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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.