Mechanism Of Antidepressant Action Of Ziziphi Spinosae And Albizia Julibrissin Flower Based On Endoplasmic Reticulum Stress PERK-ATF4-CHOP Pathway

Objective:Mechanism of antidepressant action of herbal pair of Semen ziziphi spinosae and Albizia julibrissin flower based on endoplasmic reticulum stress PERK-ATF4-CHOP pathway.Methods:Healthy male SPF SD rats were randomly divided into normal group,model group,venlafaxine group（0.008g/kg）and high（16g/kg）medium（8g/kg）and low dose（4g/kg）group of herbal pair of Semen Ziziphi spinosae and Albizia julibrissin flower.Except for the normal group,the other five groups used chronic unpredictable mild stress（CUMS）combined with solitary rearing to make rat depression models.At the same time,the normal group and the model group were given equal volume of distilled water according to the body weight of 10ml/kg,and the other groups were given equal volume of corresponding drug suspension for 21 days.Open-field experiment and sugar water preference experiment were carried out on the first day and the 21^stday before modeling,and the behavioral changes of rats in each group were observed.At the end of behavioral test on the 21^stday of modeling,the rats were dissected,the ultrastructural changes of hippocampal neurons in each group were observed under transmission electron microscope,the apoptosis of hippocampal neurons in each group was observed by TUNEL method,and the protein expression levels of PERK,CHOP,Bax and Caspase-3in hippocampus of each group were observed by Western blot.Results:Open-field experiment showed that compared with normal group,the scores of horizontal movement and standing times in model group decreased（P<0.01）.Compared with the model group,the scores of horizontal movement and standing times of rats in high,middle and low dose groups of herbal pair of Semen ziziphi spinosae and Albizia julibrissin flower and venlafaxine group were higher（P<0.01）.The scores of horizontal movement and upright times in the medium dose group were higher than those in the other dose group（P<0.01）.Sucrose preference testshowed that Compared with the normal group,the preference of sugar water in the model group decreased（P<0.01）.Compared with the model group,the preference for sugar water in high,middle and low dose herbal pair of Semen ziziphi spinosae and Albizia julibrissin flower groups and venlafaxine group were higher（P<0.01）.The preference of sugar water in the medium dose group was higher than that in the other dose group（P<0.01）.Transmission electron microscope showed,changes of neuronal damage in hippocampal were revealed in the model group,whereas those were neuronal damage reduced in herbal pair of Semen ziziphi spinosae and Albizia julibrissin flower groups and Venlafaxine group.TUNEL method showed that Compared with normal group,the number of apoptotic cells in hippocampus of model group increased,and the difference was statistically significant（P<0.01）.Compared with the model group,the high,medium and low dose groups of ziziphi spinosae and Albizia julibrissin flower and venlafaxine hydrochloride group can improve the number of apoptotic neurons in hippocampus of rats,with statistical significance（P<0.01）.The number of apoptotic neurons in hippocampus of rats in the middle dose group of ziziphi spinosae and Albizia julibrissin flower was lower than that in other doses,and the difference was statistically significant（P<0.01）.Western Blot results showed,Compared with the normal group,protein expressions of PERK,CHOP,BAX and Caspase-3 were up-regulated significantly in the model group（P<0.01）Compared with the model group,the expression levels of PERK,CHOP,Bax and Caspase-3protein in hippocampus of rats in high,middle and low dose herbal pair of Semen ziziphi spinosae and Albizia julibrissin flower groups and venlafaxine group were decreased（P<0.05 or P<0.01）,The expression levels of PERK,CHOP,Bax,Caspase-3 protein in hippocampus of middle dose group were lower than those of other dose group（P<0.01）.Conclusion（s）:1.The depression rat model can be successfully established by CUMS combined with solitary rearing,which shows that the score of open field experiment decreases and the preference of sugar water decreases.The state of depression model lasts for a long time and is stable,which has high application value.2.Depression-like behavior of depressed rats may be related to the stress degree of endoplasmic reticulum in hippocampus,and herbal pair of Semen ziziphi spinosae and Albizia julibrissin flower can improve depression-like behavior of depressed rats.3.Herbal pair of Semen ziziphi spinosae and Albizia julibrissin flower can improve the damage of hippocampal neurons in depressed rats and reduce the apoptosis of hippocampal neurons.4.8g/kg Herbal pair of Semen ziziphi spinosae and Albizia julibrissin flower may play an antidepressant role by regulating the expression of related factors in the signal pathway of PERK-ATF4-CHOP.5.Herbal pair of Semen ziziphi spinosae and Albizia julibrissin flower with the functions of soothing the liver and relieving depression,calming the heart and tranquilizing the mind,can play an antidepressant role through heart and liver.