Protective effect of N-acetylcysteine against cisplatin ototoxicity in rats: a study with hearing tests and scanning electron microscopy

Somdas, Mehmet Akıf; Güntürk, İnayet; Balcıoğlu, Esra; Avcı, Deniz; Yazıcı, Cevat; Özdamar, Saim

doi:10.1016/j.bjorl.2018.08.002

Cited by 21 publications

(12 citation statements)

References 32 publications

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“…The ototoxic side effects of aminoglycoside antibiotics seem to be related to iron chelation and free radical formation 20 . This concept is supported by reduction of ototoxicity attained by the use of antioxidants or iron chelators, including NAC and glutathione 14,21 . Animal models demonstrate generation of free radicals within the inner ear, with apoptotic cell death of the outer air cells 22 .…”

Section: Discussionmentioning

confidence: 99%

“… 20 This concept is supported by reduction of ototoxicity attained by the use of antioxidants or iron chelators, including NAC and glutathione. 14 , 21 Animal models demonstrate generation of free radicals within the inner ear, with apoptotic cell death of the outer air cells. 22 NAC has been documented to act as a substrate for glutathione production, free radical scavenger, mitochondrial protectant, lipid peroxidation inhibitor, and necrosis inhibitor in the inner ear.…”

Section: Discussionmentioning

confidence: 99%

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Does N‐acetylcysteine Improve Established Hearing Loss in Guinea Pigs?

Gill¹,

Blakley²

2022

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Objective To assess whether multiple injections of a powerful antioxidant can improve established sensorineural hearing loss in guinea pigs. Study Design Animal study. Setting Animal science laboratory, University of Manitoba. Methods A total of 16 guinea pigs were used in our study: 8 underwent unilateral intracochlear neomycin injection, and 8 underwent unilateral saline to serve as controls. After a period of 3 weeks for hearing loss to stabilize, 4 guinea pigs from each group received weekly intraperitoneal injections of N-acetylcysteine (NAC) for 4 weeks. Click auditory brainstem response (ABR) testing was conducted at baseline, weekly after the start of NAC injections, and after the last injection. Pure tone ABR tests were conducted prior to intracochlear injections and at completion of the study. Results Click ABR thresholds were significantly worse in ears treated with neomycin ( P < .001), as expected, but not significantly different when treated with NAC ( P = .664). Thresholds for pure tone ABR were also not statistically different in neomycin-treated ears with or without NAC ( P > .99). Conclusions The aggressive antioxidant therapy performed in this study was not successful in improving established hearing loss via an antioxidant regimen that is known to change the oxidation-reduction potential in the cochlea.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Does N‐acetylcysteine Improve Established Hearing Loss in Guinea Pigs?

Gill¹,

Blakley²

2022

OTO Open

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“…For nimodipine, too, with the same otoprotective efficacy in vivo, studies should be conducted on the best possible form of administration. Substances such as the antioxidant N-acetylcysteine also counteract hearing loss during chemotherapy with cisplatin [ 54 , 55 ] and, like ginkgo [ 56 ] and other substances, are the focus of current clinical studies. In particular, sodium thiosulphate stood out as a potential agent that is both well tolerated [ 57 ] and, in a phase III clinical trial, showed a significant reduction in the incidence of hearing loss during chemotherapy with cisplatin in children with standard-risk hepatoblastoma without compromising the chemotherapeutic potential [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Nimodipine Treatment Protects Auditory Hair Cells from Cisplatin-Induced Cell Death Accompanied by Upregulation of LMO4

Fritzsche

Strauß

Scheller

et al. 2022

IJMS

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Ototoxicity is one of the main dose-limiting side effects of cisplatin chemotherapy and impairs the quality of life of tumor patients dramatically. Since there is currently no established standard therapy targeting hearing loss in cisplatin treatment, the aim of this study was to investigate the effect of nimodipine and its role in cell survival in cisplatin-associated hearing cell damage. To determine the cytotoxic effect, the cell death rate was measured using undifferentiated and differentiated UB/OC−1 and UB/OC−2 cells, after nimodipine pre-treatment and stress induction by cisplatin. Furthermore, immunoblot analysis and intracellular calcium measurement were performed to investigate anti-apoptotic signaling, which was associated with a reduced cytotoxic effect after nimodipine pre-treatment. Cisplatin’s cytotoxic effect was significantly attenuated by nimodipine up to 61%. In addition, nimodipine pre-treatment counteracted the reduction in LIM Domain Only 4 (LMO4) by cisplatin, which was associated with increased activation of Ak strain transforming/protein kinase B (Akt), cAMP response element-binding protein (CREB), and signal transducers and activators of transcription 3 (Stat3). Thus, nimodipine presents a potentially well-tolerated substance against the ototoxicity of cisplatin, which could result in a significant improvement in patients’ quality of life.

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“…Another thiol compound, N-acetylcysteine was effective in ameliorating hearing loss and cochlear damage in rats [ 87 , 88 ]. D-methionine, a sulfur-containing amino acid, was shown to be effective in reducing cisplatin ototoxicity when administered systemically [ 89 ] or locally [ 83 , 90 ].…”

Section: Current Treatmentsmentioning

confidence: 99%

Oxidative Stress and Inflammation Caused by Cisplatin Ototoxicity

et al. 2021

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Hearing loss is a significant health problem that can result from a variety of exogenous insults that generate oxidative stress and inflammation. This can produce cellular damage and impairment of hearing. Radiation damage, ageing, damage produced by cochlear implantation, acoustic trauma and ototoxic drug exposure can all generate reactive oxygen species in the inner ear with loss of sensory cells and hearing loss. Cisplatin ototoxicity is one of the major causes of hearing loss in children and adults. This review will address cisplatin ototoxicity. It includes discussion of the mechanisms associated with cisplatin-induced hearing loss including uptake pathways for cisplatin entry, oxidative stress due to overpowering antioxidant defense mechanisms, and the recently described toxic pathways that are activated by cisplatin, including necroptosis and ferroptosis. The cochlea contains G-protein coupled receptors that can be activated to provide protection. These include adenosine A1 receptors, cannabinoid 2 receptors (CB2) and the Sphingosine 1-Phosphate Receptor 2 (S1PR2). A variety of heat shock proteins (HSPs) can be up-regulated in the cochlea. The use of exosomes offers a novel method of delivery of HSPs to provide protection. A reversible MET channel blocker that can be administered orally may block cisplatin uptake into the cochlear cells. Several protective agents in preclinical studies have been shown to not interfere with cisplatin efficacy. Statins have shown efficacy in reducing cisplatin ototoxicity without compromising patient response to treatment. Additional clinical trials could provide exciting findings in the prevention of cisplatin ototoxicity.

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Protective effect of N-acetylcysteine against cisplatin ototoxicity in rats: a study with hearing tests and scanning electron microscopy

Cited by 21 publications

References 32 publications

Does N‐acetylcysteine Improve Established Hearing Loss in Guinea Pigs?

Does N‐acetylcysteine Improve Established Hearing Loss in Guinea Pigs?

Nimodipine Treatment Protects Auditory Hair Cells from Cisplatin-Induced Cell Death Accompanied by Upregulation of LMO4

Oxidative Stress and Inflammation Caused by Cisplatin Ototoxicity

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