Muscone ameliorates postoperative cognitive dysfunction in aged mice by modulating PPARγ to suppress TLR4/NF-κB/NLRP3 pathway-mediated neuroinflammation

Yang Zhihua; Guo Lu; Zhao Yi; Liu Yajuan; Liang Aichen; Ma Yan; Wang Hao; Lü Xinghua

doi:10.16016/j.2097-0927.202605079

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Muscone ameliorates postoperative cognitive dysfunction in aged mice by modulating PPARγ to suppress TLR4/NF-κB/NLRP3 pathway-mediated neuroinflammation

Neuroscience | 更新时间：2026-10-01

- Muscone ameliorates postoperative cognitive dysfunction in aged mice by modulating PPARγ to suppress TLR4/NF-κB/NLRP3 pathway-mediated neuroinflammation
- Journal of Army Medical University Vol. 48, Issue 18, Pages: 2604-2621(2026)
- 作者机构：
  
  1.兰州大学第一临床医学院，甘肃兰州
  2.兰州大学第一医院日间手术中心，甘肃兰州
- 作者简介：
  
  Lü Xinghua，E-mail：ldyylxh18@163.com
- 基金信息：
  
  the Social Development Project of Key Research and Development Program of Gansu Province(26YFFA006);the Key Health Talent Program of Gansu Province(2026SWJWRC003);the General Project of Joint Research Fund of Gansu Province(24JRRA914)
- DOI：10.16016/j.2097-0927.202605079
  CLC： R285.5;R741.05;R745.44
- Received：27 May 2026，
  
  Revised：2026-08-01，
  
  Accepted：04 August 2026，
  
  Published：30 September 2026
- 稿件说明：
移动端阅览
杨治华，郭璐，赵翼，等.麝香酮通过调节PPARγ抑制TLR4/NF-κB/NLRP3通路介导的神经炎症改善老年小鼠术后认知功能障碍［J］.陆军军医大学学报，2026，48（18）：2604-2621.DOI：10.16016/j.2097-0927.202605079.

Yang Z H，Guo L，Zhao Y，et al.Muscone ameliorates postoperative cognitive dysfunction in aged mice by modulating PPARγ to suppress TLR4/NF-κB/NLRP3 pathway-mediated neuroinflammation［J］.J Army Med Univ，2026，48（18）：2604-2621.DOI：10.16016/j.2097-0927.202605079.
杨治华，郭璐，赵翼，等.麝香酮通过调节PPARγ抑制TLR4/NF-κB/NLRP3通路介导的神经炎症改善老年小鼠术后认知功能障碍［J］.陆军军医大学学报，2026，48（18）：2604-2621.DOI：10.16016/j.2097-0927.202605079. DOI：

Yang Z H，Guo L，Zhao Y，et al.Muscone ameliorates postoperative cognitive dysfunction in aged mice by modulating PPARγ to suppress TLR4/NF-κB/NLRP3 pathway-mediated neuroinflammation［J］.J Army Med Univ，2026，48（18）：2604-2621.DOI：10.16016/j.2097-0927.202605079. DOI：

摘要

目的

术后认知功能障碍（postoperative cognitive dysfunction，POCD）与围术期神经炎症、小胶质细胞促炎活化及海马神经元损伤密切相关。麝香酮（muscone，Mus）虽具有抗炎和神经保护作用，但其能否改善麻醉手术诱导的POCD及相关机制尚未明确。本研究旨在探讨Mus是否通过调节PPARγ相关信号，抑制TLR4/NF-κB/NLRP3通路介导的炎症反应，从而改善POCD。

方法

①通过SwissTargetPrediction、PharmMapper、SuperPred和TargetNet数据库预测Mus作用靶点，通过GeneCards、DisGeNET和OMIM数据库收集POCD相关靶点，筛选Mus干预POCD的潜在作用靶点，构建蛋白质-蛋白质相互作用网络并筛选核心靶点，进行GO功能注释和KEGG通路富集分析；采用分子对接评价Mus与核心靶点蛋白的潜在结合能力。②将32只12月龄老年雄性C57BL/6小鼠按随机数字表法分为（

