Ock Jiyeon, Kim Sangseop, Suk Kyoungho
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.
Pharmacol Res. 2009 Jun;59(6):414-22. doi: 10.1016/j.phrs.2009.02.008. Epub 2009 Mar 4.
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.
小胶质细胞激活通过分泌多种促炎细胞因子和神经毒性因子在神经退行性疾病的进展中起重要作用。抑制小胶质细胞激活可能会减轻神经退行性过程。为了寻找针对神经炎症性疾病的新型治疗药物，筛选了几种氟乙烯氧基乙酰胺衍生物在脂多糖（LPS）刺激的小胶质细胞中的抗炎作用。通过基于细胞的筛选，发现一种新型合成化合物KT-15087显著减弱了小胶质细胞中一氧化氮（NO）和肿瘤坏死因子（TNF）-α的产生。KT-15087还抑制了诱导型一氧化氮合酶（iNOS）、TNF-α和白细胞介素（IL）-1β的基因表达。该化合物抑制了核因子κB（NF-κB）的核转位和DNA结合以及p38丝裂原活化蛋白激酶（MAPK）和c-jun氨基末端激酶（JNK）的磷酸化。此外，KT-15087通过降低共培养中LPS刺激的小胶质细胞对B35神经母细胞瘤细胞的细胞毒性表现出神经保护活性。当在LPS刺激前用该化合物预处理小胶质细胞时，该化合物的神经保护活性最为有效。总体而言，KT-15087在小胶质细胞中具有抗炎活性，可能对神经炎症性疾病的治疗具有潜在的治疗价值。
