Orexin A protects against cerebral ischemia-reperfusion injury by enhancing reperfusion in ischemic cortex via HIF-1α-ET-1/eNOS pathway

• Published in: Brain research bulletin Vol. 218; p. 111105
• Main Authors: Zhu, Minxia, Li, Xiaofeng, Guo, Jing, Zhang, Zhaojun, Guo, Xu, Li, Zhuoqi, Lin, Junwei, Li, Pengfei, Jiang, Zixuan, Zhu, Yifan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024
• Subjects: Cerebral ischemia-reperfusion injury; eNOS; ET-1; HIF-1α; Orexin A; eNOS; Cerebral ischemia-reperfusion injury; HIF-1α; ET-1; Orexin A
• ISSN: 0361-9230; 1873-2747; 1873-2747
• DOI: 10.1016/j.brainresbull.2024.111105

The purpose of this study was to investigate the protective effect and underlying mechanism of orexin A on cerebral ischemia-reperfusion injury, specifically through vasodilation mediated by the hypoxia inducible factor-1α (HIF-1α)-Endothelin-1(ET-1)/endothelial nitric oxide synthase (eNOS) pathway. A model of middle cerebral artery occlusion was established in both wild-type SD rats with exogenous orexin A intervention and in orexin A transgenic rats. Neurological deficit scores and cerebral infarction areas were assessed, and ischemic cortical blood flow was monitored. Gene and protein expression levels of HIF-1α, HIF-2α, ET-1, and three types of NOS were detected using real-time RT-qPCR and Western blot analysis, respectively. Additionally, nitric oxide (NO) levels in the cortex were analyzed through biochemical detection methods. Orexin A demonstrated a protective effect by reducing cerebral infarction and improving neurological deficits, which was achieved by increasing cortical blood flow during reperfusion. This protective mechanism was associated with upregulated HIF-1α expression, downregulated ET-1 expression, upregulated eNOS expression, and increased NO production. This study demonstrates the protective effect of orexin A on cerebral ischemia-reperfusion injury, achieved by regulating the release of vasomotor substances to enhance cortical blood flow during reperfusion. These findings suggest that orexin A may represent a potential therapeutic strategy for ischemic stroke. [Display omitted] •Orexin A alleviates cerebral ischemia-reperfusion injury.•Orexin A elevates blood pressure and enhances reperfusion in ischemic cortex.•Orexin A promotes HIF-1α expression, subsequently suppressing ET-1, upregulating eNOS, and augmenting NO production.