Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China; Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Shaanxi Key Laboratory of Brain Disorders & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, 710021, China.
Redox Biol. 2024 Nov;77:103406. doi: 10.1016/j.redox.2024.103406. Epub 2024 Oct 22.
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.
脑缺血再灌注损伤（CIRI）是指当缺血脑组织恢复血液供应时发生的继发性脑损伤，是导致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。已初步报道甘草素（ISL）对缺血性脑损伤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，并阐明其潜在的分子机制。研究结果表明，ISL 治疗可显著减轻大脑中动脉闭塞（MCAO）诱导的脑梗死、神经功能缺损、组织病理学损伤和小鼠神经元凋亡。在体外，ISL 可有效减轻氧葡萄糖剥夺（OGD）损伤引起的 PC12 细胞活力、Na-K-ATP 酶和 MnSOD 活性以及 DNA 损伤程度的降低。机制研究表明，ISL 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-分裂平衡和线粒体自噬，明显改善氧化还原平衡和恢复线粒体功能。此外，ISL 促进 Keap1/Nrf2 的解离，增强 Nrf2 的核转位，并促进 Nrf2 与 ARE 的结合活性。最后，ISL 通过激活 Nrf2 通路和改善线粒体功能明显抑制小鼠神经元凋亡。然而，Nrf2 抑制剂溴马尿酸在体内和体外均逆转了 ISL 的线粒体保护特性和抗凋亡作用。综上所述，我们的研究结果表明，ISL 通过减轻氧化应激和改善线粒体功能对 CIRI 损伤后的小鼠表现出显著的神经保护作用，这与 Nrf2 通路的激活密切相关。
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