PMID- 23926258
OWN - NLM
STAT- MEDLINE
DCOM- 20131106
LR  - 20211021
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 33
IP  - 32
DP  - 2013 Aug 7
TI  - Protection of spiral ganglion neurons from degeneration using small-molecule TrkB 
      receptor agonists.
PG  - 13042-52
LID - 10.1523/JNEUROSCI.0854-13.2013 [doi]
AB  - 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.
FAU - Yu, Qing
AU  - Yu Q
AD  - Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, 
      Capital Medical University, Beijing, China 100730.
FAU - Chang, Qing
AU  - Chang Q
FAU - Liu, Xia
AU  - Liu X
FAU - Wang, Yunfeng
AU  - Wang Y
FAU - Li, Huawei
AU  - Li H
FAU - Gong, Shusheng
AU  - Gong S
FAU - Ye, Keqiang
AU  - Ye K
FAU - Lin, Xi
AU  - Lin X
LA  - eng
GR  - R01 DC006483/DC/NIDCD NIH HHS/United States
GR  - R01 DC010204/DC/NIDCD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (6,7-dihydroxyflavone)
RN  - 0 (7,8,3'-trihydroxyflavone)
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Connexins)
RN  - 0 (Flavones)
RN  - 0 (Gentamicins)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Tubulin)
RN  - 0 (neurotropin 3, mouse)
RN  - 127120-53-0 (Connexin 26)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Action Potentials/drug effects/genetics
MH  - Animals
MH  - Animals, Newborn
MH  - Anti-Bacterial Agents/toxicity
MH  - Brain-Derived Neurotrophic Factor/pharmacology
MH  - Cochlea/cytology/drug effects
MH  - Connexin 26
MH  - Connexins/genetics
MH  - Dose-Response Relationship, Drug
MH  - Evoked Potentials, Auditory, Brain Stem/drug effects/genetics
MH  - Female
MH  - Flavones/pharmacology/*therapeutic use
MH  - Gentamicins/toxicity
MH  - In Vitro Techniques
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Nerve Degeneration/chemically induced/genetics/*prevention & control
MH  - Nerve Growth Factors/pharmacology
MH  - Neurites/drug effects
MH  - Neurons/cytology/*drug effects
MH  - Phosphorylation/drug effects
MH  - Receptor, trkB/*agonists/deficiency/metabolism
MH  - Spiral Ganglion/cytology
MH  - Tubulin/metabolism
PMC - PMC3735884
EDAT- 2013/08/09 06:00
MHDA- 2013/11/07 06:00
PMCR- 2014/02/07
CRDT- 2013/08/09 06:00
PHST- 2013/08/09 06:00 [entrez]
PHST- 2013/08/09 06:00 [pubmed]
PHST- 2013/11/07 06:00 [medline]
PHST- 2014/02/07 00:00 [pmc-release]
AID - 33/32/13042 [pii]
AID - 0854-13 [pii]
AID - 10.1523/JNEUROSCI.0854-13.2013 [doi]
PST - ppublish
SO  - J Neurosci. 2013 Aug 7;33(32):13042-52. doi: 10.1523/JNEUROSCI.0854-13.2013.