Insulin-like growth factor 1 protects cochlear outer hair cells against cisplatin

Cisplatin, an effective anti-neoplastic drug widely used in oncology protocols, has an adverse effect such as ototoxicity, for which no current treatment exists. Histological lesions in the cochlea after cisplatin administration are most prominent in outer hair cells in the organ of Corti. We have previously reported that insulin-like growth factor 1 (IGF1) protects cochlear hair cells (HCs) against several types of damage to the cochlea, including noise exposure, ischemia, surgical trauma, and aminoglycoside, resulting in hearing recovery. In the present study, we investigated the efficacy of IGF1 as a molecule to protect inner ear auditory sensory HCs against cisplatin using cochlear explant culture systems of postnatal day 2 mice. Administration of IGF1 to the explants grown in the medium containing cisplatin markedly protected outer HCs from cisplatin-induced damage. Pharmacological inhibition of IGF1 receptor (IGF1R) using an IGF1R antagonist or inhibitor markedly attenuated the protective activity of IGF1, indicating that IGF1R is specifically required for IGF1 effects in HCs against cisplatin. As a protective mechanism against cisplatin, we found that the administration of IGF1 reduces cisplatin-induced oxidative stress. IGF1 effects on the maintenance of HC numbers are achieved by inhibiting the apoptosis of HCs, not by inducing the proliferation of HCs or supporting cells (SCs). We conclude that treatment with IGF1 could be an efficient and safe approach to treat cisplatin-induced ototoxicity.