Treadmill exercise mediates the neuroprotective effect in post-stroke depression rats through the PGC-1α/FNDC5/irisin pathway.

Post-stroke depression (PSD) leads to cognitive decline, poor rehabilitation outcomes, and increased mortality in stroke survivors. Exercise can alleviate clinical symptoms of PSD, but the underlying molecular mechanisms remain incompletely understood. This study aimed to explore the mechanism by which treadmill exercise improves depressive-like behaviors and cognitive function in PSD rats via the PGC-1α/FNDC5/irisin signaling pathway. Rats were randomly allocated into control, PSD model, low-intensity (10 m/min), and high-intensity (20 m/min) exercise groups (n = 8 per group). After PSD modeling, the exercise groups underwent treadmill training at different intensities. Behavioral tests were performed to assess emotional state and cognitive function. Serum irisin levels were measured, and the expression levels of PGC-1α and FNDC5 in the biceps brachii, as well as BDNF, PSD95, and Bax in the hippocampus, were quantified. Compared with the control group, PSD model rats exhibited obvious depressive-like behaviors, cognitive impairment, reduced serum irisin levels, downregulated expression of PGC-1α and FNDC5 in the biceps brachii, and decreased BDNF/PSD95 expression along with increased Bax expression in the hippocampus (all P < 0.05). Treadmill exercise reversed these alterations, and the beneficial effect was enhanced with increasing exercise intensity (all P < 0.05). These findings demonstrate that treadmill exercise improves emotional state and cognitive function in PSD rats by activating the PGC-1α/FNDC5/irisin signaling pathway, which enhances synaptic plasticity, inhibits neuronal apoptosis, and promotes neurotrophic support. This study provides a mechanistic basis for exercise-based rehabilitation strategies in patients with PSD.