title: 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.
authors.affiliation: Center for Hearing and Communication Research and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yamagata
authors.forename: Josef M
authors.initials: JM
authors.lastname: Miller
authors.forename: Mats
authors.initials: M
authors.lastname: Ulfendahl
authors.forename: N Petri
authors.initials: NP
authors.lastname: Olivius
authors.forename: Richard A
authors.initials: RA
authors.lastname: Altschuler
authors.forename: Ilmari
authors.initials: I
authors.lastname: Pyykkö
authors.forename: Göran
authors.initials: G
authors.lastname: Bredberg
mesh_terms: D000818:Animals; D002404:Catheterization; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D020934:Ciliary Neurotrophic Factor / Q000008:administration & dosage; D003056:Cochlear Nerve / Q000187:drug effects* / Q000502:physiology*; D003638:Deafness / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D015918:Infusion Pumps, Implantable; D009355:Neomycin / Q000633:toxicity*; D009414:Nerve Growth Factors / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D020934:Ciliary Neurotrophic Factor; D009414:Nerve Growth Factors; D009355:Neomycin