Modified Dioscorea opposita Thunb. Pill Improves Myelin Regeneration and Depressive Behavior in Mice with Vascular Dementia and Depression by Inhibiting the EphA4/RhoA/Rock Signaling Pathway
Objective To investigate the clinical effect and possible mechanism of Modified Dioscoreaopposita Thunb.Pill in mice with vascular dementia (VD)and depression.Methods Bilateral common carotid artery stenosis (BCAS)combined with chronic unpredictable stimulation (CUMS)was used to establish a mouse model of VD and depression,and the mice were di-vided into sham-operation group,model group,Modified Dioscorea opposita Thunb.Pill group,and fluoxetine group.The be-havioral test was used to observe the depressive behavior of mice;immunofluorescence assay was used to measure the fluores-cence expression levels of platelet-derived growth factor receptor α(PDGFR-α)and myelin basic protein (MBP)in the corpus callosum of mice;Western blot was used to measure the protein expression levels of MBP,myelin oligodendrocyte glycoprotein (MOG),myelin-associated glycoprotein (MAG),Ephrin receptor A4 (EphA4),Ras homolog gene family,member A (RhoA), neurite outgrowth inhibitor-A (Nogo-A),Rho-associated coiled-coil forming protein kinase (Rock),and Nogo receptor (NgR);Luxol Fast Blue (LFB)staining was used to observe the myelin structure of the corpus callosum,and a transmission electron microscope was used to observe myelin ultrastructure.Results The behavioral test showed that the Modified Dioscorea opposita Thunb.Pill group and the fluoxetine group had significant increases in the total distance of activity in the open field test (P<0.05),the percentage of sugar and water preference (P<0.05),and the immobility time in the forced swimming test (P<0.05).Immunofluorescence assay showed that both Modified Dioscoreaopposita Thunb.Pill and fluoxetine increased the fluorescence intensity of PDGFRαand MBP.LFB staining showed that compared with the control group,the model group had the absence of LFB myelin staining and the presence of demyelination changes,and Modified Dioscoreaopposita Thunb.Pill improved the degree of myelin staining in the mice with VD and depression.Western blot showed that compared with the control group,the model group had significant reductions in the expression of MBP,MOG,and MAG in the corpus callosum (P<0.05),and Modified Dioscoreaopposita Thunb.Pill significantly upregulated the expression levels of MBP,MOG,and MAG (P<0.05).The Modi-fied Dioscoreaopposita Thunb.Pill group showed significant reductions in the relative protein expression levels of EphA4, RhoA,Rock,Nogo-A,and NgR in the corpus callosum (P<0.05).Conclusion Modified Dioscoreaopposita Thunb.Pill may pro-mote myelin regeneration and improve the depressive state of VD mice by inhibiting the EphA4/RhoA/Rock pathway.
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