Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, College of Pharmacy, Xinxiang Medical University, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang, 453003, China.
School of Nursing, Pingdingshan Polytenchnic College, Pingdingshan, 467001, China.
Curr Neuropharmacol. 2023;21(6):1405-1420. doi: 10.2174/1570159X21666221129100308.
Ischemic stroke includes two related pathological damage processes: brain injury caused by primary ischemia and secondary ischemia reperfusion (I/R) injury. I/R injury has become a worldwide health problem. Unfortunately, there is still a lack of satisfactory drugs for ameliorating cerebral I/R damage. Nrf2 is a vital endogenous antioxidant protein, which combines with Keap1 to maintain a dormant state under physiological conditions. When pathological changes such as I/R occurs, Nrf2 dissociates from Keap1 and activates the expression of downstream antioxidant proteins to exert a protective effect. Recent research have shown that the activated Nrf2 not only effectively inhibits oxidative stress, but also performs the ability to repair the function of compromised mitochondria, alleviate endoplasmic reticulum stress, eliminate inflammatory response, reduce blood-brain barrier permeability, inhibit neuronal apoptosis, enhance the neural network remolding, thereby exerting significant protective effects in alleviating the injuries caused by cell oxygen-glucose deprivation, or animal cerebral I/R. However, no definite clinical application report demonstrated the efficacy of Nrf2 activators in the treatment of cerebral I/R. Therefore, further efforts are needed to elaborate the role of Nrf2 activators in the treatment of cerebral I/R. Here, we reviewed the possible mechanisms underlying its potential pharmacological benefits in alleviating cerebral I/R injury, so as to provide a theoretical basis for studying its mechanism and developing Nrf2 activators.
原发性缺血引起的脑损伤和继发性缺血再灌注（I/R）损伤。I/R 损伤已成为全球性的健康问题。不幸的是，仍然缺乏令人满意的药物来改善脑 I/R 损伤。Nrf2 是一种重要的内源性抗氧化蛋白，在生理条件下与 Keap1 结合处于休眠状态。当发生 I/R 等病理变化时，Nrf2 与 Keap1 解离并激活下游抗氧化蛋白的表达，发挥保护作用。最近的研究表明，激活的 Nrf2 不仅能有效抑制氧化应激，还能修复受损线粒体的功能，减轻内质网应激，消除炎症反应，降低血脑屏障通透性，抑制神经元凋亡，增强神经网络重塑，从而在减轻细胞氧葡萄糖剥夺或动物脑 I/R 引起的损伤方面发挥显著的保护作用。然而，目前尚无明确的临床应用报道表明 Nrf2 激活剂在治疗脑 I/R 中的疗效。因此，需要进一步努力阐述 Nrf2 激活剂在治疗脑 I/R 中的作用机制。本文综述了 Nrf2 激活剂在缓解脑 I/R 损伤方面的潜在药理作用机制，为研究其作用机制和开发 Nrf2 激活剂提供理论依据。
