Department of Pharmacology, Brain Science and Engineering Institute, Kyungpook National University School of Medicine, Daegu, Korea.
J Pharm Pharmacol. 2010 Feb;62(2):279-85. doi: 10.1211/jpp.62.02.0017.
Neurodegenerative diseases have a prominent inflammatory component. Several synthetic fluorovinyloxyacetamide derivatives were screened by microglia cell-based assay in order to identify novel compounds that inhibit the inflammatory activation of microglia.
Microglia cell-based nitric oxide assay was employed to screen the compounds. RT-PCR and ELISA were conducted to evaluate the expression of inflammatory gene expression. Molecular mechanisms were determined by western blot analysis, immunocytochemistry, EMSA, and microglia/neuroblastoma cocultures.
A fluorovinyloxyacetamide compound KT-14480 significantly suppressed nitric oxide production in lipopolysaccharide-stimulated microglia cells. KT-14480 also suppressed the secretion and expression of several inflammatory mediators such as tumour necrosis factor-alpha, interleukin-1beta and inducible nitric oxide synthase. Additional studies showed that these inhibitory effects were accompanied by the suppression of nuclear factor-kappaB and neuroprotection in the microglia/neuroblastoma coculture.
Our results indicate that the anti-inflammatory compound KT-14480 may be a novel therapeutic drug candidate against neuroinflammatory diseases.
神经退行性疾病具有显著的炎症成分。通过小胶质细胞体外测定筛选了几种合成的氟乙烯氧基乙酰胺衍生物，以鉴定出能抑制小胶质细胞炎症激活的新型化合物。
采用小胶质细胞一氧化氮测定法筛选化合物。采用 RT-PCR 和 ELISA 检测炎症基因表达。通过 Western blot 分析、免疫细胞化学、EMSA 和小胶质细胞/神经母细胞瘤共培养来确定分子机制。
一种氟乙烯氧基乙酰胺化合物 KT-14480 可显著抑制脂多糖刺激的小胶质细胞中一氧化氮的产生。KT-14480 还抑制了几种炎症介质的分泌和表达，如肿瘤坏死因子-α、白细胞介素-1β和诱导型一氧化氮合酶。进一步的研究表明，这些抑制作用伴随着核因子-κB 的抑制和小胶质细胞/神经母细胞瘤共培养中的神经保护作用。
我们的结果表明，抗炎化合物 KT-14480 可能是一种针对神经炎症性疾病的新型治疗药物候选物。
