Physical Exercise Modulates L-DOPA-Regulated Molecular Pathways in the MPTP Mouse Model of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in motor and non-motor dysfunction. Physical exercise improves these symptoms in PD patients. To explore the molecular mechanisms underlying the beneficial effects of physical exercise, we exposed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP)-treated mice to a four-week physical exercise regimen, and subsequently explored their motor performance and the transcriptome of multiple PD-linked brain areas. MPTP reduced the number of DA neurons in the SNpc, whereas physical exercise improved beam walking, rotarod performance, and motor behavior in the open field. Further, enrichment analyses of the RNA-sequencing data revealed that in the MPTP-treated mice physical exercise predominantly modulated signaling cascades that are regulated by the top upstream regulators L-DOPA, RICTOR, CREB1, or bicuculline/dalfampridine, associated with movement disorders, mitochondrial dysfunction, and epilepsy-related processes. To elucidate the molecular pathways underlying these cascades, we integrated the proteins encoded by the exercise-induced differentially expressed mRNAs for each of the upstream regulators into a molecular landscape, for multiple key brain areas. Most notable was the opposite effect of physical exercise compared to previously reported effects of L-DOPA on the expression of mRNAs in the SN and the ventromedial striatum that are involved in—among other processes—circadian rhythm and signaling involving DA, neuropeptides, and endocannabinoids. Altogether, our findings suggest that physical exercise can improve motor function in PD and may, at the same time, counteract L-DOPA-mediated molecular mechanisms. Further, we hypothesize that physical exercise has the potential to improve non-motor symptoms of PD, some of which may be the result of (chronic) L-DOPA use.Electronic supplementary materialThe online version of this article (10.1007/s12035-017-0775-0) contains supplementary material, which is available to authorized users.

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“…Briefly, 30-μm sections were incubated with an anti-TH antibody (1:1000, mouse monoclonal; EMD Millipore), followed by incubation with the respective biotinylated secondary antibody. Total numbers of TH + neurons in every sixth section of the SN were counted stereologically with the Stereo Investigator software (MBF Bioscience, Williston, VT, USA) [ 48 ] and then averaged over the total number of sections per animal [ 49 ].…”

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“…A Nikon TE300 inverted microscope was used to measure TH-positive areas in SNpc. Briefly, the number of TH-positive neurons in each section (both the left and right side) was counted by NIH ImageJ [24], and then averaged over the total number of sections per animal [25].…”

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“…Accumulating evidence shows that physical exercise and exercise-related factors can confer neuroprotection in mouse models of NDs. In recent years, physical exercise emerged as a promising non-invasive strategy to ameliorate neuronal loss, memory impairments, oxidative stress, neuroinflammation, and motor dysfunctions ( Souza et al, 2013 ; Hüttenrauch et al, 2016 ; Do et al, 2018 ; Klemann et al, 2018 ; Palasz et al, 2019 ). Remarkably, exercise seems to reverse the genetic pattern of inflammation and apoptotic markers set in motion by the progression of NDs ( Hüttenrauch et al, 2016 ; Do et al, 2018 ) probably through epigenetic mechanisms ( Ferioli et al, 2019 ).…”