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摘要Purpose:The aim of this study was to reasearch the mechanisms of down-regulation of protein phosphatase 2A activity on improving the symptoms of depression in rats.Methods:Depressive disorder model was induced by exposure to chronic unpredictable stress using Sprague Dawley rats.The model rats were randomized into 4 groups:model group(M),Low concentration OA group(LOA),medium concentration OA group(MOA)and high concentration OA group(HOA).The optimal OA concentration(OOA)was selected based on the protein phosphatase 2A activity for the follow-up study.Behavioral tests(sucrose preference test,open-field test,weight and morris water maze test)were performed in blank group,model group and the optimal OA group.Immunological assay detected the contents of noradrenaline(NE),5-hydroxytryptamine(5-HT)and cortisol(CORT).Western blot was employed to detect the expression levels of Tyrosine hydroxylase(TH),Extracellular signal regulated kinase-1(ERK1),AKT1,Glycogen synthase kinase 3β(GSK-3β)and their phosphorylated proteins.Results:The higher the concentration of OA,the stronger the inhibition to PP2A activity.The high concentration OA was selected as the optimal OA concentration.Behavioral analysis showed that sucrose preference test,open-field test,weight and morris water maze test had significant improvement in OOA group,compared to the model group(P<0.05).When compared with the model group,the contents of NE and 5-HT increased significantly(P<0.05),and the expression levels of TH,ERK1,AKT1 and the phosphorylation of TH,ERK1,AKT1 and GSK-3β up-regulated in OOA group(P<0.05);The content of CORT decreased significantly(P<0.05),and the expression levels of GSK-3βdown-regulated in OOA group(P<0.05).Conclusion:Down-regulation of the PP2A activity could improve the depression symptoms of the rats by regulating the content of NE,5-HE and CORT,TH,ERK and AKT/GSK-3β signaling pathway.PP2A may be an important intracellular targets antidepressant drugs.