Combined brain-derived neurotrophic factor and neurotrophin-3 treatment is preferred over either one separately in the preservation of the auditory nerve in deafened guinea pigs

Abstract

Severe hearing loss or deafness is often caused by cochlear hair cell loss and can be mitigated by a cochlear implant (CI). CIs target the auditory nerve, consisting of spiral ganglion cells (SGCs), which degenerate gradually, following hair cell loss. In animal models, it has been established that treatment with the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) reduce SGC degeneration. In this study, we aimed to investigate whether treatment with both BDNF and NT-3 (Cocktail) is superior to treatment with each neurotrophin separately regarding cell preservation and neural responsiveness to electrical stimulation. To this end, deafened guinea pigs received neurotrophic treatment in their right ear via a gelatin sponge on the perforated round window membrane, followed by cochlear implantation 4 weeks later in the same ear for electrophysiological recordings to various stimulation paradigms. Normal-hearing and deafened untreated guinea pigs were included as positive and negative controls, respectively. Substantial SGC loss occurred in all deafened animals. Each of the neurotrophic treatments led to enhanced SGC survival mainly in the basal turn of the cochlea, gradually decreasing toward the apex. The Cocktail treatment resulted in the highest SGC survival in the treated ear, followed by BDNF, with the least protection of SGCs following NT-3 treatment. Survival of the SGC’s peripheral processes (PPs) followed the same trend in response to the treatment. However, survival of SGCs and PPs in the contralateral untreated ears was also highest in the Cocktail group. Consequently, analysis of the ratio between the treated and untreated ears showed that the BDNF group, which showed low SGC survival in the untreated ear, had the highest relative SGC survival of the three neurotrophin-treated groups. Neurotrophic treatment had positive effects in part of the electrically evoked compound action-potential recording paradigms. These effects were only observed for the BDNF or Cocktail treatment. We conclude that treatment with either BDNF or a cocktail of BDNF and NT-3 is preferred to NT-3 alone. Furthermore, since the Cocktail treatment resulted in better electrophysiological responsiveness and overall higher SGC survival than BDNF alone, we are inclined to recommend the Cocktail treatment rather than BDNF alone.

Closing the Gap between the Auditory Nerve and Cochlear Implant Electrodes: Which Neurotrophin Cocktail Performs Best for Axonal Outgrowth and Is Electrical Stimulation Beneficial?

“…Hence, NT-3 and BDNF showed trends for distinct tonotopic effects on trk receptors at the level of the SGN somata. In contrast to previous findings [11,19,35,72], we could not identify an additive or synergistic effect of both NTs applied simultaneously. We speculate that the ratio of the total amount of available NTs to the cultured biomass may play a role, as the NTs are partly internalized after binding to the respective receptor and then degraded or recycled [73].…”

“…Another one could be that we used rather high concentrations of BDNF and NT-3 in our combined groups and, therefore, may have already reached the ceiling of outgrowth responsiveness with a single NT. Such a ceiling effect was also discussed in a recent study about single vs. combined NT treatments on SGN preservation and responsiveness in deafened guinea pigs [35].…”

“…Both brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are known as potent neurotrophins (NTs) to promote SGN survival and even to induce resprouting and regrowth of neurites in single-cell cultures [9][10][11][12][13][14][15], organotypic explant cultures [11,14,[16][17][18][19][20][21] and in vivo [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. BDNF binds with high affinity to the tyrosine receptor kinase B (trkB), while NT-3 does so to the tyrosine receptor kinase C (trkC).…”

Regeneration of Hair Cells from Endogenous Otic Progenitors in the Adult Mammalian Cochlea: Understanding Its Origins and Future Directions

“…Protection of SGNs by neurotrophins after cochlear damage has been widely studied (for review, see [56]). The four types of neurotrophin nerve growth factor (NGF), BDNF, NT-3, and NT-4/5 participate during cochlear development, and exogenous treatment has been shown to ameliorate SGN loss and improve the number of ribbon synapses after cochlear damage in animal studies [176][177][178][179][180][181]. Other novel therapies involve drugs targeting different molecules in the cochlea, such as the repulsive guidance molecule (RGMa) with antibodies or using Trk receptor agonists; these strategies have been shown to promote neuronal survival, restore synapse after damage and even restore hearing to control levels in adult mice [182][183][184].…”