杜仲-续断药对治疗抑郁症作用机制的网络药理学和动物实验研究OA

Objective To investigate the mechanism of Eucommiae Cortex-Dipsaci Radix herb pair in the treatment of depressive disorder.Methods TCMSP was used to mine the effective components of Eucommiae Cortex-Dipsaci Radix herb pair.The GeneCards,OMIM and TTD databases were used to predict the depressive disorder related targets.Venny 2.1.0 software was used to obtain intersection targets.String database and CytoScape software were used to construct the protein-protein interaction(PPI)network,and the gene ontology(GO)function enrichment analysis and the Kyoto Encyclopedia of genes and genomes(KEGG)pathway enrichment analysis were carried out.AutoDock Tools 1.5.7 software was used to carry out the molecular docking validation of the top-ranked key targets of effective components and node degree value.A total of 50 ICR mice were randomly divided into control group(equal volume distilled water),model group(equal volume distilled water),Eucommiae Cortex-Dipsaci Radix herb pair low-dose group(DXL,1.5 g/kg for Eucommiae Cortex,Dipsaci Radix,respectively),Eucommiae Cortex-Dipsaci Radix herb pair high-dose group(DXH,3 g/kg for Eucommiae Cortex,Dipsaci Radix,respectively)and paroxetine group(20 mg/kg),with 10 mice in each group.Chronic unpredictable stimuli(CUMS)method was used to replicate the model of depressive disorder in mice.After successful modeling,the mice in each group were given corresponding drugs or distilled water by gavage administration once a day for 18 d,during which CUMS method was used for continuous stimulation.The sugar water preference test,tail suspension test and forced swimming test were used to evaluate the depressive disorder of mice;enzyme linked immunosorbent assay(ELISA)test was used to detect the levels of dopamine(DA)and 5-hydroxytryptamine(5-HT)in the hippocampus of mice;RT-PCR method was used to detect the mRNA expression level of pathway related factors.Results The results of network pharmacology analysis showed that baicalein,luteolin,swertiajaponin,quercetin,keampferol and wogonin were the key effective components of Eucommiae Cortex-Dipsaci Radix herb pair in the treatment of depressive disorder,and protein kinase B1(AKT1),estrogen receptor 1(ESR1),phosphatidylinositol-4,5-diphosphate 3-kinase catalytic subunit α(PIK3CA),proto oncogene tyrosine protein kinase SRC(SRC)and epidermal growth factor receptor(EGFR)were important potential targets;the mechanism of Eucommiae Cortex-Dipsaci Radix herb pair in the treatment of depressive disorder may be related to phosphatidylinositol 3-kinase(PI3K)-AKT,calcium signal,neurodegenerative lesions and other signaling pathways;the results of molecular docking showed that the main effective components of Eucommiae Cortex-Dipsaci Radix herb pair had stable binding with PIK3CA and AKT1.The results of animal experiments showed that compared with the model group,the sugar preference rate of DXL group,DXH group and paroxetine group were significantly increased(P<0.01),and the swinging immobility time and floating immobility time were significantly shortened in the DXH group and paroxetine group(P<0.01);the levels of DA and 5-HT in hippocampus of mice in the DXH group and paroxetine group were significantly increased(P<0.05);the expression mRNA level of AKT1 in hippocampus of mice in the DXL group,and the expression mRNA levels of PIK3CA and AKT1 in the hippocampus of mice in the DXH group were significantly increased(P<0.05).Conclusion Eucommiae Cortex-Dipsaci Radix herb pair can effectively improve the depressive disorder symptoms of model mice,and its mechanism may be related to the activation of PI3K/AKT signaling pathway.