| Background: Depression is one of the common mental disorders,which causes a heavy burden on society and families.However,there are many problems,includinghigh incidence of adverse reactions and poor therapeutic response in the currently used first-line drugs.Bifidobacterium has shown potential antidepressant effects in previous studies,but the mechanism of action has not been fully elucidated.Purpose: The aim of this study is to explore the effects of Bifid triple viable capsules(BTVC)on chronic unpredictable mild stress(CUMS)rat models and the possible mechanisms underlying these effects,provide a theoretical framework for clinical trials Method: In this experiment,30 Sprague Dawley(SD)male rats were randomly divided into normal group(Normal),CUMS model group(Model),fluoxetine 2 mg/kg group(FLX),Bifidobacterium triple viable capsules 20 mg/kg(BTVC)and and fluoxetine +Bifidobacterium trifolium capsule combination(FLX 2 mg/kg + BTVC 20 mg/kg),6 animals in each group.Except for the normal group,CUMS process was performed for 34 days,and the corresponding drugs were administered on the 15 th day;the open field test and the elevated plus maze were conducted to investigate the effect of BTVC on depression-like behaviors of CUMS exposed rats;collecting serum,brain and hippocampal,the brain morphology and the number of Nissl bodies were observed by hematoxylin-eosin staining and Nissl staining;Non-targeted metabolomics techniques and Ingenuity Pathway Analysis(IPA)were used to explore serum differential metabolite changes and the mechanism of protein action in CUMS rats.Western blot was used to detect cyclic adenosine monophosphate response element binding protein(CREB)in the hippocampus,and immunohistochemistry was used to detect endothelin-1 in the CA1 region of the hippocampus Endothelin-1(End1)protein expression level in CA1 region of hippocampus.Results:(1)Open field test: Compared with Normal group,the Model group showed a decrease in the total distance of open-field exercise(P<0.05),a decrease in the distance of the central area,and an increase in the immobility time(P<0.05);Compared with Model group,the drug administration intervention group showed a longer total distance and central area distance,the immobility time was reduced.Elevated cross test: Compared with Normal group,the ratio of times and time of opening arm of Model group were significantly decreased(P<0.05);Compared with the Model group,the frequency ratio and time ratio of rats entering the open arm increased in the intervention group.(2)HE staining: Compared with the Normal group,rats in the Model group showed abnormal cone cell structure and disorganized arrangement.Compared with the Model group,the cone cells in the Model group showed normal structure and neat arrangement.Nissl’s staining: The number of Nissl’s vesicles in the CA1 region of hippocampus was significantly lower in the Model group compared with the Normal group(P<0.05);compared with the Model group,the number of Nissier vesicles in the hippocampal CA1 area of rats increased significantly(P<0.05).(3)Metabolomics: Compared with Normal group,serum PC(14:0/20:1(11z)),Lyso PC(24:0),glycyrcholate taurine,3-dehydrogen-2-deoxyecdyone,PC(O-14:0 /O-1)in Model group: 0),glycholic acid hydrate,perillyl alcohol,meprogesterone,oleyl ethanolamine,eicosapentaenoic acid and vetiver acetate had significant changes(P<0.05);Compared with Model group,serum D-phenylalanine,methoxyeugenol,(±)-myristyine,PE(18:3(6z,9z,12z)/P-18 in BVTC group: 1(11z)),propionyl-L-carnitine and arachidonic acid had significant changes(P<0.05).Compared with Model group,the content in serum of D-phenylalanines,methoxyeugenol,(±)myridamine,PE(18:3(6z,9z,12z)/ P-18:1(11z)),pyrrolidine monohydropyrrolidine and PA(13:0 /22: 0)had significant changes(P<0.05).Compared with Model group,the content in serum of methoxyeugenol,(±)-myristylocarnitine and Kalihinol A in FLX+BTVC group were significantly changed(P<0.05).Metabolite involved pathways include unsaturated fatty acid biosynthesis,glycerol phospholipid metabolism,linoleic acid metabolism and arachidonic acid metabolism.Further IPA analysis was performed to suggest that CREB signaling pathway and End1 signaling pathway may be involved in the development of depression.(4)Western Blot revealed that CREB protein expression was decreased in the hippocampus of rats in the Model group compared with the Normal group(P<0.05).Compared with the Model group,CREB protein was increased in the BTVC,FLX and FLX+BTVC groups(P<0.05).immunohistochemistry revealed that the End1 in the CA1 region was increased in the Model group compared with the Normal group(P<0.05).End1 protein was decreased in the BTVC,FLX and FLX+BTVC groups compared with the Model group(P<0.05).Conclusion: BTVC attenuates depressive-like behavior,improves hippocampal damage and regulates serum metabolism in CUMS rats,and the mechanism may be related to the regulation of hippocampal End1 protein and CREB protein. |
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