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

Sung‐Wuk Jang(Emory University), Xia Liu, Manuel Yepes(Emory University), Kennie R. Shepherd(Emory University), Gary W. Miller(Emory University), Yang Liu(Georgia State University), W. David Wilson(Centers for Disease Control and Prevention), Ge� Xiao(Centers for Disease Control and Prevention), Bruno Blanchi(University of California, Los Angeles), Yi Eve Sun(University of California, Los Angeles), Keqiang Ye
Proceedings of the National Academy of Sciences
January 25, 2010
10.1073/pnas.0913572107
Cited by 674Open Access
Full Text

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.

Related Papers

Advances in flavonoid research since 1992
Jeffrey B. Harborne, Christine A. Williams|Phytochemistry|2000|3.9k
Neurotrophin signal transduction in the nervous system
David R. Kaplan, Freda D. Miller|Current Opinion in Neurobiology|2000|1.9k
High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor
Barbara L. Hempstead, Dionisio Martín‐Zanca, David R. Kaplan et al.|Nature|1991|1.2k
Neurotrophic factors in Alzheimer’s and Parkinson’s disease brain
George J. Siegel, Neelima B. Chauhan|Brain Research Reviews|2000|492
Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches
H. Thoenen, Michael Sendtner|Nature Neuroscience|2002|331