Arctigenin protects against depression by inhibiting microglial activation and neuroinflammation via HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB pathways

Background and Purpose: Arctigenin, a major bioactive component ofFructus arctii, has been reported to have antidepressant-like effects. However, the mechanisms underlying these effects are still unclear. Neuroinflammation can be caused by excessive production of proinflammatory cytokines in microglia via high-mobility group box 1 (HMGB1)/TLR4/NF-kappa B and TNF-alpha/TNFR1/NF-kappa B signalling pathways, leading to depression. In this study, we have investigated the antidepressant mechanism of arctigenin by conducting in vitro and in vivo studies. Experimental Approach: The effects of chronic unpredictable mild stress (CUMS) on wild-type (WT) and TLR4(-/-)mice were examined. Antidepressant-like effects of arctigenin were tested using the CUMS-induced model of depression in WT mice. The effects of arctigenin were assessed on the HMGB1/TLR4/NF-kappa B and TNF-alpha/TNFR1/NF-kappa B signalling pathways in the prefrontal cortex (PFC) of mouse brain and HMGB1- or TNF-alpha-stimulated primary cultured microglia. The interaction between HMGB1 and TLR4 or TNF-alpha and TNFR1 with or without arctigenin was examined by localized surface plasmon resonance (LSPR) and co-immunoprecipitation assays. Key Results: The immobility times in the tail suspension test (TST) and forced swimming test (FST) were reduced in TLR4(-/-)mice, compared with WT mice. Arctigenin exhibited antidepressant-like effects. Arctigenin also inhibited microglia activation and inflammatory responses in the PFC of mouse brain. Arctigenin inhibited HMGB1 and TLR4 or TNF-alpha and TNFR1 interactions, and suppressed both HMGB1/TLR4/NF-kappa B and TNF-alpha/TNFR1/NF-kappa B signalling pathways. Conclusions and Implications: Arctigenin has antidepressant-like effects by attenuating excessive microglial activation and neuroinflammation through the HMGB1/TLR4/NF-kappa B and TNF-alpha/TNFR1/NF-kappa B signalling pathways. This suggests that arctigenin has potential as a new drug candidate suitable for clinical trials to treat depression.