Protection of spiral ganglion neurons from degeneration using small-molecule TrkB receptor agonists.
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.
Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China 100730.
Qing
Q
Yu
Qing
Q
Chang
Xia
X
Liu
Yunfeng
Y
Wang
Huawei
H
Li
Shusheng
S
Gong
Keqiang
K
Ye
Xi
X
Lin
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000633:toxicity; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D003051:Cochlea / Q000166:cytology / Q000187:drug effects; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000235:genetics; D005260:Female; D047309:Flavones / Q000494:pharmacology / Q000627:therapeutic use*; D005839:Gentamicins / Q000633:toxicity; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D009414:Nerve Growth Factors / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D020813:Receptor, trkB / Q000819:agonists* / Q000172:deficiency / Q000378:metabolism; D013136:Spiral Ganglion / Q000166:cytology; D014404:Tubulin / Q000378:metabolism
C485383:6,7-dihydroxyflavone; C574665:7,8,3'-trihydroxyflavone; D000900:Anti-Bacterial Agents; D019208:Brain-Derived Neurotrophic Factor; D017630:Connexins; D047309:Flavones; D005839:Gentamicins; D009414:Nerve Growth Factors; D014404:Tubulin; C518911:neurotropin 3, mouse; D000072259:Connexin 26; D020813:Receptor, trkB; D020929:Mitogen-Activated Protein Kinase Kinases