7,8,3'-Trihydroxyflavone, a potent small molecule TrkB receptor agonist, protects spiral ganglion neurons from degeneration both in vitro and in vivo

• Type of Material: Article
• Authors: Qing Yu, Emory University; Qing Chang, Emory University; Xia Liu, Emory University; Shusheng Gong, Capital Medical University; Keqiang Ye, Emory University; Xi Lin, Emory University
• Language: English
• Date: 2012-06-08
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbrc.2012.04.154
• Title of Journal or Parent Work: Biochemical and Biophysical Research Communications
• ISSN: 0006-291X
• Volume: 422
• Issue: 3
• Start Page: 387
• End Page: 392
• Grant/Funding Information: This study was supported by grants to Lin from the National Institute on Deafness and other Communication Disorders (NIDCD R01DC010204, RO1 DC006483 and 4R33DC010476) and RO1 DC010204 to KY.
• Keywords: 7,8,3’-trihydroxyflavone; neuronal degeneration; cochlea; BDNF; Gjb2 deletion; mouse model; TrkB receptor; spiral ganglion neurons
• Research Categories: Biophysics, Medical; Chemistry, Biochemistry

Abstract

Most sensorineural hearing loss cases occur as a result of hair cell loss, which results in secondary degeneration of spiral ganglion neurons (SGNs). Substantial loss of SGNs reduces the benefit of cochlear implants, which rely on SGNs for transmitting signals to the central auditory centers. Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) play essential roles in cochlear development and are required for SGN survival. Here we report that 7,8,3’-trihydroxyflavone (7,8,3’-THF), which is a small molecule agonist of tyrosine receptor kinase B (TrkB), promoted SGN survival with high potency both in vitro and in vivo. The compound protected the SGNs in a TrkB-dependent manner, as its effects on SGNs disappeared when the TrkB was blocked. Application of 7,8,3’-THF in the bulla of conditional connexin26 (cCx26)-null mice dramatically rescued SGNs in the applied ear compared to untreated control cochlea in the same animal. Our findings suggest that 7,8,3’-THF is a promising therapeutic agent protecting the SGNs from degeneration both in vitro and in vivo.