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.
Kelly
Thomas C
TC
Southern Illinois University School of Medicine, Department of Surgery, P.O. Box 19638, Springfield, IL 62794-9653, USA.
Whitworth
Craig A
CA
Husain
Kazim
K
Rybak
Leonard P
LP
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001300:Audiometry, Evoked Response; D001309:Auditory Threshold / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005500:Follow-Up Studies; D006146:Guanidines / Q000494:pharmacology*; D006316:Hearing Loss, High-Frequency / Q000139:chemically induced / Q000517:prevention & control; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced / Q000517:prevention & control; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D009569:Nitric Oxide / Q000032:analysis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D009925:Organ of Corti / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D009569:Nitric Oxide; D008315:Malondialdehyde; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D002945:Cisplatin; C004479:pimagedine