青藤碱调控CUMS抑郁大鼠突触可塑性及其对Notch和mTOR信号通路的影响  

Effects of sinomenine on synaptic plasticity,and Notch and mTOR sig⁃naling pathways in CUMS depression rats

作　　者：王志坚[1] 王晓敏 刘胜兵[1] 郭燕君[1] 潘巍巍[1] 沈忠飞[1] WANG Zhi-jian;WANG Xiao-min;LIU Sheng-bing;GUO Yan-jun;PAN Wei-wei;SHEN Zhong-fei(Jiaxing College of Medicine,Jiaxing 314000,China)

机构地区：[1]嘉兴学院医学院,浙江嘉兴314000

出　　处：《中国病理生理杂志》2021年第3期417-424,共8页Chinese Journal of Pathophysiology

基　　金：浙江省实验动物科技计划项目(No.LGD19C090002,No.2018C37092,No.2014C37019);嘉兴学院校级SRT项目(No.CD8517203238)。

摘　　要：目的:探究青藤碱(Sin)对慢性不可预见性温和应激(CUMS)所致抑郁大鼠症状的影响及可能的机制。方法:120只雄性健康SD大鼠随机分为对照(Ctrl)组、CUMS组、氟西汀(Fluo)组和Sin组(n=30)。建立CUMS抑郁大鼠模型,并分别给予Fluo(20 mg·kg^(−1)·d^(−1))或Sin(30 mg·kg^(−1)·d^(−1))灌胃治疗。通过检测体重、糖水实验及行为学检测抑郁症状;高尔基染色和苏木素-伊红染色分别检测树突棘密度和观察海马结构;qPCR和Western blot检测突触重塑相关蛋白脑源性神经营养因子(BDNF),Notch信号通路相关蛋白Notch1、Hes1和Jagged1,细胞凋亡相关蛋白Bcl-2和cleaved caspase-3(C-C3),以及哺乳动物雷帕霉素靶蛋白(mTOR)信号通路相关蛋白磷酸化mTOR(pmTOR)及磷酸化真核细胞翻译起始因子4E结合蛋白1(p-4EBP1)的变化;ELISA测定白细胞介素1β(IL-1β)、IL-6和肿瘤坏死因子α(TNF-α)的变化。结果:与Ctrl组相比,CUMS组大鼠体重、糖水偏好、旷场实验总距离和中央不动时间显著下降,强迫游泳不动时间显著增加(P<0.05)。CUMS组大鼠海马神经细胞排列紊乱,细胞间隙增大,多数细胞变性萎缩,树突棘密度减少,BDNF表达显著下调,Notch信号通路中Notch1、Hes1和Jagged1表达显著下调,细胞凋亡信号通路中Bcl-2表达下调,C-C3表达显著上调,p-mTOR和p-4EBP1下调,炎症因子IL-1β、IL-6和TNF-α表达显著上调,差异均有统计学意义(P<0.05)。Fluo和Sin均可逆转上述结果,且差异均有统计学意义(P<0.05)。结论:青藤碱能够缓解CUMS大鼠抑郁症状并改善突触可塑性,可能是通过激活Notch和mTOR信号通路,调节细胞凋亡和炎症反应来实现的。AIM:To explore the effects of sinomenine on the symptoms of chronic unpredictable mild stress(CUMS)-induced depression rats and the possible mechanism.METHODS:Healthy male SD rats(n=120)were randomly divided into control(Ctrl)group,CUMS group,fluoxetine(Fluo)group and Sin group(n=30).The CUMS depression rat model was established,and Fluo(20 mg·kg^(−1)·d^(−1))or Sin(30 mg·kg^(−1)·d^(−1))was administered intragastrically.The depressive symptoms were detected by weight measurement,sucrose preference test and behavioral test.The density of dendritic spines and the structure of hippocampus were detected by Golgi staining and Hematoxylin-Eosin staining,respectively.The levels of brain-derived neurotrophic factor(BDNF),Notch signaling proteins Notch1,Hes1 and Jagged1,apoptosis-related proteins Bcl-2 and cleaved caspase-3(C-C3),mammalian target of rapamycin(mTOR)signaling proteins phosphorylated mTOR(p-mTOR)and phosphorylated eukaryotic translation initiation factor 4E-binding protein 1(p-4EBP1)were detected by qPCR and Western blot.The changes of interleukin-1β(IL-1β),IL-6 and tumor necrosis fac‐tor-α(TNF-α)were measured by ELISA.RESULTS:Compared with Ctrl group,the weight,sucrose preference,total distance and central immobility time in CUMS group were significantly decreased,and the immobility time of forced swimming was significantly increased(P<0.05).The arrangement of hippocampal neurons was disordered with increased intercellular space,most of which were degenerated and atrophied.The density of dendritic spines was decreased(P<0.05).Additionally,the levels of BDNF,Notch1,Hes1,Jagged1,Bcl-2,p-mTOR and p-4EBP1 were down-regulated,while the levels of C-C3,IL-1β,IL-6 and TNF-αwere up-regulated in CUMS group(P<0.05).All the above results were reversed in Fluo and Sin groups,and the differences were statistically significant(P<0.05).CONCLUSION:Sinomenine alleviates the depressive symptoms and improves synaptic plasticity of CUMS rats,which may be achieved by activating Notch and mTOR signaling pathway

关 键 词：青藤碱 抑郁症 突触可塑性 NOTCH信号通路 MTOR信号通路 炎症 

分 类 号：R749.4[医药卫生—神经病学与精神病学] R363.2[医药卫生—临床医学]