Delayed neurotrophin treatment supports auditory neuron survival in deaf guinea pigs

Gillespie, Lisa N; Clark, Graeme M.; Marzella, Phillip L.

doi:10.1097/00001756-200405190-00008

Cited by 77 publications

(84 citation statements)

References 18 publications

(20 reference statements)

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“…Neurotrophins have been shown, by this study and others, to act as survival factors for mature SGNs in animal models of SNHL (12)(13)(14)(15). Other research has demonstrated that neurotrophins and electrical stimulation act in synergy to prevent SGN degeneration (25,21).…”

Section: Safety and Clinical Implicationssupporting

confidence: 52%

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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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Section: Safety and Clinical Implicationssupporting

confidence: 52%

“…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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“…Six of these animals then received BDNF treatment and six received Ringer's solution to serve as deafened controls. BDNF was chosen because it has been shown to improve SGN survival after deafness in several studies in the guinea pig (Staecker et al 1996;Miller et al 1997;Gillespie et al 2004;Shepherd et al 2005;Agterberg et al 2008) and this was a requirement of the validation of the round window delivery method developed here. Furthermore, BDNF has been the most extensively examined neurotrophin for potential use with cochlear implants Song et al 2009); thus, it seemed appropriate to begin our investigations in hearing animals with this protein.…”

Section: Experimental Subjects and Designmentioning

confidence: 99%

“…Fluid was then manually pushed through the delivery system with a syringe to test its patency in situ. Cochleae were then removed and SGN density was assessed to establish whether our delivery method resulted in the usual protection of SGNs observed with BDNF treatment (Staecker et al 1996;Miller et al 1997;Gillespie et al 2004;Shepherd et al 2005;Wise et al 2005;Agterberg et al 2008;Havenith et al 2011).…”

Section: Experimental Subjects and Designmentioning

confidence: 99%

“…Neurotrophins have been pivotal in research directed towards achieving this aim. These proteins have been shown to rescue auditory neurons from cell death after sensorineural hearing loss (Staecker et al 1996(Staecker et al , 1998Miller et al 1997;Gillespie et al 2004) and to promote the regrowth of the peripheral dendrites of surviving neurons (Wise et al 2005;Miller et al 2007;Evans et al 2009) with both effects being desirable to increase electrode specificity (Miller et al 2007; O' Leary et al 2009). …”

Section: Introductionmentioning

confidence: 99%

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

Sly

Hampson

Minter

et al. 2011

JARO

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Neurotrophins prevent spiral ganglion neuron (SGN) degeneration in animal models of ototoxin-induced deafness and may be used in the future to improve the hearing of cochlear implant patients. It is increasingly common for patients with residual hearing to undergo cochlear implantation. However, the effect of neurotrophin treatment on acoustic hearing is not known. In this study, brain-derived neurotrophic factor (BDNF) was applied to the round window membrane of adult guinea pigs for 4 weeks using a cannula attached to a mini-osmotic pump. SGN survival was first assessed in ototoxically deafened guinea pigs to establish that the delivery method was effective. Increased survival of SGNs was observed in the basal and middle cochlear turns of deafened guinea pigs treated with BDNF, confirming that delivery to the cochlea was successful. The effects of BDNF treatment in animals with normal hearing were then assessed using distortion product otoacoustic emissions (DPOAEs), pure tone, and clickevoked auditory brainstem responses (ABRs). DPOAE assessment indicated a mild deficit of 5 dB SPL in treated and control groups at 1 and 4 weeks after cannula placement. In contrast, ABR evaluation showed that BDNF lowered thresholds at specific frequencies (8 and 16 kHz) after 1 and 4 weeks posttreatment when compared to the control cohort receiving Ringer's solution. Longer treatment for 4 weeks not only widened the range of frequencies ameliorated from 2 to 32 kHz but also lowered the threshold by at least 28 dB SPL at frequencies ≥16 kHz. BDNF treatment for 4 weeks also increased the amplitude of the ABR response when compared to either the control cohort or prior to treatment. We show that BDNF applied to the round window reduces auditory thresholds and could potentially be used clinically to protect residual hearing following cochlear implantation.

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Chronic depolarization enhances the trophic effects of brain‐derived neurotrophic factor in rescuing auditory neurons following a sensorineural hearing loss

Shepherd

Coco

Epp

et al. 2005

J of Comparative Neurology

178

228

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The development and maintenance of spiral ganglion neurons (SGNs) appears to be supported by both neural activity and neurotrophins. Removal of this support leads to their gradual degeneration. Here, we examine whether the exogenous delivery of the neurotrophin brain-derived neurotrophic factor (BDNF) in concert with electrical stimulation (ES) provides a greater protective effect than delivery of BDNF alone in vivo. The left cochlea of profoundly deafened guinea pigs was implanted with an electrode array and drug delivery system. BDNF or artificial perilymph (AP) was delivered continuously for 28 days. ES induced neural activity in two cohorts (BDNF/ES and AP/ES) while control animals received BDNF or AP without ES (BDNF/-and AP/-). The right cochleae of each animal served as deafened untreated controls. Electrically-evoked auditory brainstem responses (EABRs) were recorded immediately following surgery and at completion of the drug delivery period. AP/ES and AP/-cohorts showed an increase in EABR threshold over the implantation period while both BDNF cohorts exhibited a reduction in threshold (P < 0.001, t-test). Changes in neural sensitivity were complemented by significant differences in both SGN survival and soma area. BDNF cohorts demonstrated a significant trophic or survival advantage and larger soma area compared with AP-treated and deafened control cochleae; this advantage was greatest in the base of the cochlea. Importantly, ES significantly enhanced the survival effects of BDNF throughout the majority of the cochlea (P < 0.05, Bonferroni's test), while there was no evidence of trophic support provided by ES alone. Co-treatment of SGNs with BDNF and ES provide a substantial functional and trophic advantage; this treatment may have important implications for neural prostheses.

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Delayed neurotrophin treatment supports auditory neuron survival in deaf guinea pigs

Cited by 77 publications

References 18 publications

Exogenous BDNF Rescues Rat Spiral Ganglion Neurons In Vivo

Exogenous BDNF Rescues Rat Spiral Ganglion Neurons In Vivo

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

Chronic depolarization enhances the trophic effects of brain‐derived neurotrophic factor in rescuing auditory neurons following a sensorineural hearing loss

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