Delayed neurotrophic treatment preserves nerve survival and electrophysiological responsiveness in neomycin‐deafened guinea pigs

Abstract

Benefits of cochlear prostheses for the deaf are dependent on survival and excitability of the auditory nerve. Degeneration of deafferented auditory nerve fibers is prevented and excitability maintained by immediate replacement therapy with exogenous neurotrophic factors, in vivo. It is important to know whether such interventions are effective after a delay following deafness, typical for the human situation. This study evaluated the efficacy of brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor axokine-1 analogue (CNTF Ax1) application, 2 or 6 weeks postdeafening, in preventing further degeneration and a decrease in excitability. Guinea pigs were deafened and implanted with intracochlear stimulating electrodes, a scala tympani cannula-osmotic pump system, and auditory brainstem response (ABR) recording electrodes. Subjects received BDNF + CNTF Ax1 or artificial perilymph (AP) treatment for 27 days, beginning at 2 or 6 weeks following deafening. Electrical (E) ABR thresholds increased following deafening. After 1 week, in the 2-weeks-delayed neurotrophic factor treatment group, EABR thresholds decreased relative to AP controls, which were statistically significant at 2 weeks. In the 6-week delay group, a tendency to enhanced EABR sensitivity began at 2 weeks of treatment and increased thereafter, with a significant difference between neurotrophic factor- and AP-treated groups across the treatment period. A clear, statistically significant, enhanced survival of spiral ganglion cells was seen in both neurotrophic factor treatment groups relative to AP controls. These findings demonstrate that BDNF + CNTF Ax1 can act to delay or possibly even reverse degenerative and, likely apoptotic, processes well after they have been activated. These survival factors can rescue cells from death and enhance electrical excitability, even during the period of degeneration and cell loss when the spiral ganglion cell population is reduced by >50% (6 weeks). It is noteworthy that this same degree of ganglion cell loss, secondary to receptor damage, is typically observed after a period equivalent to some years of deafness in humans.

Mechanisms of noise-induced hearing loss indicate multiple methods of prevention

“…Nerve growth factor (NGF) delivered alone (Shah et al, 1995), or a combination of BDNF, NT3, and neurotrophin-4/5 (Gillespie et al, 2004), enhanced neural survival when administration was delayed by 2 weeks. The combination of BDNF and ciliary neurotrophic factor (CNTF) enhanced auditory nerve survival even at delays of up to 6 weeks post-deafening (Yamagata et al, 2004). Consistent with an important role for FGF 1 in neurite outgrowth in the immature auditory system (Dazert et al, 1998;Hossain and Morest, 2000), we recently demonstrated the efficacy of BDNF plus FGF 1 in promoting systematic regrowth of the peripheral process of the auditory nerve even after a 6-week period of deafening (Miller et al, 2003b;2006a).…”

Effects of Brain-Derived Neurotrophic Factor (BDNF) and Electrical Stimulation on Survival and Function of Cochlear Spiral Ganglion Neurons in Deafened, Developing Cats

“…Improved EABR thresholds have also been reported after intracochlear overexpression of BDNF by adenovirus ) and intracochlear infusion of CTNF (Yamagata et al 2004) or GDNF (Maruyama et al 2008;Scheper et al 2009). Our previous study demonstrated a marked 6-dB improvement in EABR thresholds over 10 weeks of BDNF infusion in neonatally deafened, developing cats (Leake et al 2011).…”

Brain-Derived Neurotrophic Factor Modulates Auditory Function in the Hearing Cochlea

“…We postulate that the threshold of ABRs to acoustic stimulation improved through a direct trophic effect upon the auditory nerve and/or its synapse with the inner hair cells. Electrically evoked ABR thresholds have been shown to be reduced below pretreatment levels in deafened animals treated with BDNF (Shinohara et al 2002;Yamagata et al 2004;Shepherd et al 2005;Leake et al 2011). It therefore seems possible that treatment with neurotrophins may affect the auditory neurons in the hearing cochlea to a similar degree as the deafened cochlea.…”