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

Yu, Qing; Chang, Qing; Liu, Xia; Wang, Yunfeng; Li, Huawei; Gong, Shusheng; Ye, Keqiang; Lin, Xiaobo

doi:10.1523/jneurosci.0854-13.2013

Cited by 40 publications

(38 citation statements)

References 59 publications

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“…To a lesser extent, this was also noted in wild type animals, suggesting that the clustering of surviving apical neurons could be related to other mutations in the C57BL/6 mouse, such as the mitochondrial DNA mutation, PolgD257A. Clumping of SGNs in the apex of the cochlea was also observed by others who performed histology in PolgD257A and PolgD257A/+ mouse ears (Crawley et al, 2011; Willott, 2009), in the Ly5.1 mouse mutant (Jyothi et al, 2010) and in another C×26 mutant described in 2 papers (Sun et al, 2009; Yu et al, 2013). Transmission electron microscopy (TEM) analysis in the latter study showed that clumping SGNs lacked myelin cover on their soma, a feature otherwise known to be exclusive to human auditory neurons (Tylstedt et al, 1997).…”

Section: Discussionmentioning

confidence: 65%

“…Flow of fluids in the cochlea is also a factor that limits the spread of the viral vector and the secreted neurotrophin towards more apical sites (Salt et al, 2009). In a recent study that assessed neurotrophin (NT-3, BDNF and TrkB receptor agonists) treatment in developing ears (P2) of a different C×26 null mouse, protective effects of were observed in the base and middle regions of the cochlea, but not in the apex (Yu et al, 2013). Starting the treatment during the developmental period may have contributed to the more efficient protection beyond the basal turn.…”

Section: Discussionmentioning

confidence: 99%

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Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy

et al. 2014

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Mutations in the connexin 26 gene (GJB2) are the most common genetic cause of deafness, leading to congenital bilateral non-syndromic sensorineural hearing loss. Here we report the generation of a mouse model for a connexin 26 (C×26) mutation, in which cre-Sox10 drives excision of the C×26 gene from non-sensory cells flanking the auditory epithelium. We determined that these conditional knockout mice, designated Gjb2-CKO, have a severe hearing loss. Immunocytochemistry of the auditory epithelium confirmed absence of C×26 in the non-sensory cells. Histology of the organ of Corti and the spiral ganglion neurons (SGNs) performed at ages 1, 3, or 6 months revealed that in Gjb2-CKO mice, the organ of Corti began to degenerate in the basal cochlear turn at an early stage, and the degeneration rapidly spread to the apex. In addition, the density of SGNs in Rosenthal’s canal decreased rapidly along a gradient from the base of the cochlea to the apex, where some SGNs survived until at least 6 months of age. Surviving neurons often clustered together and formed clumps of cells in the canal. We then assessed the influence of brain derived neurotrophic factor (BDNF) gene therapy on the SGNs of Gjb2-CKO mice by inoculating Adenovirus BDNF (Ad.BDNF) into the base of the cochlea via the scala tympani or scala media. We determined that over-expression of BDNF beginning around 1 month of age resulted in a significant rescue of neurons in Rosenthal’s canal of the cochlear basal turn but not in the middle or apical portions. This data may be used to design therapies for enhancing the SGN physiological status in all GJB2 patients and to a sub-group of GJB2 patients where the hearing loss progresses due to ongoing degeneration of the auditory nerve, thereby improving the outcome of cochlear implant therapy in these ears.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy

et al. 2014

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“…DHF also prevents glutamate-mediated apoptosis (Jang et al, 2010). In the cochlea, DHF has been shown to promote auditory protection in mice lacking connexin 26 (Yu et al, 2013), which indicates that DHF can cross the ear-blood barrier and target cochlear TrkB. We tested whether DHF would be able to protect auditory function from night noise exposure.…”

Section: Circadian Clock Control Of Noise Sensitivitymentioning

confidence: 99%

Circadian regulation of auditory function

Basinou

Park²,

Canlon

2017

Hearing Research

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“…Like BDNF, application of 7,8-DHF promotes the survival of cortical, hippocampal, retinal ganglion, and spiral ganglion neurons and prevents various oxidative or excitotoxicity-induced cell death in a TrkB-dependent manner (Jang et al, 2010; Gupta et al, 2013; Yu et al, 2013). Hence, 7,8-DHF can be applied to alleviate the syndromes of neurological disorders related to BDNF deficiency.…”

Section: Introductionmentioning

confidence: 99%

Activation of Muscular TrkB by its Small Molecular Agonist 7,8-Dihydroxyflavone Sex-Dependently Regulates Energy Metabolism in Diet-Induced Obese Mice

Chan

Tse

Liu

et al. 2015

Chemistry & Biology

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SUMMARY Chronic activation of brain-derived neurotrophic factor (BDNF) receptor TrkB is a potential method to prevent development of obesity, but the short half-life and nonbioavailable nature of BDNF hampers validation of the hypothesis. We report here that activation of muscular TrkB by the BDNF mimetic, 7,8-dihydroxyflavone (7,8-DHF), is sufficient to protect the development of diet-induced obesity in female mice. Using in vitro and in vivo models, we found that 7,8-DHF treatment enhanced the expression of uncoupling protein 1 (UCP1) and AMP-activated protein kinase (AMPK) activity in skeletal muscle, which resulted in increased systemic energy expenditure, reduced adiposity, and improved insulin sensitivity in female mice fed a high-fat diet. This antiobesity activity of 7,8-DHF is muscular TrkB-dependent as 7,8-DHF cannot mitigate diet-induced obesity in female muscle-specific TrkB knockout mice. Hence, our data reveal that chronic activation of muscular TrkB is useful in alleviating obesity and its complications.

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

Cited by 40 publications

References 59 publications

Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy

Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy

Circadian regulation of auditory function

Activation of Muscular TrkB by its Small Molecular Agonist 7,8-Dihydroxyflavone Sex-Dependently Regulates Energy Metabolism in Diet-Induced Obese Mice

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