Cerebral ischemia-reperfusion injury (CIRI) refers to a secondary brain injury that occurs when blood supply is restored to ischemic brain tissue and is one of the leading causes of adult disability and mortality. Multiple pathological mechanisms are involved in the progression of CIRI, including neuronal oxidative stress and mitochondrial dysfunction. Isoliquiritigenin (ISL) has been preliminarily reported to have potential neuroprotective effects on rats subjected to cerebral ischemic insult. However, the protective mechanisms of ISL have not been elucidated. This study aims to further investigate the effects of ISL-mediated neuroprotection and elucidate the underlying molecular mechanism. The findings indicate that ISL treatment significantly alleviated middle cerebral artery occlusion (MCAO)-induced cerebral infarction, neurological deficits, histopathological damage, and neuronal apoptosis in mice. In vitro, ISL effectively mitigated the reduction of cell viability, Na+-K+-ATPase, and MnSOD activities, as well as the degree of DNA damage induced by oxygen-glucose deprivation (OGD) injury in PC12 cells. Mechanistic studies revealed that administration of ISL evidently improved redox homeostasis and restored mitochondrial function via inhibiting oxidative stress injury and ameliorating mitochondrial biogenesis, mitochondrial fusion-fission balance, and mitophagy. Moreover, ISL facilitated the dissociation of Keap1/Nrf2, enhanced the nuclear transfer of Nrf2, and promoted the binding activity of Nrf2 with ARE. Finally, ISL obviously inhibited neuronal apoptosis by activating the Nrf2 pathway and ameliorating mitochondrial dysfunction in mice. Nevertheless, Nrf2 inhibitor brusatol reversed the mitochondrial protective properties and anti-apoptotic effects of ISL both in vivo and in vitro. Overall, our findings revealed that ISL exhibited a profound neuroprotective effect on mice following CIRI insult by reducing oxidative stress and ameliorating mitochondrial dysfunction, which was closely related to the activation of the Nrf2 pathway.

中文翻译：

---

异甘草素通过激活 Nrf2 通路减少氧化应激和改善线粒体功能障碍来减轻脑缺血再灌注损伤


脑缺血再灌注损伤 （CIRI） 是指当缺血脑组织血液供应恢复时发生的继发性脑损伤，是成人残疾和死亡的主要原因之一。CIRI 的进展涉及多种病理机制，包括神经元氧化应激和线粒体功能障碍。异甘草素 （ISL） 已初步报道对遭受脑缺血性损伤的大鼠具有潜在的神经保护作用。然而，ISL 的保护机制尚未阐明。本研究旨在进一步探讨 ISL 介导的神经保护作用，并阐明潜在的分子机制。研究结果表明，ISL 治疗可显著缓解小鼠大脑中动脉闭塞 （MCAO） 诱导的脑梗死、神经功能缺损、组织病理学损伤和神经元凋亡。在体外，ISL 有效减轻了 PC12 细胞中细胞活力、Na+-K+-ATP 酶和 MnSOD 活性的降低，以及氧-葡萄糖剥夺 （OGD） 损伤诱导的 DNA 损伤程度。机制研究表明，ISL 的给药通过抑制氧化应激损伤和改善线粒体生物发生、线粒体融合-裂变平衡和线粒体自噬，明显改善了氧化还原稳态并恢复了线粒体功能。此外，ISL 促进 Keap1/Nrf2 的解离，增强 Nrf2 的核转移，并促进 Nrf2 与 ARE 的结合活性。最后，ISL 通过激活 Nrf2 通路和改善小鼠线粒体功能障碍，明显抑制神经元凋亡。 然而，Nrf2 抑制剂布鲁萨醇在体内和体外都逆转了 ISL 的线粒体保护特性和抗凋亡作用。总体而言，我们的研究结果表明，ISL 通过减少氧化应激和改善线粒体功能障碍，对 CIRI 损伤后的小鼠表现出深远的神经保护作用，这与 Nrf2 通路的激活密切相关。