Fengtian Zhao , Xiaoyu Zhang , Ting Liu , Jiale Sun , Xiaoqiang Li , Wen Zhang , Xuebi Tian
{"title":"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","authors":"Fengtian Zhao , Xiaoyu Zhang , Ting Liu , Jiale Sun , Xiaoqiang Li , Wen Zhang , 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":"{\"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 , Xiaoyu Zhang , Ting Liu , Jiale Sun , Xiaoqiang Li , Wen Zhang , 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}","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}
GPR55 activation alleviates cognitive dysfunction caused by neuropathic pain through modulation of microglia polarization and synaptic plasticity via the CaMKKβ/AMPK/SOCS3 signaling pathway
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.
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.