Perioperative neurocognitive disorders (PND) refer to cognitive deterioration that occurs after surgery or anesthesia. Prolonged isoflurane exposure has potential neurotoxicity and induces PND, but the mechanism is unclear. The glymphatic system clears harmful metabolic waste from the brain. This study sought to unveil the functions of glymphatic system in PND and explore the underlying molecular mechanisms. The PND mice model was established by long term isoflurane anesthesia. The glymphatic function was assessed by multiple in vitro and in vivo methods. An adeno-associated virus was used to overexpress AQP4 and TGN-020 was used to inhibit its function. This research revealed that the glymphatic system was impaired in PND mice and the blunted glymphatic transport was closely associated with the accumulation of inflammatory proteins in the hippocampus. Increasing AQP4 polarization could enhance glymphatic transport and suppresses neuroinflammation, thereby improve cognitive function in the PND model mice. However, a marked impaired glymphatic inflammatory proteins clearance and the more severe cognitive dysfunction were observed when decreasing AQP4 polarization. Therefore, long-term isoflurane anesthesia causes blunted glymphatic system by inducing AQP4 depolarization, enhanced the AQP4 polarization can alleviate the glymphatic system malfunction and reduce the neuroinflammatory response, which may be a potential treatment strategy for PND.

中文翻译：

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长期异氟烷麻醉通过 AQP4 去极化介导的类淋巴炎症蛋白清除减弱诱导认知缺陷

围手术期神经认知障碍（PND）是指手术或麻醉后发生的认知功能减退。长期接触异氟烷具有潜在的神经毒性并诱发PND，但其机制尚不清楚。类淋巴系统清除大脑中有害的代谢废物。本研究旨在揭示类淋巴系统在 PND 中的功能并探讨潜在的分子机制。采用长期异氟烷麻醉建立PND小鼠模型。通过多种体外和体内方法评估类淋巴功能。使用腺相关病毒过表达 AQP4，并使用 TGN-020 抑制其功能。这项研究表明，PND小鼠的类淋巴系统受损，而类淋巴运输的迟缓与海马炎症蛋白的积累密切相关。增加 AQP4 极化可以增强类淋巴运输并抑制神经炎症，从而改善 PND 模型小鼠的认知功能。然而，当降低 AQP4 极化时，观察到类淋巴炎症蛋白清除明显受损，认知功能障碍更严重。因此，长期异氟烷麻醉通过诱导AQP4去极化导致类淋巴系统钝化，增强AQP4极化可以缓解类淋巴系统功能障碍，减轻神经炎症反应，这可能是PND的潜在治疗策略。