Endurance, Resistance, and Combined Exercise Preconditioning Differentially Modulate Inflammatory and Immune-Associated Responses and Improve Functional Outcomes Following Experimental Ischemic Stroke in Aged Rats

Background: Exercise preconditioning has emerged as a promising non-pharmacological strategy for reducing ischemic brain injury. However, the comparative effects of endurance, resistance, and combined exercise on post-stroke inflammatory and immune-associated responses, particularly in the aging brain, remain incompletely understood. This study compared the effects of these exercise modalities on molecular, behavioral, and histological outcomes following experimental ischemic stroke in aged rats. Methods: Fifty aged male Wistar rats were randomly assigned to five groups (n = 10/group): Sham, middle cerebral artery occlusion (MCAO), Endurance, Resistance, and Combined Exercise. Animals in the intervention groups completed an 8-week exercise preconditioning program before transient middle cerebral artery occlusion induced by a 30-minute arterial occlusion followed by reperfusion. Spatial learning and memory, passive avoidance memory, motor coordination, and infarct volume were assessed using the Morris water maze, passive avoidance test, rotarod test, and 2,3,5-triphenyltetrazolium chloride (TTC) staining, respectively. Hippocampal expression of CD86, CD208, and IL-10 was quantified by real-time quantitative PCR (RT-qPCR) with qualitative western blot validation. Data were analyzed using one-way or repeated-measures analysis of variance followed by Tukey’s post hoc test. Results: Exercise preconditioning significantly improved molecular, behavioral, and histological outcomes compared with the sedentary MCAO group (p < 0.05 to p < 0.001). Combined exercise produced the lowest hippocampal expression of the pro-inflammatory marker CD86 and the highest expression of the anti-inflammatory cytokine IL-10 among all exercise interventions, while also enhancing CD208 expression. These molecular changes were accompanied by superior performance in the Morris water maze, passive avoidance, and rotarod tests, together with the greatest reduction in infarct volume. Large between-group effect sizes were observed across the primary outcomes (partial η² = 0.59–0.87). Conclusion: Combined exercise preconditioning was associated with greater improvements in inflammatory and immune-associated markers, behavioral performance, and infarct volume than endurance or resistance training alone following experimental ischemic stroke in aged rats. These findings support combined exercise as a promising preconditioning strategy for mitigating ischemic brain injury in the aging brain, although further mechanistic studies are required to establish the causal biological pathways underlying these beneficial effects.