Abstract
Hair cell loss is the leading cause of hearing and balance disorders in humans. It can be caused by many factors, including noise, aging, and therapeutic agents. Previous studies have shown the therapeutic potential of quinoxaline against drug-induced ototoxicity. Here, we screened a library of 68 quinoxaline derivatives for protection against aminoglycoside-induced damage of hair cells from the zebrafish lateral line. We identified quinoxaline-5-carboxylic acid (Qx28) as the best quinoxaline derivative that provides robust protection against both aminoglycosides and cisplatin in zebrafish and mouse cochlear explants. FM1-43 and aminoglycoside uptake, as well as antibiotic efficacy studies, revealed that Qx28 is neither blocking the mechanotransduction channels nor interfering with aminoglycoside antibacterial activity, suggesting that it may be protecting the hair cells by directly counteracting the ototoxin’s mechanism of action. Only when animals were incubated with higher doses of Qx28 did we observe a partial blockage of the mechanotransduction channels. Finally, we assessed the regulation of the NF-κB pathway in vitro in mouse embryonic fibroblasts and in vivo in zebrafish larvae. Those studies showed that Qx28 protects hair cells by blocking NF-κB canonical pathway activation. Thus, Qx28 is a promising and versatile otoprotectant that can act across different species and toxins.
Highlights
According to the World Health Organization [1], more than 5% of the world’s population is affected by moderate to profound hearing loss, with an estimated rise to over 900 million by 2050 if no action is taken
Despite their clinical utility, they carry the risk of adverse side effects, including hearing loss and kidney damage [11,12,13,14,15,16]
AGs are broad-spectrum antibiotics widely used to treat serious Gram-negative bacterial infections and they are extremely effective, they carry the risk of adverse side effects, including irreversible damage to the inner ear [12, 14, 17,18,19,20,21]
Summary
According to the World Health Organization [1], more than 5% of the world’s population is affected by moderate to profound hearing loss, with an estimated rise to over 900 million by 2050 if no action is taken. The current COVID-19 outbreak may increase these estimates due to the possible side effects of drug treatments and because of the viral infection [2, 3]. Aminoglycoside (AG) antibiotics are water-soluble molecules with potent antimicrobial properties used in the treatment of sepsis or serious opportunistic infections occurring in patients with cystic fibrosis. Despite their clinical utility, they carry the risk of adverse side effects, including hearing loss (ototoxicity) and kidney damage (nephrotoxicity) [11,12,13,14,15,16]. Because hair cells of the inner ear do not regenerate, the damage caused by AG treatment is irreversible, resulting in hearing and balance deficits in more than 25% of the patients treated with these antibiotics [4, 17]
Sign-in/Register to view highlights & summary 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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
