Preoperative Blood-Brain Barrier Integrity Influence on the Impact of Anesthesia and Surgery on Mice Brain.

IF 3.8 2区医学 Q1 ANESTHESIOLOGY

Anesthesia and analgesia Pub Date : 2025-10-01 Epub Date: 2024-12-17 DOI:10.1213/ANE.0000000000007330

Mengya Cao, Jie Chen, Gong Chen, Wen Ouyang, Jianbin Tong

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Abstract

Background: 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.

Methods: Preoperative BBB breakdown was induced in End-SCL-Cre-ctnnb1 fl//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.

Results: 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.

Conclusions: 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.

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术前血脑屏障完整性对麻醉和手术对小鼠大脑影响的影响

背景：老年手术后脑内平衡失衡，以认知功能障碍和谵妄为特征。调查为什么这种并发症只影响部分接受相同手术和麻醉的患者仍然很有趣。本研究使用条件性血脑屏障损伤小鼠，测试了术前血脑屏障（BBB）完整性在术后脑稳态失衡发生中的作用。方法：采用他莫昔芬（腹腔注射[i.p.]）诱导End-SCL-Cre-ctnnb1fl//fl （iCKO）小鼠术前血脑屏障破坏。通过Evans Blue （EB）渗漏和免疫球蛋白G （IgG）染色来评估这种破坏。术后脑内平衡失衡通过新物体识别测试、巴恩斯迷宫和神经炎症测试进行评估。用synaptophysin和PSD-95标记突触，然后用Western blotting检测突触丢失。通过比较有和没有围手术期星形胶质细胞活性遗传抑制的iCKO小鼠的认知行为、海马基因表达和突触素的星形胶质细胞吞噬，来评估星形胶质细胞在这一发病机制中的作用。结果：他莫昔芬治疗（30 mg/kg/d）诱导iCKO小鼠血脑屏障分解呈时间依赖性（时间方差分析[ANOVA]， P = 0.0006），但在同窝对照小鼠中无明显作用（nCKO, P = 0.999）。3天的他莫昔芬治疗诱导轻度血脑屏障破裂(EB渗漏：95%可信区间[CI]， 13.9-204.8, P = 0.013；IgG水平：95% CI， 12.6-51.4: P = .001)，但在iCKO小鼠的新物体识别测试中没有引起显著的认知障碍(95% CI, -7.99至6.12；P[0.99 .99]。他莫昔芬治疗3天的iCKO小鼠中，麻醉和手术引起了显著的认知障碍（新颖物体识别试验、巴恩斯迷宫试验均P < 0.0001）、神经炎症和突触丧失，但同样治疗的nCKO小鼠中没有这种情况。抑制星形胶质细胞活性减轻了麻醉和手术对接受3天他莫昔芬治疗的iCKO小鼠的认知功能（Novel Object Recognition test， Barnes Maze test均P < 0.0001）、基因表达和突触修剪的影响。结论：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影响。这些发现部分解释了术后脑内平衡失衡发生的异质性。

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来源期刊

Anesthesia and analgesia 医学-麻醉学

CiteScore

9.90

自引率

7.00%

发文量

817

审稿时长

2 months

期刊介绍： Anesthesia & Analgesia exists for the benefit of patients under the care of health care professionals engaged in the disciplines broadly related to anesthesiology, perioperative medicine, critical care medicine, and pain medicine. The Journal furthers the care of these patients by reporting the fundamental advances in the science of these clinical disciplines and by documenting the clinical, laboratory, and administrative advances that guide therapy. Anesthesia & Analgesia seeks a balance between definitive clinical and management investigations and outstanding basic scientific reports. The Journal welcomes original manuscripts containing rigorous design and analysis, even if unusual in their approach.