Degeneration Of Spiral Ganglion Neurons Research Articles

Strategies to preserve or regenerate spiral ganglion neurons

Degeneration of spiral ganglion neurons following hair cell loss carries critical implications for efforts to rehabilitate severe cases of hearing loss with cochlear implants or hair cell regeneration. This review considers recently identified neurotrophic factors and therapeutic strategies which promote spiral ganglion neuron survival and neurite growth. Replacement of these factors may help preserve or regenerate the auditory nerve in patients with extensive hair cell loss. Spiral ganglion neurons depend on neurotrophic factors supplied by hair cells and other targets for their development and continued survival. Loss of this trophic support leads to spiral ganglion neuron death via apoptosis. Hair cells support spiral ganglion neuron survival by producing several peptide neurotrophic factors such as neurotrophin-3 and glial derived neurotrophic factor. In addition, neurotransmitter release from the hair cells drives membrane electrical activity in spiral ganglion neurons which also supports their survival. In animal models, replacement of peptide neurotrophic factors or electrical stimulation with an implanted electrode attenuates spiral ganglion neuron degeneration following deafferentation. Cell death inhibitors can also preserve spiral ganglion neuron populations. Preliminary studies show that transfer of stem cells or neurons from other ganglia are two potential strategies to replace lost spiral ganglion neurons. Inducing the regrowth of spiral ganglion neuron peripheral processes to approximate or contact cochlear implant electrodes may help optimize signaling from a diminished population of neurons. Recent studies of spiral ganglion neuron development and survival have identified several trophic and neuritogenic factors which protect these specialized cells from degeneration following hair cell loss. While still preliminary, such strategies show promise for future clinical applications.

Exogenous BDNF Rescues Rat Spiral Ganglion Neurons In Vivo

To determine if exogenous neurotrophins can prevent spiral ganglion neuron degeneration in the rat cochlea. The loss of hair cells resulting in sensorineural hearing loss also leads to the secondary degeneration of spiral ganglion neurons. The effectiveness of cochlear implantation in patients with profound sensorineural hearing loss relies in part on the survival of spiral ganglion neurons; 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. Whether this effect is seen in other species remains to be determined. After documenting the rate of spiral ganglion neuron degeneration after ototoxic deafening, we investigated the trophic effects of exogenous brain-derived neurotrophic factor (BDNF) on rat spiral ganglion neurons. The left cochleae of profoundly deafened rats were implanted with a drug delivery system connected to a mini-osmotic pump. BDNF or artificial perilymph was infused for 28 days; then the cochleae were prepared for histological study. Treatment with BDNF led to a statistically significant increase in spiral ganglion neuron density and a highly significant increase in spiral ganglion neuron soma area compared with artificial perilymph-treated and untreated deafened cochleae. The study has demonstrated the trophic advantage of exogenous BDNF in the mature rat cochlea and provides confidence that spiral ganglion neuron rescue after sensorineural hearing loss with exogenous BDNF may have clinical application.

Ouabain induces apoptotic cell death in type I spiral ganglion neurons, but not type II neurons.

Application of ouabain to the intact round-window (RW) membrane of the gerbil cochlea induces apoptosis in most spiral ganglion neurons (SGNs), leaving a few neurons intact (Schmiedt et al. 2002). Here, physiological measures and immunostaining were used to examine the process of SGN degeneration at 3, 6, 12, and 24 h, 4 days, and 1 and 5 months after ouabain treatment. The few remaining neurons surviving up to 5 months after ouabain treatment were immunoreactive for peripherin, a type II neuron marker. Peripherin-positive cell counts indicate that about 7% of the SGNs in the gerbil cochlea are type II neurons, and these neurons survive intact after ouabain treatment. Ouabain exposure had little effect on the outer hair cell and lateral wall systems, even after a 5 month loss of auditory-nerve function. The cellular locations of cytochrome c, poly (ADP-ribose) polymerase (PARP), and activated caspase 3 were examined in control and ouabain-treated cochleas. A redistribution of cytochrome c in peripherin-negative (type I) neurons was observed at 3 h after ouabain exposure. Degraded PARP and activated caspase 3 were also detected in peripherin-negative SGNs at 6 and 24 h after treatment, respectively. These results suggest that the redistribution of cytochrome c is an early event during apoptosis in type I SGNs and that activation of PARP and caspase 3 are associated with apoptosis in these cells. Calcineurin and NF-kappaB are two important signaling pathways that may modulate cell survival in the central nervous system. Here, we found that calcineurin and NF-kappaB selectively labeled type II neurons. It is speculated that the high levels of calcineurin and NF-kappaB in type II SGNs, as compared with type I SGNs, may play protective roles in enhancing the survival of type II neurons exposed to ouabain.

