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Characterization of quinoxaline derivatives for protection against iatrogenically induced hearing loss
Marisa Zallocchi, … , David Z. He, Jian Zuo
Marisa Zallocchi, … , David Z. He, Jian Zuo
Published January 21, 2021
Citation Information: JCI Insight. 2021;6(5):e141561. https://doi.org/10.1172/jci.insight.141561.
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Research Article Neuroscience Therapeutics

Characterization of quinoxaline derivatives for protection against iatrogenically induced hearing loss

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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.

Authors

Marisa Zallocchi, Santanu Hati, Zhenhang Xu, William Hausman, Huizhan Liu, David Z. He, Jian Zuo

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Figure 1

Screening of quinoxaline derivatives.

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Screening of quinoxaline derivatives.
Five dpf Tg(brn3c:GFP) zebrafish w...
Five dpf Tg(brn3c:GFP) zebrafish were preincubated with quinoxaline (Qx, 300 μM) or its derivatives (Qx2–Qx70, 10 nM–300 μM) for 1 hour, followed by coincubation with neomycin (Neo) 200 μM for 30 minutes (A) or gentamicin (GM) 100 μM long-term effect (B). Hair cells were quantified employing a Zeiss AxioSkop 2 fluorescence microscope with a 40× oil objective. White dot, vehicle; blue dot, ototoxin alone; gray dot, quinoxaline 300 μM. Black dots, quinoxaline derivatives that did not show any significant differences compared with ototoxin alone. Yellow dots, quinoxaline derivatives that performed significantly better than ototoxin alone but not significantly different from quinoxaline treatment. Red dots, quinoxaline derivatives that performed significantly better than quinoxaline treatment. Results were expressed as mean ± SEM. Statistical analysis: 1-way ANOVA with correction for Dunnett’s multiple comparisons test. Significance was set at P < 0.05 versus ototoxin or quinoxaline. Six fish were used per treatment, and 3 neuromasts were inspected per fish (n = 18).

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