逍遥散通过GLP-1/GLP-1r途径改善海马突触可塑性缓解慢性束缚应激大鼠焦虑和抑郁样行为的机制OA

Objective:To observe the effects of Xiaoyaosan on glucagon-like peptide-1(GLP-1)/GLP-1 receptor(GLP-1r)and protein kinase A(PKA)/cAMP response element binding protein(CREB)/brain-derived neurotrophic factor(BDNF)signaling pathways in the hippocampal CA1 region of rats under chronic restraint stress(CRS),and to explore the mechanism of this formula to alleviate anxiety and depression-like behaviors.Methods:40 specific pathogen-free male Sprague-Dawley(SD)rats were randomly divided into normal,model,Xiaoyaosan,and fluoxetine groups,with 10 rats in each group.CRS was used to induce anxiety and depression-like behaviors.The rats in the Xiaoyaosan group were gavaged with aqueous solution of traditional Chinese medicine formula granules(7.36 g·kg-1·d-1),while those in the fluoxetine group were gavaged with aqueous solution of fluoxetine(2 mg·kg-1·d-1).Body weight was measured on days 0,7,14,and 21 of the experiment.On days 0 and 22 of the experiment,the sucrose preference test(SPT),forced swimming test(FST),and open field test(OFT)were performed.The pathological morphology of the hippocampal CA1 region was observed by Nissl staining.The relative mRNA expression of post-synaptic density protein-95(PSD95)and synapsin(SYP)was detected by reverse transcription quantitative real-time polymerase chain reaction.Immunohistochemistry and Western blot were used to detect expression of proteins in the GLP-1/GLP-1r and PKA/CREB/BDNF pathways in the hippocampal CA1 region.Results:After CRS modeling,compared with the normal group,the rats of the model group had anxiety and depression-like behavioral manifestations,neuronal damage in the hippocampal CA1 region,significantly downregulated expression of synaptic plasticity markers PSD95 and SYP genes(P<0.01),and inhibition of GLP-1/GLP-1r and PKA/CREB/BDNF signaling pathways(P<0.05,P<0.01).Compared with the model group,the Xiaoyaosan group exhibited alleviated anxiety and depression-like behaviors,reduced neuronal damage in the hippocampal CA1 region,significantly increased expression of PSD95 and SYP genes(P<0.01),and the activation of the GLP-1/GLP-1r and PKA/CREB/BDNF signaling pathways(P<0.05,P<0.01).Conclusion:Xiaoyaosan can alleviate anxiety and depression-like behaviors in CRS rats by improving synaptic plasticity in the hippocampal CA1 region.The mechanisms may be related to the activation of the GLP-1/GLP-1r pathway and its mediated PKA/CREB/BDNF signaling pathway by the formula.