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 multiple species and toxins.
Highlights
Aminoglycosides (AGs) are a class of antibiotic used to treat life-threatening bacterial infections, including tuberculosis, urinary or respiratory tract infections, and sepsis [1] as well as suspected or confirmed bacterial infections in neonates [2]
To assess whether ORC-13661 can protect against the damage caused by different AGs, zebrafish larvae (5–7 days after fertilization [dpf]) were exposed for 24 hours to either gentamicin (1–200 μM) or amikacin (100–1500 μM), or for 1 hour to neomycin (50–200 μM), in the absence or presence of varying concentrations of ORC-13661
Previous experiments have shown that the dose-response function for neomycin exposure does not differ between 1- and 24-hour exposure [50]
Summary
Aminoglycosides (AGs) are a class of antibiotic used to treat life-threatening bacterial infections, including tuberculosis, urinary or respiratory tract infections, and sepsis [1] as well as suspected or confirmed bacterial infections in neonates [2]. AG treatment generates some degree of hearing loss in about 20% of patients [7], whereas in the case of cisplatin, permanent hearing loss has been reported in up to 100% of treated patients [8]. The use of AGs in most developed countries is limited to life-threatening infections where it is important to utilize their rapid bactericidal effect, in other parts of the world they are widely used to treat less severe infections, mainly due to their stability at ambient temperature and low cost [9]. Developing methods to prevent the hearing loss associated with these two drug classes is of considerable importance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
