Antidepressant Effect And Pathogenesis Of Oridonin In CUMS-induced Depression Mouse Model

Major depressive disorder(MDD)is a kind of mental illness with the highest incidence can affect people’s mood,mobility and health,and it is characterized by prolonged feelings of hopelessness and anhedonia.The pathogenesis of MDD has not been clear,but it is known to be associated with changes in neuroinflammation,neuroendocrine and neuroplasticity caused by stress stimulation.Oridonin(Ori)is a diterpenoid substance with anti-inflammatory and neuroprotective effects,and it has potential antidepressant effect.Chronic unpredictable mild stress(CUMS)is a modeling method of depression that can realistically simulate the state of depressed mood caused by long-term chronic stress in patients.In this study,we successfully established a mouse model of depression using the CUMS regimen.We used ori to intervene the model mice,and explore its therapeutic effect and antidepressant pathogenesis.4-5 weeks-old-C57BL/6 male mice were adaptively fed for two weeks.After excluding mice with obvious behavioral deviation,they were randomly divided into two groups: control group(n=10)and CUMS group(n=30).Mice in CUMS group received two different mild stimuli during the day and night,such as wet padding and water prohibition.Each stimulus appeared discontinuous and irregular.After 28 days of modeling,the mice in CUMS group were tested for sucrose preference,open field,tail suspension and forced swimming,and the mice with depression were selected.Depressed mice were randomly divided into model group(CUMS,n=12)and Oridonin group(Ori,n=12).The Ori group was injected intraperitoneally with Ori solution(15mg/kg)for 7 days,and the control group and the model group were intraperitoneally injected with PBS solution containing 2% DMSO.One week later,all mice were tested for behavior,such as sucrose preference,open field,social interaction,tail suspension and forced swimming.Nissl staining was used to detect the morphology of neurons in mouse prefrontal cortex,caudate nucleus and hippocampus.HE staining was used to detect the number of cells,and Western blotting was used to detect the changes of protein levels in inflammation related pathways in mouse prefrontal cortex.Main conclusions are as follows:(1)We successfully constructed CUMS-induced depression mouse model.Compared with the control group,the sucrose preference of CUMS group mice decreased,the immobility time increased in tail suspension and forced swimming tests,and the distance of travelled decreased in the open field test.After Ori treatment,the weight of mice increased,the sucrose preference rate increased,the immobility time decreased in tail suspension and forced swimming tests,and the distance of travelled increased in open field test,indicating that oridonin can treat depression in mice.At the same time,Ori treatment increased the number and time of mice passing through the central area in the open field and the communication time with strange mice in the social experiment,indicating that the anxiety of mice was reduced and the desire for exploration of mice was enhanced.(2)The morphology of neurons in prefrontal cortex,caudate nucleus and hippocampus of CUMS mice changed in varying degrees,such as Nissl body reduction and cell shrinkage;The number of cells in prefrontal cortex and hippocampus decreased significantly.Compared with CUMS group,after Ori treatment,the number of cells in prefrontal cortex and hippocampus of mice increased,the morphology of neurons was regular,and Nissl bodies were clearly visible.It shows that oridonin has a significant neuroprotective effect in the treatment of depression.(3)The protein levels of p-p38 and NF-κB(p65)and NLRP3 increased significantly in prefrontal cortex of CUMS mice,indicating that depression is related to the occurrence of inflammatory response.Ori can reduce the activation of p38 MAPK /NF-κB/ NLRP3 signaling pathway,and plays an anti-inflammatory role in the treatment of depression.In conclusion,oridonin has obvious neuroprotective and anti-inflammatory effects in the treatment of depression.Oridonin can inhibit p38MAPK/NF-κB/NLRP3 signaling pathway,thus treating CUMS-induced depression mice.Oridonin is of great significance for the development of rapid antidepressants.