Laboratory of Hormonal Regulations, Institute of Developmental Biology RAS, 26 Vavilov Street, Moscow 119334, Russia.
Neuroscience. 2011 May 5;181:175-88. doi: 10.1016/j.neuroscience.2011.03.007. Epub 2011 Mar 5.
A degradation of the nigrostriatal dopaminergic (DA-ergic) system is the key component of pathogenesis of Parkinson's disease (PD). Initial clinical symptoms appear 20-30 years after the onset of neurodegeneration, at a 70% DA depletion in the striatum and a 50% loss of nigral DA-ergic neurons. Low efficacy of the therapy might be improved if preclinical diagnostics and preventive therapy are developed. The development of appropriate experimental models should precede clinical trials. This multidisciplinary study first managed to model in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) all together the following stages of parkinsonism: (a) the early presymptomatic stage manifested by a subthreshold degeneration of axons and DA depletion in the striatum without loss of nigral cell bodies; (b) the advanced presymptomatic stage manifested by a subthreshold degeneration of striatal axons and DA depletion and by a subthreshold loss of nigral cell bodies; (c) the advanced presymptomatic stage characterized by threshold depletion of striatal DA and a loss of DA-ergic axons and nigral cell bodies resulting in motor dysfunction. The degeneration of axons proceeds and prevails that of cell bodies suggesting higher sensitivity to MPTP of the former. Compensatory processes were developed in parallel to neurodegeneration that was manifested by the increase of the DA content in individual nigral cell bodies and DA turnover in the striatum. The developed models might be exploited for: (a) an examination of pathogenetic mechanisms not only in the nigrostriatal system but also in other brain regions and in the periphery; (b) a study of the compensatory mechanisms under DA deficiency; (c) a search of precursors of motor disorders and peripheral biomarkers in presymptomatic parkinsonism; (d) the development of preventive therapy aiming to slow down the neurodegeneration and strengthen compensatory processes. Thus, the models of the early and advanced presymptomaic stages and of the early symptomatic stage of parkinsonism were developed in mice with MPTP.
黑质纹状体多巴胺能（DA-ergic）系统的退化是帕金森病（PD）发病机制的关键组成部分。初始临床症状出现在神经退行性变发生后 20-30 年，纹状体中 DA 耗竭 70%，黑质 DA-ergic 神经元丢失 50%。如果开发出临床前诊断和预防性治疗，可能会改善低疗效的治疗。在进行临床试验之前，应先开发合适的实验模型。这项多学科研究首次成功地在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的小鼠模型中模拟了帕金森病的所有以下阶段：（a）早期亚临床阶段，表现为轴突亚临床变性和纹状体 DA 耗竭，而黑质细胞体无丢失；（b）晚期亚临床阶段，表现为纹状体轴突亚临床变性和 DA 耗竭，以及黑质细胞体亚临床丢失；（c）晚期亚临床阶段，特征为纹状体 DA 耗竭阈值，DA 能轴突和黑质细胞体丢失导致运动功能障碍。轴突变性先于细胞体变性进行，提示前者对 MPTP 更为敏感。神经退行性变的同时也发生了代偿过程，表现为单个黑质细胞体中 DA 含量增加和纹状体中 DA 周转率增加。开发的模型可用于：（a）研究不仅在黑质纹状体系统，而且在其他脑区和外周的发病机制；（b）研究在 DA 缺乏下的代偿机制；（c）在亚临床帕金森病中寻找运动障碍和外周生物标志物的前体；（d）开发旨在减缓神经退行性变和增强代偿过程的预防性治疗。因此，在 MPTP 诱导的小鼠中建立了早期和晚期亚临床阶段和早期有症状帕金森病的模型。
