Back to Search
Start Over
Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death.
- Source :
-
JCI insight [JCI Insight] 2017 Dec 21; Vol. 2 (24). Date of Electronic Publication: 2017 Dec 21. - Publication Year :
- 2017
-
Abstract
- 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.
- Subjects :
- Aminoglycosides antagonists & inhibitors
Animals
Cell Death drug effects
Cochlea drug effects
Drug Evaluation, Preclinical methods
Female
Gentamicins antagonists & inhibitors
Gentamicins pharmacology
Ion Channels drug effects
Male
Mice
Tissue Culture Techniques
Zebrafish
Aminoglycosides pharmacology
Anti-Bacterial Agents pharmacology
Hair Cells, Auditory drug effects
Neuroprotective Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 2
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 29263311
- Full Text :
- https://doi.org/10.1172/jci.insight.96773