Characterization of quinoxaline derivatives for protection against iatrogenically induced hearing loss
Marisa Zallocchi, Santanu Hati, Zhenhang Xu, William Hausman, Huizhan Liu, David Z. He, Jian Zuo
Marisa Zallocchi, Santanu Hati, Zhenhang Xu, William Hausman, Huizhan Liu, David Z. He, Jian Zuo
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Research Article Neuroscience Therapeutics

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.

Authors

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

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Figure 3

Qx28 protects from aminoglycoside- and CDDP-induced hair cell death.

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Qx28 protects from aminoglycoside- and CDDP-induced hair cell death. Qua...
Quantification of the number of hair cells per neuromasts after the different ototoxin treatments in the presence or absence of quinoxaline (Qx, blue dots) or Qx28 (red dots). (A) Short-term gentamicin exposure (100 μM). (B) Long-term gentamicin exposure (100 μM). (C) Neomycin exposure (200 μM). (D) CDDP exposure (400 μM). Qx66 50 μM was included to show that although it has a similar structure as Qx28, it does not protect. Results are expressed as mean ± SEM. Statistical analysis: 1-way ANOVA with correction for Dunnett’s multiple comparisons test. *P < 0.05, **P < 0.01, ****P < 0.0001 versus ototoxin alone (blue asterisks, quinoxaline treatment; red asterisks, Qx28 treatment). Neuromasts inspected: vehicle = 20; GM-STE: GM alone = 29; GM+Qx28 = 29 (1 nM, 300 μM), 31 (10 nM–100 μM); GM+Qx = 25 (1 nM–100 nM), 30 (1 μM), 16 (10 μM–300 μM). GM-LTE: GM alone = 22; GM + Qx66 = 15; GM+Qx28 = 30 (1 nM, 1 μM, 50 μM, 100 μM), 17 (10 nM, 10 μM), 25 (100 nM), 14 (300 μM); GM+Qx = 17 (1 nM–1 μM, 100 μM), 12 (10 μM, 50 μM), 42 (300 μM). Neo: Neo alone = 44; Neo+Qx66 = 11; Neo+Qx28 = 28 (1 nM, 100 μM), 22 (10 nM, 100 nM, 10 μM), 18 (1 μM), 13 (50 μM), 34 (300 μM); Neo+Qx = 4 (1 nM, 100 nM, 10 μM, 100 μM), 9 (10 nM, 50 μM), 12 (1 μM), 24 (300 μM). CDDP: CDDP alone = 14; CDDP + Q28 = 19 (1 nM, 1 μM), 27 (10 nM, 100 nM), 23 (10 μM), 10 (50 μM), 32 (100 μM), 14 (300 μM); CDDP+Qx = 19 (1 nM–100 nM, 50 μM–300 μM), 13 (1 μM), 15 (10 μM).