Protection of Spiral Ganglion Neurons from Degeneration Using Small-Molecule TrkB Receptor Agonists

• Type of Material: Article
• Authors: Qing Yu, Capital Medical University, Beijing; Qing Chang, Emory University; Xia Liu, Emory University; Yunfeng Wang, Shanghai Fudan University; Huawei Li, Shanghai Fudan University; Shusheng Gong, Capital Medical University, Beijing; Keqiang Ye, Emory University; Xi Erick Lin, Emory University
• Language: English
• Date: 2013-08-07
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 2013 the authors 0270-6474/13/3313042-11$15.00/0
• Final Published Version (URL): http://www.jneurosci.org/content/33/32/13042
• Title of Journal or Parent Work: Journal of Neuroscience
• ISSN: 0270-6474
• Volume: 33
• Issue: 32
• Start Page: 13042
• End Page: 13052
• Grant/Funding Information: This study was supported by Major State Basic Research Development Program of China Grant 2011CB504503 (S.G.), National Nature Science Foundation of China Grants 81100721 (Y.W.) and 30728029 (H.L.), National Institute on Deafness and Other Communication Disorders Grants R01 DC010204 and RO1 DC006483 (X. Lin), and National Institutes of Health Grant RO1 DC010204 (K.Y.).
• Research Categories: Biology, Neuroscience

Abstract

Neurotrophins (NTs) play essential roles in the development and survival of neurons in PNS and CNS. In the cochlea, NTs [e.g., NT-3, brain-derived neurotrophic factor (BDNF)] are required for the survival of spiral ganglion neurons (SGNs). Preservation of SGNs in the cochlea of patients suffering sensorineural deafness caused by loss of hair cells is needed for the optimal performance of the cochlear implant. Directly applying exogenous BDNF into the cochlea prevents secondary degeneration of SGNs when hair cells are lost. However, a common translational barrier for in vivo applications of BDNF is the poor pharmacokinetics, which severely limits the efficacy. Here we report that 7,8-dihydroxyflavone and 7,8,3′-trihydroxyflavone, both small-molecule agonists of tyrosine receptor kinase B (TrkB), promoted SGN survival with high potency both in vitro and in vivo. These compounds increased the phosphorylated TrkB and downstream MAPK and protected the SGNs in a TrkB-dependent manner. Their applications in the bulla of conditional connexin26 null mice offered significant protection for SGN survival. The function of survived SGNs was assessed by measuring evoked action potentials (APs) in vitro and electrically evoked auditory brainstem response (eABR) thresholds in vivo. APs were reliably evoked in cultured single SGNs treated with the compounds. In addition, eABR thresholds measured from the treated cochleae were significantly lower than untreated controls. Our findings suggest that these novel small-molecule TrkB agonists are promising in vivo therapeutic agents for preventing degeneration of SGNs.