Neuroprotective Effects of Trilobatin, a Novel Naturally Occurring Sirt3 Agonist from Lithocarpus polystachyus Rehd., Mitigate Cerebral Ischemia/Reperfusion Injury: Involvement of TLR4/NF-κB and Nrf2/Keap-1 Signaling
Neuroprotective Effects of Trilobatin, a Novel Naturally Occurring Sirt3 Agonist from Lithocarpus polystachyus Rehd., Mitigate Cerebral Ischemia/Reperfusion Injury: Involvement of TLR4/NF-κB and Nrf2/Keap-1 Signaling
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DOI：
10.1089/ars.2019.7825
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发表时间：
2020-04-23
影响因子：
6.6
通讯作者：
Gong, Qihai
中科院分区：
文献类型：
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作者：
Gao, Jianmei;Chen, Nana;Gong, Qihai
目的：神经炎症和氧化应激被认为是脑缺血/再灌注（I/R）后脑损伤的主要原因。由于沉默交配型信息调节2同源物3（Sirt 3）通路在保护神经炎症和氧化应激中起着至关重要的作用，其已被证实为治疗缺血性卒中的靶点。结果：三叶苷（Trilobatin，TLB）不仅能显著抑制大鼠大脑中动脉闭塞后神经炎症和氧化应激损伤，而且能有效减轻原代培养星形胶质细胞的缺氧缺糖/复氧损伤。这些有益作用，沿着通过抑制Toll样受体4（TLR 4）信号传导途径减少的促炎细胞因子，通过激活核因子红细胞2相关因子2（Nrf 2）信号传导途径减轻氧化损伤，与体内发现一致。有趣的是，TLR 4介导的神经炎性反应和Nrf 2抗氧化反应之间的相互作用分别通过分子对接和沉默TLR 4和Nrf 2证明，调节了TLR 4介导的脑I/R损伤的神经保护作用。最重要的是，TLB不仅能直接与Sirt 3结合，而且能增加Sirt 3的表达和活性，这表明Sirt 3可能是TLB的一个有前途的治疗靶点。创新：TLB是一种天然存在的Sirt 3激动剂，通过调节TLR 4/核因子-κ B和Nrf 2/Kelch-like ECH相关蛋白1（Keap-1）信号通路，在体内和体外都具有强大的神经保护作用。我们的研究结果表明，TLB通过TLR 4，Nrf 2和Sirt 3调节神经炎症和氧化反应，保护脑I/R诱导的神经炎症和氧化损伤，这表明TLB可能是一个有前途的Sirt 3激动剂，以防止缺血性中风。
Aims: Neuroinflammation and oxidative stress are deemed the prime causes of brain injury after cerebral ischemia/reperfusion (I/R). Since the silent mating-type information regulation 2 homologue 3 (Sirt3) pathway plays an imperative role in protecting against neuroinflammation and oxidative stress, it has been verified as a target to treat ischemia stroke. Therefore, we attempted to seek novel Sirt3 agonist and explore its underlying mechanism for stroke treatment both in vivo and in vitro.Results: Trilobatin (TLB) not only dramatically suppressed neuroinflammation and oxidative stress injury after middle cerebral artery occlusion in rats, but also effectively mitigated oxygen and glucose deprivation/reoxygenation injury in primary cultured astrocytes. These beneficial effects, along with the reduced proinflammatory cytokines via suppressing Toll-like receptor 4 (TLR4) signaling pathway, lessened oxidative injury via activating nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways, in keeping with the findings in vivo. Intriguingly, the TLB-mediated neuroprotection on cerebral I/R injury was modulated by reciprocity between TLR4-mediated neuroinflammatory responses and Nrf2 antioxidant responses as evidenced by molecular docking and silencing TLR4 and Nrf2, respectively. Most importantly, TLB not only directly bonded to Sirt3 but also increased Sirt3 expression and activity, indicating that Sirt3 might be a promising therapeutic target of TLB.Innovation: TLB is a naturally occurring Sirt3 agonist with potent neuroprotective effects via regulation of TLR4/nuclear factor-kappa B and Nrf2/Kelch-like ECH-associated protein 1 (Keap-1) signaling pathways both in vivo and in vitro.Conclusion: Our findings indicate that TLB protects against cerebral I/R-induced neuroinflammation and oxidative injury through the regulation of neuroinflammatory and oxidative responses via TLR4, Nrf2, and Sirt3, suggesting that TLB might be a promising Sirt3 agonist against ischemic stroke.