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Updated: Jul 9, 2025
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Drug screening identifies aldose reductase as a novel target for treating cisplatin-induced hearing loss
Yaqi Liao1, Huanyu Mao1, Xian Gao1
1Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230031, PR China; NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai, 200031, PR China; ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, PR China.
Abstract:
Cisplatin is a frequently used chemotherapeutic medicine for cancer treatment. Permanent hearing loss is one of the most serious side effects of cisplatin, but there are few FDA-approved medicines to prevent it. We applied high-through screening and target fishing and identified aldose reductase, a key enzyme of the polyol pathway, as a novel target for treating cisplatin ototoxicity. Cisplatin treatment significantly increased the expression level and enzyme activity of aldose reductase in the cochlear sensory epithelium. Genetic knockdown or pharmacological inhibition of aldose reductase showed a significant protective effect on cochlear hair cells. Cisplatin-induced overactivation of aldose reductase led to the decrease of NADPH/NADP+ and GSH/GSSG ratios, as well as the increase of oxidative stress, and contributed to hair cell death. Results of target prediction, molecular docking, and enzyme activity detection further identified that Tiliroside was an effective inhibitor of aldose reductase. Tiliroside was proven to inhibit the enzymatic activity of aldose reductase via competitively interfering with the substrate-binding region. Both Tiliroside and another clinically approved aldose reductase inhibitor, Epalrestat, inhibited cisplatin-induced oxidative stress and subsequent cell death and thus protected hearing function. These findings discovered the role of aldose reductase in the pathogenesis of cisplatin-induced deafness and identified aldose reductase as a new target for the prevention and treatment of hearing loss.
Insights
Cisplatin causes hearing loss by increasing aldose reductase activity. Inhibiting this enzyme with Tiliroside or Epalrestat protects hearing, revealing a new therapeutic target for chemotherapy-induced ototoxicity.
Area of Science:
- Ototoxicity
- Biochemistry
- Pharmacology
Background:
- Cisplatin is a vital chemotherapy drug, but its use is limited by severe ototoxicity, leading to permanent hearing loss.
- Currently, few effective FDA-approved medications exist to prevent cisplatin-induced hearing damage.
Purpose of the Study:
- To identify novel molecular targets for preventing cisplatin ototoxicity.
- To investigate the role of aldose reductase in cisplatin-induced hearing loss.
- To evaluate potential therapeutic inhibitors of aldose reductase for hearing protection.
Main Methods:
- High-throughput screening and target fishing to identify novel drug targets.
- Genetic knockdown and pharmacological inhibition of aldose reductase in cochlear models.
- Biochemical assays to measure enzyme activity, NADPH/NADP+, and GSH/GSSG ratios.
- Molecular docking and enzyme activity assays to identify and validate aldose reductase inhibitors.
- Assessment of hearing function in response to cisplatin and inhibitor treatments.
Main Results:
- Aldose reductase expression and activity significantly increased in the cochlea following cisplatin treatment.
- Inhibiting aldose reductase (genetically or pharmacologically) protected cochlear hair cells from cisplatin-induced damage.
- Cisplatin-induced aldose reductase overactivation disrupted redox balance (NADPH/NADP+, GSH/GSSG) and increased oxidative stress.
- Tiliroside was identified as a novel, competitive inhibitor of aldose reductase.
- Both Tiliroside and Epalrestat mitigated cisplatin-induced oxidative stress, cell death, and protected hearing function.
Conclusions:
- Aldose reductase plays a critical role in the development of cisplatin-induced hearing loss.
- Targeting aldose reductase presents a promising therapeutic strategy for preventing and treating chemotherapy-induced ototoxicity.
- Tiliroside and Epalrestat demonstrate potential as protective agents against cisplatin-induced deafness.
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