THE NEUROPROTECTIVE ROLE OF PHYSICAL ACTIVITY IN STROKE PREVENTION: MECHANISMS AND CLINICAL EVIDENCE

Abstract

Background: Stroke remains a leading cause of mortality and long-term disability worldwide. Although hypertension, diabetes, and other cardiovascular risk factors are well established, physical activity (PA) has recently emerged as a direct modulator of the brain’s resilience to ischemic injury, extending beyond its established role in cardiovascular risk reduction. This evidence is directly relevant to national health priorities, including the UAE’s National Policy for Promoting Healthy Lifestyles (2022), which designates physical activity as one of three core pillars, alongside healthy eating and tobacco control, for reducing lifestyle-related disease burden nationally. Objective / Purpose: This review aimed to synthesize mechanistic and clinical evidence, published between 2021 and 2026, describing how physical activity confers neuroprotection and reduces stroke risk. Methods: A narrative review was conducted of experimental animal studies (including middle cerebral artery occlusion models), large prospective cohort studies (e.g., UK Biobank, China Stroke Primary Prevention Trial), systematic reviews, meta-analyses, and bibliometric analyses published from 2021 to 2026 examining exercise preconditioning, molecular signaling pathways, and stroke incidence. Results: Exercise preconditioning attenuated cerebral ischemia-induced neuroinflammation and apoptosis by inhibiting the JAK2/STAT3 (Janus Kinase 2 / Signal Transducer and Activator of Transcription 3) and MAPK (Mitogen-Activated Protein Kinase) pathways, while preserving blood–brain barrier integrity through reduced matrix metalloproteinase (MMP) activity. Exercise promoted angiogenesis via VEGF (Vascular Endothelial Growth Factor) and eNOS (endothelial Nitric Oxide Synthase), and exercise-derived exosomal microRNAs (miRNAs) regulated autophagy and mitochondrial dynamics, inhibiting ferroptosis. Increased brain-derived neurotrophic factor (BDNF) and TrkB (Tropomyosin receptor kinase B) expression supported neurogenesis and synaptic plasticity. Clinically, a consistent dose–response relationship was observed: high cardiorespiratory fitness was associated with a 42% reduction in stroke risk, guideline-adherent leisure-time activity conferred a 35.7% risk reduction, and total physical activity reduced stroke risk by up to 13% at 130 MET-hours/week (Metabolic Equivalent of Task-hours per week). Conversely, sedentary time exceeding 7.5 hours daily was independently associated with increased risk, underscoring that minimizing prolonged inactivity is as clinically important as promoting structured exercise itself. Conclusion: Physical activity is a potent, modifiable neuroprotective intervention that reduces stroke risk and severity through interconnected molecular, cellular, and systemic mechanisms. These findings support structured exercise prescription, delivered and monitored by physiotherapists, as a core component of stroke prevention and rehabilitation practice, and offer an evidence base of direct relevance to the UAE’s National Policy for Promoting Healthy Lifestyles (2022), reinforcing physical activity promotion as a national priority toward its target of reducing unhealthy-lifestyle indicators by 3–6% in line with the UAE Centennial 2071 vision. Keywords: Stroke prevention; physical activity; neuroprotection; exercise preconditioning; cerebrovascular health.