Antidepressant Effects And Its Mechanism Study Of Angelica Dahurica And Its Compounds

Depression is one of the most serious mental disorders.Because of its high prevalence,high recurrence,high disability and high mortality,it has become a prominent public health problem.With the rapid economic and social development,depression has become more prevalent,there are approximately55 million people afflicted with depression in China.Although several pathogenetic hypotheses have been proposed one after another,the mechanism remains unclear.Long-term drug intervention is the main method to alleviate depression,however,there are limits such as low efficiency,slow onset,and prominent side effects in Chemical drugs.,Based on multitarget,Chinese herbal medicines such as Bajitian Oligosaccharide and Shugan Jieyu Capsule has a unique advantage in the prevention and treatment of depression.It is of great significance to find better antidepressants of Chinese herbal medicine by using modern pharmacology and Chinese medicine theory.Angelica dahurica,borneolum and Ligusticum Chuanxiong,clinically used as analgesics,play a vital role in regulating depression-related central nervous transmitters,.To selecte a optimized compound,we evaluated theantidepressant effects of Angelicae Dahuricae(AD),Angelica dahurica &borneolum(ADB)and Angelica dahurica & Ligusticum Chuanxiong(ADCX)and explored its underlying mechanisms.1.The evaluation of antidepressant effects of AD,ADB and ADCX.The anti-depressant activity of AD,ADB and ADCX were evaluated by mouse tail suspension,mouse forced swimming test and LPS-induced depression model.Single administration of AD(9g/kg,i.g.),ADB(3+0.017g/kg,9+0.05g/kg,ig)and ADCX(0.5g/kg)significantly decreased the immobility time in TST and FST in mice,and had not affect on the spontaneous activity of mice;ADB(3+0.017g/kg,9+0.05g/kg)could reverse the increase of immobility time in TST and FST caused by LPS,and ADCX doesn’t work.Based on the above results,ADB is preferred compound,the compatibility of AD and borneolum can reduce the dose of AD and show a synergistic effect.2.The evaluation of antidepressant-like effect of ADBWe evaluated the antidepressant-like effects of ADB by using Chronic unpredictable mild stress model(CUMS)in rates and learned helpless(LH)paradigm in mice.Sub-chronic ADB treatment(9+0.05g/kg,once daily for 4 consecutive days,i.g.)significantly reduced the number of escape failure and escape latency in LH mice;Chronic ADB treatment(9+0.05g/kg,once daily for 35 consecutivedays,ig)significantly reversed depressive-like behaviors in CUMS rats,including reduced sucrose preference in sucrose preference test and prolonged latency in novelty-suppressed feeding test,similar to positive drug Flu.3.The evaluation of antidepressant-like mechanisms of ADB.Using four drug interaction models of 5-HTP induced mouse head-twitch test,PCPA-induced depletion of serotonin in mouse tail suspension test,yohimbine toxicity potentiation test and reserpine-induced monoamine depletion test to evaluate the effect of ADB(9+0.05g/kg,i.g.)on mouse monoaminergic system;Using high performance liquid chromatography with electrochemical detector(HPLC-ECD)to test the level of monoamine and its metabolic rate in brain of reserpine treated mice;Using Western-blot to test the expression of brain-derived neurotrophic factor(BDNF),tyrosine kinase receptor B(TrkB),phosphor-cAMP response element binding protein(p-CREB)in the hippocampus of LH mice and CUMS rats.Using ELISA method to measure the pro-inflammatory cytokine level and Western-blot to evaluate the activation of microglia in the hippocampus of LPS induced depresson-like mice.Then comparing the distribution of furocoumarins in blood and brain tissues in rats after acute administration of AD(9g/kg,i.g.)and ADB(9+0.05g/kg,i.g.)by high performance liquid chromatography mass spectrometry(LS-MS).Based on monoamine hypothesis,acute administration of ADB(9+0.05g/kg,ig)significantly potentiated the mouse head-twitch responseinduced by 5-HTP,and decreased the immobility time in mouse tail suspension test,which was completely cancelled by PCPA pretreatment;ADB also could oppose the blepharoptosis induced by reserpine in mice,but had no effect on mortality induced by yohimbine as well as akinesia and body temperature drops induced by reserpine.These results indicated that acute treatment with ADB produced serotonergic,but not noradrenergic activation.Furthermore,ADB normalized the neurotransmitter changes,including the decreased serotonin(5-HT)and its metabolic rate induced by reserpine.ADB(9+0.05g/kg,i.g.)significantly promoted the expression of Brain-derived neurotrophic factor(BDNF),Tyrosine kinase receptor B(TrkB)and p-CPEB in LH mice and CUMS rates;ADB also reduced the expression of Tumor Necrosis Factor-α(TNF-α),interleukin-1β(IL-1β),interleukin-6(IL-6)in the hippocampal of LPS induced depression like mice,reversed activation of microglia induced by LPS.The result of LC-MS showed that the concentration of imperatorin,isoimperatorin,and bergapten in the blood,hippocampus and prefrontal cortex of rats in the ADB(9+0.05g/kg,i.g.)group were higher than the AD(9g/kg,i.g.)group;meanwhile,the tissue-to-plasma exposure ratio(Kp)of imperatorin,isoimperatorin,and bergapten in AD and ADB were almost the same,namely,the synergistic effect of of AD and B is related to that Borneolum increased the blood concentration and bioavailability of AD.Conclusion(1)AD,ADB and ADCX possesses antidepressant-like effects in multiple animal models of depression,meanwhile,ADB is the optimized compound,the synergistic effect of AD and Borneolum is associated with the increased blood concentration and bioavailability of AD induced by Borneolum.(2)The mechanisms underlying the antidepressant-like effects of ADB may bethat ADB significantly potentiates serotonergic transmission in brain,andupregulates the activity of BDNF-TrkB-CREB signaling pathway in hippocampus.In addition,ADB inhibits the activation of microglial and reduces brain inflammatory damage.