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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 10

Reduction of IκKβ expression protects against aminoglycoside- and CDDP-induced ototoxicity.

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Reduction of IκKβ expression protects against aminoglycoside- and CDDP-i...
(A–O) Tg(brn3c:GFP) zebrafish eggs were noninjected (A–E) or injected with a suboptimal dose (2 ng) of scrambled (F–J) or ikbkb morpholinos (MO) (61) (K–O). At 3 dpf animals were incubated with gentamicin (GM) 100 μM STE (B, G, and L) or LTE (C, H, and M), neomycin (Neo) 200 μM (D, I, and N), or CDDP 400 μM (E, J, and O). Animals were fixed and immunostained for GFP. The number of hair cells per neuromast was quantified (P). Results are expressed as mean ± SEM. Statistical analysis: 1-way ANOVA with correction for Dunnett’s multiple comparisons test. **P < 0.01; ***P < 0.001; ****P < 0.0001 versus the corresponding control within the group (black asterisks). Two-tailed Student’s t test. *P < 0.05; **P < 0.01 versus identical treatment in scrambled animals (red asterisks). Number of neuromasts inspected: control = 8 (noninjected), 12 (scrambled MO), 10 (IκKβ MO); GM-STE = 7 (noninjected), 5 (scrambled), 4 (ikbkb MO); GM-LTE = 7 (noninjected, scrambled), 12 (ikbkb MO); Neo = 6 (noninjected, ikbkb MO), 5 (scrambled); CDDP = 9 (noninjected), 3 (scrambled), 12 (ikbkb MO). Scale bar: 6 μm.

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