| Background: According to the data published by the WHO(the World Health Organization)on February 23 th 2017,322 million people in the world are currently suffering from depression;From 2005 to 2015,the number of depressive patients increased by at least 18%;The prevalence of depression in China has reached 4.2%,and the related years lived with disability(YLD)accounts for 7.3% of the total YLD.metformin and exercise can improve depressive behavior,but the molecular mechanism of the two functions has not been fully elucidated.The study has fully demonstrated that patients with depression have HPA axis dysfunction,abnormal monoamine function,decrease of brain derived neurotrophic factor and increase of central inflammatory response.In clinic,the phenomenon of depression in diabetics is attracting more and more attention,and vice versa.The glucagon like peptide,including glucagon like peptide-1(GLP-1)and 2(GLP-2),is an important target for the treatment of diabetes.Recent studies have shown that GLP-1,GLP-2,or its receptor agonists,and hydrolase inhibitors have antidepressant and antianxiety effects,but the mechanism of this functional molecule has not yet been fully elucidated.GLP-1 is a kind of enteric insulin secreted by enteral L cells in a nutritional dependent manner,which has a Glucose dependent insulin secretion function.It has a certain neuroprotective effect.However,it is not clear that the role of GLP-1 playing in the neurophysiological mechanism of depression.Objective: The research aims to explore the changes in the expression of GLP-1 and related signaling proteins in the brain region based on the chronic stress depression model,which further explores the effect and mechanism of metformin and exercise to improve depression.Methods: 40 male C57BL/6 mice,4-5 weeks old,weighing 18-20 g were selected inthe experiment.All the experimental mice were randomly divided into 5 groups,8 in each group:(1)group CON,normal control group;(2)group CUMS,the experimental mice received 8 weeks of chronic unpredictable mild stress;(3)group CUMS+Met(CM),the experimental mice accepted 8 weeks of chronic unpredictable mild stress,from the fourth week of stress,the mice were injected the oral antidiabetic drug metformin(Met);(4)group CUMS+Ex(CE),the experimental mice received chronic unpredictable mild stress for 8 weeks,from the fourth week of stress,the mice started appropriately adaptive exercise,from fifth week,the mice began the treadmill exercise(Ex);(5)group CUMS+Met+Ex(CME),the experimental mice received 8weeks of chronic unpredictable and mild stress,from the fourth week of stress,the mice started exercise and drug intervention.After 8 weeks of experimental intervention,all groups of mice were accepted the behavior test,including body weight,sucrose preference test,forced swimming test and open field test.After the behavior test,the mice were executed for taking blood and hippocampus tissues.The content of serum corticosterone(CORT)and glucagon like peptide-1(GLP-1)was detected by Elisa,and the expression of GLP-1 receptor(GLP-1R)in hippocampus was detected by immunohistochemical technique,and Western blotting was used to examine the protein level of GLP-1,BDNF,ERK1/2,p ERK1/2 in the hippocampus.Results:(1)Compared with the CON group,the body weight of mice in the CUMS group was significantly slower(P<0.01),the sucrose preference(P<0.01),the number of poking into holes(P<0.05)and distance of central route(P<0.01)in the open field test(OFT)decreased significantly,the floating time in the forced swimming test(FST)increased significantly(P<0.01),and the serum CORT level increased without statistical difference.Compared with the CUMS group,the sucrose preference(P<0.01)and the number of poking into holes(P<0.01)and the distanceof central route(P<0.05)in OFT were significantly increased in the CM group,but the floating time of FST(P<0.05)and the serum CORT level(P<0.01)were significantly reduced.Compared with the CUMS group,the sucrose preference(P<0.01)and the number of poking into holes(P<0.01)and the distance of central routes(P<0.01)in OFT were significantly increased in the CE group,but the floating time of FST(P<0.01)and the serum CORT level(P<0.01)were significantly decreased.Compared with the CUMS group,the the sucrose preference(P<0.05)and the number of poking into holes(P<0.01)and the distance of central routes(P<0.01)in OFT were significantly increased in the CME group,but the floating time of FST(P<0.01)and the serum CORT level(P<0.01)were significantly decreased.Compared with the CM group,the number of poking into holes(P<0.05)and distance of central route in OFT(P<0.01)were significantly increased in the CE group,the number of poking into holes(P<0.01)were significantly increased in the CME group,but the serum CORT level(P<0.01)decreased significantly;Compared with the CE group,the distance of central routes was significantly decreased in the CME group.(2)Compared with the CON group,there was no statistical difference in the serum GLP-1 level in the CUMS group,but the protein expression of GLP-1 in the hippocampus decreased significantly(P<0.05),and the expression of GLP-1R decreased without statistical significance.Compared with the CUMS group,the serum GLP-1 level(P<0.01)and the protein expression of GLP-1 in the hippocampus(P<0.05)in the CM group were significantly increased.Compared with the CUMS group,the serum GLP-1 level(P<0.01)and the protein expression in the GLP-1hippocampal(P<0.01)in the CE group were also significantly increased.There was no significant difference in the expression of GLP-1R in group CE and CME.In addition,the serum GLP-1 level in CE group was significantly increased than in CM group(P<0.05),and the serum GLP-1 level in CME group was significantly decreased than in CE group(P<0.01).(3)Compared with the CON group,the protein level of p ERK1/2 in the hippocampus of CUMS mice decreased significantly(P<0.01),the protein level of BAX increased significantly(P<0.05),and the protein levels of BDNF,ERK1/2 and Bcl-2 decreased without significant difference.Compared with the CUMS group,the protein level of p ERK1/2 in the hippocampus of CM group increased significantly(P<0.01),the protein level of BAX decreased significantly(P<0.05),the protein level of BDNF,ERK1/2 and Bcl-2 increased with no significant difference.Compared with the CUMS group,the protein level of the p ERK1/2 in the hippocampus of CE group increased significantly(p<0.05),and the protein level was significantly reduced(p<0.05).Compared with CUMS,the protein level of ERK1/2,p ERK1/2 and Bcl-2 in the hippocampus of CME mice increased significantly(P<0.05),the protein level of BAX decreased significantly(P<0.01),and the protein level of BDNF increased,but there was no significant difference in the level of BDNF.Conclusion:(1)Exercise and metformin is separately or combinedly applied in the mice,both of which could improve the depressive behavior of experimental mice in the chronic unpredictable mild stress.More importantly,metformin enhances the effect of antidepression through exercising to some extent.(2)Chronic unpredictable mild stress inducing depressive behavior is related to the expression decrease of GLP-1 in the hippocampus.Exercise and metformin may improve depressive behavior by raising the content of serum GLP-1 and the expression of GLP-1 protein in the hippocampus.(3)Chronic unpredictable mild stress inducing depressive behavior may involve the dysfunction of GLP-1//ERK/Bcl-2/BAX signaling pathway,and GLP-1 mediating exercise affecting antidepressant action may play a role through this signaling pathway.Significance: This study focuses on the possible molecular mechanisms of GLP-1-mediated depression.On this basis,it explores and compares the antidepressant effect and mechanism of exercise and metformin separately and combinedly,which demonstrates that metformin can enhance the effect of antidepression through exercise.These findings provide theoretical support for antidepressant through exercise,and offer a strategy for depression treatment with the joint intervention of medicines and exercises. |
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