Anti-inflammatory effects of a fluorovinyloxyacetamide compound KT-15087 in microglia cells.
The microglial activation plays an important role in the progression of neurodegenerative diseases by secreting various proinflammatory cytokines and neurotoxic factors. Inhibition of microglial activation may alleviate neurodegenerative processes. To search for novel therapeutic agents against neuroinflammatory diseases, several fluorovinyloxyacetamide derivatives were screened for anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated microglial cells. From cell-based screening, it was found that a novel synthetic compound KT-15087 markedly attenuated the production of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha in microglial cells. KT-15087 also suppressed the gene expression of inducible nitric oxide synthase (iNOS), TNF-alpha and interleukin (IL)-1beta. The compound inhibited the nuclear translocation and DNA binding of NF-kappaB as well as the phosphorylation of p38 mitogen-activated protein kinases (MAPK) and c-jun N-terminal kinase (JNK). Moreover, KT-15087 showed a neuroprotective activity by reducing the cytotoxicity of LPS-stimulated microglia toward B35 neuroblastoma cells in the coculture. The neuroprotective activity of the compound was most effective when microglia were pretreated with the compound prior to LPS challenge. Taken collectively, KT-15087 has an anti-inflammatory activity in microglia, and might have a therapeutic potential for the treatment of neuroinflammatory diseases.
Department of Pharmacology, Brain Science and Engineering Institute, CMRI, Kyungpook National University School of Medicine, 101 Dong-In, Joong-gu, Daegu 700-422, South Korea.
Jiyeon
J
Ock
Sangseop
S
Kim
Kyoungho
K
Suk
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014753:Vinyl Compounds / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D000081:Acetamides; D000893:Anti-Inflammatory Agents; C542622:KT-15087; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D014753:Vinyl Compounds; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases