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459 NOVEL COMPOUNDS PREVENT AMINOGLYCOSIDE OTOTOXICITY: F5 AND H10.
  1. A. Knisely1,
  2. F. Santos1,
  3. E. Rubel1
  1. 1Department of Otolaryngology-Head and Neck Surgery, Virginia M. Bloedel Hearing Research Center, University of Washington, Seattle, WA

Abstract

Background and Objectives Aminoglycoside antibiotics are known to induce sensory hair cell death in the inner ear. Loss of sensory hair cells can lead to hearing loss and vestibular dysfunction. A previous drug screen in zebrafish (Danio rerio) identified two novel compounds, F5 and H10, that prevent the toxic effects of neomycin on lateral line hair cells. We hypothesized that these compounds would protect hair cells from neomycin-induced death in mammalian inner ear utricular hair cells.

Methods Murine utricles were harvested from 3- to 6-week old CBA/CaJ mice and were cultured in an in vitro preparation. Utricles pretreated with 10 μM F5 or H10 and untreated utricles were exposed to 2 mM neomycin. Whole-mount immunohistochemistry was then performed to identify surviving striolar and extrastriolar hair cells of the utricles. Hair cell counts were then conducted using fluorescent microscopy. Statistical analysis was performed via one-way ANOVA tests.

Results Utricles (n = 5-10) pretreated with F5 and H10 and then subsequently treated with neomycin were compared with nonpretreated neomycin-exposed utricles. Both F5 and H10 showed significant protection from hair cell death in both regions compared with control, p < .001.

Conclusion In previous experiments, it has been demonstrated that the novel compounds F5 and H10, both benzothiophene carboxamides, protect hair cells from aminoglycoside-induced death in the lateral line of live zebrafish. In this study, F5 and H10 pretreatment were shown to prevent neomycin-induced hair cell death in a dose-dependent manner in the murine utricle. Both compounds are structurally similar, suggesting a similar mechanism of action. The next step in our investigation will be to elucidate this mechanism of action.

This work was funded by the National Institutes of Health NIDCD grant DC04661, NICHHD HD002274, and the NIH Roadmap for Medical Research, T32 RR023256. Information on this Multidisciplinary Clinical Research Career Development Program can be found at < http://nihroadmap.nih.gov >.

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