Identification of novel small molecule activators of nuclear factor-κB with neuroprotective action via high-throughput screening.
Identification of novel small molecule activators of nuclear factor-κB with neuroprotective action via high-throughput screening.
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DOI：
10.1002/jnr.22526
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发表时间：
2011-01
影响因子：
4.2
通讯作者：
Grimaldi, Maurizio
中科院分区：
文献类型：
--
作者：
Manuvakhova, Marina S.;Johnson, Guyla G.;White, Misti C.;Ananthan, Subramaniam;Sosa, Melinda;Maddox, Clinton;McKellip, Sara;Rasmussen, Lynn;Wennerberg, Krister;Hobrath, Judith V.;White, E. Lucile;Maddry, Joseph A.;Grimaldi, Maurizio
关键词：
神经元非细胞因子依赖性p50/p65核因子-κB（大脑中的主要NF-κB复合物）激活已被证明具有神经保护作用。因此，NF-κB的神经元活化可能代表了可行的神经保护靶点。我们已经开发了一种基于细胞的检测方法，能够检测NF-κB表达增强，并通过使用它，我们已经确定了小分子能够上调NF-κB表达，从而触发其在神经元中的激活。我们已经成功筛选了大约300，000种化合物，并鉴定了1，647种活性化合物。命中群体内的结构的聚类分析产生了14个富集的化学支架。选择这14种支架和4种单体结构中的每一种的一种高效和化学上有吸引力的代表进行随访。这里描述的实验强调了七种化合物在原代星形胶质细胞中引起非典型的持久NF-κB激活。分子NF-κB对接实验表明，化合物可以通过增强NF-κ B B与其自身启动子的结合来调节NF-κ B诱导的NF-κB表达。原型化合物增加神经元中p65的表达并引起其核转位，而不影响NF-κB抑制剂（I-κB）。其中一种原型化合物导致谷氨酸诱导的神经元死亡大幅减少。总之，我们提供的证据表明，我们可以使用小分子激活p65 NF-κB的表达在神经元中的细胞因子受体的非依赖性的方式，这将导致持久的p65 NF-κB易位/激活和降低谷氨酸神经毒性。
Neuronal noncytokine-dependent p50/p65 nuclear factor-κB (the primary NF-κB complex in the brain) activation has been shown to exert neuroprotective actions. Thus neuronal activation of NF-κB could represent a viable neuroprotective target. We have developed a cell-based assay able to detect NF-κB expression enhancement, and through its use we have identified small molecules able to up-regulate NF-κB expression and hence trigger its activation in neurons. We have successfully screened approximately 300,000 compounds and identified 1,647 active compounds. Cluster analysis of the structures within the hit population yielded 14 enriched chemical scaffolds. One high-potency and chemically attractive representative of each of these 14 scaffolds and four singleton structures were selected for follow-up. The experiments described here highlighted that seven compounds caused noncanonical long-lasting NF-κB activation in primary astrocytes. Molecular NF-κB docking experiments indicate that compounds could be modulating NF-κB-induced NF-κB expression via enhancement of NF-κB binding to its own promoter. Prototype compounds increased p65 expression in neurons and caused its nuclear translocation without affecting the inhibitor of NF-κB (I-κB). One of the prototypical compounds caused a large reduction of glutamate-induced neuronal death. In conclusion, we have provided evidence that we can use small molecules to activate p65 NF-κB expression in neurons in a cytokine receptor-independent manner, which results in both long-lasting p65 NF-κB translocation/activation and decreased glutamate neurotoxicity.
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DOI：
10.1073/pnas.92.20.9077
发表时间：
1995-09-26
影响因子：
11.1
作者：
GUERRINI, L;BLASI, F;DENISDONINI, S
通讯作者：
DENISDONINI, S
影响因子：
4.8
作者：
Guo, Q;Robinson, N;Mattson, MP
通讯作者：
Mattson, MP
影响因子：
16.2
作者：
CHENG, B;CHRISTAKOS, S;MATTSON, MP
通讯作者：
MATTSON, MP
影响因子：
11
作者：
Liu, CA;Wang, MJ;Chen, JY
通讯作者：
Chen, JY
影响因子：
64.8
作者：
Chen, FE;Huang, DB;Ghosh, G
通讯作者：
Ghosh, G