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

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

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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.