Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
PLoS One. 2023 Jan 25;18(1):e0280914. doi: 10.1371/journal.pone.0280914. eCollection 2023.
It is common for elderly patients to develop postoperative cognitive dysfunction (POCD), but the pathophysiological mechanisms have not yet been fully explored. NLRP3 inflammasome activation and mitophagy impairment was involved in neurodegenerative disease. This study investigated the interaction of NLRP3 inflammasome and mitophagy in sevoflurane-induced cognitive dysfunction. We found that sevoflurane induced cleaved caspase-1 level, IL-1β and IL-18 maturation, and activated NLRP3 inflammasome in aged mice and the primary hippocampus neuron. The cleaved caspase-1 was demonstrated in microglia of hippocampus. Ac-YVAD-cmk, a selected caspase-1 inhibitor, reduced the expression of cleaved caspase-1, IL-1β, IL-18 and NLRP3 inflammasome activation induced by sevoflurane. Ac-YVAD-cmk ameliorated learning ability impairment in aged mice induced by sevoflurane using Morris water maze. Moreover, Ac-YVAD-cmk reversed the mitophagy flux dysfunction induced by sevoflurane in aged mice by western blotting, immunostaining and mt-Keima reporters. For the first time, we found caspase-1 inhibitor mitigated mitochondria dysfunction and revised mitophagy impairment induced by sevoflurane.
术后认知功能障碍（POCD）在老年患者中很常见，但病理生理机制尚未完全阐明。NLRP3 炎性小体激活和自噬受损与神经退行性疾病有关。本研究探讨了七氟醚诱导认知功能障碍中 NLRP3 炎性小体与自噬的相互作用。我们发现，七氟醚诱导衰老小鼠和原代海马神经元中 cleaved caspase-1 水平、IL-1β 和 IL-18 成熟以及 NLRP3 炎性小体激活。cleaved caspase-1 存在于海马的小胶质细胞中。caspase-1 的选择性抑制剂 Ac-YVAD-cmk 降低了七氟醚诱导的 cleaved caspase-1、IL-1β、IL-18 和 NLRP3 炎性小体激活的表达。Ac-YVAD-cmk 改善了衰老小鼠通过 Morris 水迷宫诱导的七氟醚学习能力障碍。此外，Ac-YVAD-cmk 通过 Western blot、免疫染色和 mt-Keima 报告物逆转了七氟醚诱导的衰老小鼠自噬通量功能障碍。我们首次发现 caspase-1 抑制剂减轻了七氟醚引起的线粒体功能障碍，并纠正了七氟醚引起的自噬受损。
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