Research ResourceNeuroscience

Multiplex quantitative assays indicate a need for reevaluating reported small-molecule TrkB agonists

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Science Signaling  22 Aug 2017:
Vol. 10, Issue 493, eaal1670
DOI: 10.1126/scisignal.aal1670

Re-evaluating reported TrkB agonists

Activation of the receptor tropomyosin-related kinase B (TrkB) by brain-derived neurotrophic factor (BDNF) is important for neurodevelopment, memory, and cognition. Activation of TrkB is a potential therapeutic strategy for treating Alzheimer’s disease and other brain disorders, but the pharmacokinetic properties of BDNF preclude using BDNF to activate TrkB in therapeutic contexts. Several small molecules have been reported to act as TrkB agonists and are widely used in disease models. Boltaev et al. developed a series of assays to quantitatively measure TrkB activation and downstream signaling events in cells treated with these reported BDNF agonists. The authors found that these compounds did not activate key aspects of TrkB signaling in contrast to BDNF or other neurotrophic factors that stimulate TrkB. These findings highlight the need for careful interpretation of the results of experiments using reported BDNF agonists.


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.

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