Cisplatin ototoxicity to the rat inner ear: A role for HMG1 and iNOS

Cisplatin is a chemotherapeutic agent that causes toxic damage to the inner ear (ototoxicity). Although much attention has been directed at identifying ways to protect the inner ear against cisplatin ototoxicity, little is known about the mechanisms by which cisplatin causes damage to the inner ear. Binding of high-mobility group (HMG1) protein to cisplatin-modified DNA participates in mediating the antitumor effects of cisplatin (Ohndorf U-M, Rould MA, He Q, Pabo CO, Lippard SJ. Basis for recognition of cisplatin modified DNA by high-mobility-group proteins. Nature 1999;399:708–12). This study seeks to determine if HMG1 may also participate in the ototoxicity of cisplatin. To address this, patterns and levels of expression of HMG1 have been evaluated in the rat cochlea in response to cisplatin chemotherapy. Our findings demonstrate a marked upregulation of HMG1 protein in the spiral (auditory) ganglion cells of cisplatin-treated rats in comparison to levels of expression of HMG1 in the spiral ganglion cells of untreated control animals. Increased levels of HMG1 were observed in the cisplatin-treated kidney, a peripheral target tissue of cisplatin, but not in the heart, a tissue not typically affected by cisplatin chemotherapy, suggesting HMG1 specificity in cisplatin toxicity. Furthermore, levels of inducible nitric oxide synthase (iNOS), an HMG-regulated enzyme associated with cochlear pathology, are increased in the spiral ganglion cells of cisplatin-treated rats 1 day post the cisplatin-mediated upregulation in HMG1. This increase in HMG1 and iNOS can be prevented in the cochleae of cisplatin-treated rats by administration of l-methionine, an established method of protection against cisplatin ototoxicity (Li G, Frenz DA, Brahmblatt S, Feghali JG, Ruben RJ, Berggren D, et al. Round window membrane delivery of l-methionine provides protection from cisplatin ototoxicity without compromising chemotherapeutic efficacy. NeuroToxicology 2001;22:163–76). Our results support a role for HMG1 and iNOS in mechanisms of cisplatin ototoxicity in the rat inner ear.