Systematic Evaluation And Network Pharmacology Mechanism Study Of Shuganjieyu Capsule In The Treatment Of Post-stroke Depression

Objective: To systematically evaluate Shuganjieyu capsule in the treatment of post-stroke depression,in order to provide evidence-based medical evidence for the efficacy and safety of Shuganjieyu capsule in clinical application.The possible mechanism of Shuganjieyu capsule in the treatment of post-stroke depression was explored through network pharmacology,providing theoretical reference for the clinical application of Shuganjieyu capsule.Methods: Domestic and oversea databases,such as CNKI,WANFANG,VIP,CBM,Pubmed,SCIE,were searched online from January 1,2012 to December 31,2021.Literature was screened according to the criteria of inclusion and exclusion,meanwhile relevant information was extracted.Randomized controlled trials of Shuganjieyu capsule in the treatment of post-stroke depression were collected.Cochrane risk assessment items were used to evaluate the quality of the included literature,and Revman 5.4 software was used to systematically evaluate the effect indicators,and the heterogeneity of the results was tested.The active components and possible targets of Shuganjieyu capsule were collected by TCMSP,TCM-ID and literature databases.The related targets of post-stroke depression were collected by Drug Bank,Dis Ge NET,OMIM and Gene Cards databases.The intersection of component targets and disease targets was analyzed for protein-protein interaction.The relationship diagram of "component-target-disease" and protein-protein interaction network diagram were drawn,and then Metascape data platform was used for enrichment analysis of GO function and KEGG pathways of intersection targets,so as to explore the possible mechanism of Shuganjieyu capsule treating post-stroke depression through multi-component,multi-target together with multi-signal pathways.Results:A total of 713 patients with post-stroke depression were included in eight clinical trials（experimental group 357,control group 356）.Among the included literatures,8 were grouped according to the principle of random assignment,5 mentioned specific random method,1 adopted double-blind method,8 did not use allocation hiding,8 did not mention case data loss,and 2reported selective outcomes.Meta-analysis results showed that the total clinical effective rate of Shuganjieyu Capsule combined with SNRI antidepressants was 92.7% in the experimental group and 76.1%in the control group,indicating a statistical difference between the two groups（RR=1.22,95%CI [1.14,1.30],Z=5.96,P < 0.00001）,so the efficacy of the combined treatment group was better than that of the control group.Compared with the total clinical cure rate of Shuganjieyu Capsule combined with SNRI antidepressants and SNRI antidepressants alone,the total cure rate of the experimental group was 35.0%,and the total cure rate of the control group was23.9%,the difference between the groups was statistically significant（RR=1.47,95%CI [1.17,1.84],Z=3.33,P=0.0009）,so the combined treatment group has a greater effect on clinical cure of PSD than the SNRI antidepressant group alone.Shuganjieyu Capsule combined with SNRI antidepressants group and SNRI antidepressants group showed statistically significant difference in improving HAMD score between the two groups（MD=-3.10,95%CI [-4.50,-1.69],Z=4.32,P < 0.0001）.Therefore,the combined treatment group was more helpful to improve HAMD score than the control group.Compared with the single SNRI antidepressant group,the incidence of adverse reactions in shuganjieyu Capsule combined with SNRI was 12.1% in the experimental group and 15.3% in the control group,and there was no significant statistical difference between the two groups（RR=0.79,95%CI [0.52,1.19],Z=1.13,P=0.26）,so Shuganjieyu capsule did not increase the incidence of adverse reactions.A total of 23 active components of Shuganjieyu Capsule were obtained by searching the database,including quercetin,kaempferol,luteolin,oleanolic acid,etc.89 targets of Shuganjieyu Capsule in the treatment of post-stroke depression were obtained by Venn diagram intersection,such as IL-6,VEGF,CASP3,HTR2 A,etc.The results of enrichment analysis involved 1264 biological processes including ion transport,chemical synaptic transport and secretion regulation,and 96 cell components including membrane raft,membrane microregion,presynaptic membrane,dendrites,5-hydroxytryptamine receptor complex and neuron cell body.It involved 81 molecular functions including neurotransmitter receptor activity,signal receptor activator activity,5-HT binding and receptor ligand activity,and 159 signaling pathways including AGE-RAGE signaling pathway in diabetic complications,neuroactive ligand receptor interaction and serotonergic synapse.Conclusion: In terms of efficacy,Shuganjieyu capsule has significant efficacy in the treatment of post-stroke depression.Compared with SNRI antidepressants alone,the clinical effective rate and clinical cure rate of Shuganjieyu capsule combined with SNRI antidepressants are significantly improved,and the HAMD score is significantly improved.In terms of safety,There were a small number of minor adverse reactions in both the experimental group and the control group,indicating that Shuganjieyu capsule does not increase the frequency of adverse reactions and is safe and effective for clinical use.In terms of the mechanism of action,Shuganjieyu capsule may play a role in treating post-stroke depression by acting on IL-6,TNF,HTR2 A and other targets,through AGE-RAGE signaling pathway and serotonergic synaptic pathway,down-regulating the expression of pro-inflammatory factors including IL-6,TNF-α,up-regulating the level of HTR2 A,inhibiting the activation of hippocampal microglia,reducing oxidative stress response,inhibiting the changes of hippocampal synaptic plasticity.