Department of Anesthesiology, Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Jinan University, Guangzhou, China.
CNS Neurosci Ther. 2024 Nov;30(11):e70098. doi: 10.1111/cns.70098.
Postoperative neurocognitive disorder (PND) refers to the cognitive impairment experienced by patients after surgery. As a target of sevoflurane, a kind of inhalation anesthetic, the balance of the GABAergic system can be disrupted during the perioperative period. In this study, we explored the promoting effect of abnormal elevation of the α5 subtype of γ-aminobutyric acid type A (GABAA) receptors caused by sevoflurane and surgical trauma on PND, as well as the therapeutic effect of fasudil on PND.
Eight-week-old mice were pretreated with fasudil, and after 10 days, sevoflurane-induced femoral fracture surgery was performed to establish an animal model of PND. The Morris water maze and fear conditioning tests were used to evaluate PND induced by this model. Biochemical and electrophysiological analyses were conducted to assess the protective effect of fasudil on the GABAergic system.
Following artificial fracture, the hippocampus-dependent memory was damaged in these mice. Fasudil pretreatment, however, ameliorated cognitive function impairment in mice induced by sevoflurane and surgery. Mechanistically, fasudil was found to restore the increased hippocampus expression and function of α5GABAARs in mice with PND. In addition, pretreatment with Fasudil inhibited the enhancement in the calcium ion concentration and phosphorylation of Camk2, as well as the activation of the Radixin pathway which led to increased phosphorylation of the ERM family in the hippocampal CA1 region of the PND model.
Preadministration of fasudil improved postoperative cognitive function in PND mice by inhibiting the activation of Camk2 and Radixin pathways and finally downregulating the surface expression of α5GABAAR in hippocampus neurons.
术后认知障碍（PND）是指患者手术后出现的认知障碍。作为一种吸入麻醉剂七氟醚的作用靶点，其在围手术期可破坏γ-氨基丁酸 A 型（GABAA）受体的 GABA 能系统平衡。本研究探讨了七氟醚和手术创伤引起的 GABAA 受体α5 亚单位异常升高对 PND 的促进作用，以及法舒地尔对 PND 的治疗作用。
八周龄小鼠用法舒地尔预处理，10 天后行七氟醚诱导的股骨骨折手术，建立 PND 动物模型。采用 Morris 水迷宫和恐惧条件反射试验评价该模型引起的 PND。生化和电生理分析评估法舒地尔对 GABA 能系统的保护作用。
人工骨折后，这些小鼠的海马依赖型记忆受损。然而，法舒地尔预处理可改善七氟醚和手术诱导的小鼠认知功能障碍。机制上，法舒地尔恢复了 PND 小鼠海马中 α5GABAAR 表达和功能的增加。此外，Fasudil 预处理抑制了钙离子浓度和 Camk2 磷酸化的增强，以及 Radixin 途径的激活，导致 PND 模型中海马 CA1 区 ERM 家族的磷酸化增加。
法舒地尔预处理通过抑制 Camk2 和 Radixin 途径的激活，最终下调海马神经元α5GABAAR 的表面表达，改善 PND 小鼠术后认知功能。
