title: Is S-nitrosylation of cochlear proteins a critical factor in cisplatin-induced ototoxicity?
abstract: S-nitrosylation is a redox-sensitive protein modification, which is a highly specific, but reversible mechanism that regulates several signal transduction cascades. Oxidative stress plays a causal role in the ototoxic effects of an anti-neoplastic drug, cisplatin. Despite emerging evidence implicating nitroxidative stress as a critical factor in cisplatin toxicity, the significance of the cochlear protein S-nitrosylation in cisplatin ototoxicity is yet to be understood. In the present study, a 16-mg/kg dose of cisplatin, induced a significant shift in the amplitudes of distortion product otoacoustic emissions, a measure of outer hair cell activity, in Wistar rats, 3 days post-treatment. These ototoxic effects were accompanied by significant increases in the S-nitrosylation of at least three cochlear proteins. Biological significance of these S-nitrosylated proteins was indicated by their immunolocalization in organ of Corti, stria vascularis, and spiral ganglions, which are known cochlear targets of cisplatin toxicity. In addition, co-treatment with Trolox, an inhibitor of peroxynitrite, attenuated cisplatin-induced S-nitrosylation of cochlear proteins and prevented the associated hearing loss. The cisplatin-induced S-nitrosylation of inner ear proteins, their sensitive cochlear localization, and their potential association with cisplatin-induced hearing loss suggests that S-nitrosylation of cochlear proteins might play a crucial role in mediating cisplatin ototoxicity.
authors.affiliation: Department of Communicative Disorders and Sciences, The State University of New York, Buffalo, NY 14214, USA. sj57@buffalo.edu
authors.forename: Samson
authors.initials: S
authors.lastname: Jamesdaniel
authors.forename: Senthilvelan
authors.initials: S
authors.lastname: Manohar
authors.forename: Sneha
authors.initials: S
authors.lastname: Hinduja
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000009:adverse effects*; D003051:Cochlea / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D011506:Proteins / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D011506:Proteins; D009569:Nitric Oxide; D002945:Cisplatin