Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, PR China.
Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, PR China.
Int Immunopharmacol. 2024 Jun 30;135:112290. doi: 10.1016/j.intimp.2024.112290. Epub 2024 May 25.
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.
麻醉和手术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 MMP9 抑制剂 SB-3CT、褪黑素或溶剂的腹腔内注射，并在 3%七氟醚麻醉（麻醉/手术）下接受剖腹手术。在术前和术后 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 Western blot 测定前额叶皮质中 PDGFRβ、MMP9、紧密连接、Mfsd2a、小窝蛋白-1、突触小体和突触后密度蛋白-95（PSD-95）蛋白的水平。通过检测前额叶皮质中的 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了 MMP9，进而损伤周细胞和紧密连接，并增加了转胞吞作用，从而破坏了 BBB。受损的 BBB 允许外周炎症向中枢神经系统（CNS）迁移，从而诱导神经炎症、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的损伤和转胞吞作用，从而保持了 BBB 的功能并防止了外周炎症向 CNS 的迁移，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，我们表明褪黑素通过抑制 MMP9 发挥类似的作用。本研究表明，麻醉/手术后，炎症细胞因子的上调通过激活 MMP9参与调节老年小鼠的 BBB 通透性，提示 MMP9 可能是预防 POD 的潜在靶点。
