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01 August 2011

Dose-dependent protection on cisplatin-induced ototoxicity – an electrophysiological study on the effect of three antioxidants in the Sprague-Dawley rat animal model

Guiscardo LoritoABCEF, Stavros HatzopoulosACDE, Goran LaurellDE, Kathleen C.M. CampbellDEF, Joseph PetruccelliDE, Pietro GiordanoBD, Krzysztof KochanekDF, Lech SliwaDF, Alessandro MartiniDG, Henryk SkarzynskiDG

DOI: 10.12659/MSM.881894

Med Sci Monit 2011; 17(8): BR179-186


Background: Sprague-Dawley rats were used as an acute cisplatin ototoxicity model to compare the chemo-protective efficacy of 2 sulphur-containing antioxidants (D-methionine, N-L-acetylcysteine) and 1 seleno-organic compound (ebselen). Each putative chemo-protective agent was tested at 3 different dosages in order to assess the influence of dose on auditory preservation.
Material/Methods: A total of 40 Sprague-Dawley albino male rats were used in the study. Animals were divided into 10 groups, 3 groups of different doses for each protective agent and a cisplatin-treated control group. The animals were weight-matched before drug exposure to ensure similar weights in all groups. Auditory function was assessed with auditory brainstem responses and distortion product otoacoustic emissions at time zero and at 96 hours post-treatment.
Results: At the post-treatment follow-up no significant threshold change at 8 kHz was found in the D-Met- and NAC-treated groups. All ebselen-treated animals presented significant threshold elevations. At 12 and 16 kHz, only the groups treated with 300, 450 mg/kg of D-Met and 475 mg/kg of NAC presented thresholds comparable to the pre-treatment ABR data. The ebselen-treated animals presented significant threshold shifts and showed the highest threshold elevations. The DPOAE data analysis showed that only the animals from the 350 mg/kg D-met group presented lack of statistical differences between the pre and post recordings.
Conclusions: Considering the outcome from the ABR and DPOAE analyses together, only the 350 mg/kg D-met group presented a complete auditory preservation against the 14 mg/kg cisplatin administered i.v. Data from ebselen pre-treated Sprague-Dawley albino male rats demonstrate that ebselen dosages up to 12 mg/kg given by i.p. administration lack auditory preservation in this species.

Keywords: Hair Cells, Auditory, Outer - drug effects, Methionine - pharmacology, Evoked Potentials, Auditory, Brain Stem - physiology, Electrophysiology, Dose-Response Relationship, Drug, Cisplatin - toxicity, Azoles - pharmacology, Auditory Threshold - drug effects, Antioxidants - pharmacology, Antineoplastic Agents - toxicity, Acetylcysteine - pharmacology, Models, Animal, Organoselenium Compounds - pharmacology, Otoacoustic Emissions, Spontaneous - physiology

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750