Movement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clínica Universidad de Navarra, Pamplona, Spain.
Neurobiol Dis. 2012 Oct;48(1):79-91. doi: 10.1016/j.nbd.2012.05.018. Epub 2012 Jun 5.
Parkinson's disease (PD) is diagnosed when striatal dopamine (DA) loss exceeds a certain threshold and the cardinal motor features become apparent. The presymptomatic compensatory mechanisms underlying the lack of motor manifestations despite progressive striatal depletion are not well understood. Most animal models of PD involve the induction of a severe dopaminergic deficit in an acute manner, which departs from the typical, chronic evolution of PD in humans. We have used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered to monkeys via a slow intoxication protocol to produce a more gradual development of nigral lesion. Twelve control and 38 MPTP-intoxicated monkeys were divided into four groups. The latter included monkeys who were always asymptomatic, monkeys who recovered after showing mild parkinsonian signs, and monkeys with stable, moderate and severe parkinsonism. We found a close correlation between cell loss in the substantia nigra pars compacta (SNc) and striatal dopaminergic depletion and the four motor states. There was an overall negative correlation between the degree of parkinsonism (Kurlan scale) and in vivo PET ((18)F-DOPA K(i) and (11)C-DTBZ binding potential), as well as with TH-immunoreactive cell counts in SNc, striatal dopaminergic markers (TH, DAT and VMAT2) and striatal DA concentration. This intoxication protocol permits to establish a critical threshold of SNc cell loss and dopaminergic innervation distinguishing between the asymptomatic and symptomatic parkinsonian stages. Compensatory changes in nigrostriatal dopaminergic activity occurred in the recovered and parkinsonian monkeys when DA depletion was at least 88% of control, and accordingly may be considered too late to explain compensatory mechanisms in the early asymptomatic period. Our findings suggest the need for further exploration of the role of non-striatal mechanisms in PD prior to the development of motor features.
帕金森病（PD）是在纹状体多巴胺（DA）损失超过一定阈值并且出现主要运动特征时诊断的。尽管纹状体逐渐耗竭，但缺乏运动表现的潜在的前驱代偿机制尚不清楚。大多数 PD 动物模型涉及以急性方式诱导严重的多巴胺能缺陷，这与人类 PD 的典型慢性进展不同。我们使用 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）通过缓慢中毒方案给予猴子，以产生更渐进的黑质损伤发展。12 只对照和 38 只 MPTP 中毒的猴子被分为四组。后者包括始终无症状的猴子、表现出轻度帕金森病迹象后恢复的猴子、以及稳定、中度和重度帕金森病的猴子。我们发现黑质致密部（SNc）细胞丢失与纹状体多巴胺能耗竭以及四种运动状态之间存在密切相关性。帕金森病程度（Kurlan 量表）与体内 PET（（18）F-DOPA K(i)和（11）C-DTBZ 结合潜能）以及 SNc 中 TH 免疫反应性细胞计数、纹状体多巴胺能标志物（TH、DAT 和 VMAT2）和纹状体 DA 浓度之间存在总体负相关。该中毒方案允许确定 SNc 细胞丢失和多巴胺能神经支配的临界阈值，将无症状和帕金森病阶段区分开来。在 DA 耗竭至少达到对照的 88%时，恢复和帕金森病猴子的黑质纹状体多巴胺能活性发生代偿性变化，因此可以认为这对于解释早期无症状期的代偿机制来说为时已晚。我们的发现表明，在出现运动特征之前，需要进一步探索非纹状体机制在 PD 中的作用。
