Identification of FDA-approved drugs and bioactives that protect hair cells in the zebrafish (Danio rerio) lateral line and mouse (Mus musculus) utricle.

Publication Type:

Journal Article

Source:

Journal of the Association for Research in Otolaryngology : JARO, Volume 10, Issue 2, p.191-203 (2009)

Keywords:

2009, Animals, Anti-Bacterial Agents, Cell Survival, Center-Authored Paper, Cholinesterase Inhibitors, Clinical Research Division, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Hair Cells, Auditory, Lateral Line System, Male, Mechanotransduction, Cellular, MICE, Neomycin, Pharmaceutical Preparations, Saccule and Utricle, Scientific Imaging Core Facility, Shared Resources, Tacrine, United States, United States Food and Drug Administration, zebrafish

Abstract:

The hair cells of the larval zebrafish lateral line provide a useful preparation in which to study hair cell death and to screen for genes and small molecules that modulate hair cell toxicity. We recently reported preliminary results from screening a small-molecule library for compounds that inhibit aminoglycoside-induced hair cell death. To potentially reduce the time required for development of drugs and drug combinations that can be clinically useful, we screened a library of 1,040 FDA-approved drugs and bioactive compounds (NINDS Custom Collection II). Seven compounds that protect against neomycin-induced hair cell death were identified. Four of the seven drugs inhibited aminoglycoside uptake, based on Texas-Red-conjugated gentamicin uptake. The activities of two of the remaining three drugs were evaluated using an in vitro adult mouse utricle preparation. One drug, 9-amino-1,2,3,4-tetrahydroacridine (tacrine) demonstrated conserved protective effects in the mouse utricle. These results demonstrate that the zebrafish lateral line can be used to screen successfully for drugs within a library of FDA-approved drugs and bioactives that inhibit hair cell death in the mammalian inner ear and identify tacrine as a promising protective drug for future studies.