Background

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.

Purpose

The primary goal of this study is to verify the therapeutic effects of isoliquiritigenin on EBI after SAH and the possible molecular mechanisms.

Study design

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.

Methods

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.

Results

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.

Conclusion

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.

中文翻译：

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异甘草素通过靶向 SIRT1 调节 Nrf2 依赖性信号通路，在体内外减轻蛛网膜下腔出血后的氧化损伤

背景

氧化应激是导致蛛网膜下腔出血 (SAH) 引起的早期脑损伤 (EBI) 的关键因素。异甘草素已在多种疾病模型中被证实是一种强大的抗氧化剂，可以激活 sirtuin 1 和核因子-红细胞 2 相关因子 2 (Nrf2) 通路。然而，异甘草素对 SAH 后 EBI 的作用及其潜在机制仍不清楚。

目的

本研究的主要目的是验证异甘草素对SAH后EBI的治疗作用及可能的分子机制。

学习规划

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.

Methods

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.

Results

我们的数据表明，异甘草素显着减轻了 SAH 后的氧化损伤，活性氧过量产生减少和内在抗氧化系统增强就证明了这一点。随着氧化损伤的减少，异甘草素在 SAH 后的早期改善了神经功能并减少了神经元死亡。此外，异甘草素给药显着增强了 Nrf2 和 sirtuin 1 的表达。ML385 对 Nrf2 的抑制逆转了异甘草素对 SAH 的抗氧化和神经保护作用。此外，通过 EX527 预处理抑制 sirtuin 1 可抑制异甘草素诱导的 Nrf2 依赖性通路，并减弱异甘草素的脑保护作用。在初级皮层神经元中，异甘草素治疗还改善了氧化损伤并抑制了神经元变性。异甘草素的有益方面归因于 sirtuin 1 和 Nrf2 信号通路的促进，并被 EX527 抵消。

结论

我们的研究结果表明，异甘草素通过部分通过 sirtuin 1 激活调节 Nrf2 介导的抗氧化信号，对 SAH 诱导的氧化损伤发挥脑保护作用。异甘草素可能是 SAH 的一种新的潜在候选药物。