title: Anti-inflammatory mechanism of lonchocarpine in LPS- or poly(I:C)-induced neuroinflammation.
abstract: Neuroinflammation plays an important role in the progression of various neurodegenerative diseases. In this study, we investigated the anti-inflammatory effects of lonchocarpine, a natural compound isolated from Abrus precatorius, under in vitro and in vivo neuroinflammatory conditions induced by challenge with lipopolysaccharide (LPS)- or polyinosinic-polycytidylic acid (poly(I:C)). Lonchocarpine suppressed the expression of iNOS and proinflammatory cytokines in LPS or poly(I:C)-stimulated BV2 microglial cells. These anti-inflammatory effects were verified in brains of mice with systemic inflammation induced by administration of LPS or poly(I:C). Lonchocarpine reduced the number of Iba-1-positive activated microglia, and suppressed the mRNA expression of various proinflammatory markers in the cortex of LPS- or poly(I:C)-injected mice. Molecular mechanistic experiments showed that lonchocarpine inhibited NF-κB activity by reducing the phosphorylation and degradation of IκBα in LPS- or poly(I:C)-stimulated BV2 cells. Analysis of further upstream signaling pathways in LPS-stimulated microglia showed that lonchocarpine inhibited the phosphorylation of IκB kinase and TGFβ-activated kinase 1 (TAK1). Moreover, lonchocarpine suppressed the interaction of myeloid differentiation factor 88 (MyD88) and intereleukin-1 receptor-associated kinase 4 (IRAK4). These data suggest that toll-like receptor 4 downstream signals such as MyD88/IRAK4-TAK1-NF-κB are at least partly involved in the anti-inflammatory mechanism of lonchocarpine in LPS-stimulated microglia. Its strong anti-inflammatory effects may make lonchocarpine an effective preventative drug for neuroinflammatory disorders that are associated with systemic inflammation.
authors.affiliation: Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, South Korea.
authors.forename: Yeon-Hui
authors.initials: YH
authors.lastname: Jeong
authors.affiliation: Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, South Korea.
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, South Korea.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, South Korea.
authors.forename: Jihee Lee
authors.initials: JL
authors.lastname: Kang
authors.affiliation: Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, South Korea. Electronic address: hskimp@ewha.ac.kr.
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
mesh_terms: D029912:Abrus / Q000737:chemistry; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D047188:Chalcones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000276:immunology; D011070:Poly I-C / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D001578:Benzopyrans; D047188:Chalcones; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C000620431:lonchocarpine; D016753:Interleukin-10; D011070:Poly I-C
keywords: Lipopolysaccharide; Lonchocarpine; Microglia; Molecular mechanism; Neuroinflammation; Poly(I:C)