title: Daphnetin attenuates microglial activation and proinflammatory factor production via multiple signaling pathways.
abstract: Daphnetin, a natural coumarin derivative, is known to display anti-inflammatory properties and has been used to treat inflammatory diseases. A novel finding suggested that daphnetin might have a neuroprotective effect in stressed mice, leading us to explore its role in the microglial inflammatory response, as well as its underlying mechanism of action. We found that the production of pro-inflammatory mediators, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), induced by lipopolysaccharide (LPS) or β-amyloid (Aβ) was significantly suppressed by daphnetin in a dose-dependent manner in BV2 microglia. Also, daphnetin inhibited LPS-induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and NO formation by microglia. Mechanistically, daphnetin blunted the transcriptional activity of nuclear factor-kappa B (NF-κB), which was associated with the down-regulation of the phosphorylation and nuclear translocation of RelA/p65. Inhibitors of kappa B (IκB) phosphorylation and degradation were also affected by daphnetin, which was likely due to the reduced activation of IκB kinase (IKK). Additionally, LPS-induced activation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK, were, to a varying extent, altered by daphnetin. Finally, daphnetin blocked phosphatidylinositol-3 kinase (PI-3K)/protein kinase B (Akt) signaling in LPS-activated microglia, which appeared to at least partially account for the reduction in NF-κB transcriptional activity. Thus, daphnetin inhibited microglial activation and proinflammatory responses by modulating a series of intracellular signaling pathways, including IKK/IκB, MAPKs and PI-3K/Akt.
authors.affiliation: College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Department of Basic Medical Science, Key Lab of Inflammation and Immunoregulation, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Basic Medical Science, Key Lab of Inflammation and Immunoregulation, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Basic Medical Science, Key Lab of Inflammation and Immunoregulation, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Hangjie
authors.initials: H
authors.lastname: Ying
authors.affiliation: Department of Basic Medical Science, Key Lab of Inflammation and Immunoregulation, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Basic Medical Science, Key Lab of Inflammation and Immunoregulation, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Chen
authors.affiliation: College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Ge
authors.affiliation: Department of Basic Medical Science, Key Lab of Inflammation and Immunoregulation, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China. Electronic address: shi_liyun@msn.com.
authors.forename: Liyun
authors.initials: L
authors.lastname: Shi
mesh_terms: D016229:Amyloid beta-Peptides / Q000276:immunology; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D032364:Daphne / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014468:Umbelliferones / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D014468:Umbelliferones; C023023:lipid-linked oligosaccharides; D052247:Nitric Oxide Synthase Type II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C039952:daphnetin
keywords: Daphnetin; Inflammation; Microglia