Temporary Neurotrophin Treatment Prevents Deafness-Induced Auditory Nerve Degeneration and Preserves Function

Abstract

After substantial loss of cochlear hair cells, exogenous neurotrophins prevent degeneration of the auditory nerve. Because cochlear implantation, the current therapy for profound sensorineural hearing loss, depends on a functional nerve, application of neurotrophins is being investigated. We addressed two questions important for fundamental insight into the effects of exogenous neurotrophins on a degenerating neural system, and for translation to the clinic. First, does temporary treatment with brain-derived neurotrophic factor (BDNF) prevent nerve degeneration on the long term? Second, how does a BDNF-treated nerve respond to electrical stimulation? Deafened guinea pigs received a cochlear implant, and their cochleas were infused with BDNF for 4 weeks. Up to 8 weeks after treatment, their cochleas were analyzed histologically. Electrically evoked compound action potentials (eCAPs) were recorded using stimulation paradigms that are informative of neural survival. Spiral ganglion cell (SGC) degeneration was prevented during BDNF treatment, resulting in 1.9 times more SGCs than in deafened untreated cochleas. Importantly, SGC survival was almost complete 8 weeks after treatment cessation, when 2.6 times more SGCs were observed. In four eCAP characteristics (three involving alteration of the interphase gap of the biphasic current pulse and one involving pulse trains), we found large and statistically significant differences between normal-hearing and deaf controls. Importantly, for BDNF-treated animals, these eCAP characteristics were near normal, suggesting healthy responsiveness of BDNF-treated SGCs. In conclusion, clinically practicable short-term neurotrophin treatment is sufficient for long-term survival of SGCs, and it can restore or preserve SGC function well beyond the treatment period.

Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans

“…Based on the protective effects demonstrated in these studies, NFs are considered prime candidates for auditory nerve fiber rescue in humans and thus, improve the overall benefits from cochlear implants [2,3,4]. …”

“…Cochlear implantation, the current therapy for profound sensorineural hearing loss, is known to be contingent on the presence of spiral ganglion cells and function of the auditory nerve [1]. The ongoing degeneration of the auditory nerve that occurs following sensorineural hearing loss is considered a limiting factor in cochlear implant efficacy [2,3,4]. A reduced number of auditory nerve fibers in the human ear also underlies pertinent disorders such as hidden hearing loss [5,6].…”

“…Exogenous delivery of NFs into the cochlea of deafened animals has continually demonstrated beneficial functional and morphological preservation of the auditory nerve [4,13,14,15,16,17,18,19]. Based on these preclinical studies, it is hypothesized that NF therapy may provide beneficial effects and improve cochlear implant performance or prevent long-term neural loss after noise exposure [4,19]. However, this has not yet been clinically investigated due to safety and applicability concerns.…”

Structural changes in the inner ear over time studied in the experimentally deafened guinea pig

“…The rapid progression of degeneration obviously limits the therapeutic window. It has been shown that, when treatment (e.g., infusion of neurotrophic factors) is delayed, the positive effects on CI function are lower compared with when treatment starts shortly after the trauma (Yamagata et al, ; Agterberg et al, ; Fransson et al, ; Ramekers et al, ). The present study further demonstrates that the progression of structural degeneration is rapid and complete within 7 weeks.…”

Early Postnatal NT‐3 Gene Delivery Enhances Hearing Acquisition in the Developmental Period

“…There are many reports about NTs support in deaf animals or animals with hearing loss that showed NTs promoting nerve fiber regeneration and SGN survival . Gillespie et al postulated that delayed NT treatment could support SGN survival in deafened guinea pigs .…”