Boltaev Umed, Meyer Yves, Tolibzoda Farangis, Jacques Teresa, Gassaway Madalee, Xu Qihong, Wagner Florence, Zhang Yan-Ling, Palmer Michelle, Holson Edward, Sames Dalibor
Department of Chemistry, Columbia University, New York, NY 10027, USA.
NeuroTechnology Center at Columbia University, New York, NY 10027, USA.
Sci Signal. 2017 Aug 22;10(493):eaal1670. doi: 10.1126/scisignal.aal1670.
Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), have emerged as key regulators of brain plasticity and represent disease-modifying targets for several brain disorders, including Alzheimer's disease and major depressive disorder. Because of poor pharmacokinetic properties of BDNF, the interest in small-molecule TrkB agonists and modulators is high. Several compounds have been reported to act as TrkB agonists, and their increasing use in various nervous system disorder models creates the perception that these are reliable probes. To examine key pharmacological parameters of these compounds in detail, we have developed and optimized a series of complementary quantitative assays that measure TrkB receptor activation, TrkB-dependent downstream signaling, and gene expression in different cellular contexts. Although BDNF and other neurotrophic factors elicited robust and dose-dependent receptor activation and downstream signaling, we were unable to reproduce these activities using the reported small-molecule TrkB agonists. Our findings indicate that experimental results obtained with these compounds must be carefully interpreted and highlight the challenge of developing reliable pharmacological activators of this key molecular target.
脑源性神经营养因子（BDNF）及其受体原肌球蛋白相关激酶B（TrkB），已成为大脑可塑性的关键调节因子，并代表了包括阿尔茨海默病和重度抑郁症在内的几种脑部疾病的疾病修饰靶点。由于BDNF的药代动力学性质较差，人们对小分子TrkB激动剂和调节剂的兴趣很高。据报道，有几种化合物可作为TrkB激动剂，并且它们在各种神经系统疾病模型中的使用越来越多，这让人觉得它们是可靠的探针。为了详细研究这些化合物的关键药理学参数，我们开发并优化了一系列互补的定量测定方法，这些方法可测量不同细胞环境下的TrkB受体激活、TrkB依赖性下游信号传导和基因表达。尽管BDNF和其他神经营养因子引发了强大的、剂量依赖性的受体激活和下游信号传导，但我们无法使用已报道的小分子TrkB激动剂重现这些活性。我们的研究结果表明，必须谨慎解释用这些化合物获得的实验结果，并突出了开发该关键分子靶点可靠药理学激活剂的挑战。
