Abstract：
Postoperative cognitive dysfunction (POCD) is a common complication in elderly surgical patients, significantly affecting their quality of life. Dexmedetomidine (Dex), an anesthetic, has shown promise in alleviating POCD, but its underlying mechanism remains unclear. This study aims to explore how Dex improves POCD in aged rats by targeting the PINK1-mediated mitochondrial autophagy pathway, reducing caspase-1/11-GSDMD-induced hippocampal neuronal pyroptosis. Transcriptome sequencing identified 300 differentially expressed genes enriched in the mitochondrial autophagy pathway in Dex-treated POCD rat hippocampal tissue, with Pink1 as a key candidate. In a POCD rat model, Dex treatment upregulated hippocampal PINK1 expression. In vitro experiments using H19-7 rat hippocampal neurons revealed that Dex enhanced mitochondrial autophagy and suppressed neuronal pyroptosis by upregulating PINK1. Further mechanistic validation demonstrated that Dex activated PINK1-mediated mitochondrial autophagy, inhibiting caspase-1/11-GSDMD-induced neuronal pyroptosis. In vivo experiments confirmed Dex\'s ability to reduce caspase-1/11-GSDMD-dependent hippocampal neuronal pyroptosis and improve postoperative cognitive function in aged rats. Dexmedetomidine improves postoperative cognitive dysfunction in elderly rats by enhancing mitochondrial autophagy via PINK1 upregulation, mitigating caspase-1/11-GSDMD-induced neuronal pyroptosis.
摘要：
术后认知功能障碍(POCD)是老年手术患者常见的并发症,严重影响他们的生活质量。右美托咪定(Dex),麻醉剂,在减轻POCD方面表现出了希望，但其潜在机制仍不清楚。本研究旨在探讨Dex如何通过靶向PINK1介导的线粒体自噬通路改善老年大鼠POCD,减少caspase-1/11-GSDMD诱导的海马神经元焦亡。转录组测序在Dex处理的POCD大鼠海马组织中鉴定了300个富含线粒体自噬途径的差异表达基因，以Pink1为关键候选人。在POCD大鼠模型中,Dex治疗上调海马PINK1表达。使用H19-7大鼠海马神经元的体外实验表明，Dex通过上调PINK1增强线粒体自噬并抑制神经元的焦亡。进一步的机制验证表明Dex激活PINK1介导的线粒体自噬，抑制caspase-1/11-GSDMD诱导的神经元焦亡。体内实验证实Dex能降低caspase-1/11-GSDMD依赖的海马神经元焦亡并改善老年大鼠术后认知功能。右美托咪定通过上调PINK1增强线粒体自噬改善老年大鼠术后认知功能障碍,缓解caspase-1/11-GSDMD诱导的神经元焦亡。
