Chloroquine Kills Hair Cells in Zebrafish Lateral Line and Murine Cochlear Cultures: Implications for Ototoxicity

Davis, Samantha N.; Wu, Patricia; Camci, Esra D.; Simon, Julian A.; Rubel, Edwin W.; Raible, David W.

doi:10.1101/2020.04.14.041731

Cited by 3 publications

(6 citation statements)

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“…This observation is in line with a recent study showing that chloroquine specifically damages OHCs in mice (Davis et al, 2020). The aggravating effect of chloroquine was also found in Kv7.4 Q71fs (Fig.…”

Section: Inhibition Of the Basal Autophagy Aggravates The Cytotoxicitysupporting

confidence: 93%

“…3), it is conceivable that the basal endogenous autophagy activity in OHCs may be kept at a relatively high level in order to counteract the cytotoxicity associated with the large expression of the Kv7.4 protein. Consistent with such views, an autophagy inhibitor, chloroquine, is reported to induce hair cell loss (Davis et al, 2020). Hair cell loss was also found in conditional autophagy-deficient mice (Fujimoto et al, 2017).…”

Section: Disease Models and Mechanisms • Dmm • Accepted Manuscriptmentioning

confidence: 61%

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Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss

Kojima

Wasano

Takahashi

et al. 2021

Disease Models &Amp; Mechanisms

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KCNQ4 encodes the homotetrameric voltage-dependent potassium ion channel, Kv7.4, and is the causative gene for autosomal dominant nonsyndromic sensorineural hearing loss, DFNA2. Dominant-negative inhibition accounts for the observed dominant inheritance of many DFNA2-associated KCNQ4 variants. In addition, haploinsufficiency has been presumed as the pathological mechanism for truncated Kv7.4 variants lacking the C-terminal tetramerization region, as they are unlikely to exert a dominant-negative inhibitory effect. Such truncated Kv7.4 variants should result in relatively mild hearing loss when heterozygous; however, this is not always the case. In this study, we characterized Kv7.4Q71fs (c.211delC), Kv7.4W242X (c.725G>A), and Kv7.4A349fs (c.1044_1051del8) in heterologous expression systems and found that expressions of these truncated Kv7.4 variants induce cell death. We also found similar cell death-inducing cytotoxic effects in truncated Kv7.1 (KCNQ1) variants, pointing to the generality of our finding that could account for the dominant inheritance of many, if not most, truncated Kv7 variants. Moreover, we found that the application of autophagy inducers can ameliorate the cytotoxicity, providing a novel insight for the development of alternative therapeutic strategies for Kv7.4 variants.

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Section: Inhibition Of the Basal Autophagy Aggravates The Cytotoxicitysupporting

confidence: 93%

Section: Disease Models and Mechanisms • Dmm • Accepted Manuscriptmentioning

confidence: 61%

Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss

Kojima

Wasano

Takahashi

et al. 2021

Disease Models &Amp; Mechanisms

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“…Hence, these findings could indicate the onset of effects on cochlear structures, especially OHCs, before they are reflected in audiometric results (18). However, the effect of HCQ on OHCs can depend on the dose and duration of use (11). In this study, 80% of the patients used HCQ for 5 days, and only two patients continued to take the drug for 6 days as symptoms persisted.…”

Section: Discussionmentioning

confidence: 99%

“…However, during the COVID-19 period, numerous patients have used HCQ, especially at the beginning of a pandemic (8)(9)(10). Although a recent study showed hair cell damage after exposure to chloroquine (CQ)/HCQ in zebrafish lateral line and neonatal mouse cochlear cultures, this drop was significantly dose dependent (11). In the human domain, most of the studies that reported the ototoxic effects of HCQ on the auditory system and balance in treating other diseases were case reports and were prescribed at different doses and durations (8,10).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, this effect can be due to cochleitis with perilymphatic tissue involvement, and neuritis with vestibulocochlear nerve involvement that can lead to vertigo, tinnitus, hearing loss, and stress response resulting in the cross reaction of the inner ear antigens to viral infections. COVID-19 not only increases inflammatory processes in the cochlea and causes a cytokine storm but also can damage the hair cells, particularly those located in the basal portion of the cochlear (3,6,11,(20)(21)(22). Moreover, ischemia and hypoxia of the cochlea and semicircular canals are other possible causes that can occur in different severities of COVID-19 (3,22).…”

