ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity.

JCI Insight
Siân R KitcherCorné J Kros

Abstract

Aminoglycoside (AG) antibiotics are widely used to prevent life-threatening infections, and cisplatin is used in the treatment of various cancers, but both are ototoxic and result in loss of sensory hair cells from the inner ear. ORC-13661 is a new drug that was derived from PROTO-1, a compound first identified as protective in a large-scale screen utilizing hair cells in the lateral line organs of zebrafish larvae. Here, we demonstrate, in zebrafish larvae and in mouse cochlear cultures, that ORC-13661 provides robust protection of hair cells against both ototoxins, the AGs and cisplatin. ORC-13661 also prevents both hearing loss in a dose-dependent manner in rats treated with amikacin and the loading of neomycin-Texas Red into lateral line hair cells. In addition, patch-clamp recordings in mouse cochlear cultures reveal that ORC-13661 is a high-affinity permeant blocker of the mechanoelectrical transducer (MET) channel in outer hair cells, suggesting that it may reduce the toxicity of AGs by directly competing for entry at the level of the MET channel and of cisplatin by a MET-dependent mechanism. ORC-13661 is therefore a promising and versatile protectant that reversibly blocks the hair cell MET channel and operates across m...Continue Reading

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Citations

May 29, 2020·SLAS Discovery·Davide RubbiniVincenzo Di Donato
Aug 28, 2020·Frontiers in Cellular Neuroscience·Alexandria M HudsonAllison B Coffin
Jul 29, 2020·Frontiers in Pharmacology·Dehong YuHao Wu
Oct 22, 2020·International Journal of Immunopathology and Pharmacology·Ewa DomareckaStavros Hatzopoulos
Dec 9, 2020·Proceedings of the National Academy of Sciences of the United States of America·Mary E O'SullivanAnthony J Ricci
Dec 4, 2020·Science Advances·Matthew A IngersollTal Teitz
Jun 13, 2021·Nature Reviews. Drug Discovery·E Elizabeth PattonDavid M Langenau
Aug 3, 2021·Neural Plasticity·Peng WuHe Li

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GraphPad Prism
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Adobe Photoshop Creative Cloud
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