Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China.
Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China.
Brain Res Bull. 2024 Nov;218:111105. doi: 10.1016/j.brainresbull.2024.111105. Epub 2024 Oct 22.
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.
本研究旨在探讨内源性阿立新 A 通过缺氧诱导因子-1α（HIF-1α）-内皮素-1（ET-1）/内皮型一氧化氮合酶（eNOS）通路介导的血管舒张对脑缺血再灌注损伤的保护作用及其机制。采用野生型 SD 大鼠和阿立新 A 转基因大鼠的大脑中动脉闭塞模型，进行外源性阿立新 A 干预，评估神经功能缺损评分和脑梗死面积，监测缺血皮质血流。采用实时 RT-qPCR 和 Western blot 分析检测 HIF-1α、HIF-2α、ET-1 和三种类型 NOS 的基因和蛋白表达水平，通过生化检测方法分析皮质中一氧化氮（NO）水平。阿立新 A 通过增加再灌注期间皮质血流来减轻脑梗死和改善神经功能缺损，从而发挥保护作用。这种保护机制与 HIF-1α表达上调、ET-1 表达下调、eNOS 表达上调和 NO 生成增加有关。本研究表明，阿立新 A 通过调节血管活性物质的释放来增加再灌注期间的皮质血流，对脑缺血再灌注损伤具有保护作用。这些发现提示阿立新 A 可能成为缺血性脑卒中的一种潜在治疗策略。
