In vivo overexpression of X-linked inhibitor of apoptosis protein protects against neomycin-induced hair cell loss in the apical turn of the cochlea during the ototoxic-sensitive period.

Shan Sun,Huawei Li,Huiqian Yu,Bo Xu,Lei Wang,Yingzi He,Jian Wang,Mingzhi Sun,Muhammad Waqas,Renjie Chai,Cheng Cheng,Shankai Yin,Yanping Zhang

doi:10.3389/fncel.2014.00248

Abstract

Aminoglycoside-induced cochlear ototoxicity causes hair cell (HC) loss and results in hearing impairment in patients. Previous studies have developed the concept of an ototoxicity-sensitive period during which the cochleae of young mice are more vulnerable to auditory trauma than adults. Here, we compared neomycin-induced ototoxicity at the following four developmental ages in mice: postnatal day (P)1–P7, P8–P14, P15–P21, and P60–P66. We found that when neomycin was administered between P8 and P14, the auditory brainstem response threshold increase was significantly higher at low frequencies and HC loss was significantly greater in the apical turn of the cochlea compared to neomycin administration during the other age ranges. Quantitative real-time PCR (qPCR) data revealed that the expression of apoptotic markers, including Casp3 and Casp9, was significantly higher when neomycin was injected from P8 to P14, while the expression of the X-linked inhibitor of apoptosis protein (XIAP) gene was significantly higher when neomycin was injected from P60 to P66. Because XIAP expression was low during the neomycin-sensitive period, we overexpressed XIAP in mice and found that it could protect against neomycin-induced hearing loss at low frequencies and HC loss in the apical turn of the cochlea. Altogether, our findings demonstrate a protective role for XIAP against neomycin-induced hearing loss and HC loss in the apical turn of the cochlea during the ototoxic-sensitive period, and suggest that apoptotic factors mediate the effect of neomycin during the ototoxic-sensitive period.

Highlights

Aminoglycosides can be ototoxic when administered to adults, children, and infants
We found that when neomycin was administered between P8 and P14, the auditory brainstem response threshold increase was significantly higher at low frequencies and hair cell (HC) loss was significantly greater in the apical turn of the cochlea compared to neomycin administration during the other age ranges
Previous reports indicated that aminoglycoside-induced cochlear HC loss is more severe in neonatal mice than in adults, and this led to the development of the concept of an ototoxicitysensitive period (Chen and Aberdeen, 1981; Chen and Saunders, 1983; Eggermont, 1986; Henley and Rybak, 1993, 1995; Henley et al, 1996)

Summary

Introduction

It has been reported that the incidence of aminoglycoside-induced cochlear ototoxicity in neonates is greater than that in adults. Several hypotheses have been proposed to describe the hypersensitivity of neonates to ototoxic drugs, and caspase-mediated apoptosis is a common theme (Forge and Li, 2000; Matsui et al, 2002). As one of the primary apoptosis executioner molecules (Ashkenazi and Dixit, 1998; Debatin and Krammer, 2004; Jiang and Wang, 2004; Salvesen and Riedl, 2008), caspase-3 has been widely used to assess the apoptosis of hair cells (HCs) in aminoglycoside-induced ototoxicity (Forge, 1985; Nakagawa et al, 1997; Cunningham et al, 2002; Wei et al, 2005; Tabuchi et al, 2007).

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Conclusion