Assessing cisplatin-induced ototoxicity and otoprotection in whole organ culture of the mouse inner ear in simulated microgravity.
Cisplatin is a widely used anti-cancer drug. Ototoxicity is a major dose-limiting side-effect. A reproducible mammalian in-vitro model of cisplatin ototoxicity is required to screen and validate otoprotective drug candidates. We utilized a whole organ culture system of the postnatal mouse inner ear in a rotating wall vessel bioreactor under "simulated microgravity" culture conditions. As previously described this system allows whole organ culture of the inner ear and quantitative assessment of ototoxic effects of aminoglycoside induced hair cell loss. Here we demonstrate that this model is also applicable to the assessment of cisplatin induced ototoxicity. In this model cisplatin induced hair cell loss was dose and time dependent. Increasing exposure time of cisplatin led to decreasing EC50 concentrations. Outer hair cells were more susceptible than inner hair cells, and hair cells in the cochlear base were more susceptible than hair cells in the cochlear apex. Initial cisplatin dose determined the final extent of hair cell loss irrespective if the drug was withdrawn or continued. Dose dependant otoprotection was demonstrated by co-administration of the antioxidant agent N-acetyl l-cysteine. The results support the use of this inner ear organ culture system as an in vitro assay and validation platform for inner ear toxicology and the search for otoprotective compounds.
University of Tübingen Medical School, Department of Otorhinolaryngology - Head & Neck Surgery, Hearing Research Center, Elfriede-Aulhorn-Straße 5, D-72076 Tübingen, Germany. Electronic address: anke.tropitzsch@med.uni-tuebingen.de.
Anke
A
Tropitzsch
University of Tübingen Medical School, Department of Otorhinolaryngology - Head & Neck Surgery, Hearing Research Center, Elfriede-Aulhorn-Straße 5, D-72076 Tübingen, Germany. Electronic address: heinz.arnold@med.uni-tuebingen.de.
Heinz
H
Arnold
University of Tübingen Medical School, Department of Otorhinolaryngology - Head & Neck Surgery, Hearing Research Center, Elfriede-Aulhorn-Straße 5, D-72076 Tübingen, Germany. Electronic address: mohamed.bassiouni@med.uni-tuebingen.de.
Mohamed
M
Bassiouni
University of Tübingen Medical School, Department of Otorhinolaryngology - Head & Neck Surgery, Hearing Research Center, Elfriede-Aulhorn-Straße 5, D-72076 Tübingen, Germany. Electronic address: andrea.mueller@med.uni-tuebingen.de.
Andrea
A
Müller
University of Tübingen Medical School, Department of Otorhinolaryngology - Head & Neck Surgery, Hearing Research Center, Elfriede-Aulhorn-Straße 5, D-72076 Tübingen, Germany. Electronic address: andreas.eckhard@klinikum.uni-tuebingen.de.
Andreas
A
Eckhard
University of Tübingen Medical School, Department of Otorhinolaryngology - Head & Neck Surgery, Hearing Research Center, Elfriede-Aulhorn-Straße 5, D-72076 Tübingen, Germany. Electronic address: marcus.mueller@uni-tuebingen.de.
Marcus
M
Müller
University of Tübingen Medical School, Department of Otorhinolaryngology - Head & Neck Surgery, Hearing Research Center, Elfriede-Aulhorn-Straße 5, D-72076 Tübingen, Germany. Electronic address: hubert.loewenheim@uni-tuebingen.de.
Hubert
H
Löwenheim
D000111:Acetylcysteine / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002452:Cell Count; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D007758:Ear, Inner / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects; D006311:Hearing Disorders / Q000139:chemically induced* / Q000517:prevention & control*; D051379:Mice; D009924:Organ Culture Techniques; D014893:Weightlessness / Q000009:adverse effects*
D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D002945:Cisplatin; D000111:Acetylcysteine
Cisplatin; Hair cell loss; Organ culture; Organ of Corti; Otoprotection; Ototoxicity