Ototoxicity. Amelioration by protective agents

Area of Science:

• Ototoxicity research
• Biochemistry
• Pharmacology

Background:

• Cisplatin is a widely used chemotherapy agent.
• Cisplatin administration can lead to ototoxicity, manifesting as hearing loss and cochlear damage.
• The underlying mechanisms of cisplatin-induced ototoxicity involve oxidative stress and biochemical alterations in the cochlea.

Purpose of the Study:

• To evaluate the efficacy of four chemoprotective agents in preventing cisplatin-induced ototoxicity in a rat model.
• To compare the protective effects of DDTC, MTBA, ebselen, and alpha-lipoic acid against cisplatin's damaging effects on the cochlea.
• To investigate the impact of these agents on cochlear glutathione levels, antioxidant enzyme activities, and lipid peroxidation.

Main Methods:

• Wistar rats were used, with auditory brainstem response (ABR) testing to assess hearing thresholds before and after treatment.
• Cisplatin was administered at a dosage of 16 mg/kg intraperitoneally (i.p.).
• Protective agents (DDTC, MTBA, ebselen, alpha-lipoic acid) were administered at specific dosages and timings relative to cisplatin.
• Cochlear tissues were analyzed for glutathione (GSH), antioxidant enzyme activities (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase), and malondialdehyde levels.

Main Results:

• Cisplatin treatment resulted in significant ABR threshold shifts (27-40 dB), indicating hearing loss.
• Rats co-treated with chemoprotective agents and cisplatin exhibited minimal ABR threshold shifts (<10 dB).
• Cisplatin significantly depleted cochlear glutathione and reduced antioxidant enzyme activities, while increasing malondialdehyde levels.
• The chemoprotective agents largely prevented these biochemical changes, preserving the antioxidant defense system.

Conclusions:

• Cisplatin-induced ototoxicity is strongly linked to lipid peroxidation and oxidative stress within the cochlea.
• The evaluated chemoprotective agents (DDTC, MTBA, ebselen, alpha-lipoic acid) demonstrate significant efficacy in preventing cisplatin-induced hearing loss and cochlear damage.
• These agents protect the cochlea by preserving the endogenous antioxidant defense system and inhibiting lipid peroxidation, offering a promising strategy for mitigating chemotherapy-induced ototoxicity.