Aminoguanidine reduces cisplatin ototoxicity

Cisplatin is known to cause high-frequency neurosensory hearing loss. While reactive oxygen species have been shown to play a role, reactive nitrogen species have been implicated, but not proven to be involved, in cisplatin ototoxicity. The purpose of the present study was to investigate the role of nitric oxide (*NO) in cisplatin ototoxicity by administering aminoguanidine (AG), a relatively specific inhibitor of inducible nitric oxide synthase (iNOS), in conjunction with cisplatin. Rats were injected with cisplatin, AG, or both. Auditory brainstem evoked responses (ABR) were measured before and 3 days after cisplatin administration. The cochlear tissue was then assayed for *NO and malondialdehyde. Cisplatin alone caused significant ABR threshold shifts at all stimuli tested, whereas AG alone caused no shifts. There was a significant reduction in threshold shift for clicks and 16 kHz tone bursts (but not 32 kHz) when AG was given with cisplatin. The malondialdehyde concentration (but not the *NO concentration) in the AG/cisplatin group was significantly lower than that of the cisplatin group. This suggests that AG reduces cisplatin ototoxicity by directly scavenging hydroxyl radicals. The iNOS pathway may play a role in the generation of free radicals and hearing loss resulting from cisplatin administration, but this conclusion was not supported by our data.