Effects Of Xiaoyaosan On Depression And Regulation Of Kynureninue Metabolism Pathway

ObjectiveTo investigate the rats behavioural performance,kynurenine metabolites and related indicators of hippocampus effects of XYS in a rat model of chronic unpredictable mild stress.To study of Xiaoyaosan underlying mechanisms of antidepressant effect preliminarily,and further validation of Xiaoyaosan antidepressant effect.The study provided an objective evaluation index for the diagnosis and treatment of depresssion and the theoretical foundation and experiment for natural antidepressants.Methods30 male SD rats were randomly divided into 5 groups:(1)healthy control group(Normal,no CUMS and 0.9%saline);(2)model group(Model,CUMS plus 0.9%saline);(3)low-dose group of XYS(XYS-low,CUMS plus XYS at the dose of 5.265 g/kg);(4)high-dose group of XYS(XYS-high,CUMS plus XYS at the dose of 10.53 g/kg);(5)Paroxetine(CUMS plus paroxetine at the dose of 10 mg/kg).Rats were randomly given one or two kinds of stress every day expect healthy control group.A CUMS rat model of depression was established via 4 weeks of unpredictable stimulation.Then the rats were orally administered paroxetine and XYS for 2 weeks with continued stress.Behavioral assessments,including an open field test(OFT)and forced swim test(FST)were conducted to evaluate the antidepressant effects of XYS.Blood samples were collected in before model establishment and during this time.All rats were executed and striped hippocampus on day 43.The concentrations in rat plasma of tryptophan(TRP)and its metabolic products,including kynurenine(KYN)and quinolinic acid(QUIN),were determined using high performance liquid chromatography tandem mass spectrometry with electrochemical detection(HPLC-MS/MS).The mRNA and protein levels in rat hippocampus of depression-related brain derived neurotrophic factor(BDNF),cyclic AMP response element binding protein(CREB)and nerve cell adhesion molecule(NCAM)were determined by real-time qPCR and Western blot,respectively.ResultsThe results showed that a successful CUMS rat model was established through 6 weeks of continuous unpredictable stimulation,as indicated by the significant decrease in locomotor activity and increase in immobility time in the OFT,reduction in body weight and food intake etc(P<0.01).After the end of study,compared with the control group,the concentrations of KYN and QUIN had significantly decreased at day 28 in the model group(P<0.01),then the concentrations of KYN has increased trend(P>0.05),the concentrations of QUIN improved after drug treatment with paroxetine and XYS(P<0.01).Compared with the control group,the mRNA of NCAM(P<0.01),CREB and BDNF(P<0.05)were significantly down-regulated in the model group,BDNF gene was up-regulated by XYS-high treatment(P<0.05).Protein expressions of NCAM(P<0.05)and CREB(P<0.01)were significantly down-regulated and BDNF(P>0.05)has no significant differences in the model group.Protein expressions of BDNF and CREB were significantly increased,and NCAM was significantly reduced by XYS treatment(P<0.01).ConclusionsXYS reversed the abnormalities of the tryptophan-kynurenine metabolic pathways in depressed rats and achieved an excellent antidepressant effect.XYS also up-regulated the protein expressions of BDNF,CREB and the down-regulate protein expressions of NCAM in the hippocampus of the depressed rat.Its direct impact may be observed as changes in biological indicators in depression rat.In conclusion,these results suggest that XYS has anti-depression effect,which probably via kynurenine metabolic pathways and neurons in hippocampus,.especially Kyn,QUIN and BDNF.The mechanism of XYS on treating depression should be further studied.