Stroke Center, Department of Neurology, The First Hospital of Jilin University, Chang Chun, Jilin, China.
Stroke Center, Department of Neurology, The First Hospital of Jilin University, Chang Chun, Jilin, China; Jilin Provincial Key Laboratory of Cerebrovascular Disease, Changchun, China.
Redox Biol. 2023 Oct;66:102852. doi: 10.1016/j.redox.2023.102852. Epub 2023 Aug 16.
The protective effects of remote ischemic conditioning (RIC) on acute ischemic stroke have been reported. However, the protective mechanisms of RIC have not been fully elucidated. This study aimed to investigate whether RIC could reduce oxidative stress and inflammatory responses in middle cerebral artery occlusion (MCAO)-reperfusion mice via the nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. C57BL/6 mice were subjected to MCAO and underwent RIC twice daily at 1, 3, and 7 days after MCAO. ML385 was used to specifically inhibit Nrf2 in MCAO mice. Neurological deficit scores, infarct volume, and hematoxylin-eosin (HE) staining were assessed. Oxidative stress levels were assessed based on total antioxidant capacity (TAC), malonaldehyde (MDA), superoxide dismutase (SOD), and glutathione/glutathione disulfide (GSH/GSSG). mRNA levels were detected using real-time polymerase chain reaction (PCR), and protein levels were detected using western blotting and enzyme-linked immunosorbent assay (ELISA). Protein localization was investigated using immunofluorescence staining. RIC significantly reduced infarct volume and improved neurological function and histological changes after MCAO. RIC significantly increased TAC, SOD, and GSH/GSSG levels and decreased MDA levels. RIC significantly increased Nrf2 and HO-1 mRNA levels and decreased Keap1, NLRP3, and Cleaved Caspase-1 mRNA levels. RIC significantly increased Nrf2, HO-1, and NQO1 protein expression and decreased Keap1, NLRP3, Cleaved Caspase-1, Cleaved IL-1β, IL-6, and TNF-α protein expression. RIC promoted the activation and translocation of Nrf2 into the nucleus. The protective effects of RIC were abolished by ML385 treatment. In conclusion, our findings suggest that RIC alleviates oxidative stress and inflammatory responses via the Nrf2/HO-1 pathway, which in turn improves neurobehavioral function. RIC may provide novel therapeutic options for acute ischemic stroke.
远程缺血预处理（RIC）对急性缺血性卒中具有保护作用。然而，RIC 的保护机制尚未完全阐明。本研究旨在探讨 RIC 是否可以通过核因子-E2 相关因子 2（Nrf2）/血红素加氧酶-1（HO-1）途径减少大脑中动脉闭塞（MCAO）再灌注小鼠的氧化应激和炎症反应。C57BL/6 小鼠接受 MCAO 后，在 MCAO 后第 1、3 和 7 天每天进行两次 RIC。ML385 用于特异性抑制 MCAO 小鼠中的 Nrf2。评估神经功能缺损评分、梗死体积和苏木精-伊红（HE）染色。根据总抗氧化能力（TAC）、丙二醛（MDA）、超氧化物歧化酶（SOD）和谷胱甘肽/谷胱甘肽二硫化物（GSH/GSSG）评估氧化应激水平。使用实时聚合酶链反应（PCR）检测 mRNA 水平，使用 Western blot 和酶联免疫吸附测定（ELISA）检测蛋白水平，并使用免疫荧光染色检测蛋白定位。RIC 可显著减少 MCAO 后的梗死体积，改善神经功能和组织学变化。RIC 可显著增加 TAC、SOD 和 GSH/GSSG 水平，降低 MDA 水平。RIC 可显著增加 Nrf2 和 HO-1 mRNA 水平，降低 Keap1、NLRP3 和 Cleaved Caspase-1 mRNA 水平。RIC 可显著增加 Nrf2、HO-1 和 NQO1 蛋白表达，降低 Keap1、NLRP3、Cleaved Caspase-1、Cleaved IL-1β、IL-6 和 TNF-α蛋白表达。RIC 促进 Nrf2 激活和向核内易位。ML385 处理可消除 RIC 的保护作用。总之，我们的研究结果表明，RIC 通过 Nrf2/HO-1 途径减轻氧化应激和炎症反应，从而改善神经行为功能。RIC 可能为急性缺血性卒中提供新的治疗选择。
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