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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 11

Qx28 protects hair cells by NF-κB pathway inhibition in vivo.

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Qx28 protects hair cells by NF-κB pathway inhibition in vivo.
Five dpf T...
Five dpf Tg(NFKB:EGFP) were treated with E3 water (A and B), Qx28 1 nM (C and D), TNF-α 20 ng/mL 30 minutes (positive control) (E and F), gentamicin (GM) 100 μM 30 minutes without (G and H) or with (I and J) Qx28, neomycin (Neo) 200 μM 5 minutes without (K and L) or with (M and N) Qx28, and CDDP 400 μM 2 hours without (O and P) or with (Q and R) Qx28. Animals were transferred to E3 water for 2 hours and immunostained for GFP (green) and otoferlin (red). The green fluorescence intensity was quantified using ImageJ and expressed as percentage from control (T). (S) Cartoon depicting a neuromast (top view): hair cells are in red, supporting cells are in gray, and mantle cells are in green. Results are expressed as mean ± SEM. Statistical analysis: 2-tailed Student’s t test, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus ototoxin alone (black asterisks). One-way ANOVA with correction for Dunnett’s multiple comparisons test. **P < 0.01; ***P < 0.001; ****P < 0.0001 versus vehicle (red asterisks). Number of neuromasts quantified: n = 13 (control, CDDP), 11 (Qx28, GM), 3 (TNF-α), 15 (GM+Qx28), 9 (Neo), 20 (Neo+Qx28), 18 (CDDP+Qx28). Scale bar: 9 μm.

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