A sensitive animal model to assess acute and chronic ototoxic effects

J. Lautermann and J. Schacht
Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, Ann Arbor, USA.

BACKGROUND: Ototoxic side effects of aminoglycosides or cisplatin are strongly influenced by the nutritional state of the experimental animal. We previously demonstrated that guinea pigs fed a low-protein diet are a sensitive model to investigate chronic ototoxic effects of drugs. We now demonstrate that this model is equally sensitive to acute ototoxic insults. SUBJECTS AND DESIGN: Guinea pigs were fed either a full-protein (18.5% protein) or a low-protein (7% protein) diet. Gentamicin sulfate was given as a single injection (100 mg/kg of body weight subcutaneously), followed 90 minutes later by varying concentrations of ethacrynic acid intravenously. Auditory function was assessed by auditory brain-stem response and morphologic characteristics in surface preparations of the organ of Corti. RESULTS: In animals fed a full-protein diet, 35 mg of ethacrynic acid per kilogram of body weight was required for a significant threshold shift at all frequencies tested (3, 8, and 18 kHz). In animals fed a low-protein diet, 15 mg of ethacrynic acid per kilogram significantly elevated threshold at all frequencies, and 20 mg/kg caused a profound threshold shift (> 90 dB). Hair cell loss in the organ of Corti paralleled the pathophysiological findings. CONCLUSIONS: A metabolically challenged animal may better represent the situation of a severely ill patient undergoing drug therapy. Therefore, studies in diet-restricted animals may be more appropriated than studies in healthy animals for an assessment of potential adverse therapeutic side effects.