7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders.

Chaoyang Liu,Chi Bun Chan,Keqiang Ye

doi:10.1186/s40035-015-0048-7

Abstract

Brain-derived neurotrophic factor (BDNF) regulates a variety of biological processes predominantly via binding to the transmembrane receptor tyrosine kinase TrkB. It is a potential therapeutic target in numerous neurological, mental and metabolic disorders. However, the lack of efficient means to deliver BDNF into the body imposes an insurmountable hurdle to its clinical application. To address this challenge, we initiated a cell-based drug screening to search for small molecules that act as the TrkB agonist. 7,8-Dihydroxyflavone (7,8-DHF) is our first reported small molecular TrkB agonist, which has now been extensively validated in various biochemical and cellular systems. Though binding to the extracellular domain of TrkB, 7,8-DHF triggers TrkB dimerization to induce the downstream signaling. Notably, 7,8-DHF is orally bioactive that can penetrate the brain blood barrier (BBB) to exert its neurotrophic activities in the central nervous system. Numerous reports suggest 7,8-DHF processes promising therapeutic efficacy in various animal disease models that are related to deficient BDNF signaling. In this review, we summarize our current knowledge on the binding activity and specificity, structure-activity relationship, pharmacokinetic and metabolism, and the pre-clinical efficacy of 7,8-DHF against some human diseases.

Highlights

Neurotrophins (NT) are growth factors that regulate the development and maintenance of the peripheral and the central nervous systems [1]
brain-derived neurotrophic factor (BDNF) exerts its biological functions on neurons through two transmembrane receptors: the p75 neurotrophin receptor (p75NTR) and the TrkB receptor tyrosine kinase, while nerve growth factor (NGF) binds to TrkA, NT-4/5 binds to TrkB, and NT-3 preferentially binds to TrkC [3, 4]
BDNF is of particular therapeutic interest because of its neurotrophic actions on a number of neuronal populations including sensory neurons; motor neurons which are degenerated in amyotrophic lateral sclerosis (ALS) [7]; dopaminergic neurons of the substantia nigra, which are lost in Parkinson’s disease (PD); and cholinergic neurons of the basal forebrain, that play a significant role in in Alzheimer’s disease (AD) [8]

Summary

Introduction

Neurotrophins (NT) are growth factors that regulate the development and maintenance of the peripheral and the central nervous systems [1]. The positive hits were subjected to TrkB activation analysis in primary neurons and receptor binding assays. Discovery of TrkB receptor agonists In order to identify small molecules that mimic the neurotrophic activities of BDNF, we developed a cellbased survival assay using a cell permeable fluorescent dye MR(DERD)2, which produces red signal upon caspase-3 cleavage in apoptotic cells.

Results

Conclusion