Attenuation of aminoglycoside-induced cochlear damage with the metabolic antioxidant alpha-lipoic acid

Free radical generation is increasingly implicated in a variety of patholog ical processes, including drug toxicity. Recently, a number of studies have demonstrated the ability of gentamicin to facilitate the generation of rad ical species both in vivo and in vitro, which suggests that this process pl ays an important role in aminoglycoside-induced ototoxicity. Free radical s cavengers are compounds capable of inactivating free radicals, thereby atte nuating their tissue damaging capacity. In this study we have determined th e ability of the powerful free radical scavenger alpha-lipoic acid (100 mg/ kg/day) to attenuate the cochlear damage induced by a highly ototoxic regim en of the aminoglycoside amikacin (450 mg/kg/day, i.m.). Experiments were c arried out on pigmented guinea pigs initially weighing 200-250 g. Changes i n cochlear function were characterized as shifts in compound action potenti al (CAP) thresholds, estimated every 5 days, by use of chronic indwelling e lectrodes implanted at the round window, vertex, and contralateral mastoid. Results showed that animals receiving alpha-lipoic acid in combination wit h amikacin demonstrated a significantly less severe elevation in CAP thresh olds compared with animals receiving amikacin alone (P < 0.001; t-test). Th ese results provide further evidence of the recently reported intrinsic rol e of free radical generation in aminoglycoside ototoxicity, and highlight a potential clinical therapeutic use of alpha-lipoic acid in the management of patients undergoing aminoglycoside treatment. (C) 1999 Published by Else vier Science B.V. All rights reserved.