechanisms of MPTP-induced neurotoxicity are not yet fully understood but involve activation of N-methyl-D-aspartate (NMDA) receptors by glutamate, production of NO by nNOS and iNOS, oxidative injury to DNA, and activation of the DNA damage-sensing enzyme poly (ADP-ribose) polymerase (PARP). Recent experiments indicate that translocation of a mitochondrial protein apoptosis inducing factor (AIF) from mitochondria to the nucleus depends on PARP activation and plays an important role in excitotoxicity-induced cell death. This article briefly reviews the experimental findings regarding excitotoxicity, PARP activation, and AIF translocation in MPTP toxicity and dopaminergic neuronal cell death.
实验性中毒模型用于研究帕金森病（PD）更常见的散发性形式。1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD动物模型为探究PD中多巴胺神经元细胞死亡的分子机制提供了一种有价值的预测工具。MPTP是一种强大的神经毒素，可诱导黑质致密部神经元变性，并在多种受试哺乳动物物种中产生类似PD的症状，这一成果在表达人类基因突变的基因工程小鼠中尚未实现。MPTP诱导神经毒性的机制尚未完全阐明，但涉及谷氨酸对N-甲基-D-天冬氨酸（NMDA）受体的激活、nNOS和iNOS产生NO、DNA的氧化损伤以及DNA损伤感应酶聚（ADP-核糖）聚合酶（PARP）的激活。最近的实验表明，线粒体蛋白凋亡诱导因子（AIF）从线粒体向细胞核的转位依赖于PARP激活，并在兴奋性毒性诱导的细胞死亡中起重要作用。本文简要综述了关于MPTP毒性和多巴胺能神经元细胞死亡中兴奋性毒性、PARP激活和AIF转位的实验结果。
