Forced and voluntary exercise exert differential neuroprotective effects in cerebral ischemia-reperfusion injury by inhibiting neutrophil infiltration and blood-brain barrier disruption

Ischemic stroke is associated with high disability rates, underscoring the urgent need for effective rehabilitation strategies. While exercise rehabilitation promotes functional recovery, the differential therapeutic effects of distinct exercise modalities and their underlying mechanisms remain incompletely understood. Our previous proteomic study showed that exercise administered after cerebral ischemia-reperfusion (CI/RP) strongly inhibited major neutrophil-driven biological processes in the penumbra region, including neutrophil extracellular traps (NETs) formation and integrin-cell surface interactions. Subsequent experimental results demonstrated that forced exercise (F-Ex) more significantly reduced neutrophil infiltration and NETs formation, attenuated blood-brain barrier（BBB）leakage, and upregulated tight junction proteins (TJPs) compared to voluntary exercise (V-Ex). Furthermore, previous studies have established that matrix metalloproteinases (MMPs) are closely linked to BBB disruption. In our study, matrix metalloproteinase-25 (MMP-25/MT6-MMP), was recognized among the most differentially expressed proteins (DEPs) and its expression was associated with neutrophil infiltration. However, the role of MMP-25 in cerebral ischemia remains understudied. Overall, F-Ex conferred greater neurological improvement in early-stage CI/RP injury compared to V-Ex. These results provide evidence-based insights for selecting optimal exercise interventions in post-stroke rehabilitation, elucidate a novel mechanism underlying F-Ex-mediated protection against ischemic brain injury, and implicate MMP-25 as a potential therapeutic target for ischemic stroke.