Cao Mengya, Chen Jie, Chen Gong, Ouyang Wen, Tong Jianbin
Department of Anesthesiology, Hunan Province Key Laboratory of Brain Homeostasis, Third Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
Anesth Analg. 2024 Dec 17. doi: 10.1213/ANE.0000000000007330.
Brain homeostasis imbalance, characterized by cognitive dysfunction and delirium, frequently occurs in the elderly after surgery. Investigating why this complication only affects part of patients undergoing the same surgery, and anesthesia remains intriguing. This study tested the role of preoperative blood-brain barrier (BBB) integrity in the occurrence of postoperative brain homeostasis imbalance using mice with conditional BBB damage.
Preoperative BBB breakdown was induced in End-SCL-Cre-ctnnb1fl//fl (iCKO) mice by administering tamoxifen (intraperitoneal [i.p.]). This breakdown was assessed using Evans Blue (EB) leakage and immunoglobulin G (IgG) staining. Postoperative brain homeostasis imbalance was evaluated through the Novel Object Recognition test, the Barnes Maze, and neuroinflammation tests. Synapse loss was detected by colabeling synaptophysin and PSD-95, followed by Western blotting. The role of astrocytes in this pathogenesis was evaluated by comparing cognitive behaviors, hippocampal gene expression, and astrocytic phagocytosis of synaptophysin in iCKO mice with and without genetic inhibition of perioperative astrocyte activity.
Tamoxifen treatment (30 mg/kg/d) induced BBB breakdown of iCKO mice in a time-dependent manner (analysis of variance [ANOVA] for time, P = .0006), but not in their littermate control mice (nCKO, P > .999). A 3-day tamoxifen treatment induced slight BBB breakdown (EB leakage: 95% confidence interval [CI], 13.9-204.8, P = .013; IgG level: 95% CI, 12.6-51.4: P = .001), but did not cause significant cognitive impairment in the Novel Object Recognition test in iCKO mice (95% CI, -7.99 to 6.12; P > .999). Anesthesia and surgery-induced significant cognitive impairment (all P < .0001 for the Novel Object Recognition test, Barnes Maze test), neuroinflammation, and synaptic loss in iCKO mice with 3-day tamoxifen treatment, but not in nCKO mice with the same treatment. Inhibiting astrocyte activity alleviated the impact of anesthesia and surgery on cognitive function (all P < .0001 for the Novel Object Recognition test, Barnes Maze test), gene expression, and synapse pruning in iCKO mice with 3-day tamoxifen treatment.
Preoperative BBB integrity influences the impact of anesthesia and surgery on the brain, with astrocytes modulating this effect. These findings partly explain the heterogeneity in the occurrence of postoperative brain homeostasis imbalance.
以认知功能障碍和谵妄为特征的脑内环境稳态失衡在老年人术后经常发生。探究为何这种并发症仅影响部分接受相同手术的患者以及麻醉因素仍然很有吸引力。本研究使用条件性血脑屏障（BBB）损伤的小鼠，测试术前血脑屏障完整性在术后脑内环境稳态失衡发生中的作用。
通过给予他莫昔芬（腹腔注射[i.p.]）在End-SCL-Cre-ctnnb1fl//fl（iCKO）小鼠中诱导术前血脑屏障破坏。使用伊文思蓝（EB）渗漏和免疫球蛋白G（IgG）染色评估这种破坏情况。通过新颖物体识别测试、巴恩斯迷宫测试和神经炎症测试评估术后脑内环境稳态失衡。通过共标记突触素和PSD-95，随后进行蛋白质免疫印迹法检测突触丢失。通过比较有或没有围手术期星形胶质细胞活性基因抑制的iCKO小鼠的认知行为、海马基因表达和星形胶质细胞对突触素的吞噬作用，评估星形胶质细胞在这种发病机制中的作用。
他莫昔芬治疗（30mg/kg/d）以时间依赖性方式诱导iCKO小鼠的血脑屏障破坏（时间方差分析[ANOVA]，P = .0006），但在其同窝对照小鼠（nCKO，P > .999）中未诱导。为期3天的他莫昔芬治疗诱导轻微的血脑屏障破坏（EB渗漏：95%置信区间[CI]，13.9 - 204.8，P = .013；IgG水平：95%CI，12.6 - 51.4：P = .001），但在iCKO小鼠的新颖物体识别测试中未引起显著的认知障碍（95%CI， - 7.99至6.12；P > .999）。麻醉和手术在接受为期3天他莫昔芬治疗的iCKO小鼠中诱导显著的认知障碍（新颖物体识别测试、巴恩斯迷宫测试中所有P < .0001）、神经炎症和突触丢失，但在接受相同治疗的nCKO小鼠中未出现。抑制星形胶质细胞活性减轻了麻醉和手术对接受为期3天他莫昔芬治疗的iCKO小鼠的认知功能（新颖物体识别测试、巴恩斯迷宫测试中所有P < .0001）、基因表达和突触修剪的影响。
术前血脑屏障完整性影响麻醉和手术对大脑的影响，星形胶质细胞调节这种作用。这些发现部分解释了术后脑内环境稳态失衡发生的异质性。