=8）：NC组、POCD组、Mus组和Mus+GW9662组，其中6只纳入行为学分析。除NC组外，其余各组采用异氟烷麻醉联合胫骨骨折内固定术建立POCD模型。Mus组给予Mus 10 mg/kg腹腔注射，Mus+GW9662组在Mus给药前给予PPARγ抑制剂GW9662 1 mg/kg。术后第3天进行新物体识别实验，术后第3~8天进行Morris水迷宫实验，评价小鼠识别记忆及空间学习记忆功能。行为学实验结束后，HE和NS染色观察海马CA1区神经元损伤；采用RT-qPCR和Western blot检测小鼠的海马组织炎症因子、炎症表型相关分子及PPARγ/TLR4/NF-κB/NLRP3相关分子的表达。③采用脂多糖诱导BV2小胶质细胞建立炎症模型，分为NC组、LPS组、LPS+Mus组和LPS+Mus+GW9662组。CCK-8法评价Mus对细胞活力的影响并确定体外干预浓度，通过Griess法、流式细胞术、RT-qPCR和Western blot检测NO释放、CD86/CD206表型、炎症因子及PPARγ/TLR4/NF-κB/NLRP3相关分子的表达。进一步收集各组BV2细胞条件培养基处理HT22细胞，采用CCK-8法和流式细胞术检测HT22细胞活力及凋亡。

结果

①Mus干预POCD的潜在靶点主要富集于炎症反应、免疫调节及神经损伤相关过程，PPARG是其潜在作用靶点之一；分子对接结果提示Mus与PPARγ具有潜在结合趋势。②行为学结果显示，与NC组相比，POCD组小鼠Morris水迷宫穿越原平台次数减少［（1.33±1.03）

（5.83±1.72），

=0.000 3］，目标象限停留时间缩短［（22.11±2.94）

（44.13±6.95） s，

0.000 1］，新奇偏爱指数降低［（0.37±0.11）

（0.72±0.05），

0.000 1］，认知指数下降［（-0.26±0.23）

（0.43±0.11），

0.000 1］。与POCD组相比，Mus干预后小鼠穿越原平台次数增加［（5.83±0.75）

（1.33±1.03），

0.000 1］，目标象限停留时间延长［（42.98±7.06）

（22.11±2.94） s，

0.000 1］，新奇偏爱指数和认知指数升高（均

0.01）；GW9662可部分削弱Mus的上述改善作用。组织学结果显示，POCD组小鼠海马CA1区神经元排列紊乱、NS减弱，Mus干预后神经元损伤减轻，而GW9662处理后其保护作用减弱。分子检测结果显示，Mus可降低POCD小鼠海马组织促炎因子及iNOS表达，上调IL-10、Arg1和PPARγ表达，并下调TLR4、NF-κB p65和NLRP3表达；GW9662可部分逆转上述效应。③CCK-8结果显示，10 μmol/L Mus处理24 h对BV2和HT22细胞活力无明显抑制作用。分子检测结果显示，Mus可降低LPS诱导的BV2细胞NO释放和促炎因子表达，减轻CD86阳性促炎表型偏移，并下调TL

R4、NF-κB p65和NLRP3相关分子表达。BV2细胞条件培养基共培养实验显示，LPS诱导的炎症性条件培养基可降低HT22细胞活力并增加细胞凋亡，Mus干预后的条件培养基可减轻HT22细胞损伤，GW9662可部分削弱该作用。

结论

Mus可改善异氟烷麻醉联合手术诱导的老年小鼠POCD，其作用可能与调节PPARγ相关信号、减轻TLR4/NF-κB/NLRP3通路介导的神经炎症，以及改善小胶质细胞炎症状态并减轻炎症微环境介导的神经元继发性损伤有关。

Abstract

Objective

Postoperative cognitive dysfunction (POCD) is closely associated with perioperative neuroinflammation

proinflammatory activation of microglia

and hippocampal neuronal injury. Muscone (Mus) exerts anti-inflammatory and neuroprotective effects

yet whether it can ameliorate anesthesia- and surgery-induced POCD and the underlying mechanisms remain unclear. This study aims to investigate whether Mus ameliorates POCD by modulating PPARγ-related signaling and suppressing inflammatory responses mediated by the TLR4/NF-κB/NLRP3 pathway.

