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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.

SUBMITTER: Jang SW 

PROVIDER: S-EPMC2823863 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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

Jang Sung-Wuk SW   Liu Xia X   Yepes Manuel M   Shepherd Kennie R KR   Miller Gary W GW   Liu Yang Y   Wilson W David WD   Xiao Ge G   Blanchi Bruno B   Sun Yi E YE   Ye Keqiang K  

Proceedings of the National Academy of Sciences of the United States of America 20100125 6

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-Dihydroxyflav  ...[more]

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