Direct effects of reactive oxygen species on cochlear outer hair cell shape in vitro

Ahsfracf: This study was undertaken in order to determine the changes in auditory brainstem-evoked responses relationship with the changes in the levels of GSH, lipid peroxidation and antioxidant enzymes activity in cisplatin-induced ototoxicity and otoprotection by 4-methylthiobenzoic acid (MTBA). Male Wistar rats in different groups were treated as follows: 1) saline control; 2) cisplatin ( I 6 mg/kg. intraperitoneally); 3 ) MTBA (250 mg/kg, intraperitoneally), and 4) cisplatin plus MTBA. Post-treatment auditory brainstem-evoked responses were performed after three days and the rats were sacrificed and cochleae harvested. The cochleae were analyzed for glutathione (GSH), antioxidant enzyme activity, and malondialdehyde levels. The cisplatin injected rats showed a threshold elevation of 31.95 16.0 dB above the pretreatment thresholds using click stimulus. Rats treated with MTBA plus cisplatin did not show significant elevation of hearing threshold. Cisplatin plus MTBA administration showed a higher levels of cochlear GSH (5.59t0.35 nmoles/mg protein) compared to cisplatin alone (4.46?0. I3 nmolesimg protein). Cisplatin treated rats showed a decrease in superoxide dismutase, catalase, glutathione peroxidase (GSH-peroxidase), and glutathione reductase (GSH-reductase) activities (57"h. 83'%1, 78% and 58's of control). Cochlear superoxide dismutase, catalase and GSH-reductase activities and MDA levels were restored in the rats injected with cisplatin plus MTBA, compared to cisplatin alone. It is concluded that the protection conferred by MTBA against cisplatin ototoxicity is associated with sparing of the cochlear antioxidant system. Cisplatin (cis-diamminedichloroplatinum) is currently being used clinically as an effective antitumour agent against a variety of neoplasms, but its use is limited by the onset of side effects such as ototoxicity, nephrotoxicity, and peripheral neuropathy. High doses of cisplatin result in profound deafness (Rybak 1981; Fausti et al. 1984Fausti et al. & 1993Powis & Hacker 1991). The severity of these toxic side-effects remains an obstacle to the clinical use of high-dose cisplatin. To identify safer methods of cisplatin dose escalation, the use of chemoprotectors has been explored. al. 1992). procaine (Zhang et al. 1992), and other sulfur containing compounds (Basinger et al. 1990;Jones et al. 1991Jones et al. & 1992. The rationale for their use is the high affinity of sulfur ligands for platinum complexes.Clinical and experimental studies have demonstrated that administration of GSH is nephro-and neuroprotective but its role in otoprotection is unclear (Zunino P t al. 1989;Fontanelli et al. 1992;Hamers et a/. 1993 et ul. 1986;Zunino et a/. 1983;Hamers et al. 1993). However, the effect of GSH level in relation to ototoxicity is unknown.Ototoxicity is the dose-limiting side effect following diethyldithiocarbamate chemoprotection (Berry et 01. 1990). Preliminary results in clinical studies by Gandara et (11. (1990 & 1991) suggest possible protection against ototoxicity by diethyldit...

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“…These increases in superoxide and HzOz lead to Ca++ influx and pathological changes in cochlear cells (Ikeda et a/. 1993;Clerici et a/. 1995).…”

Section: Discussionmentioning

confidence: 99%

Protection by 4‐Methylthiobenzoic Acid Against Cisplatin‐Induced Ototoxicity: Antioxidant System

Rybak

Husain

Evenson

et al. 1997

Pharmacology & Toxicology

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“…There is evidence that the mechanism of ototoxicity is related to formation of reactive oxygen species that damage OHCs of the cochlea and trigger apoptosis. [5][6][7] Research has explored otoprotective compounds that work by interfering with this reactive oxygen species pathway, 8,9 yet otoprotective agents have not translated to clinical practice.…”

mentioning

confidence: 99%

Cisplatin‐Induced Ototoxicity and the Effects of Intratympanic Diltiazem in a Mouse Model

Naples

Parham

2015

Otolaryngol.--head neck surg.

