Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China; Hebei Key Laboratory of Integrated Traditional and Western Medicine in Osteoarthrosis Research (Preparing), Cangzhou, China; Hebei Province Key Laboratory of Integrated Traditional and Western Medicine in Neurological Rehabilitation, Cangzhou, China.
Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China.
Brain Res Bull. 2024 Oct 15;217:111059. doi: 10.1016/j.brainresbull.2024.111059. Epub 2024 Aug 30.
Cognitive dysfunction, encompassing perioperative psychological distress and cognitive impairment, is a prevalent postoperative complication within the elderly population, and in severe cases, it may lead to dementia. Building upon our prior research that unveiled a connection between postoperative mood fluctuations and cognitive dysfunction with the phosphorylation of P38, this present investigation aims to delve deeper into the involvement of the P38 MAPK/NLRP3 pathway in perioperative neurocognitive disorders (PND) in an abdominal exploratory laparotomy (AEL) aged mice model.
C57BL/6 mice (male, 18-month-old) underwent AEL with 3 % anesthesia. Then, inhibitors targeting P38 MAPK (SB202190, 1 mg/kg) and GSK3β (TWS119, 10 mg/kg) were administered multiple times daily for 7 days post-surgery. The NLRP3-cKO AEL and WT AEL groups only underwent the AEL procedure. Behavioral assessments, including the open field test (OFT), novel object recognition (NOR), force swimming test (FST), and fear conditioning (FC), were initiated on postoperative day 14. Additionally, mice designated for neuroelectrophysiological monitoring had electrodes implanted on day 14 before surgery and underwent novel object recognition while their local field potential (LFP) was concurrently recorded on postoperative day 14. Lastly, after they were euthanasized, pathological analysis and western blot were performed.
SB202190, TWS119, and astrocyte-conditional knockout NLRP3 all ameliorated the cognitive impairment behaviors induced by AEL in mice and increased mean theta power during novel location exploration. However, it is worth noting that SB202190 may exacerbate postoperative depressive and anxiety-like behaviors in mice, while TWS119 may induce impulsive behaviors.
Our study suggests that anesthesia and surgical procedures induce alterations in mood and cognition, which may be intricately linked to the P38 MAPK/NLRP3 pathway.
认知功能障碍，包括围手术期心理困扰和认知障碍，是老年人群中普遍存在的术后并发症，在严重情况下，可能导致痴呆。基于我们之前的研究发现，术后情绪波动和认知功能障碍与 P38 的磷酸化之间存在联系，本研究旨在深入探讨 P38 MAPK/NLRP3 通路在腹部探查性腹腔镜手术（AEL）老年小鼠模型围手术期神经认知障碍（PND）中的作用。
C57BL/6 小鼠（雄性，18 个月大）接受 3%麻醉的 AEL。然后，每天多次给予 P38 MAPK 抑制剂（SB202190，1mg/kg）和 GSK3β 抑制剂（TWS119，10mg/kg），术后 7 天。NLRP3-cKO AEL 和 WT AEL 组仅接受 AEL 手术。术后第 14 天开始进行行为评估，包括旷场试验（OFT）、新物体识别（NOR）、强迫游泳试验（FST）和恐惧条件反射（FC）。此外，指定用于神经电生理监测的小鼠在手术前第 14 天植入电极，并在术后第 14 天进行新物体识别，同时记录其局部场电位（LFP）。最后，在处死它们后，进行病理分析和蛋白质印迹。
SB202190、TWS119 和星形胶质细胞条件性敲除 NLRP3 均改善了 AEL 诱导的小鼠认知功能障碍行为，并增加了新位置探索期间的平均 theta 功率。然而，值得注意的是，SB202190 可能会加重术后小鼠的抑郁和焦虑样行为，而 TWS119 可能会导致冲动行为。
我们的研究表明，麻醉和手术程序会引起情绪和认知的改变，这可能与 P38 MAPK/NLRP3 通路密切相关。
