Trek1 Channel Activation As A New Analgesic Strategy Devoid Of Opioid Adverse Effects (Vol 177, Pg 4782, 2020)

Background and Purpose Arctigenin, a major bioactive component of Fructus 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.