| BackgroundDepression is a common chronic mental disease in modern clinic.It is characterized by depression,lack of pleasure and slow reaction.It is ranked as the second largest disease by the World Health Organization.It has the characteristics of high recurrence rate,high disability rate,high morbidity and high suicide rate.It seriously affects the physical and mental health of patients.Epidemiological investigation shows that depression often co-occurs with many diseases,among which diabetes mellitus or depression often accompanied by abnormal glucose metabolism is one of the major types.Many studies have shown that depression and diabetes have many common pathogenesis,depression can lead to abnormal glucose metabolism,and abnormal glucose metabolism can also increase the incidence of depression.Bile acid-TGR5-GLP-1 signaling pathway is one of the important pathways involved in glucose metabolism,and liver depression and spleen deficiency syndrome is the main type of depression in traditional Chinese medicine.Therefore,the abnormal expression of TGR5,GLP-1 gene and protein in this signaling pathway may be the research site of the pathogenesis of depression with liver depression and spleen deficiency.ObjectiveBy analyzing the expression of TGR5 and GLP-1 at gene and protein levels in colon and liver tissues,we explored the abnormal glucose metabolism and the mechanism of Xiaoyaosan in depression model rats with liver depression and spleen deficiency.Firstly,we confirm whether there is abnormal glucose metabolism in depression model rats with liver depression and spleen deficiency.Then we further analyze the source of the changes and the pathway of action.Finally,we analyze the effect of signal molecules TGR5 and GLP-1 on the glucose metabolism involved in bile acid-TGR5-GLP-1 signaling pathway,and explore the anti-depression target of Xiaoyaosan through regulating glucose metabolism.MethodsThe rat model of depression of liver-depression and spleen-deficiency type was reproduced by CUMS.The model was made by randomly giving 7 kinds of stimuli,such as heat baking,foreign body,odor,noise,tail clipping,45 degree cage inclination,fasting and water fasting for 6 weeks.After the establishment of the model,we observed the general state of hair color,body weight,food intake,behavior(open field experiment,sugar consumption experiment)of rats,and used Xiaoyaosan prescription as proof,fluoxetine as positive control drug to evaluate the success of the model replication from multiple perspectives.The concentration of serum glucose in rats was measured by glucose oxidase(GOD)to verify the disorder of glucose metabolism in model rats.The expression of TGR5 and GLP-1 in colon and liver tissues was detected by RT-q PCR,and the expression of TGR5 and GLP-1 in colon and liver tissues was detected by immunohistochemistry.Results(1)Six-week CUMS duplicated depression model rats with liver depression and spleen deficiency showed dry hair,tiredness and laziness,irregular stool knots,reduced food intake and weight gain,as well as decreased central area retention time,standing number and modification number,and decreased total exercise distance in open field experiment.After treatment with Xiaoyaosan and fluoxetine respectively,the related indexes of rats could be improved to some extent(2)The serum glucose concentration of the model rats was abnormal.Compared with the normal group,the blood glucose concentration of the model rats increased significantly(P<0.Ol).Compared with the model group,the blood sugar concentration in Xiaoyaosan group was lower,with statistical significance(P<0.05).(3)The results of RT-q PCR showed that the expression of TGR5 and GLP-1 in colon and liver tissues of rats in the model group was lower than that in the normal group,and the difference was statistically significant(P<0.01);Compared with the model group,the indexes in the Xiaoyaosan group were up-regulated,and the difference was statistically significant(P<0.01).(4)Immunohistochemical results showed that compared with the normal group,the expression of TGR5 and GLP-1 in the colonic and hepatic tissues of rats in the model group decreased;compared with the model group,the expression of TGR5 and GLP-1 in the colonic and hepatic tissues of rats in the Xiaoyaosan group increased,and the difference was statistically significant(P<0.01),and the expression of TGR5 and GLP-1 was basically consistent with the change of gene expression.Conclusion(1)Depression model rats with liver depression and spleen deficiency were successfully reproduced by CUMS method for 6 weeks.(2)The abnormal elevation of serum glucose concentration in model group indicates that there is indeed a disorder of glucose metabolism in depression model rats with liver depression and spleen deficiency.After the intervention of Xiaoyaosan,the blood sugar concentration decreased to a certain extent.It is speculated that Xiaoyaosan may play an antidepressant role by regulating glucose metabolism.(3)Bile acid-TGR5-GLP-1 pathway is an important way to regulate glucose metabolism.The signaling molecules TGR5 and GLP-1 on this pathway are significantly lower in the gene and protein levels in the colon and liver of rats in model group.After the intervention of Xiaoyaosan,the expression of each index has been up-regulated to a certain extent.It is suggested that abnormal expression of TGR5 and GLP-1 in colon and liver tissues may be one of the reasons for the imbalance of glucose metabolism in depression. |
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