Effect And Mechanism Of Of Oviductus Ranae On Perimenopausal Depression Mice

Objective: To explore the interaction between oviductus ranae(OR)and depression in perimenopausal period by network pharmacology,and to explore its mechanism by animal experiment.Methods: The chemical components of OR were obtained by reviewing literatures and Batman database,and targets in OR were screened by TCMSP database.Diseaserelated targets were obtained from Dis Ge NET and Gene Cards databases.Drug intersection targets of disease were obtained through Venny web,and then PPI network was obtained by importing String database.Then Cytoscape 3.7.0 was used to construct disease-component-target target network.Then,DAVID database was used for GO enrichment analysis and KEGG pathway analysis.Female mice were subjected to bilateral ovariectomy to simulate menopause,female mice were bilaterally ovariectomized to simulate menopausal mice,and successful depilated mice were subjected to chronic unpredictable mild stimulation(CUMS)for modeling,followed by sucrose preference test(SPT),open field test(OFT),forced swimming test(FST),tail suspension test(TST),and morris water maze(MWM)behavioral experiments to evaluate the model,and successful mice were equally divided into blank,model,fluoxetine,OR high and low dose groups,and estradiol groups,which were administered followed by behavioral experiments to observe the indices.After drug administration,a series of behavioral indicators were detected.Enzyme linked immunoassay was used to detect the contents of 5-HT and 5-HIAA in the hippocampus and the biochemical indexes of CORT,LH,FSH and E2 in serum.Histopathological changes of the hippocampus were observed by Hematoxylin eosin(HE)staining,and the p PI3 K,p AKT,p CREB,PI3 K,AKT,CREB,ERα,ERβ,CRH,BDNF.The expression of the expression of the PI3 K,AKT and ERβ in the hippocampus was observed by immunohistalization.Results: Network pharmacologic analysis revealed 18 potential targets of toad oil in the treatment of perimenopausal depression.GO enrichment and KEGG pathway analysis showed that the means of regulation were more related to receptor binding activity,multi-pathway kinase activity and regulation of ubiquitin-like protein ligase binding,and the pathways of action were related to PI3K-AKT signalling pathway,HIF-1 signalling pathway,MAPK and other signalling pathways.The key targets are ESR1,IL6,VEGFA,IL1 B,CAT,etc.The PI3K/AKT signaling pathway is likely to be significantly affected in the treatment of CUMS-induced emasculated mice by OR.The results of the behavioural experiments showed that the OR can significantly increase the sugar-water preference rate of the model mice,increase the time of staying in the central area and the total movement distance of the mice in the OFT,and reduce the time of staying in the corners and the edges,and it can also significantly shorten the cumulative despair time of the model mice in the TST and FST,and in the MWM,it can also shorten the avoidance latency of the model mice and increase the number of times crossing the effective area and the total movement distance;The expression of PI3 K,AKT,ERα and ERβ in hippocampus was also increased.Animal experiments have shown that the OR can significantly improve depressive-like behavior in CUMS castrated mice.Concentrations of 5-HT and 5-HIAA in the hippocampus were significantly increased in the drug administration group compared to the model group,serum concentrations of E2 were significantly increased,while concentrations of FSH,LH and CORT were significantly decreased.In addition,OR can enhance the level of p CREB/CREB in hippocampus of CUMS castrated mice by increasing the levels of p PI3K/PI3 K and p AKT/AKT,and further enhance the expression level of BDNF in brain.Meanwhile,after administration,there was a significant increase in expression of pathway proteins.The expression of ERα and ERβ was significantly increased,while the expression of CRH was significantly decreased.The expression of PI3 K,AKT and ERβ in hippocampus was also increased.Conclusion: Oviductus ranae can regulate PI3K-AKT signaling pathway,increase the concentration of E2 and the expression of BDNF,and has therapeutic effect on perimenopausal depression.