Xu Yaru, Gao Ge, Sun Xiaoru, Liu Qidong, Li Cheng
Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Front Cell Neurosci. 2021 Dec 15;15:770666. doi: 10.3389/fncel.2021.770666. eCollection 2021.
Postoperative delirium (POD) is one of the most important complications after surgery with general anesthesia, for which the neurotoxicity of general anesthetics is a high-risk factor. However, the mechanism remains largely unknown, which also hinders the effective treatment of POD. Here, we confirmed that a clinical concentration of the general anesthetic sevoflurane increased the expression of inflammatory factors and activated the caspase-3 by upregulating ATPase inhibitory factor 1 (ATPIF1) expression in microglia. Upregulation of ATPIF1 decreased the synthesis of ATP which is an important signaling molecule secreted by microglia. Extracellular supplementation with ATP attenuated the microglial inflammatory response and caspase-3 activation caused by sevoflurane or overexpression of ATPIF1. Additionally, the microglial inflammatory response further upregulated ATPIF1 expression, resulting in a positive feedback loop. Animal experiments further indicated that intraperitoneal injection of ATP significantly alleviated sevoflurane anesthesia-induced POD-related anxiety behavior and memory damage in mice. This study reveals that ATPIF1, an important protein regulating ATP synthesis, mediates sevoflurane-induced neurotoxicity in microglia. ATP supplementation may be a potential clinical treatment to alleviate sevoflurane-induced POD.
术后谵妄（POD）是全身麻醉术后最重要的并发症之一，全身麻醉药的神经毒性是其高危因素。然而，其机制仍 largely 未知，这也阻碍了对 POD 的有效治疗。在此，我们证实临床浓度的全身麻醉药七氟醚通过上调小胶质细胞中 ATP 酶抑制因子 1（ATPIF1）的表达增加炎症因子的表达并激活 caspase-3。ATPIF1 的上调减少了作为小胶质细胞分泌的重要信号分子的 ATP 的合成。细胞外补充 ATP 减弱了由七氟醚或 ATPIF1 过表达引起的小胶质细胞炎症反应和 caspase-3 激活。此外，小胶质细胞炎症反应进一步上调 ATPIF1 的表达，导致正反馈回路。动物实验进一步表明，腹腔注射 ATP 显著减轻了七氟醚麻醉诱导的小鼠 POD 相关焦虑行为和记忆损伤。本研究揭示，作为调节 ATP 合成的重要蛋白质，ATPIF1 介导七氟醚诱导的小胶质细胞神经毒性。补充 ATP 可能是减轻七氟醚诱导的 POD 的一种潜在临床治疗方法。
