Exercise protects against MPTP-induced neurotoxicity in mice

Abstract

Exercise has been shown to be potently neuroprotective in several neurodegenerative models, including 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). In order to determine the critical duration of exercise necessary for DA neuroprotection, mice were allowed to run for either 1, 2 or 3months prior to treatment with saline or MPTP. Quantification of DA neurons in the SNpc show that mice allowed to run unrestricted for 1 or 2months lost significant numbers of neurons following MPTP administration as compared to saline treated mice; however, 3months of exercise provided complete protection against MPTP-induced neurotoxicity. To determine the critical intensity of exercise for DA neuroprotection, mice were restricted in their running to either 1/3 or 2/3 that of the full running group for 3months prior to treatment with saline or MPTP. Quantification of DA neurons in the SNpc show that mice whose running was restricted lost significant numbers of DA neurons due to MPTP toxicity; however, the 2/3 running group demonstrated partial protection. Neurochemical analyses of DA and its metabolites DOPAC and HVA show that exercise also functionally protects neurons from MPTP-induced neurotoxicity. Proteomic analysis of SN and STR tissues indicates that 3months of exercise induces changes in proteins related to energy regulation, cellular metabolism, the cytoskeleton, and intracellular signaling events. Taken together, these data indicate that exercise potently protects DA neurons from acute MPTP toxicity, suggesting that this simple lifestyle element may also confer significant protection against developing PD in humans.

Figure 1

Pattern of average running activity for mice over the 90-day experimental period. Breaks in the Daytime Running data indicate days on which cages were changed; breaks in the nighttime running data are exclusions based on significant periods of missing values (>4h). Points represent the average running for mice (n=8) monitored either during the day or night period ± SEM.

Figure 2

(A) Exercise protects DA neurons in the SNpc against MPTP neurotoxicity. Mice kept in SH or that exercised for 1 month prior to MPTP administration had significantly fewer DA neurons in the SNpc as compared to SH+Sal. Mice that ran for at least 3 months were not significantly different in terms of neuron number as compared to SH+Sal. While mice that ran for 2 months lost a significant number of neurons compared to SH+Sal, they still lost significantly fewer DA neurons in the SNpc than those that had not been allowed to exercise. (B) Exercise-mediated protection against MPTP-induced cell death requires full running. Mice were allowed to run the average number of revolutions/24 hours (18,000), or 1/3 (6,000) or 2/3 (12,000) the amount of distance, for 3 months total. Mice that were kept in SH or whose running was restricted prior to MPTP administration lost significantly more neurons in the SNpc as compared to SH Sal (p<0.001); however, animals allowed to run unrestricted were not significantly different in terms of neuron number as compared to SH+Sal. Bars represent the average ± SEM; *p<0.05 as compared to SH+Sal; + = p<0.05 as compared to SH+MPTP.

Figure 3

Exercise functionally protects DA neurons in the SNpc against MPTP neurotoxicity. HPLC/ED analysis of DA and the metabolites DOPAC and HVAC in the STR of SH or Ex mice administered either Sal or MPTP. Exercise significantly increased the measures of DA and its metabolites in the STR. Mice that exercised for 3 months administered MPTP had significantly lower measures of DA and its metabolites in the STR as compared to SH+Sal. However, Ex+MPTP mice lost significantly less DA in the STR compared to those kept in SH+MPTP. Bars represent the average ± SEM; *p<0.05 as compared to SH Sal; + = p<0.05 as compared to SH+MPTP.