Paraquat-induced hair cell damage and protection with the superoxide dismutase mimetic M40403

Some forms of ototoxicity appear to be mediated primarily by the superoxide radical; however, the exact role the superoxide radical plays in cochlear damage is not well understood because most ototoxic drugs produce multiple reactive oxygen species. To characterize the role of the superoxide radical in cochlear damage and the protective effect of compounds that inactivate superoxide, we treated mouse cochlear organotypic cultures for 24 h with paraquat, an herbicide that produces high levels of superoxide. M40403, a highly specific, nonpeptidyl mimetic of superoxide dismutase, was added to some cultures to inactivate the superoxide radical generated by paraquat. The number of outer hair cells (OHC) and inner hair cells (IHC) systematically decreased with increasing concentration of paraquat (0.01-10 mM). M40403 (10 μM) significantly increased OHC and IHC survival in cultures treated with 0.01-1.0 mM of paraquat. These results suggest that excess production of superoxide radical is a sufficient condition for hair cell loss.