Identification of FDA-approved drugs and bioactives that protect hair cells in the zebrafish (Danio rerio) lateral line and mouse (Mus musculus) utricle.
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.
Ou
Henry C
HC
Virginia Merrill Bloedel Hearing Research Center, University of Washington, Box 357923, Seattle, WA 98195, USA. henryou@u.washington.edu
Cunningham
Lisa L
LL
Francis
Shimon P
SP
Brandon
Carlene S
CS
Simon
Julian A
JA
Raible
David W
DW
Rubel
Edwin W
EW
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006198:Hair Cells, Auditory / Q000187:drug effects*; D053403:Lateral Line System / Q000187:drug effects*; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D009355:Neomycin / Q000008:administration & dosage / Q000633:toxicity; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D012444:Saccule and Utricle / Q000187:drug effects*; D013619:Tacrine / Q000008:administration & dosage; D014481:United States; D014486:United States Food and Drug Administration; D015027:Zebrafish
D000900:Anti-Bacterial Agents; D002800:Cholinesterase Inhibitors; D004364:Pharmaceutical Preparations; D013619:Tacrine; D009355:Neomycin