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

Autor:	Bellairs JA; Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA, United States., Redila VA; Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA, United States.; Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA, United States., Wu P; Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA, United States.; Department of Biological Structure, University of Washington, Seattle, WA, United States., Tong L; Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA, United States.; Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA, United States., Webster A; Fred Hutchinson Cancer Research Center, Seattle, WA, United States., Simon JA; Fred Hutchinson Cancer Research Center, Seattle, WA, United States., Rubel EW; Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA, United States.; Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA, United States., Raible DW; Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA, United States.; Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA, United States.; Department of Biological Structure, University of Washington, Seattle, WA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular neuroscience [Front Mol Neurosci] 2022 Jul 18; Vol. 15, pp. 944846. Date of Electronic Publication: 2022 Jul 18 (Print Publication: 2022).
DOI:	10.3389/fnmol.2022.944846
Abstrakt:	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. Competing Interests: JAS, EWR, and DWR are cofounders of Oricula Therapeutics, which has licensed patents covering ORC-13661 from the University of Washington. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Bellairs, Redila, Wu, Tong, Webster, Simon, Rubel and Raible.)
Databáze:	MEDLINE
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