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

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An Erratum to this article was published on 06 August 2011

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 200 mg/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 1 h after furosemide treatment. Combined treatment with 0.5 mg/kg of cisplatin and 200 mg/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, 1 mg/kg of cisplatin plus 200 mg/kg of furosemide resulted in a permanent 40–50 dB 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.

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Abbreviations

ABR:

Auditory brainstem response

ANOVA:

Analysis of variance

dB SPL:

Decibels sound pressure level

DPOAE:

Distortion product otoacoustic emissions

IHC:

Inner hair cells

i.p.:

Intraperitoneal

OHC:

Outer hair cells

s.c.:

Subcutaneous

SGN:

Spiral ganglion neurons

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Acknowledgments

This article was supported in part by NIH grant R01DC006630.

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Authors and Affiliations

  1. Center for Hearing and Deafness, University at Buffalo, 137 Cary Hall, Buffalo, NY, 14214, USA

    Yongqi Li, Dalian Ding, Haiyan Jiang, Yong Fu & Richard Salvi

  2. The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Yongqi Li

  3. The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China

    Yong Fu

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  1. Yongqi Li
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  2. Dalian Ding
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Correspondence to Richard Salvi.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s12640-011-9262-y

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Li, Y., Ding, D., Jiang, H. et al. Co-administration of Cisplatin and Furosemide Causes Rapid and Massive Loss of Cochlear Hair Cells in Mice. Neurotox Res 20, 307–319 (2011). https://doi.org/10.1007/s12640-011-9244-0

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