Development of an ototoxicity model in the adult CBA/CaJ mouse and determination of a golden window of corticosteroid intervention for otoprotection.

ABSTRACT

OBJECTIVE: To investigate the effect of timing of dexamethasone administration on auditory hair cell survival following an ototoxic insult with kanamycin and furosemide. STUDY DESIGN: Controlled experimental study. SETTING: Translational science experimental laboratory. METHODS: 5-6 week old CBA/CaJ mice, divided into 6 groups, were injected with kanamycin (1 mg/g SC) followed by furosemide (0.5 mg/g IP). Dexamethasone (0.1 mg/g IP) was injected at either 1 hour prior to insult, +1 hr, +6 hr, +12 hr, or +72 hr post insult. Temporal bones harvested on day 7 underwent Organ of Corti dissection. Immunohistochemical staining was performed using antibodies to myosin 7a, phalloidin, and TO-PRO. RESULTS: Hair cell counts demonstrate a uniform ototoxicity model with total loss of outer hair cells (OHCs) and near-total loss of inner hair cells (IHCs). The group pre-treated with dexamethasone showed a statistically significant improvement in counts compared to controls (p = 0.004). Counts from the other experimental groups given dexamethasone after the insult were highly variable but demonstrated some apical and middle turn inner hair cell survival. CONCLUSION: Treatment of systemic dexamethasone prior to ototoxic insult attenuates hair cell loss in a reliable, novel, ototoxicity model using kanamycin and furosemide in CBA/CaJ mice. Dosing with dexamethasone following ototoxic insult shows promising yet variable response in hair cell survival.