Antidepressant effects of Yuanzhi(Polygalae Radix)extract on chronic unpredictable mild stress-induced depression in rats:modulation of the NLRP3 inflammasome and NF-κB pathway
Objective To investigate the antidepressant effects of Yuanzhi(Polygalae Radix,PR)aqueous extract on chronic unpredictable mild stress(CUMS)-induced depression rat models and the underlying mechanisms.Methods A total of 40 male Sprague Dawley(SD)rats were randomly divided into control,model,low dose of PR(PR-L,0.5 g/kg),high dose of PR(PR-H,1 g/kg),and fluoxetine(10 mg/kg)groups,with 8 rats in each group.Except for the rats in control group,those in the other four groups underwent CUMS-induced depression modeling.PR and fluoxetine were administered intragastrically once daily,30 min prior to the CUMS procedure,for 14 consecu-tive days until the behavioral tests were performed.After CUMS modeling,the sucrose prefer-ence test(SPT),open field test(OFT),novelty-suppressed feeding test(NSFT),forced swim test(FST),and tail suspension test(TST)were employed to assess the pharmacological ef-fects of PR on the mitigation of depressive-like behaviors in rat models.Additionally,the en-zyme-linked immunosorbent assay(ELISA)was utilized to quantify the serum levels of tumor necrosis factor(TNF)-α,interleukin(IL)-6,and IL-1β in the rats.Western blot analysis was al-so conducted to evaluate the protein expression levels of nuclear factor kappa-B(NF-κB),in-ducible nitric oxide synthase(iNOS),cyclooxygenase-2(COX-2),nucleotide-binding oligomerization domain(NOD)-like receptor family pyrin domain containing 3(NLRP3),apoptosis-associated speck-like protein containing caspase recruitment domain(ASC),and caspase-1 in the hippocampal tissues of the rats.Immunofluorescence staining was per-formed to observe the morphological changes in ionized calcium-binding adapter molecule 1 positive(Iba-1+)cells in the dentate gyrus(DG)of rats with CUMS-induced depression.Results(i)Treatment with PR-H and fluoxetine resulted in significant enhancements in both the total distance and time the rats moved during tests(P<0.01 and P<0.05,respectively).Post-administration of PR-H and fluoxetine also led to statistically significant increase in su-crose preference among rats(P<0.05).Besides,PR-L,PR-H,and fluoxetine treatment markedly decreased the latency of ingestion(P<0.05,P<0.05,and P<0.01,respectively).As observed from the FST,PR-L,PR-H,and fluoxetine presented antidepressant effects on rats with CUMS-induced depression,leading to the reduction in time of their immobility(P<0.05,P<0.01,and P<0.01,respectively).The results of TST indicated reduced immobility time in rats receiving PR-H and fluoxetine treatment as well(P<0.01).(ii)Rats in model group showed an increase in the levels of Iba-1+microglia in their left and right brains in compari-son with control group(P<0.01).However,such increase was negated post PR treatment(P<0.01).Treatment with PR-L,PR-H,and fluoxetine considerably reduced the levels of inflam-matory factors(TNF-α,IL-1β,and IL-6,P<0.01).In addition,treatment of PR-L and PR-H ef-fectively counteracted the elevated levels of NLRP3,ASC,and caspase-1,and markedly down-regulated the expression levels of phosphorylated p65(p-p65),COX-2,and iNOS in rats'hip-pocampus(P<0.01).Conclusion Collectively,these findings indicate that PR exerts an antidepressant effect on rats with CUMS-induced depression partially through the modulation of the NLRP3 and NF-κB signaling pathways.
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