The protective impact of exercise on neurodegenerative processes has not been confirmed, and the mechanisms underlying the benefit of exercise have not been determined in human Parkinson's disease or in chronic animal disease models. This research examined the long-term neurological, behavioral, and mechanistic consequences of endurance exercise in experimental chronic parkinsonism. We used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease with moderate neurodegeneration and examined the effects of treadmill exercise on movement and balance coordination, changes in dopamine neuron biomarkers, mitochondrial functions, and neurotrophic factor activities in the nigrostriatal system. The exercise results were compared with that of the control and sedentary chronic parkinsonian animals. After 18 weeks of exercise training in the chronic parkinsonian mice, we observed a significant deterrence in the loss of neuronal dopamine-producing cells and other functional indicators. The impaired movement and balance incoordination in the chronic parkinsonian mice were also markedly reduced following exercise. Mechanistic investigations revealed that the neuronal and behavioral recovery produced by exercise in the chronic parkinsonian mice was associated with an improved mitochondrial function and an increase in the brain region-specific levels of brain-derived and glial cell line-derived neurotrophic factors. Our findings indicate that exercise not only produces neuronal and mitochondrial protection, it also boosts nigrostriatal neurotrophic factor levels in the chronic parkinsonian mice with moderate neurodegeneration. Therefore, modifying lifestyle with increased exercise activity would be a non-pharmacological neuroprotective approach for averting neurodegenerative processes, as demonstrated in experimental chronic parkinsonism.

Background and Purpose: Dopamine is a major regulator of sodium reabsorption in proximal tubule epithelia. By binding to D1‐receptors, dopamine induces endocytosis of plasma membrane Na,K‐ATPase, resulting in a reduced capacity of the cells to transport sodium, thus contributing to natriuresis. We have previously demonstrated several aspects of the molecular mechanism by which dopamine induces Na,K‐ATPase endocytosis; however, the location of intracellular compartments containing Na,K‐ATPase molecules has not been identified. Experimental approach: In this study, we used different approaches to determine the localization of Na,K‐ATPase‐containing intracellular compartments. By expression of fluorescent‐tagged Na,K‐ATPase molecules in opossum kidney cells, a cell culture model of proximal tubule epithelia, we used fluorescence microscopy to determine cellular distribution of the fluorescent molecules and the effects of dopamine on this distribution. By labelling cell surface Na,K‐ATPase molecules from the cell exterior with either biotin or an epitope‐tagged antibody, we determined the localization of the tagged Na,K‐ATPase molecules after endocytosis induced by dopamine. Key results: In cells expressing fluorescent‐tagged Na,K‐ATPase molecules, there were intracellular compartments containing Na,K‐ATPase molecules. These compartments were in very close proximity to the plasma membrane. Upon treatment of the cells with dopamine, the fluorescence labelling of these compartments was increased. The labelling of these compartments was also observed when the endocytosis of biotin‐ or antibody‐tagged plasma membrane Na,K‐ATPase molecules was induced by dopamine. Conclusions and Implications: The intracellular compartments containing Na,K‐ATPase molecules are located just underneath the plasma membrane. British Journal of Pharmacology (2007) 151, 1006–1013; doi:

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