A single dose of neurotrophin-3 to the cochlea surrounds spiral ganglion neurons and provides trophic support

Degeneration of spiral ganglion neurons (SGNs) in the cochlea following sensorineural hearing loss is preventable by the infusion of neurotrophins into the scala tympani. This study investigates the trophic effects and distribution of a single bolus infusion of neurotrophin-3 (NT3) into the scala tympani of the cochlea. The left cochleae of 28-day deafened guinea pigs were infused with 0, 100 or 140 ng 125I NT3 via a cochleostomy in the scala tympani of the basal turn. Seven days post-infusion, cochlear sections were processed for measurements of trophic effects on SGNs and autoradiography. A single infusion of NT3 increased the soma size of SGNs in a dose-dependent and significant manner but did not contribute to SGN survival. Following infusion of 140 ng 125I NT3 into the cochlea, 0.31% of the total 125I NT3 signal in the basal turn was detected in Rosenthal’s canal, 2.4% was in peripheral processes and 0.35% was in the modiolar auditory nerve. Despite influencing SGN soma size, 125I NT3 was not observed to accumulate in SGN cell bodies. The data suggest that only a small proportion of neurotrophins infused into the scala tympani diffuses to the SGNs and their processes and produces trophic effects on SGN cell bodies.

Trophic support of mouse inner ear by neural stem cell transplantation.

In the auditory system, efforts to reduce degeneration of spiral ganglion neurons have the immediate objective of improving clinical benefits of cochlear implants, which are small devices designed to stimulate spiral ganglion neurons electronically. Recent studies have indicated several neurotrophins can enhance survival of spiral ganglion neurons. However, the strategy for application of neurotrophins in inner ear is still a matter of debate. In this study, we examined the potential of cell therapy as a strategy for application of neurotrophins in the inner ear. Neural stem cells obtained from green fluorescent protein-transgenic mice were used as donor cells. Medium containing neural stem cells was injected into mouse inner ear. Histological analysis 4 weeks later revealed that transplant-derived cells survived in inner ear and that most transplant-derived cells in the cochlea had differentiated into glial cells. Moreover, expression of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor was observed in transplant-derived cells. These findings indicate that transplantation of neural stem cells can be a useful strategy for application of neurotrophins in inner ear.

Deafness Due to Degeneration of Cochlear Neurons in Caspase-3-Deficient Mice

Mice that lack caspase-3, which functions in apoptosis, were generated by gene targeting and shown to undergo hearing loss. The ABR threshold of the caspase-3−/− mice was significantly elevated compared to that of caspase-3+/+ mice at 15 days of age and was progressively elevated further by 30 days. Distortion product otoacoustic emissions were not detectable in caspase-3−/− mice at 15 days of age. Caspase-3−/− mice exhibited marked degeneration of spiral ganglion neurons and a loss of inner and outer hair cells in the cochlea at 30 days of age, although no such changes were apparent at 15 days. The degenerating neurons manifested features, including cytoplasmic vacuolization, distinct from those characteristic of apoptosis. Spiral ganglion neurons and cochlear hair cells thus appear to require caspase-3 for survival but not for initial development. The mapping of both the human caspase-3 gene and the locus responsible for an autosomal dominant, nonsyndromic form of hearing loss (DFNA24) to chromosome 4q35 suggests that the caspase-3−/− mice may represent a model of this human condition.

Apoptosis in Auditory Brainstem Neurons after a Severe Noise Trauma of the Organ of Corti: Intracochlear GDNF Treatment Reduces the Number of Apoptotic Cells

We have studied the morphological and cellular changes in the cochlear nucleus (CN) after cochlear nerve degeneration and whether these changes can be prevented by rescuing the primary cochlear neurons from degeneration with local glial cell line derived neurotrophic factor (GDNF) treatment. Degeneration of spiral ganglion neurons was seen to lead to a reduction of the volume of the anteroventral cochlear nucleus (AVCN); the size of the cell nuclei in the AVCN also was reduced. No differences were observed in cell density. After intrascalar GDNF treatment the volume of the AVCN was significantly larger when compared to the untreated side, and the size of the cell nuclei in the AVCN was significantly larger on the treated side. After degeneration of spiral ganglion neurons, an increased number of apoptotic cell nuclei were seen in ipsilateral CN and superior olivary complex. This increase was significantly smaller after intrascalar GDNF treatment. Degeneration of primary cochlear neurons seems to lead to an increase in the number of CN neurons undergoing apoptotic cell death. This can be prevented partially by rescuing primary cochlear neurons from degeneration with local GDNF treatment.

Role of neurotrophins and lectins in prevention of ototoxicity.

