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Author Notes:

To whom correspondence should be addressed. E-mail: kye@emory.edu.

Edited by Solomon Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved December 30, 2009 (received for review November 25, 2009)

Author contributions: S.-W.J., X.L., K.R..S., G.W.M., Y.L., W.D.W., G.X., B.B., Y.E.S., and K.Y. designed research; S.-W.J., X.L., M.Y., K.R.S., Y.L., and B.B. performed research; S.-W.J., X.L., M.Y., K.R.S., G.W.M., W.D.W., G.X., B.B., Y.E.S., and K.Y. analyzed data; and S.-W.J., M.Y., K.R.S., G.W.M., and K.Y. wrote the paper.

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Research Funding:

This work was supported by National Institute of Health Grants RO1 NS045627 to K.Y. and P01 ES016731 to G.W.M.

Keywords:

  • BDNF
  • neuroprotection
  • small molecule
  • binding

A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone

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Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 107, Number 6

Publisher:

, Pages 2687-2692

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Brain-derived neurotrophic factor (BDNF), a cognate ligand for the tyrosine kinase receptor B (TrkB) receptor, mediates neuronal survival, differentiation, synaptic plasticity, and neurogenesis. However, BDNF has a poor pharmacokinetic profile that limits its therapeutic potential. Here we report the identification of 7,8-dihydroxyflavone as a bioactive high-affinity TrkB agonist that provokes receptor dimerization and autophosphorylation and activation of downstream signaling. 7,8-Dihydroxyflavone protected wild-type, but not TrkB-deficient, neurons from apoptosis. Administration of 7,8-dihydroxyflavone to mice activated TrkB in the brain, inhibited kainic acid-induced toxicity, decreased infarct volumes in stroke in a TrkB-dependent manner, and was neuroprotective in an animal model of Parkinson disease. Thus, 7,8-dihydroxyflavone imitates BDNF and acts as a robust TrkB agonist, providing a powerful therapeutic tool for the treatment of various neurological diseases.

Copyright information:

Beginning with articles submitted in Volume 106 (2009) the author(s) retains copyright to individual articles, and the National Academy of Sciences of the United States of America retains an exclusive license to publish these articles and holds copyright to the collective work.

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