抑制 P38 MAPK/NLRP3 通路可减轻腹部手术加七氟烷后老年小鼠的认知功能障碍和情绪变化

IF 3.5 3区 医学 Q2 NEUROSCIENCES
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引用次数: 0

摘要

背景:认知功能障碍包括围手术期的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,严重者可能导致痴呆。我们之前的研究揭示了术后情绪波动和认知功能障碍与 P38 磷酸化之间的联系,在此基础上,本研究旨在通过腹部探查性开腹手术(AEL)老年小鼠模型深入研究 P38 MAPK/NLRP3 通路在围手术期神经认知障碍(PND)中的参与情况:方法:C57BL/6小鼠(雄性,18个月大)在3%麻醉下接受腹部探查开腹术(AEL)。方法:C57BL/6小鼠(雄性,18个月龄)在3%麻醉下接受腹腔穿刺术(AEL),然后在术后7天内每天多次服用针对P38 MAPK(SB202190,1毫克/千克)和GSK3β(TWS119,10毫克/千克)的抑制剂。NLRP3-cKO AEL组和WT AEL组只进行AEL手术。术后第 14 天开始进行行为评估,包括开阔地测试 (OFT)、新物体识别 (NOR)、用力游泳测试 (FST) 和恐惧条件反射 (FC)。此外,指定进行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,同时记录它们的局部场电位(LFP)。最后,安乐死后进行病理分析和免疫印迹:结果:SB202190、TWS119和星形胶质细胞条件性敲除NLRP3都能改善AEL诱导的小鼠认知障碍行为,并能提高小鼠在探索新位置时的平均θ功率。但值得注意的是,SB202190可能会加重小鼠术后抑郁和焦虑样行为,而TWS119可能会诱发冲动行为:我们的研究表明,麻醉和手术过程会诱发情绪和认知的改变,这可能与 P38 MAPK/NLRP3 通路有着错综复杂的联系。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of the P38 MAPK/NLRP3 pathway mitigates cognitive dysfunction and mood alterations in aged mice after abdominal surgery plus sevoflurane

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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来源期刊
Brain Research Bulletin
Brain Research Bulletin 医学-神经科学
CiteScore
6.90
自引率
2.60%
发文量
253
审稿时长
67 days
期刊介绍: The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.
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