100 Section - Examining a role for irisin in treating cerebral ischemia

Objectives : Ischemic stroke is a leading cause of death and disability, with incidence rising in aging populations. Physical inactivity is a major modifiable risk factor, and exercise is associated with improved poststroke outcomes. Irisin, a myokine cleaved from fibronectin type III domain-containing protein 5 (FNDC5) during exercise, has emerged as a potential mediator of neuroprotection. This review aimed to synthesize current evidence on irisin’s role in ischemic stroke, including central mechanisms of action, prognostic value, relationships with exercise, and therapeutic potential of exogenous administration.

Design: A narrative literature review was conducted using PubMed and MEDLINE to identify preclinical and clinical studies examining irisin in ischemic stroke. Human observational studies, randomized controlled trials, and animal models were included. Studies were selected to address four domains: (1) central signaling mechanisms, (2) prognosis and risk stratification, (3) exercise-induced irisin responses, and (4) outcomes following exogenous irisin administration.

Results: Observational studies demonstrated that lower circulating irisin levels at admission were associated with greater stroke severity, worse functional outcomes, and higher mortality. Exercise studies showed mixed findings overall; however, high-intensity resistance training most reliably increased circulating irisin, including in older adults and poststroke populations, with positive correlations to strength and cardiorespiratory fitness. Preclinical models demonstrated that exogenous irisin administration reduced infarct volume, cerebral edema, neuroinflammation, apoptosis, and blood–brain barrier disruption. These effects were mediated through AMPK, ERK1/2, Akt, and brain-derived neurotrophic factor (BDNF) signaling pathways.

Conclusion: Irisin shows promise as a prognostic biomarker and a mediator of exercise-induced neuroprotection in ischemic stroke. Preclinical evidence supports its therapeutic potential through both endogenous release and exogenous administration; however, translation to clinical practice remains limited by the absence of human interventional trials and challenges in irisin measurement. Future research should focus on standardized measurement techniques, optimized exercise prescriptions, and clinical trials evaluating irisin-based interventions in acute and rehabilitative stroke care.