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Updated: Aug 16, 2026
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Cisplatin ototoxicity to the rat inner ear: a role for HMG1 and iNOS
Geming Li1, Wei Liu, Dorothy Frenz
1Department of Otolayngology, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461, USA.
Abstract:
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. 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. Our results support a role for HMG1 and iNOS in mechanisms of cisplatin ototoxicity in the rat inner ear.
Insights
High-mobility group 1 (HMG1) protein is upregulated in the rat inner ear following cisplatin chemotherapy, suggesting a role in chemotherapy-induced ototoxicity. This HMG1 increase and associated damage were preventable with l-methionine.
Area of Science:
- Ototoxicity Research
- Molecular Mechanisms of Drug Damage
- Chemotherapy Side Effects
Background:
- Cisplatin chemotherapy can cause significant inner ear damage (ototoxicity).
- The precise mechanisms underlying cisplatin-induced ototoxicity remain largely unknown.
- High-mobility group 1 (HMG1) protein is involved in cisplatin's anti-tumor effects via DNA binding.
Purpose of the Study:
- To investigate the potential role of HMG1 in cisplatin-induced ototoxicity.
- To evaluate the expression patterns and levels of HMG1 in the rat cochlea after cisplatin treatment.
Main Methods:
- Assessed HMG1 protein expression in the spiral ganglion cells of rats treated with cisplatin versus control rats.
- Examined HMG1 expression in kidney and heart tissues to assess specificity.
- Measured levels of inducible nitric oxide synthase (iNOS) post-HMG1 upregulation.
- Investigated the protective effect of l-methionine against HMG1 and iNOS increases.
Main Results:
- Cisplatin treatment markedly upregulated HMG1 protein in rat spiral ganglion cells.
- Increased HMG1 was observed in cisplatin-treated kidneys but not the heart, indicating tissue specificity.
- Inducible nitric oxide synthase (iNOS) levels increased in spiral ganglion cells following HMG1 upregulation.
- Administration of l-methionine prevented the cisplatin-induced increases in both HMG1 and iNOS.
Conclusions:
- Results support a role for HMG1 and iNOS in the mechanisms of cisplatin ototoxicity.
- HMG1 upregulation in the inner ear is a specific response to cisplatin chemotherapy.
- L-methionine demonstrates protective potential against cisplatin-induced inner ear damage mediated by HMG1 and iNOS.
