Effects of Exercise Preconditioning on Promoting Endogenous Recovery Responses After Ischemic Stroke in Late‐Adult Mice

BACKGROUND: Ischemic stroke causes substantial neurological impairment, and although poststroke rehabilitation can support recovery, neurological deficits often limit the feasibility of exercise in clinical settings. Prestroke exercise has emerged as a potential strategy to enhance resilience to ischemic injury, but most preclinical studies have relied on young adult rodents, in which spontaneous recovery can sometimes obscure clinically meaningful functional effects. However, the impact of exercise preconditioning in later stages of adulthood remains insufficiently characterized. Here, we investigated whether a treadmill exercise preconditioning regimen confers neuroprotection and improves recovery-related responses in late-adult mice subjected to middle cerebral artery occlusion. METHODS: Eight-month-old male mice were assigned to sedentary or exercise groups. Following 5 weeks of treadmill running (5 days per week after 1 week of acclimatization), mice underwent 45 minutes of middle cerebral artery occlusion and reperfusion. Behavioral assessments and body-weight monitoring were performed before and after middle cerebral artery occlusion. Infarct volume and cellular responses were evaluated 14 days after stroke. RESULTS: Fourteen days after stroke, lesion volume was significantly reduced in the exercise group compared with sedentary controls. Exercise preconditioning enhanced neurogenesis, oligodendrogenesis, and CD31-positive vascular responses while suppressing reactive astrocyte activation. Functional improvements were consistently observed across multiple behavioral assays in late-adult mice. CONCLUSIONS: Preconditioning with treadmill exercise provides neuroprotection against ischemic stroke in late-adult mice by reducing infarct volume and promoting recovery-associated cellular responses. These findings demonstrate that the functional benefits of prestroke exercise extend beyond the young adult stage and support the potential value of regular physical activity as a strategy to mitigate ischemic brain injury later in adulthood.