Exercise and the blood-brain barrier: Mechanistic insights and therapeutic implications

The blood-brain barrier (BBB) is a critical structure for maintaining homeostasis in the central nervous system, and its dysfunction is widely implicated in the pathogenesis and progression of various neurological disorders. In recent years, exercise, as a low-cost and low-side-effect non-pharmacological intervention, has demonstrated significant potential in modulating the structure and function of the BBB. In this article, we comprehensively review the key mechanisms regulating BBB permeability under physiological and pathological conditions, with a focus on three core pathways: oxidative stress-inflammation-mediated disruption, vascular endothelial growth factor-mediated bidirectional repair, and Wnt/Sonic hedgehog/transcription factor-dependent homeostasis maintenance. Furthermore, we compare the effects of different exercise modalities, including aerobic exercise, high-intensity interval training, and resistance training, on the BBB and discuss their differential impacts across distinct brain regions, populations, and disease states. Additionally, this review integrates rodent and human evidence supporting the therapeutic potential of exercise interventions for patients with typical neurological disorders (e.g., Alzheimer's disease, multiple sclerosis, stroke, and depression) as well as non-disease risk conditions such as obesity and aging that profoundly affect BBB integrity, highlighting its multi-pathway and multi-target mechanisms in maintaining BBB dynamic homeostasis. Overall, the collected evidences support that moderate and regular exercise may protect BBB function through multidimensional mechanisms, offering novel insights and theoretical foundations for non-pharmacological therapies for neurological disorders.