Effects of delayed treatment with combined GDNF and continuous electrical stimulation on spiral ganglion cell survival in deafened guinea pigs

Scheper, Verena; Paasche, Gerrit; Miller, Josef M.; Warnecke, Athanasia; Berkingali, Nurdanat; Lenarz, Thomas; Stöver, Timo

doi:10.1002/jnr.21964

Cited by 68 publications

(75 citation statements)

References 40 publications

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“…Our results partially correspond to results of previous studies showing that GDNF has a protective effect on antibiotics-induced ototoxicities (21)(22)(23)(24). Mutation of c-Ret at Y1062 has been shown to fail to respond to GDNF in vitro (19).…”

Section: Discussionsupporting

confidence: 91%

c-Ret–mediated hearing loss in mice with Hirschsprung disease

Ohgami

Ida-Eto

Shimotake

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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A significantly increased risk for dominant sensorineural deafness in patients who have Hirschsprung disease (HSCR) caused by endothelin receptor type B and SOX10 has been reported. Despite the fact that c-RET is the most frequent causal gene of HSCR, it has not been determined whether impairments of c-Ret and c-RET cause congenital deafness in mice and humans. Here, we show that impaired phosphorylation of c-Ret at tyrosine 1062 causes HSCR-linked syndromic congenital deafness in c-Ret knockin (KI) mice. The deafness involves neurodegeneration of spiral ganglion neurons (SGNs) with not only impaired phosphorylation of Akt and NF-κB but decreased expression of calbindin D28k in inner ears. The congenital deafness involving neurodegeneration of SGNs in c-Ret KI mice was rescued by introducing constitutively activated RET. Taken together with our results for three patients with congenital deafness with c-RET-mediated severe HSCR, our results indicate that c-Ret and c-RET are a deafness-related molecule in mice and humans. spiral ganglion neuron | syndromic congenital deafness | tyrosine kinase A bout 30% of the 120 million people worldwide who suffer from congenital (early-onset) hearing loss are syndromic, and the remaining 70% are nonsyndromic (1-3). To elucidate the etiologies for the hearing losses, inner ears have been morphologically investigated as one of the target tissues. The inner ears contain the organ of Corti and the stria vascularis. The stria vascularis serves to maintain the endolymph potential. The organ of Corti, which consists of two kinds of sensory cells (inner hair cells and outer hair cells) is responsible for mechanotransduction, by which sound impulses are converted into neural impulses. Auditory information from the sensory cells is transmitted to spiral ganglion neurons (SGNs) as the primary carrier, followed by eventual transmission to the auditory cortex (1, 2

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Section: Discussionsupporting

confidence: 91%

c-Ret–mediated hearing loss in mice with Hirschsprung disease

Ohgami

Ida-Eto

Shimotake

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Improved EABR thresholds have also been reported after intracochlear overexpression of BDNF by adenovirus ) and intracochlear infusion of CTNF (Yamagata et al 2004) or GDNF (Maruyama et al 2008;Scheper et al 2009). Our previous study demonstrated a marked 6-dB improvement in EABR thresholds over 10 weeks of BDNF infusion in neonatally deafened, developing cats (Leake et al 2011).…”

Section: Longitudinal Eabr Threshold Datamentioning

confidence: 85%

Effects of Brain-Derived Neurotrophic Factor (BDNF) and Electrical Stimulation on Survival and Function of Cochlear Spiral Ganglion Neurons in Deafened, Developing Cats

Leake

Stakhovskaya

Hetherington

et al. 2013

JARO

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Both neurotrophic support and neural activity are required for normal postnatal development and survival of cochlear spiral ganglion (SG) neurons. Previous studies in neonatally deafened cats demonstrated that electrical stimulation (ES) from a cochlear implant can promote improved SG survival but does not completely prevent progressive neural degeneration. Neurotrophic agents combined with an implant may further improve neural survival. Short-term studies in rodents have shown that brain-derived neurotrophic factor (BDNF) promotes SG survival after deafness and may be additive to trophic effects of stimulation. Our recent study in neonatally deafened cats provided the first evidence of BDNF neurotrophic effects in the developing auditory system over a prolonged duration Leake et al. (J Comp Neurol 519:1526-1545. Ten weeks of intracochlear BDNF infusion starting at 4 weeks of age elicited significant improvement in SG survival and larger soma size compared to contralateral. In the present study, the same deafening and BDNF infusion procedures were combined with several months of ES from an implant. After combined BDNF + ES, a highly significant increase in SG numerical density (950 % improvement re: contralateral) was observed, which was significantly greater than the neurotrophic effect seen with ES-only over comparable durations. Combined BDNF + ES also resulted in a higher density of myelinated radial nerve fibers within the osseous spiral lamina. However, substantial ectopic and disorganized sprouting of these fibers into the scala tympani also occurred, which may be deleterious to implant function. EABR thresholds improved (re: initial thresholds at time of implantation) on the chronically stimulated channels of the implant. Terminal electrophysiological studies recording in the inferior colliculus (IC) revealed that the basic cochleotopic organization was intact in the midbrain in all studied groups. In deafened controls or after ES-only, lower IC thresholds were correlated with more selective activation widths as expected, but no such correlation was seen after BDNF + ES due to much greater variability in both measures.

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“…While multipotent cells from other species are well characterized, data on guinea-pig-derived cells are lacking. However, the guinea pig is an important model in hearing research since its inner ear spaces are easily accessible [21][22][23] . Due to the lack of data on autologous stem cells, recent studies primarily use xenogenic stem cell applications for cellbased otological experiments in the guinea pig model [1 5] .…”

Section: Discussionmentioning

confidence: 99%

Multipotent Stromal Cells for Autologous Cell Therapy Approaches in the Guinea Pig Model

Frölich

Scherzed²,

Mlynski³

et al. 2010

ORL

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Multipotent stromal cells have become of increasing interest due to their potential to provide therapeutic approaches for autologous tissue repair. However, these cells are not well defined in the guinea pig, which represents an important model in hearing research. Adipose-tissue-derived stem cells (ADSC) and bone-marrow-derived stem cells (BMSC) were isolated from different donor sites, and growth curves were generated to judge the proliferation potential. Adipogenic, chondrogenic and osteogenic differentiation was induced and confirmed histologically. Finally, the capability of guinea pig ADSC to differentiate into neuron-like cells was investigated. With regard to the expansion potential, total cell number and doubling time, ADSC from the neck were the most suitable cells of the tested donor sites. Both ADSC and BMSC showed nearly identical behaviour and ability to undergo multilineage differentiation. Thus, we identified ADSC from the neck as a promising cell source for autologous cell-based approaches in hearing research using the guinea pig model.

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Effects of delayed treatment with combined GDNF and continuous electrical stimulation on spiral ganglion cell survival in deafened guinea pigs

Cited by 68 publications

References 40 publications

c-Ret–mediated hearing loss in mice with Hirschsprung disease

c-Ret–mediated hearing loss in mice with Hirschsprung disease

Effects of Brain-Derived Neurotrophic Factor (BDNF) and Electrical Stimulation on Survival and Function of Cochlear Spiral Ganglion Neurons in Deafened, Developing Cats

Multipotent Stromal Cells for Autologous Cell Therapy Approaches in the Guinea Pig Model

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