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.