Co-administration of Cisplatin and Furosemide Causes Rapid and Massive Loss of Cochlear Hair Cells in Mice

Abstract

The expanding arsenal of transgenic mice has created a powerful tool for investigating the biological mechanisms involved in ototoxicity. However, cisplatin ototoxicity is difficult to investigate in mice because of their small size and vulnerability to death by nephrotoxicity. To overcome this problem, we developed a strategy for promoting cisplatin-induced ototoxicity by coadministration of furosemide a loop diuretic. A dose-response study identified 200mg/kg of furosemide as the optimal dose for disrupting the stria vascularis and opening the blood-ear barrier. Our analysis of stria pathology indicated that the optimal period for administering cisplatin was 1h after furosemide treatment. Combined treatment with 0.5mg/kg of cisplatin and 200mg/kg furosemide resulted in only moderate loss of outer hair cells in the basal 20% of the cochlea, only mild threshold shifts and minimal loss of distortion product otoacoustic emission (DPOAE). In contrast, 1mg/kg of cisplatin plus 200mg/kg of furosemide resulted in a permanent 40-50dB elevation of auditory brainstem response thresholds, almost complete elimination of DPOAE, and nearly total loss of outer hair cells. The widespread outer hair cell lesions that develop in mice treated with cisplatin plus furosemide could serve as extremely useful murine model for investigating techniques for regenerating outer hair cells, studying the mechanisms of cisplatin and furosemide ototoxicity and assessing the perceptual and electrophysiological consequences of outer hair cell loss on central auditory plasticity.