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

• Authors: Sung-Wuk Jang, Emory University; Xia Liu, Emory University; Manuel Yepes, Emory University; Kennie R. Shepherd, Emory University; Gary W Miller, Emory University; Yang Liu, Georgia State University; W. David Wilson, Georgia State University; Ge Xiao, Centers for Disease Control and Prevention; Bruno Blanchi, University of California, Los Angeles; Yi E. Sun, University of California, Los Angeles; Keqiang Ye, Emory University
• Journal Title: Proceedings of the National Academy of Sciences
• Volume: Volume 107, Number 6
• Publisher: National Academy of Sciences | 2010-02-09, Pages 2687-2692
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1073/pnas.0913572107
• Subjects: Health Sciences, Pathology; Biology, Neuroscience
• Keywords: BDNF; neuroprotection; small molecule; binding

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.