Purpose This review article summarizes our current understanding of the mechanisms underlying acquired hearing loss from hospital-prescribed medications that affects as many as 1 million people each year in Western Europe and North America. Yet, there are currently no federally approved drugs to prevent or treat the debilitating and permanent hearing loss caused by the life-saving platinum-based anticancer drugs or the bactericidal aminoglycoside antibiotics. Hearing loss has long-term impacts on quality-of-life measures, especially in young children and older adults. This review article also highlights some of the current knowledge gaps regarding iatrogenic causes of hearing loss. Conclusion Further research is urgently needed to further refine clinical practice and better ameliorate iatrogenic drug-induced hearing loss.

https://pubs.asha.org/doi/pdf/10.1044/2021_AJA-21-00006

Mechanisms of Aminoglycoside- and Cisplatin-Induced Ototoxicity

Mechanisms of Ototoxicity and Otoprotection

Abstract There are no approved therapeutics for the prevention of hearing loss and vestibular dysfunction from drugs like aminoglycoside antibiotics. While the mechanisms underlying aminoglycoside ototoxicity remain unresolved, there is considerable evidence that aminoglycosides enter inner ear mechanosensory hair cells through the mechanoelectrical transduction (MET) channel. Inhibition of MET-dependent uptake with small molecules or modified aminoglycosides is a promising otoprotective strategy. To better characterize mammalian ototoxicity and aid in the translation of emerging therapeutics, a biomarker is needed. In the present study we propose that neonatal mice systemically injected with the aminoglycosides G418 conjugated to Texas Red (G418-TR) can be used as a histologic biomarker to characterize in vivo aminoglycoside toxicity. We demonstrate that postnatal day 5 mice, like older mice with functional hearing, show uptake and retention of G418-TR in cochlear hair cells following systemic injection. When we compare G418-TR uptake in other tissues, we find that kidney proximal tubule cells show similar retention. Using ORC-13661, an investigational hearing protection drug, we demonstrate in vivo inhibition of aminoglycoside uptake in mammalian hair cells. This work establishes how systemically administered fluorescently labeled ototoxins in the neonatal mouse can reveal important details about ototoxic drugs and protective therapeutics. 

An in vivo biomarker to characterize ototoxic compounds and novel protective therapeutics

Purpose: Acquired vestibulotoxicity from hospital-prescribed medications such as aminoglycoside antibiotics affects as many as 40,000 people each year in North America. However, there are no current federally approved drugs to prevent or treat the debilitating and permanent loss of vestibular function caused by bactericidal aminoglycoside antibiotics. This review will cover our current understanding of the impact of, and mechanisms underlying, aminoglycoside-induced vestibulotoxicity and highlight the gaps in our knowledge that remain. Conclusions: Aminoglycoside-induced vestibular deficits have long-term impacts on patients across the lifespan. Additionally, the prevalence of aminoglycoside-induced vestibulotoxicity appears to be greater than cochleotoxicity. Thus, monitoring for vestibulotoxicity should be independent of auditory monitoring and encompass patients of all ages from young children to older adults before, during, and after aminoglycoside therapy. 

Mechanisms and Impact of Aminoglycoside-Induced Vestibular Deficits

There are no approved therapeutics for the prevention of hearing loss and vestibular dysfunction from drugs like aminoglycoside antibiotics. While the mechanisms underlying aminoglycoside ototoxicity remain unresolved, there is considerable evidence that aminoglycosides enter inner ear mechanosensory hair cells through the mechanoelectrical transduction (MET) channel. Inhibition of MET-dependent uptake with small molecules or modified aminoglycosides is a promising otoprotective strategy. To better characterize mammalian ototoxicity and aid in the translation of emerging therapeutics, a biomarker is needed. In the present study we propose that neonatal mice systemically injected with the aminoglycosides G418 conjugated to Texas Red (G418-TR) can be used as a histologic biomarker to characterize in vivo aminoglycoside toxicity. We demonstrate that postnatal day 5 mice, like older mice with functional hearing, show uptake and retention of G418-TR in cochlear hair cells following systemic injection. When we compare G418-TR uptake in other tissues, we find that kidney proximal tubule cells show similar retention. Using ORC-13661, an investigational hearing protection drug, we demonstrate in vivo inhibition of aminoglycoside uptake in mammalian hair cells. This work establishes how systemically administered fluorescently labeled ototoxins in the neonatal mouse can reveal important details about ototoxic drugs and protective therapeutics.

/pdf/an-in-vivo-biomarker-to-characterize-ototoxic-compounds-and-1pa32pgk.pdf

An in vivo Biomarker to Characterize Ototoxic Compounds and Novel Protective Therapeutics

Intratympanic injection of gentamicin has proven to be an effective therapy for intractable vestibular dysfunction. However, most studies to date have focused on the cochlea, so little is known about the distribution and uptake of gentamicin by the counterpart of the auditory system, specifically vestibular hair cells (HCs). Here, with a combination of in vivo and in vitro approaches, we used a gentamicin-Texas Red (GTTR) conjugate to investigate the mechanisms of gentamicin vestibulotoxicity in the developing mammalian utricular HCs. In vivo, GTTR fluorescence was concentrated in the apical cytoplasm and the cellular membrane of neonatal utricular HCs, but scarce in the nucleus of HCs and supporting cells. Quantitative analysis showed the GTTR uptake by striolar HCs was significantly higher than that in the extrastriola. In addition, the GTTR fluorescence intensity in the striola was increased gradually from 1 to 8 days, peaking at 8-9 days postnatally. In vitro, utricle explants were incubated with GTTR and candidate uptake conduits, including mechanotransduction (MET) channels and endocytosis in the HC, were inhibited separately. GTTR uptake by HCs could be inhibited by quinine, a blocker of MET channels, under both normal and stressed conditions. Meanwhile, endocytic inhibition only reduced GTTR uptake in the CoCl2 hypoxia model. In sum, the maturation of MET channels mediated uptake of GTTR into vestibular HCs. Under stressed conditions, MET channels play a pronounced role, manifested by channel-dependent stress enhanced GTTR permeation, while endocytosis participates in GTTR entry in a more selective manner.

Alisa Hetrick

Papers

Hair cell uptake of gentamicin in the developing mouse utricle