The Therapeutic Role of Physical Activity in Epilepsy: Potential Mechanisms and Clinical Implications

Neuroinflammation, characterized by activation of immune cells and release of inflammatory mediators in the central nervous system, plays a critical role in the onset and progression of epilepsy. Elevated inflammatory activity has been documented in both peripheral blood and epileptogenic brain tissue, implicating mediators such as interleukin-1β (IL-1β), IL-6, tumor necrosis factor-alpha, and glutaminergic and MDMA pathways. Beyond seizure generation, neuroinflammation may contribute to psychiatric comorbidities, including anxiety and depression. Anti-inflammatory strategies, encompassing pharmacologic agents such as glucocorticoids, adrenocorticotropic hormone, and vigabatrin, as well as dietary approaches like the ketogenic diet, have demonstrated reductions in seizure frequency and inflammatory signaling. Leukotriene receptor antagonists, established in asthma therapy, show promise in animal models and retrospective human studies, particularly in older adults who exhibit a pro-inflammatory state due to immunosenescence. Physical activity exerts systemic and central anti-inflammatory effects, modulating gene expression, metabolism, antioxidant defense, and neuroprotective pathways. Preclinical evidence demonstrates that endurance and swimming exercises can reduce seizure susceptibility, hippocampal inflammation, oxidative stress, and apoptotic signaling, while improving blood-brain barrier integrity. Human studies remain limited but suggest that regular physical activity may lower the risk of focal epilepsy. Collectively, these findings support the potential of integrating exercise-based interventions to mitigate neuroinflammation and seizure burden, particularly in aging populations. Further research is needed to clarify underlying mechanisms and optimize protocols for clinical translation.