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Updated: May 23, 2026
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Cisplatin-induced ototoxicity is mediated by nitroxidative modification of cochlear proteins characterized by
Samson Jamesdaniel1, Donald Coling, Sneha Hinduja
1Department of Communicative Disorders and Sciences, The State University of New York, Buffalo, New York 14214, USA. sj57@buffalo.edu
Abstract:
Tyrosine nitration is an important sequel of cellular signaling induced by reactive oxygen species. Cisplatin is an anti-neoplastic agent that damages the inner ear through reactive oxygen species and by the formation of DNA adducts. This study reveals a correlation between cisplatin-mediated hearing loss and nitroxidative modification of cochlear proteins and is the first to report nitration of Lmo4. Cisplatin induced a dose-dependent increase in hearing loss in Wistar rats. A 10-15-dB decrease in distortion product amplitude and massive loss of outer hair cells at the basal turn of the cochlea was observed 3 days post-treatment after a 16 mg/kg dose. Cisplatin induced nitration of cellular proteins within the organ of Corti, spiral ganglion, and stria vascularis, which are known targets of cisplatin ototoxicity. Nitration of a 76-kDa cochlear protein correlated with cisplatin dose. The nitrated protein was identified as Lmo4 (LIM domain only 4) by MALDI-TOF (matrix-assisted laser desorption/ionization time of flight) mass spectrometry and confirmed by reciprocal immunoprecipitation and immunoblotting. Co-localization of nitrotyrosine and Lmo4 was particularly high in outer hair cell nuclei after cisplatin treatment. Cochlear levels of Lmo4 were decreased in rats treated with cisplatin. In vitro studies supported the repression of Lmo4 in nitroxidative conditions and the induction of apoptosis upon repression of Lmo4. Inhibition of cochlear protein nitration prevented cisplatin-induced hearing loss. As Lmo4 is a transcriptional regulator that controls the choice between cell survival and cell death, these results support the hypothesis that nitration of Lmo4 influences cisplatin-induced ototoxicity.
Insights
Cisplatin causes hearing loss by nitrating cochlear proteins, including Lmo4 (LIM domain only 4). Inhibiting this nitration prevents ototoxicity, suggesting Lmo4 nitration is key to cisplatin-induced damage.
Area of Science:
- Ototoxicity research
- Cellular signaling
- Biochemistry
Background:
- Cisplatin, an anti-cancer drug, causes hearing loss via reactive oxygen species and DNA damage.
- Tyrosine nitration, a modification of proteins by reactive oxygen species, is linked to cellular signaling.
- The specific mechanisms of cisplatin-induced ototoxicity are not fully understood.
Purpose of the Study:
- To investigate the correlation between cisplatin-induced hearing loss and nitroxidative stress in the cochlea.
- To identify specific cochlear proteins affected by nitration following cisplatin treatment.
- To explore the role of Lmo4 (LIM domain only 4) in cisplatin ototoxicity.
Main Methods:
- Dose-dependent administration of cisplatin to Wistar rats.
- Auditory testing using distortion product otoacoustic emissions.
- Histological analysis of cochlear tissues (organ of Corti, spiral ganglion, stria vascularis).
- Protein identification using MALDI-TOF mass spectrometry, immunoprecipitation, and immunoblotting.
- In vitro studies on Lmo4 repression and apoptosis.
Main Results:
- Cisplatin induced a dose-dependent increase in hearing loss and outer hair cell damage.
- Cisplatin treatment led to increased tyrosine nitration of cochlear proteins, including Lmo4.
- Lmo4 levels decreased in cisplatin-treated rats, and its nitration co-localized with outer hair cell nuclei.
- In vitro, nitroxidative conditions repressed Lmo4, and Lmo4 repression induced apoptosis.
- Inhibition of cochlear protein nitration prevented cisplatin-induced hearing loss.
Conclusions:
- Cisplatin-induced ototoxicity is associated with nitration of cochlear proteins, particularly Lmo4.
- Nitration of Lmo4, a transcriptional regulator, influences the balance between cell survival and death in cochlear cells.
- Targeting protein nitration may offer a strategy to prevent cisplatin-induced hearing loss.
