基于TLR4/MyD88/NF-κB通路探讨艾司氯胺酮对抑郁症大鼠抑郁样行为及小胶质细胞活化的影响OA
The Effects of Esketamine on Depressive-Like Behaviour and Microglial Activation in Rats with Depression via the TLR4/MyD88/NF-κB Pathway
目的:探讨艾司氯胺酮(ESK)调控 Toll 样受体 4(TLR4)/髓样分化因子 88(MyD88)/核因子κB(NF-κB)通路对抑郁症大鼠抑郁样行为及小胶质细胞活化的影响.方法:构建抑郁症大鼠,将建模成功的大鼠分为,Model组、L-ESK、H-ESK(腹腔注射 10、20mg/kg ESK)、ESK+RS09 组(腹腔注射20mg/kg ESK+25μg/kg RS09),每组各10 只.另选择 10 只正常饲养大鼠作为 Ctrl 组,Model 组和 Ctrl组腹腔注射等量生理盐水,1 次/d,连续3 周.给药结束后对各组大鼠进行称重、强制游泳测试、蔗糖偏好试验、旷场测试;ELISA检测大鼠血清中TNF-α、IL-6、IL-10 表达;HE染色检测大鼠海马组织病理变化;免疫组化检测海马组织中 Iba-1、CD206、iNOS 的表达;Western blot 检测大鼠海马组织中 TLR4、MyD88、NF-κB蛋白的表达.结果:与Ctrl 组比较,Model 组海马神经元排列杂乱疏松,可见空泡、核固缩变形等现象,不动时间、TNF-α、IL-6、Iba-1、iNOS、TLR4、MyD88、NF-κB 升高,体质量、蔗糖偏好度、爬行格数、站立次数、IL-10、CD206 降低(P<0.05);与 Model 组比较,L-ESK、H-ESK 组海马组织损伤依次减轻,不动时间、TNF-α、IL-6、Iba-1、iNOS、TLR4、MyD88、NF-κB 降低,体质量、蔗糖偏好度、爬行格数、站立次数、IL-10、CD206 升高(P<0.05);与 H-ESK 组比较,ESK+RS09 组不动时间、TNF-α、IL-6、Iba-1、iNOS、TLR4、MyD88、NF-κB 升高,体质量、蔗糖偏好度、爬行格数、站立次数、IL-10、CD206 降低(P<0.05).结论:ESK 可能通过抑制 TLR4/MyD88/NF-κB 通路,抑制抑郁症大鼠的小胶质细胞活化,改善抑郁样行为.
Objective:To explore the effects of esketamine(ESK)on depressive-like behaviors and ac-tivation of microglia in rats with depression by regulating the Toll-like receptor 4(TLR4)/myeloid differentia-tion factor 88(MyD88)/nuclear factor-κB(NF-κB)pathway.Methods:The rats with depression were con-structed,and successfully modeled rats were separated into model group,L-ESK group,H-ESK group(in-traperitoneal injection of 10 and 20mg/kg ESK),and ESK+RS09 group(intraperitoneal injection of 20mg/kg ESK+25μg/kg RS09),with 10 rats in each group.Another 10 normally fed rats were marked as the control group.The model group and control group were intraperitoneally injected with an equal amount of physiological saline,once a day for three consecutive weeks.After the administration,rats in each group was weighed,sub-jected to forced swimming test,sucrose preference test,and open field test.ELISA was used to measure the TNF-α,IL-6,and IL-10 in rat serum.HE staining was used to measure pathological changes in rat hipp-ocampal tissue.Immunohistochemistry was applied to measure the Iba-1,CD206,and iNOS in hippocampal tissues.Moreover,Western blot was applied to detect the TLR4,MyD88,and NF-κB proteins in rat hipp-ocampal tissues.Results:Compared with the control group,the arrangement of hippocampal neurons in the model group was disordered and loose,with phenomena such as vacuoles and nuclear degeneration and trans-formation observed.The levels of TNF-α,IL-6,Iba-1,iNOS,TLR4,MyD88,and NF-κB were elevated,while the body weight,sucrose preference,number of crawling steps,standing times,IL-10,and CD206 were decreased(P<0.05).Compared with the model group,the damage of hippocampal tissues in the L-ESK and H-ESK groups was alleviated successively.The levels of inactive time,TNF-α,IL-6,Iba-1,iN-OS,TLR4,MyD88,and NF-κB were decreased,while the body weight,sucrose preference,number of crawling steps,standing times,IL-10,and CD206 were increased(P<0.05).Compared with the H-ESK group,the levels of inactive time,TNF-α,IL-6,Iba-1,iNOS,TLR4,MyD88,and NF-κB were increased in the ESK+RS09 group,while the body weight,sucrose preference,number of crawling steps,standing times,IL-10,and CD206 were decreased(P<0.05).Conclusion:ESK may inhibit the activation of micro-glia in rats with depression and improve depressive-like behaviors by suppressing the TLR4/MyD88/NF-κB pathway.
刘璇;张晓敏;刘进婷;郝岩;汪业铭;陈红
河北北方学院附属第一医院,河北 张家口 075000河北北方学院附属第一医院,河北 张家口 075000河北北方学院附属第一医院,河北 张家口 075000河北北方学院附属第一医院,河北 张家口 075000河北北方学院附属第一医院,河北 张家口 075000河北北方学院附属第一医院,河北 张家口 075000
艾司氯胺酮Toll样受体4髓样分化因子88核因子κB抑郁症抑郁样行为小胶质细胞活化
EsketamineToll-like receptor 4Myeloid differentiation factor 88Nuclear factor-κBDepressionDepressive-like behaviorsActivation of microglia
《河北医学》 2026 (1)
13-19,7
张家口市重点研发计划项目任务书,(编号:2421055D)
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