Identifying inducers of BDNF gene expression from pharmacologically validated compounds; antipyretic drug dipyrone increases BDNF mRNA in neurons
Identifying inducers of BDNF gene expression from pharmacologically validated compounds; antipyretic drug dipyrone increases BDNF mRNA in neurons
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DOI：
10.1016/j.bbrc.2020.02.019
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发表时间：
2020-04-16
影响因子：
3.1
通讯作者：
Fukuchi, Mamoru
中科院分区：
文献类型：
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作者：
Fukuchi, Mamoru
低水平的脑源性神经营养因子（BDNF）是突触可塑性的关键调节因子，与神经系统疾病有关，包括抑郁症和阿尔茨海默病。因此，BDNF是这些疾病的药物靶点。在这里，我们筛选诱导剂的神经元BDNF的表达，从一个经过验证的化合物库，使用我们最近开发的筛选试验的基础上，在培养的皮层神经元荧光素酶活性。我们确定了18种经过验证的化合物，其中大部分被推断为通过其验证的药理作用诱导BDNF表达，例如GS偶联受体激活或神经元兴奋。出乎意料的是，筛选试验确定了解热药物安乃近，以增加BDNF的表达。安乃近诱导内源性BDNF表达的钙内流诱发通过L-型电压依赖性钙通道和N-甲基-D-天冬氨酸受体，表明安乃近诱导活性调节神经元中的BDNF表达。然而，联吡酮诱导的Bdnf表达与已验证的药理作用无关。虽然我们的筛选试验很难揭示活性化合物如何诱导BDNF表达，但这种方法便于鉴定原代神经元中BDNF表达的诱导剂。我们的筛选试验评估了神经元BDNF的诱导，并可用于筛选药物重新定位，以及新的候选药物，用于脑中BDNF水平低的神经系统疾病。(C)2020爱思唯尔公司All rights reserved.
Low levels of brain-derived neurotrophic factor (BDNF), a key regulator of synaptic plasticity, are associated with neurological diseases, including depression and Alzheimer's disease. Therefore, BDNF is a drug target for these diseases. Here we screened for inducers of neuronal Bdnf expression from a pharmacologically validated compound library using our recently developed screening assay based on luciferase activity in cultured cortical neurons. We identified 18 pharmacologically validated compounds, most of which were inferred to induce Bdnf expression by their validated pharmacological actions, such as Gs-coupled receptor activation or neuronal excitation. Unexpectedly, the screening assay identified the antipyretic drug, dipyrone, to increase Bdnf expression. Dipyrone induced endogenous Bdnf expression by Ca2+ influx evoked via L-type voltage-dependent Ca2+ channels and the N-methyl-D-aspartate receptor, indicating that dipyrone induced activity-regulated Bdnf expression in neurons. However, dipyrone-induced Bdnf expression is independent of validated pharmacological effects. Although our screening assay is difficult to reveal how active compounds induce Bdnf expression, this method is convenient to identify inducers of Bdnf expression in primary neurons. Our screening assay evaluated neuronal BDNF induction and can be used to screen for drug re-positioning, as well as novel candidate drugs, for neurological diseases that have low levels of BDNF in the brain. (C) 2020 Elsevier Inc. All rights reserved.