title: Newly synthesized 'hidabeni' chalcone derivatives potently suppress LPS-induced NO production via inhibition of STAT1, but not NF-κB, JNK, and p38, pathways in microglia.
abstract: Chalcones are open-chain flavonoids that are biosynthesized in various plants. Some of them possess anti-inflammatory activity. We previously found that chalcone glycosides from Brassica rapa L. 'hidabeni' suppress lipopolysaccharide (LPS)-induced nitric oxide (NO) production in rat microglia highly aggressively proliferating immortalized (HAPI) cells. In this study, to explore chalcone derivatives with potent NO inhibitory activity, we synthesized ten compounds based on 'hidabeni' chalcone and examined their effects on LPS-triggered inducible NO synthase (iNOS) expression and NO production. Compounds C4 and C10 potently inhibited NO production (IC50: 4.19, 2.88 µM, respectively). C4 and C10 suppressed LPS-induced iNOS expression via the inhibition of the signal transduction and activator of transcription 1 (STAT1), but not nuclear factor-kappa B (NF-κB), c-Jun N terminal kinase (JNK), and p38, pathways. C10, but not C4, inhibited activation of the MEK/extracellular signal-regulated kinase (ERK) pathway. C4 and C10 also suppressed LPS-induced expression of interferon regulatory factor 1 (IRF-1), which is an important transcription factor involved in iNOS expression. Our findings indicate that these chalcone derivatives are candidate compounds for preventing microglia-mediated neuroinflammation.
authors.affiliation: Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hara
authors.forename: Ryoko
authors.initials: R
authors.lastname: Ikeda
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ninomiya
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kamiya
authors.forename: Mamoru
authors.initials: M
authors.lastname: Koketsu
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Adachi
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D002599:Chalcone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D051381:Rats; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors*
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D009569:Nitric Oxide; D002599:Chalcone; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat