Herkenham M, Little M D, Bankiewicz K, Yang S C, Markey S P, Johannessen J N
Section on Functional Neuroanatomy, NIMH, Bethesda, MD 20892.
Neuroscience. 1991;40(1):133-58. doi: 10.1016/0306-4522(91)90180-v.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively destroys dopaminergic neurons of the substantia nigra pars compacta in humans and other primates, producing a parkinsonian condition. MPTP is metabolized to the toxin 1-methyl-4-phenylpyridine (MPP+) which is taken up by dopamine terminals. The subsequent events culminating in cell death in the substantia nigra pars compacta are not understood. To examine these events we first produced a chronic hemiparkinsonian condition in monkeys by administering a toxic dose of MPTP via the right carotid artery. One year later, these monkeys were given a trace dose of [14C]MPTP intravenously and allowed to survive 1, 3, or 10 days. In two acute conditions, monkeys were either given the radiolabeled trace dose intravenously immediately following the toxic intracarotid dose, or were given a single toxic intracarotid radiolabeled dose, and allowed to survive 1, 3, or 10 days. We show by histology and autoradiography that the chronic hemiparkinsonian condition is characterized by selective unilateral loss of nigrostriatal dopamine neurons and absence of MPP+ retention in the caudate-putamen. In the acute conditions, MPP+ is accumulated and selectively retained in high concentrations in the caudate-putamen bilaterally and throughout the nigrostriatal pathway only on the side receiving the toxic dose. In the substantia nigra pars compacta. MPP+ is accumulated in very low concentrations in the dopamine cell bodies and is not selectively retained there. At 10 days survival, the caudate-putamen on the side receiving the toxic dose loses its ability to retain MPP+. The apparent degeneration of the dopamine axon terminals in the caudate-putamen and the development of Parkinson-like behavioral signs seen at 10 days survival were observed to precede the loss of cell bodies in the substantia nigra, which appeared normal by the criteria of Nissl staining and neuromelanin content at all time points in the acute conditions. Other areas of dense MPP+ retention in all cases include noradrenergic and serotonergic cell groups and noradrenergic pathways. MPP+ in the locus coeruleus and other caudal catecholaminergic cell groups is apparently retrogradely transported there after uptake in terminal regions, and although it is retained in high concentrations, no cell loss occurs. These findings suggest that experimentally induced Parkinsonism results from molecular events initiated in the neostriatum and selectively elaborated in the nigrostriatal pathway, ultimately resulting in the death of substantia nigra pars compacta dopamine neurons. They do not support a significant role for neuromelanin binding in the toxicity of MPP+.
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）可选择性破坏人类和其他灵长类动物黑质致密部的多巴胺能神经元，引发帕金森病状态。MPTP代谢为毒素1-甲基-4-苯基吡啶（MPP+），后者被多巴胺终末摄取。最终导致黑质致密部细胞死亡的后续事件尚不清楚。为研究这些事件，我们首先通过经右颈动脉给予毒性剂量的MPTP，在猴子中制造了慢性偏侧帕金森病状态。一年后，给这些猴子静脉注射微量的[14C]MPTP，并使其存活1、3或10天。在两种急性情况下，猴子要么在经颈动脉给予毒性剂量后立即静脉注射放射性标记的微量剂量，要么给予单次经颈动脉放射性标记的毒性剂量，并使其存活1、3或10天。我们通过组织学和放射自显影表明，慢性偏侧帕金森病状态的特征是黑质纹状体多巴胺神经元选择性单侧缺失，尾状核-壳核中不存在MPP+滞留。在急性情况下，MPP+在双侧尾状核-壳核中积累并选择性地高浓度滞留，且仅在接受毒性剂量的一侧的整个黑质纹状体通路中存在。在黑质致密部，MPP+在多巴胺细胞体中以非常低的浓度积累，且未在那里选择性滞留。在存活10天时，接受毒性剂量一侧的尾状核-壳核失去了保留MPP+的能力。观察到在存活10天时尾状核-壳核中多巴胺轴突终末的明显变性以及帕金森样行为体征的出现，早于黑质中细胞体的丢失，在急性情况下，根据尼氏染色和神经黑色素含量的标准，黑质在所有时间点看起来都是正常的。在所有情况下，MPP+大量滞留的其他区域包括去甲肾上腺素能和5-羟色胺能细胞群以及去甲肾上腺素能通路。蓝斑和其他尾侧儿茶酚胺能细胞群中的MPP+显然在终末区域摄取后逆向转运到那里，尽管它以高浓度保留，但没有细胞丢失。这些发现表明，实验性诱导的帕金森病是由新纹状体中启动并在黑质纹状体通路中选择性发展的分子事件导致的，最终导致黑质致密部多巴胺神经元死亡。它们不支持神经黑色素结合在MPP+毒性中起重要作用。
