Anti-inflammatory mechanism of lonchocarpine in LPS- or poly(I:C)-induced neuroinflammation.
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.
['Jeong|Yeon-Hui|YH|', 'Park|Jin-Sun|JS|', 'Kim|Dong-Hyun|DH|', 'Kang|Jihee Lee|JL|', 'Kim|Hee-Sun|HS|']
D029912:Abrus D000818:Animals D000893:Anti-Inflammatory Agents D001578:Benzopyrans D002460:Cell Line D047188:Chalcones D007249:Inflammation D016753:Interleukin-10 D015850:Interleukin-6 D008070:Lipopolysaccharides D051379:Mice D017628:Microglia D011070:Poly I-C D014409:Tumor Necrosis Factor-alpha
Lonchocarpine Neuroinflammation Lipopolysaccharide Poly(I:C) Microglia Molecular mechanism