The role of Autophagy Compounds in ototoxicity: An in vitro screening study

Background:

Autophagy is a process by which cells degrade and recycle dysfunctional components without excessive damage. While autophagy appears to occur during hair cell (HC) damage, its function remains unclear. Our goal was to screen compounds targeting different aspects of autophagy and to assess their effects on HC death due to gentamicin (GM) toxicity.

Methods:

A SELLECKChem autophagy compound library was used to screen an in vitro murine model of HC damage. Organ of Corti (oC) from neonatal pou4f3/GFP transgenic mice were used in which HCs selectively express green fluorescent protein (GFP). Basal and middle turn oC samples were divided into segments (micro-explants), which were placed into a single well of a 96-well plate. Explants were treated with 200µM GM plus three dosages of a test compound. The highest compound dose served as a control for compound toxicity. Wells with media alone served as negative control, and three wells were treated only with 200µM GM (positive control). The samples were cultured for three days post GM treatment and HCs counted each day.

Results:

In addition to some compounds previously tested on HCs, novel autophagy compounds were evaluated. The majority of the 154 autophagy-inducing or -inhibiting compounds had no effect on GM-induced HC loss. However, a subgroup of compounds exhibited a significant, dose-dependent protective effect. Another subset enhanced HC loss, some in the absence of GM.

Conclusions:

The disparate results point out the complexity of the role of autophagy in HC damage due to an ototoxin. Our findings identify compounds that could be potential drug targets.

Publikationsverlauf

Publikationsdatum:
23. April 2019 (online)