Pittsburgh Institute for Neurodegenerative Disease, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Parkinsonism Relat Disord. 2009 Dec;15 Suppl 3:S42-5. doi: 10.1016/S1353-8020(09)70778-3.
We are testing the hypothesis that exercise is neuroprotective in animal models of the dopamine (DA) deficiency in Parkinson's disease. Our studies include mice or rats provided access to a running wheel and subsequently treated with MPTP (mice) or 6-hydroxydopamine (rats) and monkeys provided access to a treadmill and subsequently treated with MPTP. Typically, the exercise occurs for 3 months prior to the toxin treatment and often for 1-2 months thereafter. Our findings indicate that exercise reduces the behavioral impairments elicited by the dopaminergic neurotoxins as well as the loss of DA neurons as assessed by PET imaging and biochemical or histochemical assessment of tissue samples. Our studies are focused on one of several possible explanations for the beneficial effects of exercise: an exercise-induced increase in the expression of neurotrophic factors, particularly GDNF. Our observations indicate that GDNF can reduce the vulnerability of DA neurons, in part due to the activation of key intracellular cascades. We also find that mild cellular stress itself can provide protection against more intensive stress, a form of preconditioning. We conclude that dopamine neurons have the capacity to respond to intracellular and extracellular signals by triggering endogenous neuroprotective mechanisms. This raises the possibility that some individuals with Parkinson's disease suffer from a reduction of these neuroprotective mechanisms, and that treatments that boost these mechanisms - including exercise - may provide therapeutic benefit.
我们正在测试运动对帕金森病多巴胺（DA）缺乏动物模型的神经保护作用这一假说。我们的研究包括让小鼠或大鼠使用跑步轮，随后用 MPTP（小鼠）或 6-羟多巴胺（大鼠）处理；以及让猴子使用跑步机，随后用 MPTP 处理。通常，运动发生在毒素处理前 3 个月，之后往往还会持续 1-2 个月。我们的研究结果表明，运动可以减轻多巴胺能神经毒素引起的行为障碍，以及通过正电子发射断层扫描成像和对组织样本的生化或组织化学评估来评估 DA 神经元的损失。我们的研究集中在运动有益作用的几种可能解释之一：运动诱导的神经营养因子表达增加，特别是 GDNF。我们的观察表明，GDNF 可以降低 DA 神经元的易损性，部分原因是关键细胞内级联的激活。我们还发现，轻度细胞应激本身就可以提供针对更强烈应激的保护，这是一种预处理形式。我们得出结论，多巴胺神经元有能力通过触发内源性神经保护机制来响应细胞内和细胞外信号。这就提出了这样一种可能性，即一些帕金森病患者可能由于这些神经保护机制的减少而受到影响，而增强这些机制的治疗方法——包括运动——可能会带来治疗益处。
