Induction of selective inner hair cell damage by carboplatin

Abstract

Carboplatin (diammine [1,1 cyclobutane dicarboxylato (2)-0,0'] platinum) is an anti-cancer agent which can be toxic to the inner ear. We have explored the nature of this ototoxicity in the chinchilla. In this species, initial degenerative changes appear to be restricted to the inner hair cell (IHC) regions of the organ of Corti. This finding is intriguing and unusual since all other known ototoxic drugs, such as aminoglycosides, are predominantly associated with outer hair cell damage. In the present study, the mechanism of ototoxicity was investigated by comparing two different routes of carboplatin administration. Carboplatin was administered either intravenously (i.v.) or intraperitoneally (i.p.). The mode of administration influenced electrophysiological and morphological changes. Hearing thresholds were elevated in the i.v. group significantly more than in the i.p. group at all tested frequencies. The degree of hair cell damage was evaluated by scanning electron microscopy at four frequency regions in each cochlea. IHC damage in the i.v. group was significantly more severe than in the i.p. group. Carboplatin effects on a different species, the guinea pig, were also determined to clarify interspecies differences. In the guinea pig, outer hair cell damage occurred sporadically and inner hair cells remained intact. In contrast, chinchilla inner hair cells are susceptible to the ototoxic effects of carboplatin. The degree of hair cell damage appears to be dependent on the peak level of carboplatin rather than on the total dose. This animal model provides a new tool for the investigation of inner and outer hair cell function.