Methods

① Network pharmacology: Mus target prediction was performed using SwissTargetPrediction

PharmMapper

SuperPred

and TargetNet databases. POCD-related targets were collected from GeneCards

DisGeNET

and OMIM databases. Potential targets through which Mus may act against POCD were screened

a protein-protein interaction (PPI) network was constructed

and core targets were selected. GO functional annotation and KEGG pathway enrichment analyses were subsequently performed. Molecular docking was used to evaluate the potential binding affinity of Mus with the core target proteins. ② Animal experiments: 32 aged male C57BL/6 mice (12 months old) were randomly divided into an NC group

a POCD group

a Mus group

and a Mus+GW9662 group

with 8 mice in each group initially and 6 mice per group finally included in behavioral analysis. Except for the NC group

all other groups underwent isoflurane anesthesia combined with tibial fracture internal fixation to establish a POCD model. The Mus group received an intraperitoneal injection of 10 mg/kg Mus

whereas the Mus+GW9662 group received PPARγ inhib

itor

GW9662 at 1 mg/kg before Mus administration. Novel object recognition test was carried out on postoperative day 3

and Morris water maze test was conducted from postoperative days 3 to 8 to assess recognition memory and spatial learning and memory. After behavioral tests

3 mice from each group were subjected to HE and Nissl staining to evaluate neuronal injury in the hippocampal CA1 region. RT-qPCR and Western blot were used to detect the expression of inflammatory factors

inflammation phenotype-related molecules

and PPARγ/TLR4/NF-κB/NLRP3-related molecules in hippocampal tissues. ③ Cell experiments: An inflammatory model was established in BV2 microglial cells induced by lipopolysaccharide (LPS)

and then the cells were divided into NC

LPS

LPS+Mus

and LPS+Mus+GW9662 groups. CCK-8 assay was used to evaluate the effect of Mus on cell viability and determine the

in vitro

intervention concentration. Griess assay

flow cytometry

RT-qPCR

and Western blot were used to detect NO release

CD86/CD206 phenotypes

inflammatory factors

and expression of PPARγ/TLR4/NF-κB/NLRP3-related molecules. Conditioned media from the 4 groups of BV2 cells were subsequently collected to treat HT22 cells

and CCK-8 assay and flow cytometry were carried out to detect cell viability and apoptosis of HT22 cells

respectively.

Results

① Potential targets of Mus intervention in POCD were mainly enriched in biological processes related to inflammatory responses

immune regulation and neural injury

and PPARG was identified as a potential target. Molecular docking suggested a potential binding interaction between Mus and PPARγ. ② The results of behavioral tests showed that

compared with the NC group

the POCD group exhibited fewer crossing number in Morris water maze test (1.33±1.03

5.83±1.72

=0.000 3)

a shorter duration in the target quadrant (22.11±2.94 s

44.13±6.95 s

0.000 1)

a lower novelty prefer

ence index (0.37±0.11

0.72±0.05

0.000 1)

and a decreased cognitive index (-0.26±0.23

0.43±0.11

0.000 1). Compared with the POCD group

Mus treatment increased crossing number (5.83±0.75

1.33±1.03

0.000 1)

prolonged time spent in the target quadrant (42.98±7.06 s

22.11±2.94 s

0.000 1)

and increased both the novelty preference index and cognitive index (both

0.01). GW9662 partially attenuated the above improvements induced by Mus. Histological examination showed disorganized neuronal arrangement and reduced Nissl staining in the hippocampal CA1 region of the POCD mice. Mus treatment alleviated neuronal injury

whereas GW9662 weakened this protective effect. Molecular analysis showed that Mus reduced the expression of proinflammatory cytokines and iNOS

increased the expression of IL-10

Arg1

and PPARγ

and decreased the expression of TLR4

NF-κB p65

and NLRP3 in the hippocampus of POCD mice. GW9662 partially reversed the above effects. ③ CCK-8 assay showed that treatment of 10 μmol/L Mus for 24 h had no significant inhibitory effect on viability of BV2 or HT22 cells. Molecular analysis demonstrated that Mus reduced LPS-induced NO release and proinflammatory cytokine expression in BV2 cells

attenuated the shift toward a CD86-positive proinflammatory phenotype

and downregulated the TLR4/NF-κB/NLRP3 pathway-related molecules. The BV2 cell-conditioned medium co-culture experiment showed that LPS-induced inflammatory conditioned medium reduced the viability and increased the apoptosis of HT22 cells

whereas the conditioned medium from Mus-treated BV2 cells attenuated HT22 cell injury

and GW9662 partially attenuated this effect.

Conclusion

Mus ameliorates POCD induced by isoflurane anesthesia combined with surgery in aged mice. Its effects may be associated with regulation of PPARγ-related signaling

alleviating TLR4/NF-κB/NLRP3 pathway-mediated neuroinflammation

improving inflammatory status of microglial cells

and alleviating inflammatory microenvironment-mediated secondary neuronal injury.

关键词

Keywords

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