Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, China.
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, China.
Neuroscience. 2021 Jul 1;466:87-100. doi: 10.1016/j.neuroscience.2021.05.003. Epub 2021 May 13.
Sepsis-associated encephalopathy (SAE) is characterized by diffuse cerebral and central nervous system (CNS) dysfunction. Microglia play a vital role in protecting the brain from neuronal damage, which is closely related to inflammatory responses. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway has an impact on microglial and neuronal injury. Here, we mainly explored the molecular mechanism by which Hydrogen (H) regulates neuroinflammation in SAE and the role of Nrf2 in this process. An in vivo model of SAE was generated by cecal ligation and puncture (CLP). Primary microglia and neurons were cultured to establish an in vitro model. Microglia, neurons and brain tissue were obtained to detect Nrf2 expression, inflammation, cell injury, apoptosis, and microglial polarization. Escape latency, the number of platform crossings and the time spent in the target quadrant were measured to assess cognitive function. H attenuated microglial polarization from the M1 to the M2 phenotype, cytokine release and TLR/NF-κb activation and protected neurons from lipopolysaccharide (LPS)-activated microglia-induced injury via the Nrf2 pathway. SAE activated Nrf2 expression, and H further improved Nrf2 expression in SAE mice. H alleviated microglial polarization from the M1 to the M2 phenotype and cytokine release in the cerebral cortex and improved neuronal injury or cognitive dysfunction in SAE mice and wild-type mice but not in Nrf2-/- mice. H exerts antineuroinflammatory effects associated with TLR4/NF-κB signaling activation and neuroprotective effects by inhibiting the excessive release of proinflammatory cytokines, neuronal loss and apoptosis in vitro and in vivo through the Nrf2 pathway.
脓毒症相关性脑病 (SAE) 的特征是弥漫性大脑和中枢神经系统 (CNS) 功能障碍。小胶质细胞在保护大脑免受神经元损伤方面发挥着重要作用，这与炎症反应密切相关。核因子红细胞 2 相关因子 2 (Nrf2) 信号通路对小胶质细胞和神经元损伤有影响。在这里，我们主要探讨了氢 (H) 调节 SAE 神经炎症的分子机制以及 Nrf2 在这一过程中的作用。通过盲肠结扎和穿孔 (CLP) 建立 SAE 的体内模型。培养原代小胶质细胞和神经元，建立体外模型。获取小胶质细胞、神经元和脑组织，检测 Nrf2 表达、炎症、细胞损伤、凋亡和小胶质细胞极化。测量逃避潜伏期、平台穿越次数和目标象限停留时间，以评估认知功能。H 通过 Nrf2 通路减轻小胶质细胞从 M1 向 M2 表型的极化、细胞因子释放和 TLR/NF-κb 激活，并保护神经元免受脂多糖 (LPS) 激活的小胶质细胞诱导的损伤。SAE 激活了 Nrf2 的表达，H 进一步提高了 SAE 小鼠中 Nrf2 的表达。H 减轻了 SAE 小鼠大脑皮质中小胶质细胞从 M1 向 M2 表型的极化和细胞因子的释放，并改善了神经元损伤或认知功能障碍，而在 Nrf2-/- 小鼠中则没有。H 通过抑制 TLR4/NF-κB 信号通路的过度激活和小胶质细胞的过度激活以及炎症因子的过度释放，发挥抗神经炎症作用，通过 Nrf2 通路在体外和体内发挥神经保护作用。
