Lund Søren, Porzgen Peter, Mortensen Anne Louise, Hasseldam Henrik, Bozyczko-Coyne Donna, Morath Siegfried, Hartung Thomas, Bianchi Marina, Ghezzi Pietro, Bsibsi Malika, Dijkstra Sipke, Leist Marcel
Disease Biology, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
J Neurochem. 2005 Mar;92(6):1439-51. doi: 10.1111/j.1471-4159.2005.03014.x.
CEP-1347 is a potent inhibitor of the mixed lineage kinases (MLKs), a distinct family of mitogen-activated protein kinase kinase kinases (MAPKKK). It blocks the activation of the c-Jun/JNK apoptotic pathway in neurons exposed to various stressors and attenuates neurodegeneration in animal models of Parkinson's disease (PD). Microglial activation may involve kinase pathways controlled by MLKs and might contribute to the pathology of neurodegenerative diseases. Therefore, the possibility that CEP-1347 modulates the microglial inflammatory response [tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1)] was explored. Indeed, the MLK inhibitor CEP-1347 reduced cytokine production in primary cultures of human and murine microglia, and in monocyte/macrophage-derived cell lines, stimulated with various endotoxins or the plaque forming peptide Abeta1-40. Moreover, CEP-1347 inhibited brain TNF production induced by intracerebroventricular injection of lipopolysaccharide in mice. As expected from a MLK inhibitor, CEP-1347 acted upstream of p38 and c-Jun activation in microglia by dampening the activity of both pathways. These data imply MLKs as important, yet unrecognized, modulators of microglial inflammation, and demonstrate a novel anti-inflammatory potential of CEP-1347.
CEP - 1347是混合谱系激酶（MLK）的强效抑制剂，MLK是有丝分裂原活化蛋白激酶激酶激酶（MAPKKK）的一个独特家族。它能阻断暴露于各种应激源的神经元中c - Jun/JNK凋亡途径的激活，并减轻帕金森病（PD）动物模型中的神经退行性变。小胶质细胞激活可能涉及由MLK控制的激酶途径，并且可能促成神经退行性疾病的病理过程。因此，研究了CEP - 1347调节小胶质细胞炎症反应[肿瘤坏死因子 - α（TNF - α）、白细胞介素 - 6（IL - 6）和单核细胞趋化蛋白 - 1（MCP - 1）]的可能性。事实上，MLK抑制剂CEP - 1347降低了人源和鼠源小胶质细胞原代培养物以及单核细胞/巨噬细胞衍生细胞系中细胞因子的产生，这些细胞系用各种内毒素或斑块形成肽Abeta1 - 40刺激。此外，CEP - 1347抑制了小鼠脑室内注射脂多糖诱导的脑TNF产生。正如从MLK抑制剂所预期的那样，CEP - 1347通过抑制小胶质细胞中p38和c - Jun两条途径的活性，在它们的激活上游发挥作用。这些数据表明MLK是小胶质细胞炎症的重要但未被认识的调节因子，并证明了CEP - 1347具有新的抗炎潜力。
