key: cord-0275451-8uujhk5a
authors: Davis, Samantha N.; Wu, Patricia; Camci, Esra D.; Simon, Julian A.; Rubel, Edwin W; Raible, David W.
title: Chloroquine Kills Hair Cells in Zebrafish Lateral Line and Murine Cochlear Cultures: Implications for Ototoxicity
date: 2020-04-16
journal: bioRxiv
DOI: 10.1101/2020.04.14.041731
sha: ddbef93b27ebbc2c6d9a68ab35c06d815ea5a802
doc_id: 275451
cord_uid: 8uujhk5a

Hearing and balance deficits have been reported during and following treatment with the antimalarial drug chloroquine. However, experimental work examining the direct actions of chloroquine on mechanoreceptive hair cells in common experimental models is lacking. This study examines the effects of chloroquine on hair cells using two common experimental models: the zebrafish lateral line and neonatal mouse cochlear cultures. Zebrafish larvae were exposed to varying concentrations of chloroquine phosphate or hydroxychloroquine for 1 hr or 24 hr, and hair cells assessed by antibody staining. A significant, dose-dependent reduction in the number of surviving hair cells was seen across conditions for both exposure periods. Hydroxycholroquine showed similar toxicity. In mouse cochlear cultures, chloroquine damage was specific to outer hair cells in tissue from the cochlear basal turn, consistent with susceptibility to other ototoxic agents. These findings suggest a need for future studies employing hearing and balance monitoring during exposure to chloroquine and related compounds, particularly with interest in these compounds as therapeutics against viral infections including coronavirus.

lacking. This study examines the effects of chloroquine on hair cells using two common 31 experimental models: the zebrafish lateral line and neonatal mouse cochlear cultures. 32

Zebrafish larvae were exposed to varying concentrations of chloroquine phosphate or 33 hydroxychloroquine for 1 hr or 24 hr, and hair cells assessed by antibody staining. A 34 significant, dose-dependent reduction in the number of surviving hair cells was seen 35 across conditions for both exposure periods. Hydroxycholroquine showed similar toxicity. 36

In mouse cochlear cultures, chloroquine damage was specific to outer hair cells in tissue 37 from the cochlear basal turn, consistent with susceptibility to other ototoxic agents. As hydroxychloroquine is often used to replace chloroquine in clinical settings, 183 these two drugs were compared for relative hair cell toxicity. Both drugs showed dose-184 dependent hair cell loss ( Figure 2 ). Hydroxychloroquine showed slightly more toxicity than 185 chloroquine (F=4.774, p=0.03; two-way ANOVA). These results demonstrate that both 186 clinically-relevant chloroquine drugs show hair cell toxicity in the zebrafish model. 187

Previous work has demonstrated that quinoline drugs, including chloroquine, can 188 inhibit aminoglycoside ototoxicity by partially blocking mechanotransduction-dependent 189 toxin uptake (Ou et al., 2012) . We reasoned that the asymptotic nature of the chloroquine 190 dose-response function might be due to its ability to block its own uptake. We implying that chloroquine uptake is rapid and affects hair cells soon after they are exposed. 

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Identification of genetic and chemical modulators of 399 zebrafish mechanosensory hair cell death

An overview of autophagy: Morphology, mechanism, 402 and regulation

Block by amiloride and its derivatives of 422 mechano-electrical transduction in outer hair cells of mouse cochlear cultures

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COVID-19): Chloroquine or Hydroxychloroquine

Lateral line hair cell 431 maturation is a determinant of aminoglycoside susceptibility in zebrafish

Lysosomal Physiology

COVID-19: a recommendation to examine the effect 453 of hydroxychloroquine in preventing infection and progression