title: Neoechinulin A suppresses amyloid-β oligomer-induced microglia activation and thereby protects PC-12 cells from inflammation-mediated toxicity.
abstract: A pathological hallmark of Alzheimer's disease (AD), aggregation and deposition of amyloid-β peptides, has been recognized as a potent activator of microglia-mediated neuroinflammation and neuronal dysfunction. Therefore, downregulation of microglial activation has a significant therapeutic demand. In this study, focus was given to evaluate the ability of neoechinulin A, an indole alkaloid isolated from marine-derived Microsporum sp., to attenuate microglial activation by oligomeric amyloid-β 1-42 (Aβ42). Neoechinulin A treatment significantly inhibited the generation of reactive oxygen and nitrogen species in Aβ42-activated BV-2 microglia cells. In addition, we found that neoechinulin A significantly suppressed the production of neurotoxic inflammatory mediator tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) in activated BV-2 cells. Moreover, the treatment downregulated the protein and gene expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, IL-1β and IL-6. Further, activated microglia-mediated apoptosis of PC-12 pheochromocytoma cells was significantly repressed by neoechinulin A. The molecular mechanism studies suggested that neoechinulin A may block the phosphorylation of mitogen-activated protein kinase (MAPK) molecule p38, apoptosis signal-regulating kinase 1 (ASK-1) and nuclear translocation of nuclear factor-κB (NF-κB) p65 and p50 subunits. Regulation of these signalling pathways have most probably contributed to the anti-inflammatory activity of neoechinulin A. Collectively, these results suggest that with further studies neoechinulin A have a potential to be developed as a modulator of neuroinflammatory process in AD.
authors.affiliation: Marine Biochemistry Laboratory, Department of Chemistry, Pukyong National University, Busan 608-737, Republic of Korea.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Dewapriya
authors.forename: Yong-Xin
authors.initials: YX
authors.lastname: Li
authors.forename: S W A
authors.initials: SW
authors.lastname: Himaya
authors.forename: Ratih
authors.initials: R
authors.lastname: Pangestuti
authors.forename: Se-Kwon
authors.initials: SK
authors.lastname: Kim
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D026121:Indole Alkaloids / Q000494:pharmacology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D026121:Indole Alkaloids; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010879:Piperazines; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); C490266:neoechinulin A; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D015232:Dinoprostone