The Translational Research Institute for Neurological Disorders of Wannan Medical College, Department of Neurosurgery, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu 241001, PR China.
Department of Neurosurgerya, Beijing Friendship Hospital, Capital Medical University, Beijing 100053, China.
Phytomedicine. 2022 Oct;105:154262. doi: 10.1016/j.phymed.2022.154262. Epub 2022 Jun 21.
Oxidative stress is a crucial factor leading to subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). Isoliquiritigenin has been verified as a powerful anti-oxidant in a variety of diseases models and can activate sirtuin 1 and nuclear factor-erythroid 2-related factor 2 (Nrf2) pathways. However, the effects of isoliquiritigenin against EBI after SAH and the underlying mechanisms remain elusive.
The primary goal of this study is to verify the therapeutic effects of isoliquiritigenin on EBI after SAH and the possible molecular mechanisms.
A prechiasmatic cistern SAH model in rats and a hemoglobin incubation SAH model in primary neurons were established. Isoliquiritigenin was administered after SAH induction. EX527 was employed to inhibit sirtuin 1 activation and ML385 was used to suppress Nrf2 signaling.
In our study, neurological scores, brain edema, biochemical estimation, western blotting, and histopathological study were performed to explore the therapeutic action of isoliquiritigenin against SAH.
Our data revealed that isoliquiritigenin significantly mitigated oxidative damage after SAH as evidenced by decreased reactive oxygen species overproduction and enhanced intrinsic anti-oxidative system. Concomitant with the reduced oxidative insults, isoliquiritigenin improved neurological function and reduced neuronal death in the early period after SAH. Additionally, isoliquiritigenin administration significantly enhanced Nrf2 and sirtuin 1 expressions. Inhibition of Nrf2 by ML385 reversed the anti-oxidative and neuroprotective effects of isoliquiritigenin against SAH. Moreover, inhibiting sirtuin 1 by EX527 pretreatment suppressed isoliquiritigenin-induced Nrf2-dependent pathway and abated the cerebroprotective effects of isoliquiritigenin. In primary cortical neurons, isoliquiritigenin treatment also ameliorated oxidative insults and repressed neuronal degeneration. The beneficial aspects of isoliquiritigenin were attributed to the promotion of sirtuin 1 and Nrf2 signaling pathways and were counteracted by EX527.
Our findings suggest that isoliquiritigenin exerts cerebroprotective effects against SAH-induced oxidative insults by modulating the Nrf2-mediated anti-oxidant signaling in part through sirtuin 1 activation. Isoliquiritigenin might be a new potential drug candidate for SAH.
氧化应激是导致蛛网膜下腔出血（SAH）后早期脑损伤（EBI）的关键因素。甘草素已被证实可在多种疾病模型中发挥强大的抗氧化作用，并能激活 Sirtuin 1 和核因子-红细胞 2 相关因子 2（Nrf2）通路。然而，甘草素对 SAH 后 EBI 的影响及其潜在机制仍不清楚。
本研究旨在验证甘草素对 SAH 后 EBI 的治疗作用及其可能的分子机制。
建立了大鼠视交叉前池蛛网膜下腔出血模型和原代神经元血红蛋白孵育 SAH 模型。在 SAH 诱导后给予甘草素。使用 EX527 抑制 Sirtuin 1 激活，使用 ML385 抑制 Nrf2 信号。
本研究通过神经功能评分、脑水肿、生化评估、Western blot 和组织病理学研究，探讨了甘草素对 SAH 的治疗作用。
我们的数据表明，甘草素显著减轻了 SAH 后的氧化损伤，表现为活性氧（ROS）生成减少和内源性抗氧化系统增强。伴随着氧化应激的减轻，甘草素改善了 SAH 后早期的神经功能和减少了神经元死亡。此外，甘草素给药显著增强了 Nrf2 和 Sirtuin 1 的表达。用 ML385 抑制 Nrf2 可逆转甘草素对 SAH 的抗氧化和神经保护作用。此外，用 EX527 预处理抑制 Sirtuin 1 可抑制甘草素诱导的 Nrf2 依赖性通路，并减弱甘草素的脑保护作用。在原代皮质神经元中，甘草素治疗也改善了氧化应激并抑制了神经元变性。甘草素的有益作用归因于促进 Sirtuin 1 和 Nrf2 信号通路，而 EX527 则对抗了这些作用。
本研究表明，甘草素通过调节 Nrf2 介导的抗氧化信号通路发挥对 SAH 诱导的氧化应激的脑保护作用，部分通过 Sirtuin 1 激活。甘草素可能是一种治疗 SAH 的新的潜在药物候选物。
