PMID- 31867739 OWN - NLM STAT- MEDLINE DCOM- 20210107 LR - 20210107 IS - 2042-7158 (Electronic) IS - 0022-3573 (Linking) VI - 72 IP - 3 DP - 2020 Mar TI - 7-methoxyflavanone alleviates neuroinflammation in lipopolysaccharide-stimulated microglial cells by inhibiting TLR4/MyD88/MAPK signalling and activating the Nrf2/NQO-1 pathway. PG - 385-395 LID - 10.1111/jphp.13219 [doi] AB - OBJECTIVES: Neuroprotective potential of 7-methoxyflavanone (7MF) and its underlying mechanism was investigated. METHODS: Inhibitory effects of 7MF on microglial activation and neuroinflammation were evaluated by employment of lipopolysaccharide (LPS)-induced BV2 microglial cells. Changes in expression of genes and proteins of interest were investigated by RT-qPCR analysis and Western blot analysis. Inhibitory effects of 7MF on microglial overactivation were verified in LPS-treated C57BL/6J mice using ionized calcium-binding adaptor molecule-1 (Iba1) in the brain and interleukin-6 (IL-6) in serum as indicators. KEY FINDINGS: In BV2 cells, pretreatment with 7MF antagonized LPS-induced production of inflammatory factors IL-6, tumour necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1). Mechanistic studies revealed reduced expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor-88 (MyD88), phosphorylated forms of c-Jun N-terminal kinase (p-JNK) and extracellular signal-regulated kinases 1/2 (p-ERK) but increased nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and cellular expression of NAD(P)H quinone dehydrogenase-1 (NQO-1) by 7MF. In LPS-treated mice, pretreatment with 7MF reduced the brain level of Iba1 and serum level of IL-6. CONCLUSIONS: 7-methoxyflavanone inhibited LPS-stimulated TLR4/MyD88/MAPK signalling and activated Nrf2-mediated transcription of antioxidant protein NQO-1, showing antineuroinflammatory effect, so it is a potential neuroprotective agent. CI - (c) 2019 Royal Pharmaceutical Society. FAU - Qu, Zhao AU - Qu Z AD - Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China. FAU - Chen, Yan AU - Chen Y AD - Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China. FAU - Luo, Zhuo-Hui AU - Luo ZH AD - Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China. FAU - Shen, Xiao-Ling AU - Shen XL AD - Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China. FAU - Hu, Ying-Jie AU - Hu YJ AD - Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China. LA - eng GR - A1-AFD018161Z01028/Excellent Doctoral Thesis Supporting Project/ GR - E1-KFD015161K04/Innovation Team Project for New Chinese Herbal Drug Discovery of of Guangzhou University of Chinese Medicine/ GR - 2014ZX10005002/National Major Project of Science and Technology/ GR - 2016A020217015/S & T Projects of Guangdong Province, P.R. China/ PT - Journal Article DEP - 20191222 PL - England TA - J Pharm Pharmacol JT - The Journal of pharmacy and pharmacology JID - 0376363 RN - 0 (Flavanones) RN - 0 (Flavones) RN - 0 (Inflammation Mediators) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharides) RN - 0 (Myd88 protein, mouse) RN - 0 (Myeloid Differentiation Factor 88) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NF-kappa B) RN - 0 (Nfe2l2 protein, mouse) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.13.39 (Nos2 protein, mouse) RN - EC 1.14.99.- (Ptgs2 protein, mouse) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)) RN - EC 1.6.5.2 (Nqo1 protein, mouse) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 2.7.11.24 (Mapk3 protein, mouse) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - XK561AP5UR (7-methoxyflavone) SB - IM MH - Animals MH - Cell Line MH - Cell Survival/drug effects MH - Cyclooxygenase 2/metabolism MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Flavanones/*pharmacology MH - Flavones/pharmacology MH - Inflammation/chemically induced MH - Inflammation Mediators/metabolism MH - Interleukin-6/metabolism MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Lipopolysaccharides/pharmacology MH - Mice MH - Mice, Inbred C57BL MH - Microglia/*drug effects MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Myeloid Differentiation Factor 88/metabolism MH - NAD(P)H Dehydrogenase (Quinone)/metabolism MH - NF-E2-Related Factor 2/metabolism MH - NF-kappa B/metabolism MH - Nitric Oxide Synthase Type II/metabolism MH - Phosphorylation MH - Signal Transduction/*drug effects MH - Toll-Like Receptor 4/metabolism MH - Tumor Necrosis Factor-alpha/metabolism OTO - NOTNLM OT - 7-methoxyflavanone OT - Nrf2/NQO-1 signalling OT - TLR4/MyD88/MAPK signalling OT - lipopolysaccharide-induced microglia overactivation OT - neuroinflammation EDAT- 2019/12/24 06:00 MHDA- 2021/01/08 06:00 CRDT- 2019/12/24 06:00 PHST- 2019/07/15 00:00 [received] PHST- 2019/11/29 00:00 [accepted] PHST- 2019/12/24 06:00 [pubmed] PHST- 2021/01/08 06:00 [medline] PHST- 2019/12/24 06:00 [entrez] AID - 10.1111/jphp.13219 [doi] PST - ppublish SO - J Pharm Pharmacol. 2020 Mar;72(3):385-395. doi: 10.1111/jphp.13219. Epub 2019 Dec 22.