Abstract
There is considerable interest in discovering drugs with the potential to protect inner ear hair cells (HCs) from damage. One means of discovery is to screen compound libraries. Excellent screening protocols have been developed employing cell lines derived from the cochlea and zebrafish larvae. However, these do not address the differentiated mammalian hair cell. We have developed a screening method employing micro-explants of the mammalian organ of Corti (oC) to identify compounds with the ability to influence aminoglycoside-induced HC loss. The assay is based on short segments of the neonatal mouse oC, containing ~80 HCs which selectively express green fluorescent protein (GFP). This allows the screening of hundreds of potential protectants in an assay that includes both inner and outer HCs. This review article describes various screening methods, including the micro-explant assay. In addition, two micro-explant screening studies in which antioxidant and kinase inhibitor libraries were evaluated are reviewed. The results from these screens are related to current models of HC damage and protection.
Highlights
Ototoxicity is a significant side effect of some valuable medications that have been used for life-threatening diseases
hair cells (HCs)-specific fluorescent green fluorescent protein (GFP) expression allows continuous monitoring of HC survival throughout the period of the screening assay, instead of a snapshot provided by HCs that must be labeled at the end of an experiment
This permits the discovery of entirely novel protectants, and the identification of unsuspected damage and protective mechanisms
Summary
Ototoxicity is a significant side effect of some valuable medications that have been used for life-threatening diseases. Ototoxic drugs can cause irreversible damages in the inner ear that lead to loss of function in hearing and balance. Mammalian Hair Cell Ototoxicity Screening in treating multi-drug resistance tuberculosis, neonatal sepsis, cystic fibrosis and pseudomonas-induced respiratory infections (Forge and Schacht, 2000). Since other forms of sensorineural cell damage may occur via similar mechanisms, research on ototoxicity may accelerate the development of treatments for other types of hearing loss. Ototoxic drugs generally target the sensory hair cells (HCs) of the inner ear (Wong and Ryan, 2015). Aminoglycoside-induced HC death occurs initially in basal turn outer HCs, and extends to more apical outer HCs and inner HCs with increasing cumulative dose (Ryan and Dallos, 1975; Forge and Schacht, 2000). We summarize results from micro-explant screening and interpret those results linking them with reference to HC damage mechanisms
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