Ototoxicity. Amelioration by protective agents

The findings of studies from this laboratory are summarized to compare the efficacy of four chemoprotective agents against the effects of cisplatin-induced hearing loss and biochemical damage in the rat cochlea. A number of studies have shown that cisplatin is ototoxic, resulting in hearing loss, morphologic damage, and biochemical changes in the cochlea. These studies used Wistar rats, which underwent pre- and posttreatment ABR testing using clicks and tonebursts stimuli at 8, 16, and 32 kHz. Controls received i.p. saline injection. Cisplatin-treated rats were given 16 mg/kg cisplatin i.p. Animals received protective agents in the following dosage: DDTC protected rats received 600 mg/kg subcutaneously an hour after cisplatin. MTBA-protected animals were given 250 mg/kg i.p. 30 minutes before cisplatin. Animals protected with ebselen received 16 mg/kg i.p. an hour before cisplatin. One hundred mg/kg of alpha-lipoic acid was injected i.p. 30 minutes before cisplatin. Rats were sacrificed three days after treatment and the cochleae were harvested and frozen in liquid nitrogen and stored at -80 degrees C until analysis of glutathione (GSH), the activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase) and malondialdehyde was performed. Cisplatin-treated rats were found to have ABR threshold shifts of 27-40 dB, and rats treated with chemoprotective agents plus cisplatin all had ABR thresholds shifts of less than 10 dB. Significant depletion of glutathione and decrease of the activities of the antioxidant enzymes were observed in cisplatin-treated rats. These changes were accompanied by a marked elevation of malondialdehyde. These changes were almost completely prevented by the use of the chemoprotective agents. These findings suggest that cisplatin ototoxicity is related to lipid peroxidation and that the use of protective agents prevents hearing loss and lipid peroxidation by sparing the antioxidant defense system in the cochlea.