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

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-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. 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.