Mounayar Stéphanie, Boulet Sabrina, Tandé Dominique, Jan Caroline, Pessiglione Mathias, Hirsch Etienne C, Féger Jean, Savasta Marc, François Chantal, Tremblay Léon
Institut National de la Santé et de la Recherche Médicale, Unité 679, Paris F-75013, France.
Brain. 2007 Nov;130(Pt 11):2898-914. doi: 10.1093/brain/awm208. Epub 2007 Sep 13.
The cardinal symptoms in Parkinson's disease (PD), akinesia, rigidity and tremor, are only observed when the striatal level of dopamine is decreased by 60-80%. During the preclinical phase of PD, compensatory mechanisms are probably involved in delaying the appearance of motor symptoms. In a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of PD, a spontaneous recovery has been reported after initial intoxication suggesting that compensatory mechanisms are activated in this model as well. Assuming that mechanisms are similar in these phenomena, the study of recovery in monkeys following MPTP intoxication may enable identification of compensatory mechanisms involved in the preclinical phase of PD. In order to maximize the temporal similarity between PD and the MPTP model, we assessed a new progressive monkey model in which spontaneous recovery is expressed systematically and to characterize it based on (1) its behavioural features, and (2) the presence of compensatory mechanisms revealed by an immunohistological approach comparing dopaminergic and serotoninergic innervation between monkeys either exhibiting behavioural recovery or stable motor symptoms. This immunohistological study focused on the substantia nigra, striatum and pallidum, and their anatomical and functional subdivisions: sensorimotor, associative and limbic. The behavioural analysis revealed that with progressive MPTP intoxication motor symptoms were initially expressed in all monkeys. Observable recovery from these symptoms occurred in all monkeys (7/7) within 3-5 weeks after the last MPTP injection, and most exhibited a full recovery. In contrast, acute intoxication induced stable motor symptoms. Despite this obvious behavioural difference, immunohistological methods revealed that the loss of dopaminergic cell bodies in substantia nigra was substantial and similar in both MPTP-treated groups. However, quantification of fibres revealed that recovered monkeys displayed more dopaminergic and serotoninergic fibres than those with stable motor symptoms in sensorimotor and associative territories of striatum and more dopaminergic fibres in internal pallidum. This study provides a new model of PD where all monkeys expressed functional recovery from motor symptoms despite a large dopaminergic neuronal loss. The immunohistological results suggest that both dopamine and serotonin could be implicated in the compensatory mechanisms.
帕金森病（PD）的主要症状，即运动不能、僵硬和震颤，只有在纹状体多巴胺水平降低60 - 80%时才会出现。在PD的临床前期，代偿机制可能参与延缓运动症状的出现。在MPTP（1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶）诱导的PD猴模型中，有报道称在最初中毒后出现了自发恢复，这表明该模型中也激活了代偿机制。假设这些现象中的机制相似，对MPTP中毒后猴子恢复情况的研究可能有助于识别PD临床前期所涉及的代偿机制。为了使PD与MPTP模型在时间上的相似性最大化，我们评估了一种新的渐进性猴模型，在该模型中自发恢复会系统性地出现，并基于以下两点对其进行特征描述：（1）其行为特征；（2）通过免疫组织学方法揭示的代偿机制的存在，该方法比较了表现出行为恢复或运动症状稳定的猴子之间多巴胺能和5 - 羟色胺能神经支配情况。这项免疫组织学研究聚焦于黑质、纹状体和苍白球及其解剖和功能细分：感觉运动、联合和边缘区域。行为分析表明，随着MPTP中毒的进展，所有猴子最初都会出现运动症状。在最后一次注射MPTP后的3 - 5周内，所有猴子（7/7）都出现了可观察到的这些症状的恢复，并且大多数表现出完全恢复。相比之下，急性中毒会导致运动症状稳定。尽管存在这种明显的行为差异，但免疫组织学方法显示，两个MPTP处理组黑质中多巴胺能细胞体的损失都很严重且相似。然而，纤维定量显示，恢复的猴子在纹状体的感觉运动和联合区域比运动症状稳定的猴子表现出更多的多巴胺能和5 - 羟色胺能纤维，在内侧苍白球中多巴胺能纤维也更多。这项研究提供了一种新的PD模型，尽管多巴胺能神经元大量丢失，但所有猴子都表现出运动症状的功能恢复。免疫组织学结果表明，多巴胺和5 - 羟色胺可能都参与了代偿机制。
