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

Sung‐Wuk Jang1, Xia Liu2, Manuel Yepes3, Kennie R. Shepherd4, Gary W. Miller4, Yang Liu5, W. David Wilson6,5, Gui Xiao7, Bruno Blanchi8, Yi Eve Sun8, Keqiang Ye2
1Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
2Department of Pathology and Laboratory Medicine, and
3Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322;
4Department of Environmental and Occupational Health, Rollins Public School of Health, Emory University, Atlanta, GA 30322;
5Department of Chemistry, Georgia State University, Atlanta, GA 30302;
6Centers for Disease Control and Prevention, Atlanta, GA 30322;
7Centers for Disease Control and Prevention, Atlanta, GA 30322; and
8Neuropsychiatric Institute, Medical Retardation Research Center, University of California, Los Angeles, Los Angeles, CA 90095

Tóm tắt

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.

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