Characterization of quinoxaline derivatives for protection against iatrogenically induced hearing loss

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.

In silico transcriptomics identifies FDA-approved drugs and biological pathways for protection against cisplatin-induced hearing loss

“…For fish studies, 5 dpf larvae were maintained at 28.5°C in E3 water (5 mM NaCl, 0.17 mM KCl, 0.33 mM CaCl 2 , and 0.33 mM MgSO 4 , pH 7.2) and treated as previously described (54). HCs were counted from SO3 and O1-2 neuromasts.…”

“…For the screenings, 5-day post-fertilization (dpf) Tg(brn3c:mGFP ) larvae were pre-incubated with each of the 30 drug candidates at 0.002, 0.0183, 0.165, 1.48, and 13.3 µM for as previously described (25, 54).…”

“…Each neuromast was considered a biological replicate. No explicit power analysis was performed to compute the sample size for the zebrafish experiments, sample size was based on previous studies from our laboratory (54). Only one experiment was performed for the initial screening of all the compounds and results were expressed as percentage of protection respect to controls.…”

Apigenin alleviates neomycin-induced oxidative damage via the Nrf2 signaling pathway in cochlear hair cells

“…The interfering effect of apigenin on the antibiotic efficacy of neomycin was assessed as previously reported [26]. First, 5 mm filter discs were soaked overnight in PBS, 20 μmol/L apigenin, 1 mmol/L neomycin, 20 μmol/L apigenin + 1 mmol/L neomycin, or 50 μmol/L apigenin + 1 mmol/L neomycin.…”

Novel Application of Eupatilin for Effectively Attenuating Cisplatin-Induced Auditory Hair Cell Death via Mitochondrial Apoptosis Pathway

“…At least 700 million people worldwide suffer from sensorineural hearing loss caused by ototoxic antibiotics, noise, chemotherapy, and aging [ 1 ]. There are currently no pharmacological agents aimed at preventing or treating sensorineural hearing loss that have been approved by the Food and Drug Administration (FDA).…”