The role of challenging exercise in improving behavioral dysfunction in a mouse model of Parkinson’s disease

Objective To investigate whether accelerated rotarod exercise preconditioning provides greater neuroprotection than constant-speed training in a 6-OHDA mouse model of Parkinson’s disease (PD). Methods Male C57BL/6 mice were assigned to four groups: sham-operated sedentary (Con), PD sedentary (PD), constant-speed exercise + PD (Gen+PD, 10 rpm), and accelerated exercise + PD (Acc+PD, 5–40 rpm). Both exercise groups completed 4 weeks of rotarod training (240 s/session, 6 sessions/day, 5 days/week) before unilateral intrastriatal 6-OHDA injection. Con mice received vehicle at identical coordinates. Motor function was assessed by APO-induced rotation, negative geotaxis, pole, and open field tests. Striatal dopamine (DA) was quantified by ELISA; BDNF, TrkB, and TH expression were measured at the mRNA (RT-qPCR) and protein (Western blot) levels in the striatum and substantia nigra. Results Relative to the PD group, Acc+PD mice showed significant reductions in negative geotaxis turning latency, T-turn, and T-total (all P < 0.01), and significant increases in total locomotor distance, mean speed, and central zone dwell time (all P < 0.01). Striatal DA content was markedly elevated in the Acc+PD group ( P < 0.01). BDNF and TrkB mRNA were significantly upregulated in both the striatum and substantia nigra ( P < 0.01), and TH, BDNF, and TrkB protein levels in the substantia nigra were substantially increased ( P < 0.01). Improvements in the Gen+PD group were more modest and restricted in scope. Across all indices, the Acc+PD group consistently outperformed the Gen+PD group. Conclusion Four weeks of acceleration-based rotarod preconditioning substantially delayed behavioral deficits in 6-OHDA-lesioned mice, accompanied by greater preservation of striatal DA and broader upregulation of TH, BDNF, and TrkB compared with constant-speed training. These findings identify exercise intensity as a critical determinant of preconditioning efficacy and support accelerated rotarod training as a more effective neuroprotective strategy in this PD model.