Liuwei Kangyiyu(六味抗抑郁)Decoction Mitigates Depression-Like Behaviors in Mice by Regulating TLR4/MyD88/NF-κB/NLRP3 Pathway and Inhibiting Inflammatory Cytokines
Objective:To explore the effects of Liuwei Kangyiyu(六味抗抑郁)Decoction on the neurons and Toll-like receptor 4(TLR4)/mye-loid differentiation factor 88(MyD88)/nuclear factor-κB(NF-κB)/NOD-like receptor protein 3(NLRP3)signaling pathway in depressed mice.Methods:Male C57BL/6J mice were randomized into a blank control group,a model(chronic mild unpredictable stress,CUMS)group,Liuwei Kangyiyu Decoction(9.62,19.24,and 38.48 g/kg)groups,and a fluoxetine(5.20 mg/kg)group,with 12 mice in each group.The CUMS method was employed to establish the mouse model of depression.Each group was administrated with the corresponding drug by gavage,while the normal control group and the model group were administrated with equal volume of distilled water once a day for 4 consecutive weeks.The sucrose preference,forced swimming,tail suspension,open field,and Morris water maze tests were carried out to ex-amine the behaviors of mice.The levels of inflammatory mediators[inducible nitric oxide synthase(iNOS),nitric oxide(NO),cyclooxygen-ase-2(COX-2),and prostaglandin E2(PGE2)]and cytokines[tumor necrosis factor(TNF)-α,interleukin(IL)-1β,IL-18,IL-6,and interfer-on(IFN)-γ]in blood and hippocampal tissue were determined.The histopathological changes of the hippocampus were examined.Real-time PCR was employed to measure the relative mRNA levels of genes in the TLR4/MyD88/NF-KB/NLRP3 signaling pathway in the hippocampal tissue.Results:Compared with the normal control group,the model group showed reduced sucrose consumption,number of crossings,number of rearings,percentage in target quadrants,and number of platform crossings,increased duration of forced swimming and tail suspension,and prolonged swimming latency.The levels of iNOS,NO,COX-2,PGE2,TNF-α,IL-1β,IL-18,IL-6,and IFN-γ in blood and hippocampal tissue were significantly increased in the model group.In addition,the modeling led to disarrangement of hippocampal neurons,increased number of vacuoles in the cells,infiltration of inflammatory cells,and up-regulated mRNA levels of Tlr4,Myd88,Irak1,Irak4,Tak1,Traf6,Nf-κb,Nlrp3,Asc,Capsase-1,Nek7,Txnip,Gsdmd,Il-1β,and Il-18 in the hippocampus(P＜0.01).Compared with the model group,Liuwei Kangyiyu De-coction significantly increased the sucrose consumption,number of crossings,number of rearings,percentage in target quadrants,and number of platform crossings,reduced the time of forced swimming and tail suspension,and shortened swimming latency.In addition,the decoction low-ered the levels of iNOS,NO,COX-2,PGE2,TNF-α,IL-1β,IL-18,IL-6,and IFN-γ in blood and hippocampal tissue,alleviated the disarrange-ment of hippocampal neurons,and reduced vacuoles in cells and inflammatory cell infiltration.Moreover,the decoction down-regulated the mRNA levels of Tlr4,Myd88,Irak1,Irak 4,Tak1,Traf6,Nf-κb,Nlrp3,Asc,Capsase-1,Nek7,Txnip,Gsdmd,Il-1β,and Il-18 in the hippocampus of model mice(P＜0.05 or P＜0.01).Conclusion:Liuwei Kangyiyu Decoction alleviates depression in mice by inhibiting the activation of the TLR4/MyD88/NF-KB/NLRP3 signaling pathway and reducing the inflammation and neuronal inflammatory damage in the hippocampus of the mouse model of CUMS-induced depression.
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