Anti-inflammatory effects of higenamine (Hig) on LPS-activated mouse microglia (BV2) through NF-κB and Nrf2/HO-1 signaling pathways
Anti-inflammatory effects of higenamine (Hig) on LPS-activated mouse microglia (BV2) through NF-κB and Nrf2/HO-1 signaling pathways
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去甲乌药碱 (Hig) 通过 NF-κB 和 Nrf2/HO-1 信号通路对 LPS 激活的小鼠小胶质细胞 (BV2) 的抗炎作用
DOI：
10.1016/j.intimp.2020.106629
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发表时间：
2020
影响因子：
5.6
通讯作者：
Nai-hong Chen
中科院分区：
文献类型：
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作者：
Song-wei Yang;Shi-feng Chu;Qi-di Ai;Zhao Zhang;Yan Gao;Mei-yu Lin;Ying-Jiao Liu;Yao-mei Hu;Xun Li;Ye Peng;Ya-wen Pan;Qing-hui He;Nai-hong Chen
• 我们首次在体外证实了去甲乌药碱（Hig）对小鼠小胶质细胞具有抗炎和抗氧化作用。
• 我们的研究结果将有助于开发治疗神经系统疾病的新型治疗药物。
• 我们证明了Hig的抗炎和抗氧化作用与抑制核因子κ（NF-κ）以及激活Nrf2信号通路有关，该信号通路在神经炎症性疾病的治疗中起着关键作用。小胶质细胞是大脑中功能最为完备的保护性细胞，在神经系统疾病的发生发展中起着关键作用。炎症反应和氧化应激是小胶质细胞激活的重要危险因素，可能引发各种神经系统疾病。去甲乌药碱（Hig）是一种从乌头块根中分离出的植物生物碱，具有多种特性，主要用于治疗心力衰竭。此外，Hig对神经退行性疾病也显示出潜在的保护作用。然而，Hig对脂多糖（LPS）激活的小鼠小胶质细胞的作用及机制尚未得到充分研究。因此，我们评估了Hig对LPS激活的BV2小胶质细胞的抗炎作用，并揭示了其潜在机制。我们的数据表明，Hig显著抑制了LPS激活的BV2细胞中肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、活性氧（ROS）以及一氧化氮（NO，由诱导型一氧化氮合酶（iNOS）介导）和前列腺素E2（PGE2，由环氧化酶2（COX2）介导）的产生。随后我们发现，Hig通过抑制NF-κB/p65亚基的核转位以及细胞质中IκBα的降解和磷酸化来抑制NF-κB信号通路，且Hig的这种作用与NF-κB抑制剂BAY-11-7082密切相关。此外，我们还发现Hig的抗炎作用伴随着血红素加氧酶-1（HO-1）和核因子E2相关因子2（Nrf2）表达的增加，而原卟啉（SnPP）和Nrf2小干扰RNA（siRNA）分别能部分逆转这种增加。综上所述，我们的研究结果表明，Hig通过抑制NF-κB并激活Nrf2/HO-1信号通路，表现出显著的抗炎和抗氧化作用。
• We demonstrated for the first time in vitro the anti-inflammatory and antioxidant effects of Hig on mouse microglia. • Our results would help to develop new therapeutic drug for treating neurological diseases. • We demonstrated that the anti-inflammatory and antioxidant effects of Hig were associated with inhibition of NF-κ and activation of the Nrf2 signaling pathway, which plays a key role in the treatment of neuroinflammatory diseases. Microglia are the most widely equipped protective cells in the brain and play a pivotal role in the development of neurological diseases. Inflammatory response and oxidative stress are critical risk factors in the activation of microglia which may cause various neurological diseases. Higenamine (Hig), a plant-based alkaloid and isolated from Aconite tuber, exhibits various properties and is mainly applied to treat heart failure. In addition, Hig expresses potential protective effects for neurodegenerative diseases. However, the effects and mechanisms of Hig on lipopolysaccharide (LPS) activated mouse microglia has not been fully explored. Therefore, we evaluated the anti-inflammatory effects of Hig on LPS-activated BV2 microglia and revealed the underlying mechanisms. Our data showed that Hig significantly inhibited the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), reactive oxygen species (ROS) as well as NO (mediated by iNOS) and PGE 2 (mediated by COX2) in LPS-activated BV2 cells. Then we found that Hig suppressed NF-κB signaling pathway by inhibiting nuclear translocation of NF-κB/p65 subunit as well as degradation and phosphorylation of IκBα in cytoplasm, and the effect of Hig was intimately related to NF-κB inhibitor BAY-11-7082. Furthermore, we found that the anti-inflammatory effect of Hig were accompanied by the promotion of heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor-2 (Nrf2) expression, which was partly reversed by protoporphyrin (SnPP) and Nrf2 siRNA, respectively. Taken together, our results demonstrated that Hig expressed significant anti -inflammatory and -oxidative effects by inhibiting NF-κB and activating Nrf2/HO-1 signaling pathways.