SELECTIVE RETENTION OF MPP+ WITHIN THE MONOAMINERGIC SYSTEMS OF THE PRIMATE BRAIN FOLLOWING MPTP ADMINISTRATION - AN INVIVO AUTORADIOGRAPHIC STUDY
SELECTIVE RETENTION OF MPP+ WITHIN THE MONOAMINERGIC SYSTEMS OF THE PRIMATE BRAIN FOLLOWING MPTP ADMINISTRATION - AN INVIVO AUTORADIOGRAPHIC STUDY
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DOI：
10.1016/0306-4522(91)90180-v
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发表时间：
1991-01-01
期刊：
影响因子：
3.3
通讯作者：
JOHANNESSEN, JN
中科院分区：
文献类型：
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作者：
HERKENHAM, M;LITTLE, MD;JOHANNESSEN, JN
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）选择性地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，导致帕金森病。MPTP被代谢为毒素1-甲基-4-苯基吡啶（MPP+），被多巴胺末端吸收。导致致密黑质细胞死亡的后续事件尚不清楚。为了检查这些事件，我们首先通过右颈动脉给予有毒剂量的MPTP，在猴子中产生慢性偏帕金森病。一年后，给这些猴子静脉注射微量的[C-14]MPTP，让它们存活1天、3天或10天。在两种急性情况下，猴子要么在颈动脉内毒性剂量后立即静脉注射放射性标记的微量剂量，要么在颈动脉内单独注射放射性标记的毒性剂量，并存活1天、3天或10天。我们通过组织学和放射自显影显示，慢性半帕金森病的特征是黑质纹状体多巴胺神经元的选择性单侧丧失和尾状壳核中MPP+保留的缺失。在急性情况下，MPP+在双侧尾状核-壳核和整个黑纹状体通路中积累并选择性地保留在高浓度，仅在接受毒性剂量的一侧。在黑质致密部，MPP+以极低浓度积聚在多巴胺细胞体中，并没有选择性地保留在那里。存活10天后，接受毒性剂量的一侧尾状壳核失去保留MPP+的能力。存活10天后，观察到尾壳核多巴胺轴突终末的明显变性和帕金森样行为体征的出现，先于黑质细胞体的丢失，急性期各时间点的尼氏染色和神经黑色素含量标准均显示正常。所有病例中高密度MPP+滞留的其他区域包括去甲肾上腺素能和血清素能细胞群和去甲肾上腺素能通路。蓝斑座和其他尾侧儿茶酚胺能细胞群中的MPP+在末端区域摄取后明显逆行转运到那里，尽管它以高浓度保留，但不发生细胞损失。这些发现表明，实验诱导的帕金森病是由新纹状体中启动的分子事件引起的，这些分子事件在黑质纹状体通路中选择性地进行了阐述，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+毒性中的重要作用。
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 [C-14]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+.