title: Identification of KT-15073 as an inhibitor of lipopolysaccharide-induced microglial activation.
abstract: Neuroinflammation has recently been implicated as an important mechanism responsible for the progression of neurodegenerative diseases. Activated microglia produce various proinflammatory cytokines and nitric oxide (NO) that are toxic to neurons. Thus, inhibition of microglial activation may alleviate neuroinflammatory and neurodegenerative processes. Among several fluorovinyloxyacetamide derivatives that were screened by microglia cell-based assay, a novel synthetic compound KT-15073 was identified to strongly attenuate the microglial production of NO and tumor necrosis factor-alpha (TNF-alpha). This compound also suppressed the gene expression of interleukin-1beta, inducible nitric oxide synthase, and TNF-alpha. KT-15073 inhibited the nuclear translocation and DNA binding of nuclear factor-kappaB as well as phosphorylation of p38 mitogen-activated protein kinase. In addition, KT-15073 reduced the cytotoxicity of lipopolysaccharide (LPS)-stimulated microglia toward B35 neuroblastoma cells in the microglia/neuroblastoma coculture, suggesting that the compound might exhibit the neuroprotective activity. Thus, KT-15073 has an anti-inflammatory activity in microglia, and may have a therapeutic potential for the treatment of neuroinflammatory or neurodegenerative diseases.
authors.affiliation: Department of Pharmacology, School of Medicine, Brain Science and Engineering Institute, CMRI, Kyungpook National University, Daegu,700-412, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Ock
authors.forename: Su Hyung
authors.initials: SH
authors.lastname: Hong
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004247:DNA / Q000378:metabolism; D015870:Gene Expression; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000081:Acetamides; D000814:Aniline Compounds; D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C552201:KT 15073; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D004247:DNA; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases