Protection of auditory neurons from aminoglycoside toxicity by neurotrophin-3

Ernfors, Patrik; Duan, Mao Li; ElShamy, Wael M.; Canlon, Barbara

doi:10.1038/nm0496-463

Cited by 239 publications

(158 citation statements)

References 37 publications

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“…Within the developing cochlea, neurotrophins are differentially distributed, with NT-3 expressed predominantly in the supporting cells of the organ of Corti, and BDNF expressed only in hair cells (Farinas, et al, 2001). Further, many in vivo studies have reported that exogenous administration of neurotrophins (Ernfors et al, 1996;Kanzake et al, 2002;McGuinnes and Shepherd, 2005;Miller et al, 1997;Schindler et al 1995;Shepherd et al, 2005;Staecker et al, 1996Staecker et al, , 1998Zheng et al, 1995;Zheng and Gao, 1996) and other neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) (Ylikoski et al, 1998;Yagi et al, 2000) can protect SG neurons in adult animals from injury and promote improved survival after various insults, including ototoxic drugs.…”

Section: The Role Of Neurotrophins In Survival Of Sg Neurons After Nementioning

confidence: 99%

Factors influencing neurotrophic effects of electrical stimulation in the deafened developing auditory system

et al. 2008

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Research in animal models has demonstrated that electrical stimulation from a cochlear implant (CI) may help prevent degeneration of the cochlear spiral ganglion (SG) neurons after deafness. In cats deafened early in life, effective stimulation of the auditory nerve with complex signals for several months preserved a greater density of SG neurons in the stimulated cochleae as compared to the contralateral deafened ear. However, SG survival was still far from normal even with early intervention with an implant. Thus, pharmacologic agents and neurotrophic factors that might be used in combination with an implant are of great interest. Exogenous administration of GM1 ganglioside significantly reduces SG degeneration in deafened animals studied at 7-8 weeks of age, but after several months of stimulation, GM1-treated animals show only modestly better preservation of SG density compared to age-matched non-treated animals. A significant factor influencing neurotrophic effects in animal models is insertion trauma, which results in significant regional SG degeneration. Thus, an important goal is to further improve human CI electrode designs and insertion techniques to minimize trauma.Another important issue for studies of neurotrophic effects in the developing auditory system is the potential role of critical periods. Studies examining animals deafened at 30 days of age (rather than at birth) have explored whether a brief initial period of normal auditory experience affects the vulnerability of the SG or cochlear nucleus (CN) to auditory deprivation. Interestingly, SG survival in animals deafened at 30-days was not significantly different from age-matched neonatally deafened animals, but significant differences were observed in the central auditory system. CN volume was significantly closer to normal in the animals deafened at 30 days as compared to neonatally deafened animals. However, no difference was observed between the stimulated and contralateral CN volumes in either deafened group. Measurements of AVCN spherical cell somata showed that after later onset of deafness in the 30-day deafened group, mean cell size was significantly closer to normal than in the neonatally deafened group. Further, electrical stimulation elicited a significant increase in spherical cell size in the CN ipsilateral to the implant as compared to the contralateral CN in both deafened groups.Neuronal tracer studies have examined the primary afferent projections from the SG to the CN in neonatally deafened cats. CN projections exhibit a clear cochleotopic organization despite severe auditory deprivation from birth. However, when normalized for the smaller CN size after deafness, projections were 30-50% broader than normal. After unilateral electrical stimulation there was no difference between projections from the stimulated and non-stimulated ears. These findings suggest that early normal auditory experience may be essential for the normal development (or subsequent Publisher's Disclaimer: This is a PDF file of an unedited manuscript...

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Section: The Role Of Neurotrophins In Survival Of Sg Neurons After Nementioning

confidence: 99%

Factors influencing neurotrophic effects of electrical stimulation in the deafened developing auditory system

et al. 2008

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“…This degeneration has been associated with discontinued neurotrophic support from the organ of Corti (Ernfors et al 1995;Fritzsch et al 1999;Zilberstein et al 2012). Administration of exogenous neurotrophic factors has prevented SGC degeneration in multiple animal models of SNHL (for a review, see Ramekers et al 2012); SGCs are larger and more numerous after neurotrophic treatment than in untreated controls (Ernfors et al 1996;Richardson et al 2005;Shepherd et al 2005;Glueckert et al 2008;Agterberg et al 2008Agterberg et al , 2009Leake et al 2011;van Loon et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Auditory-Nerve Responses to Varied Inter-Phase Gap and Phase Duration of the Electric Pulse Stimulus as Predictors for Neuronal Degeneration

Ramekers

Versnel

Strahl

et al. 2014

JARO

155

268

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After severe hair cell loss, secondary degeneration of spiral ganglion cells (SGCs) is observed-a gradual process that spans years in humans but only takes weeks in guinea pigs. Being the target for cochlear implants (CIs), the physiological state of the SGCs is important for the effectiveness of a CI. For assessment of the nerve's state, focus has generally been on its response threshold. Our goal was to add a more detailed characterization of SGC functionality. To this end, the electrically evoked compound action potential (eCAP) was recorded in normal-hearing guinea pigs and guinea pigs that were deafened 2 or 6 weeks prior to the experiments. We evaluated changes in eCAP characteristics when the phase duration (PD) and inter-phase gap (IPG) of a biphasic current pulse were varied. We correlated the magnitude of these changes to quantified histological measures of neurodegeneration (SGC packing density and SGC size). The maximum eCAP amplitude, derived from the input-output function, decreased after deafening, and increased with both PD and IPG. The eCAP threshold did not change after deafening, and decreased with increasing PD and IPG. The dynamic range was wider for the 6-weeks-deaf animals than for the other two groups. Excitability increased with IPG (steeper slope of the input-output function and lower stimulation level at the half-maximum eCAP amplitude), but to a lesser extent for the deafened animals than for normal-hearing controls. The latency was shorter for the 6-weeks-deaf animals than for the other two groups. For several of these eCAP characteristics, the effect size of IPG correlated well with histological measures of degeneration, whereas effect size of PD did not. These correlations depend on the use of high current levels, which could limit clinical application. Nevertheless, their potential of these correlations towards assessment of the condition of the auditory nerve may be of great benefit to clinical diagnostics and prognosis in cochlear implant recipients.

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“…Moreover, these neurotrophins are also thought to contribute to neuronal maintenance in the adult inner ear (5). In the absence of hair cells, the neuroprotective effects of chronically delivered exogenous BDNF or NT-3 on SGNs in vivo has been demonstrated (11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Exogenous BDNF Rescues Rat Spiral Ganglion Neurons In Vivo

McGuinness¹,

Shepherd²

2005

Otology &Amp; Neurotology

106

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The loss of hair cells resulting in a sensorineural hearing loss (SNHL) also leads to the secondary degeneration of spiral ganglion neurons (SGNs). The effectiveness of cochlear implantation in patients with a profound SNHL relies, in part, upon the survival of SGNs; therefore any therapy that can prevent or halt the loss of these neurons would be of potential clinical benefit. Previous research has shown that intracochlear infusion with neurotrophins can provide trophic support to SGNs in deafened guinea pigs. It remains to be determined whether this effect is seen in other species. After documenting the rate of SGN degeneration following ototoxic deafening, we investigated the trophic effects of exogenous brain-derived neurotrophic factor (BDNF) on rat SGNs. The left cochleae of profoundly deafened rats were implanted with a drug delivery system connected to a mini-osmotic pump. BDNF or artificial perilymph (AP) was infused for 28 days and the cochleae were then prepared for histology. Treatment with BDNF led to a statistically significant increase in SGN density and a highly significant increase in SGN soma area compared to AP-treated and untreated deafened cochleae. This work has demonstrated the trophic advantage of exogenous BDNF in the mature rat cochlea and provides confidence that SGN rescue following SNHL with exogenous BDNF may have clinical application.

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Protection of auditory neurons from aminoglycoside toxicity by neurotrophin-3

Cited by 239 publications

References 37 publications

Factors influencing neurotrophic effects of electrical stimulation in the deafened developing auditory system

Factors influencing neurotrophic effects of electrical stimulation in the deafened developing auditory system

Auditory-Nerve Responses to Varied Inter-Phase Gap and Phase Duration of the Electric Pulse Stimulus as Predictors for Neuronal Degeneration

Exogenous BDNF Rescues Rat Spiral Ganglion Neurons In Vivo

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