| Autor: |
Kenyon EJ; Sussex Neuroscience, School of Life Sciences., Kirkwood NK; Sussex Neuroscience, School of Life Sciences., Kitcher SR; Sussex Neuroscience, School of Life Sciences., O'Reilly M; Sussex Neuroscience, School of Life Sciences., Derudas M; Sussex Drug Discovery Centre, School of Life Sciences, and., Cantillon DM; Wellcome Trust Centre for Global Health Research, Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom., Goodyear RJ; Sussex Neuroscience, School of Life Sciences., Secker A; Sussex Neuroscience, School of Life Sciences., Baxendale S; Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom., Bull JC; Department of Biosciences, College of Science, Swansea University, Swansea, United Kingdom., Waddell SJ; Wellcome Trust Centre for Global Health Research, Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom., Whitfield TT; Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom., Ward SE; Sussex Drug Discovery Centre, School of Life Sciences, and.; Medicines Discovery Institute, Cardiff University, Cardiff, United Kingdom., Kros CJ; Sussex Neuroscience, School of Life Sciences., Richardson GP; Sussex Neuroscience, School of Life Sciences. |
| Abstrakt: |
Aminoglycoside antibiotics are used to treat life-threatening bacterial infections but can cause deafness due to hair cell death in the inner ear. Compounds have been described that protect zebrafish lateral line hair cells from aminoglycosides, but few are effective in the cochlea. As the aminoglycosides interact with several ion channels, including the mechanoelectrical transducer (MET) channels by which they can enter hair cells, we screened 160 ion-channel modulators, seeking compounds that protect cochlear outer hair cells (OHCs) from aminoglycoside-induced death in vitro. Using zebrafish, 72 compounds were identified that either reduced loading of the MET-channel blocker FM 1-43FX, decreased Texas red-conjugated neomycin labeling, or reduced neomycin-induced hair cell death. After testing these 72 compounds, and 6 structurally similar compounds that failed in zebrafish, 13 were found that protected against gentamicin-induced death of OHCs in mouse cochlear cultures, 6 of which are permeant blockers of the hair cell MET channel. None of these compounds abrogated aminoglycoside antibacterial efficacy. By selecting those without adverse effects at high concentrations, 5 emerged as leads for developing pharmaceutical otoprotectants to alleviate an increasing clinical problem. |