Degeneration of hair cells (HC) and/or spiral ganglion neurons (SGN) is a major cause of hearing loss. Postnatal rat cochlear explant cultures are used to study the toxic actions of different classes of ototoxins and to identify molecules that can protect SGN and HC from ototoxic damage. Various ototoxins induce differential damage to HC and/or SGN. While gentamicin preferentially causes HC death, sodium salicylate selectively induces degeneration of SGN. In contrast, cisplatin results in destruction of both SGN and HC. Specific neurotrophins, including NT-4/5, BDNF, and NT-3, greatly protect SGN from all three types of ototoxins. In contrast, NGF and other growth factors have no effect. Of the 51 compounds examined, only concanavalin A (Con A), a lectin molecule, significantly protects HC from gentamicin. A dose-dependent study of Con A shows that maximal protection occurred at 100 nM. Further experiments indicates that preincubation of Con A with gentamicin does not form a complex, and coaddition of Con A and gentamicin to bacterial cultures, such as E. Coli cultures, does not interfere with the antibiotic activity of gentamicin. When the other 21 lectins are examined, Erythrina cristagalli lectin and Detura stramonium lectin also show activity similar to Con A. These findings may help elucidate the mechanisms of ototoxins and suggest that specific neurotrophins and lectins may be of therapeutic value in the prevention of ototoxin-induced hearing loss.

4-Methylcatechol, a Potent Inducer of Nerve Growth Factor Synthesis, Protects Spiral Ganglion Neurons from Aminoglycoside Ototoxicity: Preliminary Report

The degeneration of spiral ganglion neurons after hair cell destruction following aminoglycoside ototoxicity is associated not only with the direct effect on the neurons, but also with a loss of neurotrophic factors provided by auditory hair cells. The neurotrophic factors, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), have been reported to be effective in enhancing neuronal survival against aminoglycoside ototoxicity in vivo . To determine whether 4-methylcatechol (4-MC), a potent inducer of nerve growth factor synthesis, can protect spiral ganglion neurons after aminoglycoside treatment in vivo , we studied the spiral ganglion neurons of gentamicin (GM)-treated mice with or without 4-MC administration. We found that the number of surviving spiral ganglion neurons of 4-MC-treated animals was significantly greater than for those treated with GM alone. Our results suggest that 4-MC promotes synthesis of NGF (and/or other neurotrophins), which enhances spiral ganglion neuron survival after gentamicin treatment.

Therapeutic potential of neurotrophins for treatment of hearing loss.

Degeneration of spiral ganglion neurons (SGNs) and hair cells in the cochlea induced by aging, injury, ototoxic drugs, acoustic trauma, and various diseases is the major cause of hearing loss. Discovery of growth factors that can either prevent SGN and hair-cell death or stimulate hair-cell regeneration would be of great interest. Studies over the past several years have provided evidence that specific neurotrophins are potent survival factors for SGNs and protect these neurons from ototoxic drugs in vitro and in vivo. Current research focuses more on understanding the mechanism of hair-cell regeneration/differentiation and identification of growth factors that can stimulate hair-cell regeneration. SGNs are required to relay the signal to the central nervous system even when a cochlear implant is used to replace hair-cell function or in the case that cochlear sensory epithelium can be stimulated to regenerate new hair cells successfully. Therefore, neurotrophins may have their therapeutic value in prevention and treatment of hearing impairment.

Brain derived neurotrophic factor gene therapy prevents degeneration of spiral ganglion neurons in a mouse model of aminoglycoside ototoxicity

Otolaryngology–Head and Neck SurgeryVolume 117, Issue 2 p. P95-P95 Original Article Brain Derived Neurotrophic Factor Gene Therapy Prevents Degeneration of Spiral Ganglion Neurons in a Mouse Model of Aminoglycoside Ototoxicity Hinrich Staecker MD, PhD, Hinrich Staecker MD, PhD (presenter) City Island, Bronx Rochester, N.Y.Search for more papers by this authorRamin Gabaizedeh, Ramin Gabaizedeh City Island, Bronx Rochester, N.Y.Search for more papers by this authorHoward Federott MD, Howard Federott MD City Island, Bronx Rochester, N.Y.Search for more papers by this authorThomas R. Van De Water PhD, Thomas R. Van De Water PhD (presenter) City Island, Bronx Rochester, N.Y.Search for more papers by this author Hinrich Staecker MD, PhD, Hinrich Staecker MD, PhD (presenter) City Island, Bronx Rochester, N.Y.Search for more papers by this authorRamin Gabaizedeh, Ramin Gabaizedeh City Island, Bronx Rochester, N.Y.Search for more papers by this authorHoward Federott MD, Howard Federott MD City Island, Bronx Rochester, N.Y.Search for more papers by this authorThomas R. Van De Water PhD, Thomas R. Van De Water PhD (presenter) City Island, Bronx Rochester, N.Y.Search for more papers by this author First published: 01 August 1997 https://doi.org/10.1016/S0194-59989780138-6Read the full textAboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume117, Issue2August 1997Pages P95-P95 RelatedInformation