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confidence: 99%

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Slight High-Frequency Hearing Loss, Effect of COVID-19 or Hydroxychloroquine Usage?

2022

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Background and ObjectivesConcerns about ototoxic and vestibulotoxic effects have been raised with the use of antiviruses in the treatment of COVID-19. This study aimed to determine the effect of hydroxychloroquine (HCQ) and examine the auditory system and its associated auditory and vestibular symptoms in patients with COVID-19.Study DesignProspective study.PatientsThirty patients with a history of HCQ (HCQ+) and 30 patients without drug use (HCQ−), and 30 healthy adults as the control group participated.Main Outcome Measure(s)Audiological assessments and evaluation of audio-vestibular symptoms. Evaluations were also repeated 1 month later.ResultsBoth HCQ+ and HCQ− groups showed poor pure-tone audiometry (PTA) thresholds and decreased transient evoked otoacoustic emission amplitudes at high frequencies in comparison to the healthy group. Despite the lack of significant differences in PTA between the two groups of patients, the differences in transient evoked otoacoustic emission amplitudes were significant. PTA thresholds and otoacoustic emission showed improvement after 1 month. Dizziness was the most common symptom that was reduced after 1 month.ConclusionSlight hearing loss was seen in patients with COVID-19 with or without HCQ. Also, hearing thresholds in the HCQ+ group did not show a significant difference compared with the HCQ− group. Nevertheless, it seems that more damage is done to the hair cells of patients with HCQ intake than in other patients. Hence, the ototoxicity effect of high doses of HCQ use in the COVID-19 patients should be considered. A relative improvement in the hearing was seen over time in both patient groups.

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Diclofenac, ibuprofen, and paracetamol biodegradation: overconsumed non-steroidal anti-inflammatories drugs at COVID-19 pandemic

Ferreira,

Borges

et al. 2023

Front. Microbiol.

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The consumption of non-steroidal anti-inflammatory drugs (NSAIDs) have increased significantly in the last years (2020–2022), especially for patients in COVID-19 treatment. NSAIDs such as diclofenac, ibuprofen, and paracetamol are often available without restrictions, being employed without medical supervision for basic symptoms of inflammatory processes. Furthermore, these compounds are increasingly present in nature constituting complex mixtures discarded at domestic and hospital sewage/wastewater. Therefore, this review emphasizes the biodegradation of diclofenac, ibuprofen, and paracetamol by pure cultures or consortia of fungi and bacteria at in vitro, in situ, and ex situ processes. Considering the influence of different factors (inoculum dose, pH, temperature, co-factors, reaction time, and microbial isolation medium) relevant for the identification of highly efficient alternatives for pharmaceuticals decontamination, since biologically active micropollutants became a worldwide issue that should be carefully addressed. In addition, we present a quantitative bibliometric survey, which reinforces that the consumption of these drugs and consequently their impact on the environment goes beyond the epidemiological control of COVID-19.

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Chloroquine Kills Hair Cells in Zebrafish Lateral Line and Murine Cochlear Cultures: Implications for Ototoxicity

Abstract: 22 98195-7420 23 24

Cited by 3 publications

References 45 publications

Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss

Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss

Slight High-Frequency Hearing Loss, Effect of COVID-19 or Hydroxychloroquine Usage?

Diclofenac, ibuprofen, and paracetamol biodegradation: overconsumed non-steroidal anti-inflammatories drugs at COVID-19 pandemic

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