Irisin/FNDC5 Regulates Endothelial Function to Improve Post‐Stroke‐Induced Cognitive Dysfunction by Stimulating AMPK‐eNOS Signaling

Cognitive impairment is one of the main complications after a stroke and seriously affects the quality of life and survival time of patients, thereby causing a heavy burden on the social economy and public health. Although exercise is an effective non-pharmacological strategy for prevention and treatment of cognitive impairment, the mechanism(s) of this effect remain unclear. The current study investigated the effects of irisin treatment on the behavioral characteristics of mice with post-stroke cognitive impairment (PSCI). The expression levels of platelet endothelial cell adhesion molecule 1 (PECAM, PECAM-1, CD31), glial fibrillary acidic protein (GFAP), vascular endothelial growth factor (VEGF), and molecules in the adenosine 5-monophosphate (AMP)-activated protein kinase (AMPK)-endothelial nitric oxide synthase (eNOS) signaling cascade in the hippocampus were then measured. Irisin significantly enhances learning and memory functions in cases of PSCI. This improvement correlates with a reduction in cerebral infarction size and decreased neuronal death. Additionally, irisin treatment resulted in a marked decrease in the levels of astrocytic scar formation in the cortex. Furthermore, irisin activates the AMPK-eNOS signaling pathway, which promotes the expression of VEGF. The irisin compounds are involved in the process of brain angiogenesis and play a critical role in endothelial and reactive astrocytes function. The study revealed a potential mechanism by which exercise-induced irisin secretion may attenuate PSCI. Irisin improved endothelial dysfunction and neuroinflammation, suggesting it may be a promising target for PSCI therapy.