title: Dose-dependent cochlear and vestibular toxicity of trans-tympanic cisplatin in the rat.
abstract: In vivo studies are needed to study cisplatin ototoxicity and to evaluate candidate protective treatments. Rats and mice are the preferred species for toxicological and pharmacological pre-clinical research, but systemic administration of cisplatin causes high morbidity in these species. We hypothesized that trans-tympanic administration of cisplatin would provide a good model for studying its auditory and vestibular toxicity in the rat. Cisplatin was administered by the trans-tympanic route in one ear (50μl, 0.5-2mg/ml) of rats of both sexes and two different strains. Cochlear toxicity was corroborated by histological means. Vestibular toxicity was demonstrated by behavioral and histological analysis. Cisplatin concentrations were assessed in inner ear after trans-tympanic and i.v. administration. In all experiments, no lethality and only scant body weight loss were recorded. Cisplatin caused dose-dependent cochlear toxicity, as demonstrated by hair cell counts in the apical and middle turns of the cochlea, and vestibular toxicity, as demonstrated by behavioral analysis and hair cell counts in utricles. High concentrations of cisplatin were found in the inner ear after trans-tympanic administration. In comparison, i.v. administration resulted in lower inner ear concentrations. We conclude that trans-tympanic administration provides an easy, reproducible and safe model to study the cochlear and vestibular toxicity of cisplatin in the rat. This route of exposure may be useful to address particular questions on cisplatin induced ototoxicity and to test candidate protective treatments.
authors.affiliation: Departament de Ciències Fisiològiques, Universitat de Barcelona, 08907 L'Hospitalet de Llobregat, Catalonia, Spain; Unitat Funcional d'Otorinolaringologia i Al·lèrgia, Institut Universtiari Dexeus, 08028 Barcelona, Catalonia, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Callejo
authors.affiliation: Sensorion S.A., Montpellier, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Durochat
authors.affiliation: Sensorion S.A., Montpellier, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bressieux
authors.affiliation: Sensorion S.A., Montpellier, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Saleur
authors.affiliation: Aix-Marseille Université, Marseille, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Chabbert
authors.affiliation: Unitat Funcional d'Otorinolaringologia i Al·lèrgia, Institut Universtiari Dexeus, 08028 Barcelona, Catalonia, Spain; Institut de Neurociències, Universitat de Barcelona, Catalonia, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Domènech Juan
authors.affiliation: Departament de Ciències Fisiològiques, Universitat de Barcelona, 08907 L'Hospitalet de Llobregat, Catalonia, Spain; Institut de Neurociències, Universitat de Barcelona, Catalonia, Spain; Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), 08907 L'Hospitalet de Llobregat, Catalonia, Spain. Electronic address: jllorens@ub.edu.
authors.forename: Jordi
authors.initials: J
authors.lastname: Llorens
authors.affiliation: Sensorion S.A., Montpellier, France. Electronic address: gaboyard@yahoo.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gaboyard-Niay
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000473:pathology; D008297:Male; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D012444:Saccule and Utricle / Q000187:drug effects / Q000473:pathology; D014432:Tympanic Membrane / Q000187:drug effects*; D014722:Vestibule, Labyrinth / Q000187:drug effects* / Q000503:physiopathology
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin
keywords: Cisplatin; Hair cells; Ototoxicity; Rat; Trans-tympanic administration; Vestibular and cochlear pathology