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

被引：565

作者：

Jang, Sung-Wuk ^{[1
]}

Liu, Xia ^{[1
]}

Yepes, Manuel ^{[2
]}

Shepherd, Kennie R. ^{[3
]}

Miller, Gary W. ^{[3
]}

Liu, Yang ^{[4
]}

Wilson, W. David ^{[4
]}

Xiao, Ge ^{[5
]}

Blanchi, Bruno ^{[6
]}

Sun, Yi E. ^{[6
]}

Ye, Keqiang ^{[1
]}

机构：

[1] Emory Univ, Dept Pathol & Lab Med, Sch Med, Atlanta, GA 30322 USA

[2] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

[3] Emory Univ, Rollins Publ Sch Hlth, Dept Environm & Occupat Hlth, Atlanta, GA 30322 USA

[4] Georgia State Univ, Dept Chem, Atlanta, GA 30302 USA

[5] Ctr Dis Control & Prevent, Atlanta, GA 30322 USA

[6] Univ Calif Los Angeles, Med Retardat Res Ctr, Inst Neuropsychiat, Los Angeles, CA 90095 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2010年 / 107卷 / 06期

关键词：

BDNF; neuroprotection; small molecule; binding; AMYOTROPHIC-LATERAL-SCLEROSIS; LIGAND-BINDING DOMAINS; NERVOUS-SYSTEM; BRAIN; RECEPTOR; ACTIVATION; NEURONS; AROMATASE; MIMETICS; MEMORY;

D O I：

10.1073/pnas.0913572107

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：2687 / 2692

页数：6

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