Protective Effect And Mechanism Of Water Extract Of Eucommia Ulmoides Oliver On The Neuroinflammation Induced By Chronic Unpredictable Mild Stress In Hippocampus Of Mice

Depression is a kind of mental illness characterized by abnormal feelings and emotions,vegetative neurological disorders(including eating and sleeping problem),cognitive impairments(such as inappropriate guilt and worry),and other abnormal mental activities.At present,the incidence of depression is higher than past,seriously affects the quality of life of patients,and can even lead to suicide.But the pathogenesis of depression is not clear,there are many hypotheses and has no effective treatment in clinical.Since Eucommia ulmoides has a variety of pharmacological components,certain neuroprotective effects and anti-inflammatory properties,it may be a potential drug to improve depression.This experiment is based on Chronic Unpredictable Mild Stress(CUMS)to build the depression mice model.We used the Water Extract of Eucommia ulmoides(WEU)to intervene the model mice,and finally the therapeutic effect was observed and the mechanism was explored.2-month-old ICR mice were randomly divided into two groups: control group(n=15)and CUMS group(n=40).Mice in the CUMS group were subjected to seven different chronic unpredictable mild stimuli,such as: Ice bath,tail suspension,cliping tail,damp bedding,electrical stimulation,forced swimming,shackles,etc.The modeling cycle is 4weeks.After completion of modeling,we used the behavioral tests,such as the tail suspension test,forced swimming,open field test and elevated maze test screening CUMS successfully induced mice model of depression,and all the depressive mice were randomly divided into 2 groups: Model group(CUMS,n=13)and WEU treatment group(WEU,n=13).Mice in the WEU group were given a maintenance diet containing 3%(w/w)water extract of ulcommia skin for 2 weeks,as for mice in the control group and CUMS group were given a normal diet for 2 weeks.After that,mice in each group were subjected to behavioral tests,and immunofluorescence staining was used to detect the number and morphology of microglia cells,the number of new neurons and the differentiation of neural progenitor cells in the hippocampus of mice.The changes of protein levels in inflammationrelated pathways were detected by Western Blot.The changes of intestinal microorganism in mouse cecum were detected by 16 Sr RNA high-throughput sequencing.Main conclusions are as follows:1.We sccessfully build the CUMS depressive mice model,the model of mice in the forced swimming test and tail suspension test showed longer immobility time.After WEU treatment,the immobility time of mice in tail suspension test and forced swimming test was significantly reduced,indicating that the depression-like behavior of mice was improved.At the same time,WEU treatment increased the movement distance in the central area of the open field test and the movement distance in the elevated plus maze,indicating that the desire to explore was enhanced and the anxiety of mice was reduced.2.WEU significantly inhibited the activation of microglia cells,decreased the number and complexity of microglia,and reduced the activation of microglia cells by inhibiting the activation of TLR4/NF κBp38/MAPK signaling pathway,thus alleviating the occurrence of neuroinflammation in the hippocampus of mice.3.The total number of proliferating cells in the hippocampus of mice in each group had no significant effect,but compared with the control group,the number of new granule cells in the hippocampus of mice in the CUMS group was significantly reduced,and the number of new granule cells was significantly increased after treatment with WEU.Compared with the control group,CUMS can significantly decrease the proportion of radial glia-like progenitors in proliferating cells,while WEU can inhibit this decrease induced by CUMS.4.CUMS caused the disturbance of intestinal microflora in mice and changed the original intestinal microflora structure,while WEU treatment could inhibit this change to a certain extent,making the composition of intestinal microflora in the treatment group more similar to that in the control group.These conclusions above suggest that Eucommia ulmoides may be a potential antidepressant drug,which can correct depressive-like behavior,improve neuroinflammation,and correct the disordered intestinal flora,which providing a new idea for the development of drugs for depression.