The Novel Nrf2 Activator Omaveloxolone Regulates Microglia Phenotype and Ameliorates Secondary Brain Injury after Intracerebral Hemorrhage in Mice.
The Novel Nrf2 Activator Omaveloxolone Regulates Microglia Phenotype and Ameliorates Secondary Brain Injury after Intracerebral Hemorrhage in Mice.
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DOI：
10.1155/2022/4564471
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发表时间：
2022
影响因子：
--
通讯作者：
Chen G
中科院分区：
文献类型：
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作者：
Hu L;Cao Y;Chen H;Xu L;Yang Q;Zhou H;Li J;Yu Q;Dou Z;Li Y;Yan F;Liu F;Chen G
脑出血后小胶质细胞的极化被认为是减轻神经炎症、促进血肿清除的重要因素。以往的研究表明，氧化还原成分参与了小胶质细胞极化的调节。最近，新的NRF2激活剂奥马韦洛酮(Omav)已被证实通过调节抗氧化反应来改善神经退行性疾病患者的神经功能。在这项研究中，我们考察了奥马夫治疗脑出血的疗效。OMAV可显著促进BV2细胞中Nrf2的核聚集和HO-1、NQO1的表达。此外，体外和体内实验表明，OMAV处理抑制了M1样活化，促进了M2样小胶质细胞表型的激活。OMAV抑制OxyHb诱导的BV2细胞ROS生成，保护线粒体功能。在脑出血小鼠模型中，腹膜腔内注射奥马夫可改善感觉运动功能。重要的是，这些作用可被Nrf2的选择性抑制剂ML385预先阻断。总之，OMAV通过激活Nrf2和抑制脑出血模型中ROS的产生来调节小胶质细胞的极化，这表明它可能是治疗脑出血的一种有前途的候选药物。
The polarization of microglia is recognized as a crucial factor in reducing neuroinflammation and promoting hematoma clearance after intracerebral hemorrhage (ICH). Previous studies have revealed that redox components participate in the regulation of microglial polarization. Recently, the novel Nrf2 activator omaveloxolone (Omav) has been validated to improve neurological function in patients with neurodegenerative disorders by regulating antioxidant responses. In this study, we examined the efficacy of Omav in ICH. Omav significantly promoted Nrf2 nuclear accumulation and the expression of HO-1 and NQO1 in BV2 cells. In addition, both in vitro and in vivo experiments showed that Omav treatment inhibited M1-like activation and promoted the activation of the M2-like microglial phenotype. Omav inhibited OxyHb-induced ROS generation and preserved the function of mitochondria in BV2 cells. Intraperitoneal administration of Omav improved sensorimotor function in the ICH mouse model. Importantly, these effects were blocked by pretreatment with ML385, a selective inhibitor of Nrf2. Collectively, Omav modulated microglial polarization by activating Nrf2 and inhibiting ROS generation in ICH models, suggesting that it might be a promising drug candidate for the treatment of ICH.