麻醉和手术会激活基质金属蛋白酶 9 (MMP9)，导致血脑屏障 (BBB) 破坏和术后谵妄 (POD) 样行为，尤其是在老年人中。老年小鼠接受腹腔注射 MMP9 抑制剂 SB-3CT、褪黑激素或溶剂，并在 3% 七氟烷麻醉（麻醉/手术）下进行剖腹手术。术前和术后 24 小时进行行为测试。使用 ELISA 测量血清和皮质组织中白细胞介素 (IL)-1β、IL-6 和肿瘤坏死因子-α (TNF-α) 的水平。使用蛋白质印迹法测定前额皮质中 PDGFRβ、MMP9、紧密连接、Mfsd2a、caveolin-1、突触素和突触后致密蛋白 (PSD)-95 蛋白的水平。通过检测前额皮质中的 IgG 和血清 S100β 水平来评估 BBB 通透性。麻醉/手术引起的外周炎症激活 MMP9，进而损伤周细胞和紧密连接并增加转胞吞作用，从而破坏 BBB。 BBB 受损使得周围炎症迁移至中枢神经系统 (CNS)，从而诱发神经炎症、突触功能障碍和 POD 样行为。然而，MMP9 抑制减少了周细胞和紧密连接损伤以及转胞吞作用，从而保留了 BBB 功能并防止外周炎症迁移到 CNS，从而减轻了突触功能障碍和 POD 样行为。此外，为了进一步验证上述发现，我们发现褪黑素通过抑制MMP9发挥类似的作用。本研究表明，麻醉/手术后，炎症细胞因子上调通过激活 MMP9 参与调节老年小鼠的 BBB 通透性，表明 MMP9 可能是预防 POD 的潜在靶点。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Anesthesia and surgery activate matrix metalloproteinase 9 (MMP9), leading to blood-brain barrier (BBB) disruption and postoperative delirium (POD)-like behavior, especially in the elderly. Aged mice received intraperitoneal injections of either the MMP9 inhibitor SB-3CT, melatonin, or solvent, and underwent laparotomy under 3 % sevoflurane anesthesia(anesthesia/surgery). Behavioral tests were performed 24 h pre- and post-operatively. Serum and cortical tissue levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were measured using ELISA. Levels of PDGFRβ, MMP9, tight junction, Mfsd2a, caveolin-1, synaptophysin, and postsynaptic densin (PSD)-95 proteins in the prefrontal cortex were assayed using Western blotting. BBB permeability was assessed by detecting IgG in the prefrontal cortex and serum S100β levels. Anesthesia/surgery-induced peripheral inflammation activated MMP9, which in turn injured pericytes and tight junctions and increased transcytosis, thereby disrupting the BBB. Impaired BBB allowed the migration of peripheral inflammation into the central nervous system (CNS), thereby inducing neuroinflammation, synaptic dysfunction, and POD-like behaviors. However, MMP9 inhibition reduced pericyte and tight junction injury and transcytosis, thereby preserving BBB function and preventing the migration of peripheral inflammation into the CNS, thus attenuating synaptic dysfunction and POD-like behavior. In addition, to further validate the above findings, we showed that melatonin exerted similar effects through inhibition of MMP9. The present study shows that after anesthesia/surgery, inflammatory cytokines upregulation is involved in regulating BBB permeability in aged mice through activation of MMP9, suggesting that MMP9 may be a potential target for the prevention of POD.Copyright © 2024 Elsevier B.V. All rights reserved.