Activation of the Nrf2-ARE Signaling Pathway Mediates the Neuroprotective Effects of Exercise in a Mouse Model of Chronic Parkinson’s Disease

Currently, effective disease-modifying treatments for Parkinson’s disease (PD) remain lacking. Although exercise has been confirmed to exert neuroprotective effects against PD, its specific molecular mechanisms remain unclear. In particular, the causal role of the Nuclear Factor E2-related Factor 2 (Nrf2)–antioxidant response element (ARE) signaling axis in this process has not been clearly elucidated. This study aimed to provide direct causal evidence that regular treadmill exercise protects the substantia nigra pars compacta (SNc)–striatal dopaminergic system by activating the Nrf2-ARE pathway. The results showed that exercise significantly improved motor function deficits in PD mice, preserved the number of TH-positive neurons, and restored striatal dopamine homeostasis. Mechanistically, exercise activated the Nrf2-ARE pathway, thereby inhibiting the accumulation of mitochondrial ROS (mtROS) and the activation of pro-inflammatory amoeboid microglia in the substantia nigra. Crucially, the improvements in behavioral, neuropathological, and neurochemical indicators induced by exercise were completely reversed, returning to levels comparable to those in the sedentary model group. In conclusion, this study provides clear pharmacological evidence that the neuroprotective effect of regular treadmill exercise against chronic PD strictly depends on the Nrf2-ARE pathway. These findings indicate that Nrf2 is a key mechanistic node linking exercise and neuroprotection, providing reliable preclinical evidence for Nrf2-targeted disease-modifying strategies in PD rehabilitation.