Effect of transgenic GDNF expression on gentamicin-induced cochlear and vestibular toxicity

Suzuki, Michitaka; Yagi, Minoru; Brown, Jaclyn N.; Miller, AL; Miller, Josephine B.; Raphael, Yehoash

doi:10.1038/sj.gt.3301180

Cited by 81 publications

(58 citation statements)

References 40 publications

(51 reference statements)

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“…Our results partially correspond to results of previous studies showing that GDNF has a protective effect on antibiotics-induced ototoxicities (21)(22)(23)(24). Mutation of c-Ret at Y1062 has been shown to fail to respond to GDNF in vitro (19).…”

Section: Discussionsupporting

confidence: 81%

c-Ret–mediated hearing loss in mice with Hirschsprung disease

Ohgami

Ida-Eto

Shimotake

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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A significantly increased risk for dominant sensorineural deafness in patients who have Hirschsprung disease (HSCR) caused by endothelin receptor type B and SOX10 has been reported. Despite the fact that c-RET is the most frequent causal gene of HSCR, it has not been determined whether impairments of c-Ret and c-RET cause congenital deafness in mice and humans. Here, we show that impaired phosphorylation of c-Ret at tyrosine 1062 causes HSCR-linked syndromic congenital deafness in c-Ret knockin (KI) mice. The deafness involves neurodegeneration of spiral ganglion neurons (SGNs) with not only impaired phosphorylation of Akt and NF-κB but decreased expression of calbindin D28k in inner ears. The congenital deafness involving neurodegeneration of SGNs in c-Ret KI mice was rescued by introducing constitutively activated RET. Taken together with our results for three patients with congenital deafness with c-RET-mediated severe HSCR, our results indicate that c-Ret and c-RET are a deafness-related molecule in mice and humans. spiral ganglion neuron | syndromic congenital deafness | tyrosine kinase A bout 30% of the 120 million people worldwide who suffer from congenital (early-onset) hearing loss are syndromic, and the remaining 70% are nonsyndromic (1-3). To elucidate the etiologies for the hearing losses, inner ears have been morphologically investigated as one of the target tissues. The inner ears contain the organ of Corti and the stria vascularis. The stria vascularis serves to maintain the endolymph potential. The organ of Corti, which consists of two kinds of sensory cells (inner hair cells and outer hair cells) is responsible for mechanotransduction, by which sound impulses are converted into neural impulses. Auditory information from the sensory cells is transmitted to spiral ganglion neurons (SGNs) as the primary carrier, followed by eventual transmission to the auditory cortex (1, 2

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Section: Discussionsupporting

confidence: 81%

c-Ret–mediated hearing loss in mice with Hirschsprung disease

Ohgami

Ida-Eto

Shimotake

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…OHCs have also proven more vulnerable to GM ototoxicity than IHCs. [35][36][37] It is still unclear why IHCs could tolerate aminoglycoside ototoxicity better than OHCs. Similar results were observed in mice, as observation of OHC loss by GM ototoxicity precedes IHC loss.…”

Section: Discussionmentioning

confidence: 99%

Transient ischemia/hypoxia enhances gentamicin ototoxicity via caspase-dependent cell death pathway

Kao

Tsai

Lai

et al. 2011

Laboratory Investigation

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Aminoglycoside ototoxicity is a common cause of drug-induced hearing loss. Toxicity is dose related, but some patients may still develop hearing loss even under safe dosage. Apart for genetic idiosyncrasy, indirect evidences imply that ischemia may increase the aminoglycoside ototoxic sensitivity because common clinical situations associated with cochlear ischemia such as noise, sepsis, and shock are known to augment the development of aminoglycoside ototoxicity. At present, a direct interaction of cochlear ischemia and aminoglycoside ototoxicity is still lacking. This study demonstrated a direct evidence of increased gentamicin (GM) ototoxic sensitivity in chronic guinea pig models of transient cochlear ischemia. No permanent auditory changes were observed after a single dose of GM (125 mg/kg) or after transient cochlear ischemia for 30 min. Persistent and significant auditory threshold shift was detected when GM was given after transient cochlear ischemia. Cochlear hair cells and spiral ganglion neurons are the major regions affected. Apoptosis contributes to hair cell death during acute interaction of ischemia and GM ototoxicity. Increased apoptotic cell death was also depicted when GM crossreacted with hypoxia in vitro, using cochlear cell lines. Generation of reactive oxygen species, loss of mitochondrial membrane potential, calcium release, and caspase-dependent apoptotic cell death were shown during the interaction of hypoxia and GM ototoxicity in vitro. This synergistic ototoxicity may be critical to aminoglycoside-induced hearing loss in clinical scenarios. The results should improve our understanding of the interacting mechanism and potential preventive strategy to aminoglycoside ototoxicity.

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“…There are growing numbers of compounds that have been found to protect the cochlea from gentamicin toxicity (Yokota et al 1989;Garetz et al 1994;Xuan and Dong 1995;Song et al 1998;Gao 1999;Sha and Schacht 1999;Suzuki et al 2000;Sinswat et al 2000;Pirvola et al 2000). It is generally assumed that the protective effects of these compounds are due to direct effects upon hair cells.…”

Section: Implications For Protective Measuresmentioning

confidence: 99%

Changes in Cytochemistry of Sensory and Nonsensory Cells in Gentamicin-Treated Cochleas

Imamura

Adams

2003

JARO - Journal of the Association for Research in Otolaryngolog

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Effects of a single local dose of gentamicin upon sensory and nonsensory cells throughout the cochlea were assessed by changes in immunostaining patterns for a broad array of functionally important proteins. Cytochemical changes in hair cells, spiral ganglion cells, and cells of the stria vascularis, spiral ligament, and spiral limbus were found beginning 4 days post administration. The extent of changes in immunostaining varied with survival time and with cell type and was not always commensurate with the degree to which individual cell types accumulated gentamicin. Outer hair cells, types I and II fibrocytes of the spiral ligament, and fibrocytes in the spiral limbus showed marked decreases in immunostaining for a number of constituents. In contrast, inner hair cells, type III fibrocytes and root cells of the spiral ligament, cells of the stria vascularis, and interdental cells in the spiral limbus showed less dramatic decreases, and in some cases they showed increases in immunostaining. Results indicate that, in addition to damaging sensory cells, local application of gentamicin results in widespread and disparate disruptions of a variety of cochlear cell types. Only in the case of ganglion cells was it apparent that the changes in nonsensory cells were secondary to loss or damage of hair cells. These results indicate that malfunction of the ear following gentamicin treatment is widespread and far more complex than simple loss of sensory elements. The results have implications for efforts directed toward detecting, preventing, and treating toxic effects of aminoglycosides upon the inner ear.

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Effect of transgenic GDNF expression on gentamicin-induced cochlear and vestibular toxicity

Cited by 81 publications

References 40 publications

c-Ret–mediated hearing loss in mice with Hirschsprung disease

c-Ret–mediated hearing loss in mice with Hirschsprung disease

Transient ischemia/hypoxia enhances gentamicin ototoxicity via caspase-dependent cell death pathway

Changes in Cytochemistry of Sensory and Nonsensory Cells in Gentamicin-Treated Cochleas

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