Department of Anesthesiology, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, Zhejiang Province, China.
Department of Nursing, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, Zhejiang Province, China.
Exp Brain Res. 2024 Feb;242(2):417-427. doi: 10.1007/s00221-023-06724-4. Epub 2023 Dec 26.
Postoperative cognitive dysfunction (POCD) is a common postoperative complication, not only affects the quality of life of the elderly and increases the mortality rate, but also brings a greater burden to the family and society. Previous studies demonstrated that Nod-like receptor protein 3 (NLRP3) inflammasome participates in various inflammatory and neurodegenerative diseases. However, possible mitophagy mechanism in anesthesia/surgery-elicited NLRP3 inflammasome activation remains to be elucidated. Hence, this study clarified whether mitophagy dysfunction is related to anesthesia/surgery-elicited NLRP3 inflammasome activation. POCD model was established in aged C57BL/6 J mice by tibial fracture fixation under isoflurane anesthesia. Morris Water Maze (MWM) was used to evaluate learning and memory abilities. We found that in vitro experiments, lipopolysaccharide (LPS) significantly facilitated NLRP3 inflammasome activation and mitophagy inhibition in BV2 cells. Rapamycin restored mitophagy and improved mitochondrial function, and inhibited NLRP3 inflammasome activation induced by LPS. In vivo experiments, anesthesia and surgery caused upregulation of hippocampal NLRP3, caspase recruitment domain (ASC) and interleukin-1β (IL-1 β), and downregulation of microtubule-associated protein light chain 3II (LC3II) and Beclin1 in aged mice. Olaparib inhibited anesthesia/surgery-induced NLRP3, ASC, and IL-1β over-expression in the hippocampus, while upregulated the expression of LC3II and Beclin1. Furthermore, Olaparib improved cognitive impairment in older mice. These results revealed that mitophagy was involved in NLRP3 inflammasome-mediated anesthesia/surgery-induced cognitive deficits in aged mice. Overall, our results suggested that mitophagy was related in NLRP3 inflammasome-induced cognitive deficits after anesthesia and surgery in aged mice. Activating mitophagy may have clinical benefits in the prevention of cognitive impairment induced by anesthesia and surgery in elderly patients.
术后认知功能障碍（POCD）是一种常见的术后并发症，不仅影响老年人的生活质量并增加死亡率，而且给家庭和社会带来更大的负担。先前的研究表明，Nod 样受体蛋白 3（NLRP3）炎性小体参与各种炎症和神经退行性疾病。然而，麻醉/手术引发的 NLRP3 炎性小体激活中可能存在的自噬机制仍有待阐明。因此，本研究阐明了自噬功能障碍是否与麻醉/手术引发的 NLRP3 炎性小体激活有关。通过异氟烷麻醉下胫骨骨折固定在老年 C57BL/6J 小鼠中建立 POCD 模型。通过 Morris 水迷宫（MWM）评估学习和记忆能力。我们发现，在体外实验中，脂多糖（LPS）显著促进了 BV2 细胞中 NLRP3 炎性小体的激活和自噬抑制。雷帕霉素恢复自噬并改善线粒体功能，并抑制 LPS 诱导的 NLRP3 炎性小体激活。在体内实验中，麻醉和手术导致老年小鼠海马 NLRP3、半胱氨酸天冬氨酸蛋白酶募集结构域（ASC）和白细胞介素 1β（IL-1β）上调，微管相关蛋白轻链 3II（LC3II）和 Beclin1 下调。奥拉帕尼抑制麻醉/手术诱导的 NLRP3、ASC 和 IL-1β在海马中的过度表达，同时上调 LC3II 和 Beclin1 的表达。此外，奥拉帕尼改善了老年小鼠的认知障碍。这些结果表明，自噬参与了 NLRP3 炎性小体介导的老年小鼠麻醉/手术诱导的认知功能障碍。总之，我们的研究结果表明，自噬与老年小鼠麻醉和手术后 NLRP3 炎性小体诱导的认知障碍有关。激活自噬可能在预防老年患者麻醉和手术引起的认知障碍方面具有临床意义。
