Targeted amelioration of cisplatin-induced ototoxicity in guinea pigs

Abstract

This pilot study compared otoprotection provided by trans-tympanic formulations and systemic intraperitoneal administration of L-N-acetylcysteine from cisplatin-induced cochlear oxidative stress. Protection was assessed by measures of hearing loss and cochlear glutathione levels. All groups received an equivalent single dose of L-N-acetylcysteine followed by cisplatin. Cisplatin was administered subcutaneously for 3 days (5.5 mg/kg/day). Two hours prior to day 1 cisplatin, L-N-acetylcysteine was administered either intraperitoneally (250 mg/kg), trans-tympanic as 2% L-N-acetylcysteine in gel, or trans-tympanic as L-N-acetylcysteine-loaded nanocapsules in gel. Hearing was assessed prior to and 3 days after cisplatin followed by microdissection of cochlear tissue. The levels of reduced (GSH) and oxidized (GSSG) glutathione in homogenized tissue supernatants were determined via luminometry. Intraperitoneal L-N-acetylcysteine administration preceding cisplatin resulted in less hearing loss and a higher GSH/GSSG ratio than either trans-tympanic formulation. This suggests that for equivalent doses of L-N-acetylcysteine, systemic rather than targeted cochlear delivery provides increased otoprotection from cisplatin ototoxicity.

Keywords: ABR; L-N-acetylcysteine; ROS; drug delivery; glutathione; nanocapsules; otoprotection; systemic; trans-tympanic.