Abstract
Objectives: Determine if local intratympanic (IT) administration of N-acetylcysteine (LNAC) improves cochlear glutathione levels versus systemic LNAC intraperitoneal (IP) administration, as indicated by decreased oxidized (GSSG)/reduced (GSH) glutathione ratios. Cisplatin is a platinum based ototoxic chemotherapeutic agent that induces injury secondary to the accumulation of reactive oxygen species. This pilot study assesses if different LNAC formulations or modes of administration decrease cochlear oxidative stress (GSSG/GSH ratio). Methods: Cisplatin was administered subcutaneously for 3 days (5.5 mg/kg SC/day x 3). Single LNAC formulations were administered to guinea pigs either via IT (solution), IT (nanocapsular gel), or IP (250mg/kg) 2 hours prior to Day 1 cisplatin dosing. On Day 3, cochlear tissue was microdissected, flash frozen, stored -70ºC, and assayed within 21 days. The levels of GSSG and GSH in homogenized cochlear tissue supernatants were determined in white half area 96-well plates (Corning) by assay kits (Promega) via luminometry (Dynex) and referenced per total protein (BCA assay, Pierce). Results: The greatest reduction in cisplatin induced GSSG/GSH occurred for LNAC 250 mg/kg IP pretreated animals, compared to the IT formulations and cisplatin only control groups. Conclusions: The greatest decrease of cochlear oxidative stress was seen when L-NAC was delivered IP prior to cisplatin treatment. Further studies are needed to determine the effects on hearing thresholds and the utility of this proposed cisplatin protective treatment.
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