Brain Derived Neurotrophic Factor Gene Therapy Prevents Degeneration of Spiral Ganglion Neurons in a Mouse Model of Aminoglycoside Ototoxicity

Otolaryngology–Head and Neck SurgeryVolume 117, Issue 2 p. P95-P95 Original Article Brain Derived Neurotrophic Factor Gene Therapy Prevents Degeneration of Spiral Ganglion Neurons in a Mouse Model of Aminoglycoside Ototoxicity Hinrich Staecker MD, PhD, Hinrich Staecker MD, PhD (presenter) City Island, Bronx Rochester, N.Y.Search for more papers by this authorRamin Gabaizedeh, Ramin Gabaizedeh City Island, Bronx Rochester, N.Y.Search for more papers by this authorHoward Federott MD, Howard Federott MD City Island, Bronx Rochester, N.Y.Search for more papers by this authorThomas R. Van De Water PhD, Thomas R. Van De Water PhD (presenter) City Island, Bronx Rochester, N.Y.Search for more papers by this author Hinrich Staecker MD, PhD, Hinrich Staecker MD, PhD (presenter) City Island, Bronx Rochester, N.Y.Search for more papers by this authorRamin Gabaizedeh, Ramin Gabaizedeh City Island, Bronx Rochester, N.Y.Search for more papers by this authorHoward Federott MD, Howard Federott MD City Island, Bronx Rochester, N.Y.Search for more papers by this authorThomas R. Van De Water PhD, Thomas R. Van De Water PhD (presenter) City Island, Bronx Rochester, N.Y.Search for more papers by this author First published: 01 August 1997 https://doi.org/10.1016/S0194-59989780138-6Read the full textAboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume117, Issue2August 1997Pages P95-P95 RelatedInformation

Cochlear pathology of long term neomycin induced deafness in cats.

The long term sequelae of hair cell destruction consequent from administration of the ototoxic aminoglycoside antibiotic, neomycin sulfate, were evaluated in histological and ultrastructural studies of cochlear morphology in cats. Complete hearing loss, as defined by an absence of brainstem evoked responses to click stimulation at 120 dB peak SPL, was induced by intramuscular injections of neomycin at 50 mg/kg body weight/day, and cochlear pathology was studied at 6 months and 1, 3 and 4 years following onset of profound deafness. In these long term ototoxicity cases the organ of Corti was collapsed and resorbed over the basal one-quarter to three-quarters of the cochlear spiral, depending on duration of deafness. Significant progressive reduction in the spiral ganglion cell population and sequential degenerative alterations in the remaining neurons were observed with increasing time elapsed after induced hearing loss. The sequence of pathological alterations in spiral ganglion neurons appeared to be: a) swelling, demyelination and degeneration of the peripheral dendrites; b) demyelination and shrinkage of the cell soma with preservation of the central axon; and c) demyelination of the central axon and degeneration of the cell perikaryon. In apical cochlear regions, severe degeneration of the spiral ganglion preceded the collapse of the tunnel of Corti and regional loss of pillar cells. Residual populations of spiral ganglion neurons were as low as 1-2% of the normal values in the most severely degenerated cochleae in the series. Light microscopic and ultrastructural studies revealed a selective survival advantage for the unmyelinated type II neurons over the myelinated type I neurons with these long survival periods. The prolonged time course and atrophic nature of these pathological alterations suggests that degeneration of spiral ganglion neurons progresses continuously following drug-induced insult to the cochlea. Some possible factors contributing to this long term progressive degeneration will be discussed.

Variability of the hereditary deafness in the white cat. II. Histology.

Cochlear degeneration in white cats was investigated by light- and electron-microscopic examinations. A great variety of histological damage was encountered both in completely and partially deaf animals. These variable features are discussed mainly with regard to the rate of degeneration and the site of the first damage. Atypical findings, such as primary degeneration of spiral ganglion neurons, are presented. The possibility for some damaged cochleas to work without hair cells is described. These results clearly demonstrate that hereditary degeneration in the cochlea of white cats is not a unique and regular process.

Auditory dysfunction in Friedreich ataxia: result of spiral ganglion degeneration.

We performed behavioral audiometric tests and brainstem auditory evoked potentials in four patients with Friedreich ataxia. None of the patients had symptomatic hearing difficulties. Results of the audiometric tests pointed to a disorder of the eighth nerve. In none of the patients could we elicit normal-appearing waves of the brainstem auditory evoked potentials. These abnormalities could be attributed to degeneration of spiral ganglion neurons. Our patients had useful and functional hearing despite very abnormal brainstem auditory evoked potentials.