Neurotrophic factor intervention restores auditory function in deafened animals

Abstract

A primary cause of deafness is damage of receptor cells in the inner ear. Clinically, it has been demonstrated that effective functionality can be provided by electrical stimulation of the auditory nerve, thus bypassing damaged receptor cells. However, subsequent to sensory cell loss there is a secondary degeneration of the afferent nerve fibers, resulting in reduced effectiveness of such cochlear prostheses. The effects of neurotrophic factors were tested in a guinea pig cochlear prosthesis model. After chemical deafening to mimic the clinical situation, the neurotrophic factors brain-derived neurotrophic factor and an analogue of ciliary neurotrophic factor were infused directly into the cochlea of the inner ear for 26 days by using an osmotic pump system. An electrode introduced into the cochlea was used to elicit auditory responses just as in patients implanted with cochlear prostheses. Intervention with brain-derived neurotrophic factor and the ciliary neurotrophic factor analogue not only increased the survival of auditory spiral ganglion neurons, but significantly enhanced the functional responsiveness of the auditory system as measured by using electrically evoked auditory brainstem responses. This demonstration that neurotrophin intervention enhances threshold sensitivity within the auditory system will have great clinical importance for the treatment of deaf patients with cochlear prostheses. The findings have direct implications for the enhancement of responsiveness in deafferented peripheral nerves.

Figure 1

Mean and SD of the eABR thresholds observed in the AP and NTF treatment groups at different days after the onset of deafness. On day 31, the thresholds for the AP group ranged from ≈450 to 650 μA, whereas the thresholds for the NTF group ranged from ≈150 to 400 μA. There was no overlap between the two treatment groups. The mean eABR thresholds were significantly different between these groups on days 17, 24, and 31 (P = 0.019, 0.014, and 0.007, respectively; Student's t test).

Figure 2

Representative sections of Rosenthal's canal in the base of the cochlea from an AP-treated subject (Upper) and a subject of the NTF-treated subject (Lower). There is a clear difference in the survival of SGCs in these two subjects.

Figure 3

The observed mean and SEM of SGC density in AP- and NTF-treated groups. In the AP group, SGC density ranged from ≈5,000 to 20,000 cells per 10,000 μm². In the NTF-treated group, survival ranged from 11,000 to 39,000 cells per 10,000 μm². The mean difference was significant. *, P < 0.05.