title: Anti-Neuroinflammatory Effects of Fucoxanthin via Inhibition of Akt/NF-κB and MAPKs/AP-1 Pathways and Activation of PKA/CREB Pathway in Lipopolysaccharide-Activated BV-2 Microglial Cells.
abstract: Microglia play a critical role in controlling the homeostasis of the brain, but over-activated microglia secrete pro-inflammatory mediators and cytokines, which induce neuronal cell death. Fucoxanthin (Fx), a marine carotenoid, has demonstrated a variety of beneficial health effects. Despite accumulating evidence supporting the immune-modulating effects of Fx in vitro, the underlying signaling pathways remain unknown. In the present study, Fx dose-dependently inhibited the secretion of lipopolysaccharide (LPS)-induced pro-inflammatory mediators including interleukin (IL)-6, tumor necrosis factor (TNF)-α, reactive oxygen species (ROS), prostaglandin (PG) E2, and nitric oxide (NO) productions, and also suppressed the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 enzymes. Further, the reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated IL-6, TNF-α, iNOS, and COX-2 mRNA expression were suppressed by treatment with Fx in a dose-dependently manner. The mechanism studies indicated that Fx blocks protein kinase B (Akt)/nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPKs)/transcription factor (AP)-1 pathways. In addition, we demonstrated that Fx increases nuclear factor erythroid 2-related factor (Nrf)-2 activation and heme oxygenase (HO)-1 expression in LPS-activated BV-2 microglia. Subsequently, we found that Fx also mediates the reactive oxygen species (ROS) by activating protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) pathway, and promotes the production of brain-derived neurotrophic factor (BDNF). These results indicate that Fx may be more effective and potential than other candidates via either decreasing the pro-inflammatory factors production or increasing the neuroprotective molecules expression for therapy of neurodegenerative diseases.
authors.affiliation: Natural Product Research Center, KIST Gangneung Institute of Natural Products, Gangneung, 210-340, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon, 305-333, Republic of Korea.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Natural Product Research Center, KIST Gangneung Institute of Natural Products, Gangneung, 210-340, Republic of Korea.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: Natural Product Research Center, KIST Gangneung Institute of Natural Products, Gangneung, 210-340, Republic of Korea.
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Chun
authors.affiliation: Natural Product Research Center, KIST Gangneung Institute of Natural Products, Gangneung, 210-340, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon, 305-333, Republic of Korea.
authors.forename: Ming-Yao
authors.initials: MY
authors.lastname: Gu
authors.affiliation: Natural Product Research Center, KIST Gangneung Institute of Natural Products, Gangneung, 210-340, Republic of Korea. hoyang@kist.re.kr.|Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon, 305-333, Republic of Korea. hoyang@kist.re.kr.
authors.forename: Hyun Ok
authors.initials: HO
authors.lastname: Yang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D024341:Xanthophylls / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D024341:Xanthophylls; C025164:fucoxanthin; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: BV-2 microglia; Fucoxanthin; Neuro-inflammation; PKA/CREB pathway