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Publication Detail

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

Authors: Jang, Sung-Wuk; Liu, Xia; Yepes, Manuel; Shepherd, Kennie R; Miller, Gary W; Liu, Yang; Wilson, W David; Xiao, Ge; Blanchi, Bruno; Sun, Yi E; Ye, Keqiang

Published In Proc Natl Acad Sci U S A, (2010 Feb 09)

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.

PubMed ID: 20133810 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis/drug effects*; Brain-Derived Neurotrophic Factor/pharmacology; Cell Line; Cell Line, Tumor; Cell Survival/drug effects; Cells, Cultured; Flavones/chemistry; Flavones/pharmacology*; Hippocampus/cytology; Hippocampus/drug effects; Hippocampus/metabolism; Humans; Immunoblotting; Mice; Mice, Inbred C57BL; Molecular Structure; Neurons/cytology; Neurons/drug effects*; Neurons/metabolism; Neuroprotective Agents/chemistry; Neuroprotective Agents/pharmacology; Phosphorylation/drug effects; Protein Multimerization/drug effects; Receptor, trkB/agonists*; Receptor, trkB/genetics; Receptor, trkB/metabolism; Signal Transduction/drug effects

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