title: α-Iso-cubebenol inhibits inflammation-mediated neurotoxicity and amyloid beta 1-42 fibril-induced microglial activation.
abstract: OBJECTIVE
  To examine the antineuroinflammatory and neuroprotective activity of α-iso-cubebenol and its molecular mechanism of action in amyloid β (Aβ) 1-42 fibril-stimulated microglia.
  
  
  METHODS
  Aβ 1-42 fibrils were used to induce a neuroinflammatory response in murine primary microglia and BV-2 murine microglia cell lines. Cell viability was monitored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, protein expression and phosphorylation were determined by Western blot analysis, and matrix metalloproteinase-9 (MMP-9) activity was determined by gelatin zymography assay. In addition, prostaglandin E2 (PGE2), pro-inflammatory cytokines and chemokines were measured by ELISA, and the transactivity of nuclear factor (NF)-κB was determined by a reporter assay.
  
  
  RESULTS
  α-Iso-cubebenol significantly inhibited Aβ 1-42 fibril-induced MMP-9, inducible nitric oxide synthase and cyclooxygenase-2 expressions and activity, without affecting cell viability. α-Iso-cubebenol also suppressed the production of tumour necrosis factor-α, IL-1β, IL-6, monocyte chemoattractant protein-1 and reactive oxygen species in a dose-dependent manner, while decreasing the nuclear translocation and transactivity of NF-κB by inhibiting the phosphorylation and degradation of the inhibitor of κB (IκB)α. α-Iso-cubebenol suppressed the phosphorylation of mitogen-activated protein kinase (MAPK) in Aβ 1-42 fibril-stimulated microglia. Primary cortical neurons were protected by the inhibitory effect of α-iso-cubebenol on Aβ 1-42 fibril-induced neuroinflammatory response.
  
  
  CONCLUSIONS
  α-Iso-cubebenol suppresses Aβ 1-42 fibril-induced neuroinflammatory molecules in primary microglia via the suppression of NF-κB/inhibitor of κBα and MAPK. Importantly, the antineuroinflammatory potential of α-iso-cubebenol is critical for neuroprotection.
authors.affiliation: Bio-IT Fusion Technology Research Institute, Pusan National University, Busan, South Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Park
authors.forename: Tae Gyeong
authors.initials: TG
authors.lastname: Park
authors.forename: Sang-Joon
authors.initials: SJ
authors.lastname: Lee
authors.forename: Yoe-Sik
authors.initials: YS
authors.lastname: Bae
authors.forename: Min J
authors.initials: MJ
authors.lastname: Ko
authors.forename: Young-Whan
authors.initials: YW
authors.lastname: Choi
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; C571662:alpha-iso-cubebenol; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone
keywords: amyloid β; microglia; neuroinflammation; nuclear factor-κB; reactive oxygen species; α-iso-cubebenol