Portal de Periódicos da CAPES

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

2010; National Academy of Sciences; Volume: 107; Issue: 6 Linguagem: Inglês

10.1073/pnas.0913572107

1091-6490

Sung‐Wuk Jang, Xia Liu, Manuel Yepes, Kennie R. Shepherd, Gary W. Miller, Yang Liu, W. David Wilson, Ge� Xiao, Bruno Blanchi, Yi Eve Sun, Keqiang Ye,

Bioactive Compounds in Plants

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.