Antidepressant Effect Of Peiyuan Jieyufang On Depression Induced By Chronic Stress And Its Regulatory Mechanism On TRP-KYN Pathway

As the pace of life speeds up,the incidence of depression is rising year by year.According to World Health Organization(WHO)prediction,depression will become the second largest diseases in the world by 2020.Depression seriously affects the mental and physical health of the patients and brings a heavy burden and bad influence to the families and society.Therefore,it is urgent to study the biologic mechanisms and treatment drug of depression.At present,several pathogenesis hypothesis of depression have been put forward,including cytokine hypothesis,monoaminergic hypothesis,neural plasticity hypothesis and so on.The usual clinical agent contain MAO inhibitors,tricyclic antidepressants,SSRIs and SNRI.But there exist many problems when people use these medicines,which include low cure rate,great side effects and poor compliance.In recent years,the abnormality of tryptophan metabolism has become the starting point of the study on depression.Tryptophan is the material of serotonin(5-HT),milling at tryptophan hydroxylase.When the TRP-KYN metabolism is abnormal,tryptophan will be depleted,resulting in the reduction of serotonin,which will lead to depression.In this study,the antidepressant effect of Peiyuan Jieyufang and its regulatory mechanism on TRP-KYN pathway were explored.1.Antidepressant effect of Peiyuan Jieyufang on chronic stress BALB/c mice and its regulation on TRP-KYN pathway.Objective:To study the antidepressant effects of Sini Powder,Tiansi Liquid and Peiyuan Jieyufang as well as the influences on corticosrone and tryptophan 2,3-double enzyme(TDO),the key metabolism enzyme of the TRP-KYN pathway.Methods:The model was established by chronic stress.The immobility time of forced swimming test was acquired and analysed by Noldus EthoVision XT9 system.The content of trptophan(TRP),kynurenine(KYN),kynurenic acid(KA),quinolinic acid(Q)and corticosrone in serum was detected by HPLC-MS/MS technique.The mRNA level of TDO expressed in liver was detected by real-time PCR.Results:After fives days chronic stress,the immobility time of model group prolonged and the serum corticosterone level,KYN/TRP and KYN/KA specific value increased and KYN/Q specific value decreased.Tiansi Liquid,Sini Powder and Peiyuan Jieyufang could shorten the immobility time(P<0.1).It could also cut the corticosterone level(P<0.05),and increase KYN/TRP and KYN/Q specific value(P<0.05)and reduce the KYN/KA specific value.Conclusion:Sini powder,Tiansi Liquid and Peiyuan Jieyufang could reduce the immobility time of chronic stress BALB/c mices,antagonize the increasing of serum corticosterone induced by stress and inhibit metabolite Q in TRP-KYN pathway which has neurotoxic effect.Among them,Peiyuan Jieyufang and Tiansi Liquid eff,ect the immobility time of forced swimming more significantly and Sini powder affects on corticosterone content more obviously.Peiyuan Jieyufang can also promote the generation of KA which has neuroprotective effect.Therefore,all the three components have antidepressant effect,and the Peiyuan Jieyufang is more obvious in shortening the swimming time and regulating the metabolism of TRP-KYN2.The effect of Peiyuan Jieyufang on depression rats reduced by glucocorticoid and its regulation on TRP-KYN pathway.Objective:To study the antidepressant effect of Tiansi Liquid,Sini Powder and different doses of Peiyuan Jieyufang on depression rats reduced by glucocorticoid;its regulation on TRP-KYN pathway and level of TDO and IDO expressed which are the key metabolism enzyme of the TRP-KYN pathway.In addition,its influence on plasticity of hippocampus and cortex were also studied.Methods:The depression model was established by glucocorticoid injection for 28 days and the behavior of the rats was observed by open-field test and sugar water consumption test at the end of the model establishing.The content of TRP,KYN,KA and Q in serum was detected by HPLC.The mRNA expressed levels of IDO,CREB,NMDA,BDNF,TrkB in hippocampus and cortex and the TDO in liver tissues were evaluated.Results:1.Sugar water consumption test:Compared with the control group,the sugar water consumption of model group decreased significantly(p<0.05).Compared with the model group,the sugar water consumption of the honokiol group and the high dose of Peiyuan Jieyufang group increased(p<0.05).2.Open-field test results:Compared with control group,the total score in open-field test of model group decreased significantly(p<0.05).Compared with model group,the total score of fluoxetine,Tiansi Liquid,middle and high dose Peiyuan Jieyufang group was increased significantly(p<0.05).The results of behavioral test show that Peiyuan Jieyufang can improve the depressive behavior of model rats reduced by glucocorticoid.3.TRP-KYN pathway:Compared with the control group,the ratios of KYN/TRP and KYN/KA in model group increased significantly(p<0.05).The expression levels of IDO and TDO mRNA decreased significantly(p<0.05).Compared with the model group(p<0.05),the ratios of KYN/TRP and KYN/KA of the high dose of Peiyuan Jieyufang group decreased significantly(p<0.05);the ratio of KYN/Q increased significantly(p<0.05);the ratio of KYN/TRP in the middle dose of Peiyuan Jieyufang group decreased significantly(p<0.05);the ratios of KYN/KA in fluoxetine and Tiansi Liquid group decreased significantly(p<0.05).Except honokiol group,the expression levels of TDO mRNA in all the drug groups increased significantly(p<0.05).4.Cortical and hippocampal neural plasticity:Compared with control group,the expression levels of BDNF,5-HT1A in the hippocampus and TrkB in the cortex decreased significantly(p<0.05)and the expression levels of NMDA and GR in cortex increased significantly(p<0.05).Compared with model group,the expression levels of BDNF,5-HT1A in hippocampus of middle and high dose Peiyuan Jieyufang group decreased significantly(p<0.05);the expression levels of GR and NMDA increased significantly(p<0.05)and the expression levels of TrkB in cortex of the high dose Peiyuan Jieyufang group increased significantly(p<0.05).Conclusion:The high dose of Peiyuan Jieyufang can improve the activity of open-field test and the consumption of sugar water.But Tiansi Liquid only increased the consumption of sugar water and Sini powder has no obvious effect on open-field activity and sucrose consumption.Peiyuan Jieyufang can reduce the metabolism level of TRP-KYN pathway;inhibit metabolite Q which has neurotoxic effect and promote the generation of KA which has neuroprotective effect.Tiansi Liquid only promote the production of KA and Sini powder had no obvious effect on the regulation of TRP-KYN pathway.Peiyuan Jieyufang can reduce the expression levels of GR and NMD A receptor and improve that of BDNF,5-HT1A in hippocampus and cortex.Sini powder and Tiansi Liquid had no obvious effect on hippocampus and the action of cortex was similar to that of Peiyuan Jieyufang,but the effect of Sini powder on BDNF was not obvious.In conclusion,Peiyuan Jieyufang can reduce the metabolism level of TRP-KYN pathway;inhibit neurotoxicity and improve neuroprotection.It can also improve depression through regulating the neural plasticity of cortex and hippocampus,especially cortex.