BDNF Outperforms TrkB Agonist 7,8,3'-THF in Preserving the Auditory Nerve in Deafened Guinea Pigs.

Henk A Vink,Huib Versnel,Dyan Ramekers,Willem C Van Dorp,Hans G X M Thomeer

doi:10.3390/brainsci10110787

Henk A Vink, Huib Versnel + Show 3 more

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https://doi.org/10.3390/brainsci10110787

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Abstract

In deaf subjects using a cochlear implant (CI) for hearing restoration, the auditory nerve is subject to degeneration, which may negatively impact CI effectiveness. This nerve degeneration can be reduced by neurotrophic treatment. Here, we compare the preservative effects of the naturally occurring tyrosine receptor kinase B (TrkB) agonist brain-derived neurotrophic factor (BDNF) and the small-molecule TrkB agonist 7,8,3′-trihydroxyflavone (THF) on the auditory nerve in deafened guinea pigs. THF may be more effective than BDNF throughout the cochlea because of better pharmacokinetic properties. The neurotrophic compounds were delivered by placement of a gelatin sponge on the perforated round window membrane. To complement the histology of spiral ganglion cells (SGCs), electrically evoked compound action potential (eCAP) recordings were performed four weeks after treatment initiation. We analyzed the eCAP inter-phase gap (IPG) effect and measures derived from pulse-train evoked eCAPs, both indicative of SGC healthiness. BDNF but not THF yielded a significantly higher survival of SGCs in the basal cochlear turn than untreated controls. Regarding IPG effect and pulse-train responses, the BDNF-treated animals exhibited more normal responses than both untreated and THF-treated animals. We have thus confirmed the protective effect of BDNF, but we have not confirmed previously reported protective effects of THF with our clinically applicable delivery method.

Highlights

Damage to or loss of cochlear hair cells in the organ of Corti leads to sensorineural hearing loss (SNHL)
In case of severe to profound SNHL, hearing can be partially restored by a cochlear implant (CI), which provides direct electrical stimulation of the spiral ganglion cells (SGCs) that make up the auditory nerve, bypassing the impaired and/or lost hair cells
We compared the effects of brain-derived neurotrophic factor (BDNF) and 7,8,30 -THF on SGC survival and neural responsiveness in a guinea pig model of sensorineural hearing loss, when administered to the cochlea in a clinically feasible fashion by means of a gelatin sponge on the round window membrane, a similar approach as used by Havenith et al [34,35] and Yu et al [46]

Summary

Introduction

Damage to or loss of cochlear hair cells in the organ of Corti leads to sensorineural hearing loss (SNHL). In case of severe to profound SNHL, hearing can be partially restored by a cochlear implant (CI), which provides direct electrical stimulation of the spiral ganglion cells (SGCs) that make up the auditory nerve, bypassing the impaired and/or lost hair cells. SGCs by means of neurotrophic support [1,2,3], damage to this structure, including loss of hair cells, leads to degeneration of SGCs [4,5,6,7,8,9]. Great efforts in animal studies have been made to prevent nerve degeneration with the aim of improving the hearing of CI users.

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