Nootkatone Improves Chronic Unpredictable Mild Stress-Induced Depressive-Like Behaviors by Repressing NF-κB/NLRP3-Mediated Neuroinflammation

Objective:To explore the effect of nootkatone(NKT) on chronic unpredictable mild stress(CUMS)-induced depressive-like behaviors and the mechanism underlying NKT improving the depressivelike behaviors.Methods:The CUMS-induced depression model was established in mice.Fifty mice were randomized into 5 groups(n=10) in accordance with a random number table:control group,CUMS group,CUMS+NKT(6 mg/kg) group,CUMS+NKT(12 mg/kg) group,and CUMS+ketamine group.From the 22th day,NKT(6 or 12 mg/kg) or ketamine(0.5 mg/kg) was given with intragastric administration every day for21 days.Behavioral tests including forced swimming test(FST),tail suspension test(TST),sucrose preference test(SPT) and open-field test(OFT) were carried out.The mRNA and protein expressions of interleukin(IL)-1β,IL-18,IL-6,and tumor necrosis factor(TNF)-α in hippocampus were assessed using quantitative realtime polymerase chain reaction(PCR),Western blot analysis,and enzyme linked immunosorbent assay.The nuclear factor-κB(NF-κB)/NOD-like receptor 3(NLRP3) inflammasome pathway was analyzed using Western blot and immunofluorescence analysis.Results:NKT treatment improved CUMS-induced depressivelike behaviors in mice(P<0.05 or P<0.01).NKT significantly decreased the mRNA and protein levels of IL-1β,IL-18,IL-6,and TNF-α in hippocampus of CUMS mice(P<0.05 or P<0.01).Furthermore,NKT repressed CUMS-induced activation of NF-κB signaling and NLRP3 inflammasome(P<0.01).More important,Nigericin,a NLRP3 activator,destroyed the effect of NKT on repressing neuroinflammation and improving depressive-like behaviors(P<0.05 or P<0.01).Conclusion:NKT ameliorates the depressive-like symptoms,in part by repressing NF-κB/NLRP3-mediated neuroinflammation.