Department of Anesthesiology, The First Affiliated Hospital of AnHui Medical University, Hefei, 230022, PRC, China.
Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PRC, Zhejiang Province Key Lab of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, PRC, China.
Neurotox Res. 2022 Jun;40(3):775-790. doi: 10.1007/s12640-022-00511-9. Epub 2022 Apr 26.
Inhaled anesthetics are known to induce neurotoxicity in the developing brains of rodents, although the mechanisms are not well understood. The aim of this study was to elucidate the molecular mechanisms underlying anesthetics-induced neurodevelopmental toxicity by VEGF receptor 2 (VEGFR2) through the interaction between microglia and neural stem cells (NSCs) in postnatal day 7 (P7) rats. Cognitive function of P7 rats exposed to isoflurane and sevoflurane were assessed using Morris Water Maze and T maze tests. We also evaluated the expression levels of NSC biomarkers (Nestin and Sox2), microglia biomarker (CD11b or or IBA1), pro-inflammatory cytokines (IL-6 and TNF-α), and VEGFR2 using western blotting and immunohistochemistry in the brains of control and anesthesia-treated rats. We found spatial learning and working memory was impaired 2 weeks after anesthetics exposure in rats. Isoflurane induced stronger and more prolonged neurotoxicity than sevoflurane. However, cognitive functions were recovered 6 weeks after anesthesia. Isoflurane and sevoflurane decreased the levels of Nestin, Sox2, and p-VEGFR2, activated microglia, decreased the number of NSCs and reduced neurogenesis and the proliferation of NSCs, and increased the levels of IL-6, TNF-α, and CD11b. Our results suggested that isoflurane and sevoflurane induced cognitive impairment in rats by inhibiting NSC development and neurogenesis via microglial activation, neuroinflammation, and suppression of VEGFR2 signaling pathway.
吸入麻醉剂已知会在啮齿动物发育中的大脑中引起神经毒性，尽管其机制尚不清楚。本研究旨在通过小胶质细胞和神经干细胞（NSC）之间的相互作用，阐明 VEGF 受体 2（VEGFR2）在新生后 7 天（P7）大鼠中麻醉诱导神经发育毒性的分子机制。通过 Morris 水迷宫和 T 迷宫测试评估 P7 大鼠暴露于异氟烷和七氟醚后的认知功能。我们还使用 Western blot 和免疫组织化学法评估了麻醉处理和对照大鼠大脑中 NSC 生物标志物（Nestin 和 Sox2）、小胶质细胞生物标志物（CD11b 或 IBA1）、促炎细胞因子（IL-6 和 TNF-α）和 VEGFR2 的表达水平。我们发现，麻醉暴露 2 周后，大鼠的空间学习和工作记忆受损。异氟烷诱导的神经毒性比七氟醚更强且持续时间更长。然而，麻醉后 6 周认知功能恢复。异氟烷和七氟醚降低了 Nestin、Sox2 和 p-VEGFR2 的水平，激活了小胶质细胞，减少了 NSCs 的数量，降低了神经发生和 NSCs 的增殖，并增加了 IL-6、TNF-α 和 CD11b 的水平。我们的结果表明，异氟烷和七氟醚通过抑制 NSC 发育和神经发生、激活小胶质细胞、神经炎症和抑制 VEGFR2 信号通路，导致大鼠认知障碍。
