• Hongguang Chen, Beibei Dong, Yuan Shi, Yonghao Yu, and Keliang Xie.
• 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.

AbstractSepsis-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 (H2) 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. H2 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 H2 further improved Nrf2 expression in SAE mice. H2 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. H2 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.Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.

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