| Objective:Our study was to observe the mechanism of antidepressant effects of NMDA receptor antagonist MK-801 through the expression of BDNF protein and BDNF mRNA transcripts in the dentate gyrus of the hippocampus in a rat model of depression,and to provide new ideas for the pathophysiology of depression and clinical treatment.Methods:SD male rats,weight 200-250 g,were randomly divided into control group and model group,2 rats per cage were housed under light/dark 12h/12 h and allowed access to rodent chow and water ad libitum.Animals were allowed to acclimate to laboratory conditions for at least 5 days prior to use in experiments.The control group was given a2.4% ethanol solution alone.The model group was oral administrated with corticosterone(CORT)for 14 days.Animals were then weaned as follows 3 days with 50% of the original CORT concentration,4 days with 25%.The body weight changes were observed on day 7,day 14 and day 21.The forced swimming,elevated plus maze test,open field test and sucrose preference test were performed to evaluate the effects of depression model.Rats were randomly selected from the model group for Western Blot and qPCR experiments to quantify BDNF protein and BDNF mRNA.The rest rats were randomly divided into 4 groups,model group,MK-801 group(0.3 mg/kg,i.p.),SAHA group(50mg/kg,i.p.)and MK-801+SAHA group.To analyze the mechanism of antidepressant action of MK-801,the improvement effect of depressive behavior in rats was observed bybehavior experiments,and the expression of BDNF protein in each group was detected by Western Blot.Results:1.In the elevated plus maze test,CORT group had shorter residence time in the open arm and prolonged residence time in the closed arm,which was significantly different from that of the control group(p < 0.05).Compared with the model group,the time of stay in the closed arm in the control group,MK-801 group,SAHA group and MK-801+SAHA group was significantly reduced(p < 0.05),and the time of stay in the open arm was significantly increased(p < 0.05).There was no significant difference between the MK-801 group,SAHA group and MK-801+SAHA group compared with the normal control group.2.In the open field test,the time of stay in the corner in the CORT group was prolonged,and the time of stay in the center was shortened,which was significantly different from that of the control group(p < 0.05).Compared with the model group,the time of stay in the corner in the control group,MK-801 group,SAHA group and MK-801+SAHA group was significantly reduced(p < 0.05),and the time of stay in the center was significantly increased(p < 0.05).There was no significant difference between the MK-801 group,SAHA group and MK-801+SAHA group compared with the normal control group.3.In the forced swimming test,the immibility time in the CORT group was significantly different from that of the control group(p < 0.05).Compared with the model group,the immibility time in the control group,MK-801 group,SAHA group and MK-801+SAHA group was significantly reduced(p < 0.05).There was no significant difference between the MK-801 group,SAHA group and MK-801+SAHA group compared with the normal control group.4.In sucrose preference test,the sucrose preference in the CORT group was significantly different from that of the control group(p < 0.05).Compared with the modelgroup,the sucrose preference of the control group,MK-801 group,SAHA group and MK-801+SAHA group was significantly increased(p < 0.05).There was no significant difference between the MK-801 group,SAHA group and MK-801+SAHA group compared with the normal control group.5.QPCR results showed that the expression of DH-DG BDNF mRNA I,BDNF mRNA IIa,BDNF mRNA IIb,BDNF mRNA III,BDNF mRNA IV,BDNF mRNA V,BDNF mRNA VI,BDNF mRNA VIIa,BDNF mRNA VIII were increased significantly compared with the normal control group(p < 0.05),the expression of BDNF mRNA IIc was decreased(p < 0.05).The expression of BDNF mRNA IX had no obvious change.The expression of VH-DG BDNF mRNA IIb,BDNF mRNA IIc,BDNF mRNA III,BDNF mRNA IV,BDNF mRNA V,BDNF mRNA VI,BDNF mRNA VII,BDNF mRNA VIII,BDNF mRNA IX were decreased significantly compared with control group(p <0.05).The expression of BDNF mRNA I,mRNA IIa had no obvious change.6.Western Blot results showed that the expression of proBDNF in VH-DG was significantly lower than that of mBDNF in the control group(p < 0.05),that is,the ratio of mBDNF and proBDNF was greater than 1.The expression of proBDNF in the model group was significantly higher than that of mBDNF(p < 0.05),that is,the ratio of mBDNF and proBDNF was lower in the depression model group.In the DH-DG,the expression of proBDNF in the model group was significantly higher than that in mBDNF(p < 0.01).Compared with the model group,the expression of mBDNF in the control group,MK-801 group,SAHA group and MK-801+SAHA group was significantly increased,and the expression of proBDNF was decreased(p < 0.05).There was no significant difference between the MK-801 group,SAHA group and MK-801+SAHA group compared with the normal control group.Conclusion:1.There were different BDNF mRNA transcripts in the dorsal DG and ventral DG of the hippocampus of the depressed rats.The mRNA in the dorsal region was increased,while in the ventral region was decreased.2.Alterations in BDNF mRNA transcripts lead to changes in the amount of translated mBDNF and proBDNF.The ratio of mBDNF and proBDNF in the ventral DG region of depressed rats was decreased.3.The antidepressant effects of MK-801 was correlated with histone acetylation and mBDNF/proBDNF ratio in the ventral DG region of rats. |
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