The Effect of Delayed Systemically Administered n-Acetylcysteine on the Cochlear Oxidative State and on Cisplatin Induced Ototoxicity In Vivo in Guinea Pigs

Abstract

Cisplatin is an effective antineoplastic drug which is often limited in it‘s use by an ototoxic side effect. After cisplatin enters the cochlea, a large amount reactive oxygen species (ROS) is generated. This large production of ROS appears to overwhelm the cells’ mechanisms of ROS regulation and is thought to mediate damage to cells within the cochlea. Past studies have shown that the ototoxicity of cisplatin can be diminished when it is administered concurrently with an antioxidant such as n-acetylcysteine (NAC). It is thought that the mechanism of NAC’s action is through it’s ability to counteract the overwhelming ROS production. Unfortunately, a concern exists that the efficacy of cisplatin is reduced by the NAC when the two agents are administered concurrently. Our study was designed to circumvent this concern by administering NAC long after the cisplatin treatments have ended. Thus we could determine if the delayed administration of NAC could reverse the ototoxic effect of cisplatin, possibly without affecting the efficacy of cisplatin. In our study, guinea pigs were administered a course of cisplatin treatments. NAC was then administered 30 days after the completion of the cisplatin treatments. Auditory brainstem responses were used to determine hearing loss. A redox probe was used to measure the intracochlear oxidative states in vivo. NAC did not reverse the ototoxicity of cisplatin and was found to not change the intracochlear oxidative state. The results of this study suggest the possibility of a tolerance to the effect of systemically administered antioxidants.