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

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.
Authors	Sung-Wuk Jang, Xia Liu, Manuel Yepes, Kennie R Shepherd, Gary W Miller, Yang Liu, W David Wilson, Ge Xiao, Bruno Blanchi, Yi E Sun, Keqiang Ye
Journal	Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 6 Pg. 2687-92 (Feb 09 2010) ISSN: 1091-6490 [Electronic] United States
PMID	20133810 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	6,7-dihydroxyflavone Brain-Derived Neurotrophic Factor Flavones Neuroprotective Agents Receptor, trkB
Topics	Animals Apoptosis (drug effects) Brain-Derived Neurotrophic Factor (pharmacology) Cell Line Cell Line, Tumor Cell Survival (drug effects) Cells, Cultured Flavones (chemistry, pharmacology) Hippocampus (cytology, drug effects, metabolism) Humans Immunoblotting Mice Mice, Inbred C57BL Molecular Structure Neurons (cytology, drug effects, metabolism) Neuroprotective Agents (chemistry, pharmacology) Phosphorylation (drug effects) Protein Multimerization (drug effects) Receptor, trkB (agonists, genetics, metabolism) Signal Transduction (drug effects)

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