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

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.

Correlation of Electrically Evoked Compound Action Potential Amplitude Growth Function Slope and Anamnestic Parameters in Cochlear Implant Patients—Identification of Predictors for the Neuronal Health Status

“…At least, the presence of a healthy and sufficiently large population of SGN that is able to transduce the encoded auditory information via the afferent auditory system to the auditory cortex has to be considered as prerequisite for cochlear implant outcome. The function and number of SGN correlates, at least in rodents, with the slopes of the electrically evoked compound action potential (ECAP) of the auditory nerve [ 4 , 5 ]. ECAP measurements in human CI users were also indicating such correlation [ 6 , 7 , 8 , 9 ].…”

No Protective Effects of Hair Cells or Supporting Cells in Ototoxically Deafened Guinea Pigs upon Administration of BDNF

“…Also, the overall SCs number was correlated with SGC packing density in individual animals. SGC data were obtained from previous analyses [15,32]. Table 1.…”

“…Therefore, progressive SGC death, which occurs as a consequence of the degeneration of the organ of Corti, would lead to reduced efficacy of CIs. For this reason, protective strategies to stop or delay SGC degeneration are needed, and several studies are ongoing in order to achieve this objective and allow prolonged hearing performance in CI users [ 14 , 15 , 16 ]. More attention has also been drawn to the role of SCs in the organ of Corti in pathological conditions, since the death of HCs is also accompanied by prominent structural alterations of the organ of Corti involving the SCs, and resulting in their degeneration as well [ 17 , 18 , 19 , 20 , 21 ].…”

“…BDNF is the most abundant neurotrophin of the brain and is essential for inner ear development and survival [ 28 , 29 ]. Notably, recombinant human BDNF administration was effective in preventing SGC death following hair cell degeneration in vivo [ 15 , 30 , 31 , 32 ], and therefore represents a promising therapeutic strategy for the treatment of sensorineural hearing loss. In particular, it could be used to further improve the hearing outcomes of patients with a CI by stimulating and sustaining neural health after implantation through the administration of exogenous BDNF.…”

A Broadly Applicable Method for Characterizing the Slope of the Electrically Evoked Compound Action Potential Amplitude Growth Function

“…One challenge in comparing the slope of the eCAP AGF across studies is the difference in input/output (I/O) units used to create the AGF. The stimulation level (i.e., input) has been specified in terms of charge in nanocoulombs (nC) (Ramekers et al 2014; Adenis et al 2018; He et al 2020a, b; Vink et al 2020; Xu et al 2020), current in mA or µA (Gantz et al 1994; Miller et al 1998; Pfingst et al 2015a, b, 2017; Schvartz-Leyzac et al 2018, 2019, 2020b), current normalized to the threshold current (Miller et al 1998) or logarithmic units in dB or current level (Abbas et al 1999; Hughes et al 2001, 2018; Cafarelli Dees et al 2005; Brown et al 2010; Kim et al 2010; Nehmé et al 2014; Jahn & Arenberg 2020a, b; Luo et al 2020). The eCAP amplitude (i.e., output) is typically specified in terms of voltage in mV or µV (Abbas et al 1999; Cafarelli Dees et al 2005; Nehmé et al 2014; Ramekers et al 2014; Pfingst et al 2015a, b, 2017; Schvartz-Leyzac et al 2018, 2019, 2020b; He et al 2020a; Jahn & Arenberg 2020a, b; Luo et al 2020), or normalized to the maximum eCAP (He et al 2018, 2020b; Xu et al 2020).…”