GPR55 activation alleviates cognitive dysfunction caused by neuropathic pain through modulation of microglia polarization and synaptic plasticity via the CaMKKβ/AMPK/SOCS3 signaling pathway

IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Fengtian Zhao , Xiaoyu Zhang , Ting Liu , Jiale Sun , Xiaoqiang Li , Wen Zhang , Xuebi Tian
{"title":"GPR55 activation alleviates cognitive dysfunction caused by neuropathic pain through modulation of microglia polarization and synaptic plasticity via the CaMKKβ/AMPK/SOCS3 signaling pathway","authors":"Fengtian Zhao ,&nbsp;Xiaoyu Zhang ,&nbsp;Ting Liu ,&nbsp;Jiale Sun ,&nbsp;Xiaoqiang Li ,&nbsp;Wen Zhang ,&nbsp;Xuebi Tian","doi":"10.1016/j.cellsig.2025.112070","DOIUrl":null,"url":null,"abstract":"<div><div>Cognitive impairment induced by neuropathic pain substantially diminishes quality of life, with hippocampal neuroinflammation identified as a critical pathogenic factor. Although G protein-coupled receptor 55 (GPR55) demonstrates anti-inflammatory, analgesic, and neuroprotective properties, its therapeutic potential and molecular mechanisms in neuropathic pain-induced cognitive deficits remain uncharacterized. Using a spared nerve injury (SNI) mouse model, we systematically investigated GPR55's neuroprotective mechanisms. Pharmacological activation of GPR55 effectively ameliorated cognitive dysfunction and attenuated hippocampal neuroinflammation and preserved synaptic plasticity by shifting microglial polarization toward the neuroprotective M2 phenotype in SNI mice. Mechanistic studies revealed that the immunomodulatory effects operate through the CaMKKβ/AMPK/SOCS3 signaling axis, as confirmed by pathway blockade using the specific inhibitor Compound C. These results demonstrate that GPR55 activation modulates microglial polarization, mitigates neuroinflammatory cascades, and preserves synaptic plasticity, thus alleviating neuropathic pain-associated cognitive dysfunction through a mechanism involving the CaMKKβ/AMPK/SOCS3 signaling pathway.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112070"},"PeriodicalIF":3.7000,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular signalling","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0898656825004851","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Cognitive impairment induced by neuropathic pain substantially diminishes quality of life, with hippocampal neuroinflammation identified as a critical pathogenic factor. Although G protein-coupled receptor 55 (GPR55) demonstrates anti-inflammatory, analgesic, and neuroprotective properties, its therapeutic potential and molecular mechanisms in neuropathic pain-induced cognitive deficits remain uncharacterized. Using a spared nerve injury (SNI) mouse model, we systematically investigated GPR55's neuroprotective mechanisms. Pharmacological activation of GPR55 effectively ameliorated cognitive dysfunction and attenuated hippocampal neuroinflammation and preserved synaptic plasticity by shifting microglial polarization toward the neuroprotective M2 phenotype in SNI mice. Mechanistic studies revealed that the immunomodulatory effects operate through the CaMKKβ/AMPK/SOCS3 signaling axis, as confirmed by pathway blockade using the specific inhibitor Compound C. These results demonstrate that GPR55 activation modulates microglial polarization, mitigates neuroinflammatory cascades, and preserves synaptic plasticity, thus alleviating neuropathic pain-associated cognitive dysfunction through a mechanism involving the CaMKKβ/AMPK/SOCS3 signaling pathway.
GPR55激活通过CaMKKβ/AMPK/SOCS3信号通路调节小胶质细胞极化和突触可塑性,减轻神经性疼痛引起的认知功能障碍
神经性疼痛引起的认知障碍大大降低了生活质量,海马神经炎症被认为是一个关键的致病因素。尽管G蛋白偶联受体55 (GPR55)具有抗炎、镇痛和神经保护特性,但其在神经性疼痛引起的认知缺陷中的治疗潜力和分子机制尚不清楚。利用SNI小鼠模型,我们系统地研究了GPR55的神经保护机制。药理激活GPR55可有效改善SNI小鼠的认知功能障碍,减轻海马神经炎症,并通过将小胶质细胞极化向神经保护性M2表型转移来保持突触可塑性。机制研究表明,GPR55的免疫调节作用是通过CaMKKβ/AMPK/SOCS3信号轴起作用的,特异性抑制剂化合物c的通路阻断证实了这一点。这些结果表明,GPR55的激活通过CaMKKβ/AMPK/SOCS3信号通路调节小胶质细胞极化,减轻神经炎症级联反应,保持突触可塑性,从而减轻神经性疼痛相关的认知功能障碍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Cellular signalling
Cellular signalling 生物-细胞生物学
CiteScore
8.40
自引率
0.00%
发文量
250
审稿时长
27 days
期刊介绍: Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo. Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信