| First Author | Xu X | Year | 2020 |
| Journal | Br J Pharmacol | Volume | 177 |
| Issue | 22 | Pages | 5224-5245 |
| PubMed ID | 32964428 | Mgi Jnum | J:317471 |
| Mgi Id | MGI:6856463 | Doi | 10.1111/bph.15261 |
| Citation | Xu X, et al. (2020) Arctigenin protects against depression by inhibiting microglial activation and neuroinflammation via HMGB1/TLR4/NF-kappaB and TNF-alpha/TNFR1/NF-kappaB pathways. Br J Pharmacol 177(22):5224-5245 |
| abstractText | 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-kappaB and TNF-alpha/TNFR1/NF-kappaB 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-kappaB and TNF-alpha/TNFR1/NF-kappaB 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-kappaB and TNF-alpha/TNFR1/NF-kappaB signalling pathways. CONCLUSIONS AND IMPLICATIONS: Arctigenin has antidepressant-like effects by attenuating excessive microglial activation and neuroinflammation through the HMGB1/TLR4/NF-kappaB and TNF-alpha/TNFR1/NF-kappaB signalling pathways. This suggests that arctigenin has potential as a new drug candidate suitable for clinical trials to treat depression. |
