A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone
- 25 January 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (6), 2687-2692
- https://doi.org/10.1073/pnas.0913572107
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.This publication has 26 references indexed in Scilit:
- Effects of homocysteine on metabolic pathways in cultured astrocytesProceedings of the Nutrition Society, 2008
- Gambogic amide, a selective agonist for TrkA receptor that possesses robust neurotrophic activity, prevents neuronal cell deathProceedings of the National Academy of Sciences of the United States of America, 2007
- Activation of pro‐survival Akt and ERK1/2 signalling pathways underlie the anti‐apoptotic effects of flavanones in cortical neuronsJournal of Neurochemistry, 2007
- Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memoryProceedings of the National Academy of Sciences of the United States of America, 2006
- Caspase-1 activation of caspase-6 in human apoptotic neuronsCell Death & Differentiation, 2005
- A Chemical-Genetic Approach to Studying Neurotrophin SignalingNeuron, 2005
- Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approachesNature Neuroscience, 2002
- Intravenous Brain-Derived Neurotrophic Factor Reduces Infarct Size and Counterregulates Bax and Bcl-2 Expression After Temporary Focal Cerebral IschemiaStroke, 2000
- Neurotrophic factor therapy for nervous system degenerative diseasesJournal of Neurobiology, 1994
- Brain‐derived Neurotrophic Factor is a Survival Factor for Cultured Rat Cerebellar Granule Neurons and Protects them Against Glutamate‐induced NeurotoxicityEuropean Journal of Neuroscience, 1993