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Updated: May 22, 2026
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
siRNA-mediated knock-down of NOX3: therapy for hearing loss?
Leonard P Rybak1, Debashree Mukherjea, Sarvesh Jajoo
1Department of Surgery, Division of Otolaryngology, Southern Illinois University, School of Medicine, Springfield, IL 62794-9649, USA. lrybak@sumed.edu
Abstract:
Cisplatin is a widely used chemotherapeutic agent that causes significant hearing loss. Previous studies have shown that cisplatin exposure is associated with increase in reactive oxygen species (ROS) in the cochlea. The inner ear expresses a unique isoform of NADPH oxidase, NOX3. This enzyme may be the primary source of ROS generation in the cochlea. The knockdown of NOX3 by pretreatment with siRNA prevented cisplatin ototoxicity, as demonstrated by preservation of hearing thresholds and inner ear sensory cells. Trans-tympanic NOX3 siRNA reduced the expression of NOX3 and biomarkers of cochlear damage, including transient receptor vanilloid 1 (TRPV1) channel and kidney injury molecule-1 (KIM-1) in cochlear tissues. In addition, siRNA against NOX3 reduced apoptosis as demonstrated by TUNEL staining, and prevented the increased expression of Bax and abrogated the decrease in Bcl2 expression following cisplatin administration. Trans-tympanic administration of siRNA directed against NOX3 may provide a useful method of attenuating cisplatin ototoxicity. In this paper, we review recent publications dealing with the role of NOX3 in ototoxicity and the effects of siRNA against cisplatin-induced hearing loss.
Insights
Cisplatin causes hearing loss by increasing reactive oxygen species (ROS). Targeting NOX3 with siRNA protected against cisplatin ototoxicity, preserving hearing and cochlear cells.
Area of Science:
- Ototoxicity research
- Molecular biology
- Pharmacology
Background:
- Cisplatin chemotherapy can cause significant hearing loss.
- Reactive oxygen species (ROS) are implicated in cisplatin-induced cochlear damage.
- NADPH oxidase 3 (NOX3) is a key enzyme in ROS generation in the inner ear.
Purpose of the Study:
- To investigate the role of NOX3 in cisplatin ototoxicity.
- To evaluate the efficacy of NOX3 knockdown using small interfering RNA (siRNA) in preventing cisplatin-induced hearing loss.
Main Methods:
- Trans-tympanic administration of NOX3-targeting siRNA in a cisplatin ototoxicity model.
- Assessment of hearing thresholds, inner ear sensory cell survival, and cochlear tissue biomarkers.
- Evaluation of apoptosis markers (TUNEL, Bax, Bcl2) and NOX3 expression.
Main Results:
- NOX3 siRNA pretreatment preserved hearing thresholds and inner ear sensory cells.
- NOX3 knockdown reduced NOX3 expression and cochlear damage biomarkers (TRPV1, KIM-1).
- siRNA against NOX3 attenuated apoptosis and modulated apoptosis-related proteins (Bax, Bcl2).
Conclusions:
- NOX3 plays a critical role in cisplatin-induced ototoxicity.
- Trans-tympanic NOX3 siRNA administration is a potential therapeutic strategy to mitigate cisplatin-induced hearing loss.
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