Oxidative Stress and Inflammation Caused by Cisplatin Ototoxicity

Ramkumar, Vickram; Mukherjea, Debashree; Dhukhwa, Asmita; Rybak, Leonard P.

doi:10.3390/antiox10121919

Cited by 54 publications

(44 citation statements)

References 108 publications

(138 reference statements)

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“…Over the past decades it became clear that oxidative stress is a common denominator of many forms of acquired sensorineural hearing loss ( Henderson et al, 2006 ; Rousset et al, 2015 ; Fetoni et al, 2019 ; Ramkumar et al, 2021 ). Noise-induced oxidative damages, including hair cell membrane lipid peroxidation or DNA oxidation, appear as early as a few hours following the insult ( Maulucci et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

NADPH Oxidase 3 Deficiency Protects From Noise-Induced Sensorineural Hearing Loss

Rousset

Nacher-Soler

Kokje

et al. 2022

Front. Cell Dev. Biol.

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The reactive oxygen species (ROS)-generating NADPH oxidase NOX3 isoform is highly and specifically expressed in the inner ear. NOX3 is needed for normal vestibular development but NOX-derived ROS have also been implicated in the pathophysiology of sensorineural hearing loss. The role of NOX-derived ROS in noise-induced hearing loss, however, remains unclear and was addressed with the present study. Two different mouse strains, deficient in NOX3 or its critical subunit p22phox, were subjected to a single noise exposure of 2 h using an 8–16 kHz band noise at an intensity of 116–120 decibel sound pressure level. In the hours following noise exposure, there was a significant increase in cochlear mRNA expression of NOX3 in wild type animals. By using RNAscope in situ hybridization, NOX3 expression was primarily found in the Rosenthal canal area, colocalizing with auditory neurons. One day after the noise trauma, we observed a high frequency hearing loss in both knock-out mice, as well as their wild type littermates. At day seven after noise trauma however, NOX3 and p22phox knockout mice showed a significantly improved hearing recovery and a marked preservation of neurosensory cochlear structures compared to their wild type littermates. Based on these findings, an active role of NOX3 in the pathophysiology of noise-induced hearing loss can be demonstrated, in line with recent evidence obtained in other forms of acquired hearing loss. The present data demonstrates that the absence of functional NOX3 enhances the hearing recovery phase following noise trauma. This opens an interesting clinical window for pharmacological or molecular intervention aiming at post prevention of noise-induced hearing loss.

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Section: Introductionmentioning

confidence: 99%

NADPH Oxidase 3 Deficiency Protects From Noise-Induced Sensorineural Hearing Loss

Rousset

Nacher-Soler

Kokje

et al. 2022

Front. Cell Dev. Biol.

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“…Cisplatin-induced oxidative stress contributes to the cellular damage of the inner ear and ototoxicity [ 9 , 19 ]. In this study, we found that hypBMSC-Exo could be considered a post-exposure treatment option to diminish the production of reactive oxygen species to alleviate hearing loss.…”

Section: Discussionmentioning

confidence: 99%

Exosomes Derived from Bone Marrow-Mesenchymal Stem Cells Attenuates Cisplatin-Induced Ototoxicity in a Mouse Model

Yang

Peng

et al. 2022

JCM

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Background: Both hypoxia preconditioning and exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exo) have been adopted to alleviate hair-loss-related ototoxicity. Whether hypoxic BMSCs-derived exosomes (hypBMSC-Exo) could alleviate cisplatin-induced ototoxicity is investigated in this study. Methods: Cisplatin intraperitoneally injected C57BL/6 mice were trans-tympanically administered BMSC-Exo or hypBMSC-Exo in the left ear. Myosin 7a staining was utilized to detect mature hair cells. Auditory brainstem response (ABR) was assessed to indicate auditory sensitivity at 8, 16, 24, and 32 kHz. The relative expressions of hypoxia-inducible factor-1α (HIF-1α), superoxide dismutase 1 (SOD1), and SOD2 were determined with RT-PCR and Western blot. The content of hydrogen peroxide (H2O2), malondialdehyde (MDA), SOD, and glutathione (GSH) in the middle turns of the cochlea were measured. Results: Up-regulated HIF-1α expression was observed in hypBMSC-Exo compared with BMSC-Exo. Diminished auditory sensitivity and increased hair cell loss was observed in the cisplatin-exposed mice with increased content of H2O2 and MDA and decreased content of SOD and GSH, which could be reversed by hypBMSC-Exo or BMSC-Exo administration. It is worth noting that hypBMSC-Exo demonstrated more treatment benefits than BMSC-Exo with up-regulated SOD1 and SOD2 expression in the middle turns of the cochlea tissues. Conclusions: Hypoxic preconditioning may provide a new therapeutic option in regenerative medicine, and hypBMSC-Exo could be utilized to alleviate cisplatin-induced ototoxicity.

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“…Antioxidant signaling may also be involved in the protective effect of LPZ against CIO. CDDP generates oxidative stress which leads to apoptosis and necroptosis of auditory hair cells (Ramkumar et al, 2021). LPZ can exert antioxidant effects through activation of nuclear factor erythroid 2-related factor 2 (Takagi et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Repositioning of Lansoprazole as a Protective Agent Against Cisplatin-Induced Ototoxicity

Wakai

Ikemura²,

Mizuno³

et al. 2022

Front. Pharmacol.

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Cisplatin (CDDP) is a well-known chemotherapeutic drug approved for various cancers. However, CDDP accumulates in the inner ear cochlea via organic cation transporter 2 (OCT2) and causes ototoxicity, which is a major clinical limitation. Since lansoprazole (LPZ), a proton pump inhibitor, is known to inhibit OCT2-mediated transport of CDDP, we hypothesized that LPZ might ameliorate CDDP-induced ototoxicity (CIO). To test this hypothesis, we utilized in vivo fluorescence imaging of zebrafish sensory hair cells. The fluorescence signals in hair cells in zebrafish treated with CDDP dose-dependently decreased. Co-treatment with LPZ significantly suppressed the decrease of fluorescence signals in zebrafish treated with CDDP. Knockout of a zebrafish homolog of OCT2 also ameliorated the reduction of fluorescence signals in hair cells in zebrafish treated with CDDP. These in vivo studies suggest that CDDP damages the hair cells of zebrafish through oct2-mediated accumulation and that LPZ protects against CIO, possibly inhibiting the entry of CDDP into the hair cells via oct2. We also evaluated the otoprotective effect of LPZ using a public database containing adverse event reports. The analysis revealed that the incidence rate of CIO was significantly decreased in patients treated with LPZ. We then retrospectively analyzed the medical records of Mie University Hospital to examine the otoprotective effect of LPZ. The incidence rate of ototoxicity was significantly lower in patients co-treated with LPZ compared to those without LPZ. These retrospective findings suggest that LPZ is also protective against CIO in humans. Taken together, co-treatment with LPZ may reduce the risk of CIO.

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Oxidative Stress and Inflammation Caused by Cisplatin Ototoxicity

Cited by 54 publications

References 108 publications

NADPH Oxidase 3 Deficiency Protects From Noise-Induced Sensorineural Hearing Loss

NADPH Oxidase 3 Deficiency Protects From Noise-Induced Sensorineural Hearing Loss

Exosomes Derived from Bone Marrow-Mesenchymal Stem Cells Attenuates Cisplatin-Induced Ototoxicity in a Mouse Model

Repositioning of Lansoprazole as a Protective Agent Against Cisplatin-Induced Ototoxicity

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