MECHANISM OF CISPLATIN OTOTOXICITY - ANTIOXIDANT SYSTEM

The dose and duration limiting toxic effects of cisplatin are ototoxic ity and nephrotoxicity. While several studies have attempted to shed s ome light on the causes of nephrotoxicity, the reasons for ototoxicity induced by cisplatin are poorly understood. Therefore, this investiga tion was undertaken to delineate the potential mechanisms underlying c isplatin ototoxicity. The role of glutathione (GSH), oxidized glutathi one (GSSG) and malondialdehyde levels, and antioxidant enzyme activiti es [superoxide dismutase, catalase, GSH peroxidase, and GSH reductase] were examined in cochlear toxicity following an acute dose of cisplat in. Male Wistar rats were treated with various doses of cisplatin. Pre treatment auditory brain stem evoked responses (ABR) were performed an d then post-treatment ABRs and endocochlear potentials were also perfo rmed after three days. Acute cochlear toxicity (ototoxicity) was evide nced as elevated hearing thresholds and prolonged wave I latencies in response to various stimuli (clicks and tone bursts at 2, 8, 16 and 32 kHz) on ABRs. The endocochlear potentials were reduced (50% control) in cisplatin-treated rats as compared to control animals. The rats wer e sacrified and cochleae isolated. The GSH, GSSG and malondialdehyde l evels, and antioxidant enzyme activities were determined. Cisplatin ot otoxicity correlated with a decrease in cochlear GSH [0.45+/-0.012 nmo l/mg] after cisplatin administration compared to 0.95+/-012 nmol/mg in control cochleae (P<0.05). Superoxide dismutase, catalase activities and malondialehyde levels were significantly increased in the cochleae of cisplatin injected rats. Cochlear GSH-peroxidase and GSH reductase activity significantly decreased after cisplatin administration. Alte rations in the activity of antioxidant enzymes, an increase in malondi aldehyde levels, and depletion of cochlear GSH suggest a role for reac tive oxygen species mediated damage of the cochlea in cisplatin toxici ty. These biochemical changes were accompanied by the elevation of ABR threshold that appears to correlate well with alterations in antioxid ant systems which could be the cause of cisplatin ototoxicity.