Study On The Antidepressant Effect And Mechanism Of Atractylenolide Ⅲ

Background: Depression is a mental illness that seriously threatens human physical and mental health,with etiology and pathogenesis not yet been clarified.Studies have shown that tumor necuosis factor-α(TNF-α),integrated-6(IL-6)and integrated-1β(IL-1β)play a very important role in the pathological process of depression.Atractylenolide III(AT Ⅲ)is an extract of the traditional Chinese medicine Atractylodes macrocephala,which has various activities such as anti-inflammatory and neuroprotective activities.Pharmacological network analysis shows that in the biological processes related to depression-related energy metabolism-immune-signal transformation,AT Ⅲ involves 11 targets.However,whether AT Ⅲ have antidepressant effects in animal models remains unknown.Objective: This study aims to explore the antidepressant effect of AT Ⅲ and its mechanism by investigating the effects of AT Ⅲ on the behavior of depression model rats and content of TNF-α,IL-6 and IL-1β in the hippocampus.Methods:In the current study,AT Ⅲ were administrated with either an acute(1 gavage)or a chronic(1 gavage/day for 28 consecutive days)way.First,the forced swimming test(FST)and the open field test(OFT)were used to assess the antidepressant and anti-anxiety effects of AT Ⅲ.The doses of AT Ⅲ were 3 mg/kg,10 mg/kg and 30 mg/kg,and 10 mg/kg fluoxetine was used as a positive control.Then,the behavioral changes of rats were observed by the FST and OFT;Secondly,we adopted the acute lipopolysaccharide(LPS)induced depression model,the dose of AT Ⅲ is10mg/kg and 30mg/kg,respectively,the FST,sucrose preference test(SPT),novelty suppressed feeding test(NSFT)and OFT were used to observe the behavioral changes of rats.TNF-α,IL-6 and IL-1β in the hippocampus were also detected by ELISA;Finally,the 30mg/kg dose of AT Ⅲ was used in the chronic unpredictable mild stress(CUMS)model.Behavioral changes were assessed by the FST,SPT,NSFT and OFT.Levels of TNF-α,IL-6 and IL-1β in the hippocampus were detected by ELISA.Results:1.In the experiment of acute AT Ⅲ administration to observe its antidepressant effect,we found that the 3 mg/kg,10 mg/kg and 30 mg/kg AT Ⅲ group had no significant effect on the immobility time of normal rats in forced swimming test;In the experiment of chronic AT Ⅲ administration to observe its antidepressant effect,we found that the 3mg/kg and 10 mg/kg AT Ⅲ group have no significant effect on the immobility time of the forced swimming test in normal rats.However,in the 30 mg/kg AT Ⅲ(the chronic administration)the immobility time of normal rats was significantly prolonged in the forced swimming test.In the open field test,there was no significant difference in crossing times between acute and chronic administration groups.2.In LPS-induced depression model in rats,we found that compared with the normal group,the percentage of sugar water consumption in LPS group was significantly reduced,the immobility time of the FST was significantly prolonged,the latency to immobility of the FST was significantly shortened,the feeding latency of the NSFT was prolonged,and the time spent in center of the OFT was shortened.Acute administration of 10 mg/kg and 30 mg/kg AT Ⅲ group had no significant influence on LPS-induced depression-like behavior;Chronic administration of 10 mg/kg AT Ⅲ group had no significant effect on LPS induced depression-like behavior,while chronic 30 mg/kg administration of AT Ⅲ can significantly reversed the depression-like behavior of the LPS-induced depression model rats;The levels of TNF-α,IL-6 and IL-1βin the hippocampus of the LPS group were significantly increased;Chronic 10 mg/kg AT Ⅲ administration had no significant effect on the levels of TNF-α,IL-6 and IL-1β in the hippocampus of depression model rats,while chronic 30 mg/kg AT Ⅲ administration significantly reduced the levels of TNF-α,IL-6 and IL-1β in the hippocampus of depression model rats.3.In CUMS-induced depression model rats,we found that compared with the normal group,the percentage of sugar water consumption in CUMS group was significantly reduced,the immobility time of the FST was significantly prolonged,the latency to immobility of the FST was significantly shortened,the feeding latency of the NSFT was prolonged,and the time spent in center of the OFT was shortened.Acute30 mg/kg AT Ⅲ administration had no significant effect on CUMS-induced depression behavior,while chronic 30 mg/kg AT Ⅲ administration significantly reversed the behavioral performance of the CUMS-induced depression model rats.The levels of TNF-α,IL-6 and IL-1β in the hippocampus of the CUMS group were significantly increased,while the chronic 30 mg/kg AT Ⅲ administration significantly reduced levels of TNF-α,IL-6 and IL-1β in the hippocampus of the CUMS-induced depression model rats.Conclusion:1.Chronic AT Ⅲ administration had significant antidepressant and anti-anxiety effects;2.The antidepressant and anti-anxiety effects of chronic AT Ⅲ administration(30 mg/kg,i.g.)had a dose effect;3.Chronic AT Ⅲ administration had significant antidepressant and anti-anxiety effects on LPS-induced acute depression model rats as well as CUMS-induced depression model rats;4.The inflammatory factors such as TNF-α,IL-6 and IL-1β in the hippocampus may underlie the mechanism of antidepressant and anti-anxiety effects of chronic AT Ⅲ administration.