The Role Of MAPK Signaling Pathway In Depression Rat Model

BackgroundDepression is a chronic and easily recurring psychiatric disorder and the pathogenesis is complicated.There is no hypothesis that can explain the cause of the disease completely and the treatment is also hindered.With the development of molecular research of depression in recent years,the study of cellular signal pathway has attracted widespread attention.MAPK is an important cell signaling pathway,involved in cell proliferation,differentiation,apoptosis and a series of cellular processes.MKP-1 is a MAPK phosphorylase that regulates its activity,and participates the pathophysiology of depression.In this study,chronic unpredictable mild stress(CUS)rat model was taken as the research object,and fluoxetine was used as an intervention drug to investigate the role of MKP-1 and MAPK pathway in depression.Objective1.To observe the effect of chronic unpredictable mild stress on the behavior of SD rats.2.To investigate the protein expression of MKP-1,p-ERK,ERK,p-JNK,JNK,p-p38 and p38 in hippocampus of brain area of each group rats.Methods1.Grouping and CUS modeling of SD rats50 SPF male SD rats,according to the first open field test eliminated 10 outlier rats,the remaining rats were randomly divided into normal group,CUS group,CUS+ saline group and CUS+fluoxetine group with 10 rats in each group.CUS group,CUS+ saline group and CUS+ fluoxetine group received 8 weeks of CUS modeling.10 kinds of stimulis were randomly arranged,1 kind of daily,1 week does not appear the same stimulation,so that the rats can not predict the next stimulus.2.Drug interventionThe rats in the CUS+ fluoxetine group was given fluoxetine for 4 weeks,and the rats were given intragastric administration of 10 mg / kg per day.The rats in the CUS+ saline group were given saline for 4 weeks.Rats of the same body weight were given the same volume of saline as fluoxetine.Intragastric administration was performed from fifth to eighth weeks in the experiment.3.The behavioral assessmentFour methods such as body mass increase,open field test,sucrose preference test and forced swimming were used to evaluate the behavior of SD rats before and after CUS modeling and after treatment.4.Detection of protein expression of MKP-1,ppERK,ERK,ppJNK,JNK,p-p38 and p38The protein expression of MKP-1,p-ERK,ERK,p-JNK,JNK,p-p38 and p38 in the hippocampus of rats were detected by Western blotting.5.Statistical methodsSPSS 19.0 software was used to process the data.The data were presented as mean ± SD(x ± s).Multiple groups of measurement data were analyzed by one-way analysis of variance(one-way ANOVA).When there was homogeneity of variance,LSD method was applied,or Tamhane test was applied.The data was considered significant at a p-value < 0.05.Results1.behavioral assessmentThere were no statistically significant differences in the body weight,horizontal movement distance,vertical movement times,crossing cells times in the open field test,the sucrose preference index and forced swimming immobility before the stimulation of CUS in each group(P> 0.05).After 4 weeks of modeling,compared with the normal group,the body weight decreased,the distance of horizontal movement decreased,vertical movement times decreased,crossing cells times decreased,the sucrose preference index decreased and the immobility time of forced swimming increased in the CUS group,the CUS + saline group and the CUS + fluoxetine group and the difference was statistically significant(P<0.05).But there were no significant differences in the body weight,the open field test(horizontal movement distance,vertical movement times,crossing cells times),the sucrose preference index and forced swimming immobility among the CUS group,the CUS + saline group and the CUS + fluoxetine group(P> 0.05).Compared with rats of CUS group,after 4 weeks of intragastric administration of saline,the body weight gain,open field test(horizontal distance,vertical frequency and the number of passing cells),sucrose preference index and forced swimming immobility time showed no significant difference(P> 0.05);Compared with the normal group,the body weight gain decreased,the horizontal distance decreased,vertical frequency decreased,the number of passing cells decreased,the sucrose preference index decreased,and the immobility time of forced swimming increased,the difference was statistically significant(P <0.05).Compared with rats of CUS group,after 4 weeks of intragastric administration of fluoxetine,the body weight gain increased,the horizontal distance increased,vertical frequency increased,the number of passing cells increased,the sucrose preference index increased,and the immobility time of forced swimming reduced,the difference was statistically significant(P <0.05).Compared with the normal group,the body weight gain,open field test(horizontal distance,vertical frequency and the number of passing cells),sucrose preference index and forced swimming immobility time showed no significant difference(P > 0.05).2.Immunoblotting results(1)The expression of MKP-1 proteinMKP-1 protein expression: Compared with the normal group,the MKP-1expression were significantly increased in the CUS rats and the difference was statistically significant(P < 0.05).After saline intervention,compared with CUS rats,the expression of MKP-1 had no significant difference(P > 0.05).But the rats after intervention of fluoxetine compared with CUS group,the expression of MKP-1 was down regulated and the difference was statistically significant(P < 0.05)and there was no significant difference between CUS + fluoxetine group and normal group(P> 0.05).(2)The expression of p-ERK/ERK proteinp-ERK / ERK protein expression: Compared with the normal group,the expression of p-ERK/ERK were significantly reduced in the CUS rats and the difference was statistically significant(P < 0.05).After saline intervention,compared with CUS rats,p-ERK/ERK expression did not change significantly(P > 0.05).But after intervention of fluoxetine,the expression of p-ERK/ERK were significantly compared with the CUS rats(P < 0.05)and there was no significant difference between CUS + fluoxetine group and normal group(P> 0.05).There was no significant difference in ERK expression among the four groups(P> 0.05).(3)The expression of p-JNK/JNK proteinThere was no significant statistically difference in the expression of p-JNK/JNK and JNK in normal group,CUS group,CUS+ saline group and CUS+ fluoxetine group(P > 0.05).(4)The expression of p-p38/p38 proteinThere was no significant statistically difference in the expression of p-p38/ p38 and p38 in normal group,CUS group,CUS+ saline group and CUS+ fluoxetine group(P > 0.05).Conclusions1.MKP-1 may be an important gene for the onset of depression and may be a potential therapeutic target for the treatment of depression.2.The ERK pathway may be the most closely related to the pathogenesis of depression in the MAPK signaling pathway.3.MKP-1-ERK may be the point of action of fluoxetine in the treatment of depression.