Study On The Antidepressant Activity And Related Mechanism Of Xylanin

Depression is an illness that severely affects the mental health and the life quality of human.The prevalence of depression increased annually,which has gradually become a global health problem.In light of the deficiencies of current antidepressants,the development of new antidepressants has been a main research direction.Cajaninstilbene acid(CSA)is a bioactive stilbene isolated from pigeon pea leaves and has exhibited various pharmacological activities,including anti-oxidative,anti-tumor,hypoglycemic and antibacterial effects.Our previous studies have shown that CSA exhibits an obvious neuroprotective effect by inhibiting oxidative stress and endoplasmic reticulum(ER)stress-mediated apoptosis.Based on those,it is hypothesized that CSA might exhibit antidepressant-like effects,which have never been reported previously.Hence,aimed to find out a relatively safe candidate that can be further developed into a new antidepressant,this study first evaluated the antidepressant effects of CSA by adopting several animal models of depression.In addition,this study also explored the possible mechanisms of CSA,mainly focusing on the HPA axis,neurotransmitter,tryptophan(TRP)metabolism and synaptic plasticity which are all closely related to the pathogenesis of depression.The details are as follows:1.The antidepressant effect in behavioral despair model mice and the acute toxicity of CSA.Tail suspension test(TST)and forced swimming test(FST)were conducted in male BALB/c mice after the oral administration of CSA for 7 days.The results showed that CSA(30 mg/kg)significantly reduced the immobility time of mice in TST.CSA(30 mg/kg3 60 mg/kg)significantly reduced the immobility time of mice in FST.These results reveal that CSA can exert antidepressant-like effects at certain doses.Acute toxicity test showed that the LD50 of CSA was 674.5 mg/kg,95%confidence interval was 572.8-798.2 mg/kg.According to the oral acute toxicity grading standard,CSA is assessed as a low toxic substance.2.The antidepressant effect of CSA in chronic unpredictable mild stress(CUMS)mice.CUMS model was carried out in male BALB/c mice,and the behavioral tests were conducted after CUMS procedure,including body weight test,sucrose preference test,open field test,novelty-suppressed feeding(NSF)test,TST and FST.The CUMS procedure could cause depressive-like behaviors of mice,that were reflected by decreased sucrose preference,increased latency to feed in NSF and increased immobility time in TST.While,CSA(15,30 mg/kg)was found to significantly increase the sucrose preference and decrease the latency to feed in NSF of CUMS mice.And CSA(30 mg/kg)obviously reversed the increased immobility time and the decreased work that induced by CUMS in TST.These results further prove that CSA have antidepressant-like effects.And CSA seemed to have no effects on body weight and locomotion of mice in body weight test and open field test.Compared with the normal control group,the immobility time of CUMS mice in FST was not significantly prolonged,and neither paroxetine nor CSA significantly changed the immobility time of CUMS mice.3.The effect of CSA on serum corticosterone levels of CUMS mice.Serum corticosterone levels were detected by ELISA.It was found that CSA could reverse the increase of serum corticosterone level induced by CUMS,suggesting that CSA may exert antidepressant effects through suppressing HPA axis activation.4.The effect of CSA on brain neurotransmitters levels of CUMS mice.The concentrations of several neurotransmitters in cortex and hippocampus of mice were determined by LC-MS/MS.It was found that CUMS paradigm induced a significant decrease in the levels of norepinephrine(NE),dopamine(DA),glutamate(Glu)and y-aminobutyric acid(GABA)in cortex of mice when compared to the normal control group.And CSA 7.5 mg/kg markedly raised the levels of NE,Glu and GABA.CSA treatment significantly raised the levels of NE,Glu and DA at 15 mg/kg,and increased the levels of 5-hydroxytryptamine(5-HT)at 30 mg/kg.Moreover,there is a significant decrease in the levels of acetylcholine(ACh)in hippocampus of CUMS mice as compared to the normal control mice,and this could be reversed by CSA(7.5 mg/kg,15 mg/kg)treatment.These results showed that CSA may produce antidepressant-like effects by regulating the levels of brain neurotransmitters.5.The effect of CSA on TRP metabolism of CUMS mice.The levels of TRP and its metabolites in the cortex,hippocampus and serum of mice were determined by LC-MS/MS,including TRP,5-HT,kynurenine(KYN),kynurenic acid(KYNA),3-Hydroxykynurenine(3-HK)and 5-Hydroxyindoleacetic acid(5-HIAA).The results showed that the TRP and KYNA levels in the cortex of CUMS mice were significantly reduced as compared with the normal group.CSA 7.5 and 15 mg/kg significantly increased the KYNA level,while CSA 30 mg/kg obviously increased the 5-HT level in the cortex of CUMS mice.In hippocampus,compared with the normal group,The KYN level of CUMS mice was significantly increased.However,neither paroxetine nor CSA significantly changed the levels of TRP and its metabolites in the hippocampus of CUMS mice.In serum,CUMS paradigm induced a significant decrease in the levels of 5-HT,KYNA,and an increase in the level of KYN when compared to the normal control group.Paroxetine and CSA 7.5 mg/kg significantly reduced the KYN level,and CSA 30 mg/kg significantly increased the KYNA level in the serum of CUMS mice.It,s suggested that the antidepressant-like effects of CSA might be related to its regulation on TRP metabolism.6.The effect of CSA on synaptic plasticity related proteins and pathways in the cortex of CUMS mice.CUMS could induce a significant decrease in the levels of brain derived neurophic factor(BDNF),tropomyosin receptor-related kinase B(TrkB)and postsynaptic density protein-95(PSD-95),and also suppressed the phosphorylation of protein kinase B(Akt)and mammalian target of rapamycin(mTOR)in the cortex of mice.While these alterations could be reversed by CSA treatment.These findings raise the possibility that CSA treatment might produce antidepressant-like effects through upregulating BDNF/TrkB and Akt/mTOR pathway and promoting postsynaptic protein synthesis in the cortex of CUMS mice.7.The effects of CSA on the levels of neurotransmitters,TRP and its metabolites in the mPFC intercellular fluid of rats.Based on brain microdialysis techniques,the microdialysis samples in mPFC of male SD rats and CUMS male SD rats were dynamically collected within 6 h after intravenously administration of CSA(10 mg/kg).And the samples were determined by LC-MS/MS method.The results showed that CSA could increase the levels of NE,Glu and ACh and decrease the level of KYN in the mPFC interstitial fluid of normal awake rats.For CUMS rats,CSA could increase the level of KYNA and reduce the levels of 5-HIAA and KYN.The results indicate that CSA can rapidly regulate the levels of neurotransmitters and TRP metabolism in mPFC of rats.In conclusion,the present study suggests that CSA could effectively reverse the depressive-like behaviors of depression model animals.And the antidepressant-like effects of CSA might be attributed to its regulation on HPA axis,neurotransmitters levels,TRP metabolism and synaptic plasticity related proteins and pathways.