Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
Department of Anesthesiology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210018, China.
BMC Med. 2023 Jan 5;21(1):7. doi: 10.1186/s12916-022-02705-6.
Perioperative neurocognitive disorders (PND) with a high incidence frequently occur in elderly surgical patients closely associated with prolonged anesthesia-induced neurotoxicity. The neuromorphopathological underpinnings of anesthesia-induced neurotoxicity have remained elusive.
Prolonged anesthesia with sevoflurane was used to establish the sevoflurane-induced neurotoxicity (SIN) animal model. Morris water maze, elevated plus maze, and open field test were employed to track SIN rats' cognitive behavior and anxiety-like behaviors. We investigated the neuropathological basis of SIN through techniques such as transcriptomic, electrophysiology, molecular biology, scanning electron microscope, Golgi staining, TUNEL assay, and morphological analysis. Our work further clarifies the pathological mechanism of SIN by depleting microglia, inhibiting neuroinflammation, and C1q neutralization.
This study shows that prolonged anesthesia triggers activation of the NF-κB inflammatory pathway, neuroinflammation, inhibition of neuronal excitability, cognitive dysfunction, and anxiety-like behaviors. RNA sequencing found that genes of different types of synapses were downregulated after prolonged anesthesia. Microglial migration, activation, and phagocytosis were enhanced. Microglial morphological alterations were also observed. C1qa, the initiator of the complement cascade, and C3 were increased, and C1qa tagging synapses were also elevated. Then, we found that the "Eat Me" complement pathway mediated microglial synaptic engulfment in the hippocampus after prolonged anesthesia. Afterward, synapses were remarkably lost in the hippocampus. Furthermore, dendritic spines were reduced, and their genes were also downregulated. Depleting microglia ameliorated the activation of neuroinflammation and complement and rescued synaptic loss, cognitive dysfunction, and anxiety-like behaviors. When neuroinflammatory inhibition or C1q neutralization occurred, complement was also decreased, and synaptic elimination was interrupted.
These findings illustrated that prolonged anesthesia triggered neuroinflammation and complement-mediated microglial synaptic engulfment that pathologically caused synaptic elimination in SIN. We have demonstrated the neuromorphopathological underpinnings of SIN, which have direct therapeutic relevance for PND patients.
围手术期神经认知障碍（PND）在与长时间麻醉诱导的神经毒性密切相关的老年手术患者中发病率较高。麻醉诱导的神经毒性的神经形态病理学基础仍不清楚。
使用七氟醚长时间麻醉建立七氟醚诱导的神经毒性（SIN）动物模型。采用 Morris 水迷宫、高架十字迷宫和旷场实验跟踪 SIN 大鼠的认知行为和焦虑样行为。我们通过转录组学、电生理学、分子生物学、扫描电子显微镜、高尔基染色、TUNEL 检测和形态学分析等技术研究了 SIN 的神经病理学基础。我们通过耗竭小胶质细胞、抑制神经炎症和 C1q 中和进一步阐明了 SIN 的病理机制。
本研究表明，长时间麻醉会引发 NF-κB 炎症途径的激活、神经炎症、神经元兴奋性抑制、认知功能障碍和焦虑样行为。RNA 测序发现，长时间麻醉后，不同类型突触的基因表达下调。小胶质细胞迁移、激活和吞噬作用增强。还观察到小胶质细胞形态的改变。C1qa，补体级联的启动子，和 C3 增加，C1qa 标记突触也增加。然后，我们发现，在长时间麻醉后，“吃我”补体途径介导了小胶质细胞对海马突触的吞噬。随后，海马中的突触明显丢失。此外，树突棘减少，其基因也下调。耗竭小胶质细胞可改善神经炎症和补体的激活，并挽救突触丢失、认知功能障碍和焦虑样行为。当发生神经炎症抑制或 C1q 中和时，补体也减少，突触消除被中断。
这些发现表明，长时间麻醉引发了神经炎症和补体介导的小胶质细胞突触吞噬，从而导致 SIN 中的病理性突触丢失。我们已经证明了 SIN 的神经形态病理学基础，这对 PND 患者具有直接的治疗意义。
