Triggering endogenous neuroprotective processes
through exercise in models of dopamine deficiency

演 者

Michael J. Zigmond, PhD, Professor of Neurology
Beth A. Fischer, PhD, Department of Family Medicine
(University of Pittsburgh, Pittsburgh, PA, USA)

日 時

平成22年5月17日(月)16:00 〜17:00

場 所

基礎研究棟2階 教職員ロビー


Although many drugs are helpful in controlling the motor symptoms of Parkinson’s disease (PD), none appear to prevent PD or attenuate its progression. However, a number of studies suggest that exercise might be an effective intervention. We are examining this possibility using MPTP or 6-OHDA, toxins that destroy the dopamine (DA) neurons associated with the motor deficits of PD. Mice, rats, or monkeys are provided access to a running wheel or treadmill prior to and/or after toxin treatment and the impact of the exercise is assessed via PET imaging, biochemical or histochemical assessment of phenotypic markers of the DA neuron, and analysis of gene expression. Our findings strongly suggest that exercise is indeed neuroprotective. There are several possible explanations for these effects. Our studies are currently focused on one of them: an increase in the expression of neurotrophic factors such as GDNF. For these studies we have used both mouse and rat models as well as cultures of transformed cells and primary DA neurons. Our observations indicate that GDNF can attenuate the toxic effects of 6-OHDA in these models and that this depends in part on the activation of key intracellular cascades, including those involving ERK and Akt. We also find that mild cellular stress itself can trigger an activation of these kinases, and that this preconditions the cells, reducing the impact of subsequent toxin exposure. We conclude that DA neurons have the capacity to respond to intracellular and extracellular signals by triggering endogenous neuroprotective mechanisms. This raises the possibility that in some individuals PD results in part from an inadequacy of these mechanisms, and that exercise can provide therapeutic benefit by activating the otherwise deficient pathways. Given that exercise also has a great many other health benefits, this raises a much more general question regarding the match between our current lifestyle and that for which evolution has prepared us: Is it possible that we have evolved to engage in a much higher level of physical activity than in now typical of our species and that exercise is actually helping us achieve a more “natural” state? [Our research has been supported by several sources, including the US National Institutes of Health and the US Army.]

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