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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 6

AG uptake in the presence of Qx28.

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AG uptake in the presence of Qx28.
Five dpf zebrafish were incubated wit...
Five dpf zebrafish were incubated with Texas Red–conjugated AG (AGTR) in the absence or presence of Qx28 (1 nM–100 μM). AGTR incorporation was followed over time. (A–H) Fish incubated for 45 seconds (A–D) or 30 minutes (E–H) with 50 μM of Texas Red–conjugated gentamicin (GMTR) in E3 media alone (A and E) or with Qx28 1 nM (B and F), 1 μM (C and G), or 100 μM (D and H). (I–P) Fish incubated for 45 seconds (I–L) or 15 minutes (M–P) with 100 μM of Texas Red conjugated neomycin (NeoTR) in E3 media alone (I and M) or with Qx28 1 nM (J and N), 1 μM (K and O), or 100 μM (L and P). Fish were counterstained with phalloidin (green). (Q) The fluorescence intensity incorporated was calculated using ImageJ and expressed as a percentage from the corresponding control without Qx28. (R–T) Texas Red (TR) incubation for 45 seconds (R), 15 minutes (S), or 30 minutes (T). Results are expressed as mean ± SEM. Statistical analysis: 1-way ANOVA with correction for Dunnett’s multiple comparisons test. ***P < 0.01, ****P < 0.0001 versus the corresponding control. Number of neuromasts quantified per treatment: GMTR 45 seconds = 12 (alone), 18 (+Qx28 1 nM, 1 μM), 16 (+Qx28 100 μM); GMTR 30 minutes = 17 (alone), 16 (+Qx28 1 nM), 20 (+Qx28 1 μM), 13 (+Qx28 100 μM); NeoTR 45 seconds = 15; NeoTR 15 minutes = 12 (alone, +Qx28 1 μM), 15 (+Qx28 1 nM), 16 (+Qx28 100 μM). Scale bars: 8 μm (A–P), 9 μm (R–T).

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