title: Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model.
abstract: Cisplatin (CDDP) is a widely used chemotherapeutic agent that is highly ototoxic. Animal studies and clinical trials have shown that thiosulfates can protect against platinum-induced ototoxicity. This study investigated a new model for CDDP ototoxicity in the rat, and tested the potential chemoprotective effect of administering N-acetylcysteine (NAC) before giving CDDP. Long Evans rats were treated with CDDP 6 mg/kg delivered to the aorta via a retrograde right external carotid artery infusion, 15 min after intravenous (IV) infusion of saline (n=8) or NAC 400 mg/kg (n=8), such that the vertebral arteries were perfused. Subsequent groups were similarly treated with NAC 30 min before (n=7) and 4 h after (n=7) CDDP. Auditory brainstem response (ABR) thresholds were tested at 4-20 kHz, 7 days after treatment and compared to baseline ABR values. The NAC-treated rats exhibited no significant change from baseline values at all time intervals, while the saline-treated rats showed marked ototoxicity, especially at higher frequencies. Furthermore, the rats treated with NAC 15 min before CDDP exhibited less overall toxicity to CDDP, as evidenced in weight loss 7 days post-treatment (mean for saline=-39.63 g; mean for NAC=-21.13 g; p=0.0084). These data show that treatment with NAC can prevent CDDP-induced ototoxicity in rats.
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland, OR 97201-3098, USA.
authors.forename: D
authors.initials: D
authors.lastname: Thomas Dickey
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Muldoon
authors.forename: Dale F
authors.initials: DF
authors.lastname: Kraemer
authors.forename: Edward A
authors.initials: EA
authors.lastname: Neuwelt
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000506:poisoning*; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000506:poisoning*; D004334:Drug Administration Schedule; D004427:Ear Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D034381:Hearing Loss / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D000111:Acetylcysteine