Abstract Title:

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

Abstract Source:

Br J Pharmacol. 2020 Sep 10. Epub 2020 Sep 10. PMID: 32964428

Abstract Author(s):

Xiang Xu, Hu-Nan Piao, Fumie Aosai, Xiao-Yu Zeng, Jia-Hui Cheng, Yue-Xian Cui, Jing Li, Juan Ma, Hu-Ri Piao, Xuejun Jin, Lian-Xun Piao

Article Affiliation:

Xiang Xu


BACKGROUND AND PURPOSE: Arctigenin (AG), a major bioactive component of Fructus arctii, has been reported to have antidepressant-like effects. However, the precise mechanism of AG as an antidepressant is still unclear. Neuroinflammation can be caused by excessive production of proinflammatory cytokines in microglia via high-mobility group box 1 (HMGB1)/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signaling pathways, leading to depression. In this study, we have investigated the antidepressant mechanism of AG by conducting in vitro and in vivo studies.

EXPERIMENTAL APPROACH: The antidepressant-like effects of AG were tested using the chronic unpredictable mild stress (CUMS)-induced model of depression in mice. The effects of CUMS on TLR4mice were examined. The action of AG on HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signaling pathways in the prefrontal cortex (PFC) of mouse brain and HMGB1- or TNF-α-stimulated primary cultured microglia. The interaction between HMGB1 and TLR4 or TNF-α and TNFR1 with or without AG was examined by LSPR and co-immunoprecipitation assays.

KEY RESULTS: AG exhibited antidepressant-like effects. Immobility times in the TST and FST were reduced in TLR4mice compared with WT mice. AG inhibited microglia activation, inflammatory responses in the PFC of the mouse brain. AG inhibited HMGB1 and TLR4 or TNF-α and TNFR1 interactions. AG suppressed both HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signaling pathways.

CONCLUSIONS AND IMPLICATIONS: Our results provide the first evidence that AG has antidepressant-like effects by attenuating excessive microglial activation and neuroinflammation through the HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways. This suggests that AG has potential as a new drug candidate suitable for clinical trials to treat depression.

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