Screening Mammalian Cochlear Hair Cells to Identify Critical Processes in Aminoglycoside-Mediated Damage

Lim, Hyun Woo; Pak, Kwang; Ryan, Allen F.; Kurabi, Arwa

doi:10.3389/fncel.2018.00179

Cited by 8 publications

(7 citation statements)

References 76 publications

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“…Most attempts to identify compounds that could be co-administered with aminoglycosides to provide otoprotection without diminishing bactericidal activity have focussed on testing antioxidants and anti-apoptotic agents (10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Other attempts have screened libraries of FDAapproved drugs (20), or libraries of molecules that interact with ion channels (21).…”

Section: Introductionmentioning

confidence: 99%

Identification of a series of hair-cell MET channel blockers that protect against aminoglycoside-induced ototoxicity

Kenyon¹,

Kirkwood²,

Kitcher³

et al. 2021

JCI Insight

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To identify small molecules that shield mammalian sensory hair cells from the ototoxic side effects of aminoglycoside antibiotics, 10,240 compounds were initially screened in zebrafish larvae selecting those that protected lateral-line hair cells against neomycin and gentamicin. When the 64 hits from this screen were retested in mouse cochlear cultures, 8 protected outer hair cells (OHCs) from gentamicin in vitro without causing hair-bundle damage. These 8 hits share structural features and all block, to varying degrees, the OHC's mechano-electrical transducer (MET) channel, a known route of aminoglycoside entry into hair cells. Further characterisation of one of the strongest MET-channel blockers, UoS-7692, revealed it additionally protects against kanamycin and tobramycin, and does not abrogate the bactericidal activity of gentamicin. UoS-7692 behaves, like the aminoglycosides, as a permeant blocker of the MET channel, significantly reduces gentamicin-Texas Red loading into OHCs, and preserves lateral-line function in neomycin-treated zebrafish. Trans-tympanic injection of UoS-7692 protects mouse OHCs from furosemide/kanamycin exposure in vivo and partially preserves hearing. The results confirm the hair-cell MET channel as a viable target for the identification of compounds that protect the cochlea from aminoglycosides, and provide a series of hit compounds that will inform the design of future otoprotectants.

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Section: Introductionmentioning

confidence: 99%

Identification of a series of hair-cell MET channel blockers that protect against aminoglycoside-induced ototoxicity

Kenyon¹,

Kirkwood²,

Kitcher³

et al. 2021

JCI Insight

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“…Efforts to establish cell lines that produce fully differentiated mechanosensory hair cells with their characteristic stereocilia and mechanotransduction channels have been unsuccessful and investigations rely on the use of animal tissues and organoids (Koehler et al 2017;Lim et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…The preclinical research phase of the drug development pipeline relies on screens with cell line and animal models that share molecular, cellular, and physiological properties with human cells and organs. Efforts to establish cell lines that produce fully differentiated mechanosensory hair cells with their characteristic stereocilia and mechanotransduction channels have been unsuccessful and investigations rely on the use of animal tissues and organoids (Koehler et al 2017; Lim et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

AXenopusneuromast bioassay for chemical ototoxicity

Knight

Luna

Serrano

2022

Preprint

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Background: Ototoxic chemicals can impair the senses of hearing and balance in mammals through irreversible damage to the mechanosensory bundles of inner ear hair cells. Fish and amphibians are useful models for investigating ototoxicity because their inner ear hair cells, like those of mammals, are susceptible to damage by ototoxins. Moreover, amphibian mechanosensation is augmented by a lateral line organ on the body surface that comprises external mechanosensory hair cells. The lateral line hair cells are arranged in clusters (neuromasts) and are structurally and functionally similar to inner ear hair cells, but are more accessible for experimental manipulation. Herein, we implemented neuromasts of the amphibian (Xenopus) lateral line as an organ system for evaluating the effects of ototoxic chemicals, such as antibiotics, on mechanosensory hair cell bundles. Methods: We examined the ultrastructure of larval Xenopus laevis neuromasts with scanning electron microscopy (SEM) after larvae were continuously exposed to ototoxic aminoglycoside antibiotics at sub-lethal concentrations (gentamicin; streptomycin; neomycin) for 72 hours. Results: SEM images demonstrated that 72 hours of exposure to antibiotic concentrations greater than 25 μM reduced the hair cell bundle number in lateral line neuromasts. Conclusion: Therapeutic drug studies will benefit from the incorporation of bioassay strategies that evaluate ototoxicity across multiple species including genera of amphibian origin such as Xenopus. Our outcomes support the use of the Xenopus lateral line for identification of potential ototoxic chemicals and suggest that Xenopus neuromast hair cell bundles can withstand antibiotic exposure. The Xenopus bioassay presented here can be incorporated into drug discovery methodology as a high-resolution phenotypic screen for ototoxic effects.

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“…Therefore, promoting hair cell regeneration after injury may be another way to solve the problem of drug ototoxicity. The study on the mechanism of inducing zebrafish hair cell regeneration has become a research hotspot 38 . In this study, we focused not only on the recovery of HCs amount after injury but also on the changes in their function.…”

Section: Discussionmentioning

confidence: 99%

Naringin attenuates cisplatin‐ and aminoglycoside‐induced hair cell injury in the zebrafish lateral line via multiple pathways

Liu

et al. 2020

J Cellular Molecular Medi

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Ototoxicity refers to the pathological and functional impairments of auditory nervous system caused by the application of some therapeutic drugs. Although drug-induced hearing loss is not fatal, it will seriously damage the social and health-related quality of patients, with significant implications for careers, education and society. In children, even minor hearing loss can impede speech, language, cognition and social development, which can lead to poor academic performance and psychosocial functioning. 1-5 Worldwide, around 30 thousand children suffer from cytotoxic agents every year. Currently, there are more than 600 drugs having ototoxic properties, such as aminoglycoside antibiotics, platinum-based chemotherapy drugs, cyclic diuretics, macrolides and

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Screening Mammalian Cochlear Hair Cells to Identify Critical Processes in Aminoglycoside-Mediated Damage

Cited by 8 publications

References 76 publications

Identification of a series of hair-cell MET channel blockers that protect against aminoglycoside-induced ototoxicity

Identification of a series of hair-cell MET channel blockers that protect against aminoglycoside-induced ototoxicity

AXenopusneuromast bioassay for chemical ototoxicity

Naringin attenuates cisplatin‐ and aminoglycoside‐induced hair cell injury in the zebrafish lateral line via multiple pathways

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