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Objective. To evaluate whether the calcium-channel blocker diltiazem has protective effects against cisplatin-induced ototoxicity in a mouse model. Study Design. Original basic science in vivo investigation.Setting. Academic setting: Otolaryngology-Head and Neck Surgery laboratory at University of Connecticut Health Center.Subjects. Thirty-nine female CBA/J mice.Methods. Pure tone-or click-evoked auditory brainstem responses (ABRs) were recorded in CBA/J mice to determine auditory thresholds. All mice had baseline ABRs recorded. They were then given a single cisplatin bolus (14 mg/kg), followed by 5 consecutive days of intratympanic diltiazem or saline control. Follow-up thresholds were recorded on days 7, 14, and 21 postcisplatin. Tone-evoked ABRs evaluated the otoprotective effect of 2-mg/kg diltiazem in 9 mice, and dose effect was examined in response to click-evoked ABR with 2-or 4-mg/kg diltiazem in 2 groups of 15 mice.Results. Saline-treated ears had significantly elevated toneevoked auditory thresholds when compared with diltiazemtreated ears (P = .038) on day 7 postcisplatin only. Clickevoked ABR thresholds were significantly elevated in salinetreated ears versus diltiazem-treated ears for the 2-mg/kg group (P = .001) and 4-mg/kg group (P = .011) on days 7, 14, and 21 postcisplatin. Conclusion.Intratympanic diltiazem has significant protective effects against cisplatin ototoxicity at 2 and 4 mg/kg. This is the first in vivo study to demonstrate that diltiazem offers a potentially novel therapy for cisplatininduced ototoxicity.

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“…The experimental studies on rats showed that cisplatin has effects, such as compression, strial edema, bulging, rupture, and reduction in cytoplasmic organelles of marginal cells in the basal fold of the stria vascularis [18] . At the molecular level, cisplatin induces the formation of ROS, such as superoxide anion [19,20] . Glutathione and antioxidant enzymes are depleted with increased ROS [21] .…”

Section: Discussionmentioning

confidence: 99%

The Protective Effect of Intratympanic Alpha Lipoic Acid on Cisplatin-Induced Ototoxicity on Rats

Altıntoprak¹,

Aydın²,

Şanlı³

et al. 2015

Int Adv Otol

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OBJECTIVE:The objective of this study is to investigate the effect of intratympanic alpha lipoic acid (α-LA) on cisplatin-induced ototoxicity by using distortion product otoacoustic emission (DPOAE). MATERIALS and METHODS:A total of 24 Wistar albino rats were randomly divided into three groups: group 1 received intraperitoneal (IP) saline + intratympanic (IT) saline as a control group for 4 days (n=8), group 2 received IP cisplatin (20 mg/kg) + IT saline (0.1-0.3 mL) for 4 days (n=8), and group 3 received IP cisplatin (20 mg/kg) + IT α-LA (25 mg/mL) for 4 days (n=8). DPOAEs were performed prior to the procedure and at the end of the experiment on day 5. RESULTS:Statistically significant DPOAE amplitude reductions were found in the group 2 at all frequencies (2-9 kHz) that demonstrate severe cisplatin ototoxicity (p<0.01). IT α-LA injection provided a protective effect against cisplatin-induced ototoxicity at 3.2, 3.8, 4.5, 5.4, 6.3, and 7.6 kHz frequencies (p<0.05). CONCLUSION:In our study IT α-LA showed a protective effect against cisplatin-induced ototoxicity in a large frequency range.

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Direct effects of reactive oxygen species on cochlear outer hair cell shape in vitro

Cited by 147 publications

References 68 publications

Protection by 4‐Methylthiobenzoic Acid Against Cisplatin‐Induced Ototoxicity: Antioxidant System

Protection by 4‐Methylthiobenzoic Acid Against Cisplatin‐Induced Ototoxicity: Antioxidant System

Cisplatin‐Induced Ototoxicity and the Effects of Intratympanic Diltiazem in a Mouse Model

The Protective Effect of Intratympanic Alpha Lipoic Acid on Cisplatin-Induced Ototoxicity on Rats

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