The role of antioxidants in protection from ototoxic drugs.
A number of studies have shown that cisplatin and gentamicin ototoxic effects may result from free radical-mediated damage due to the reduction of antioxidant substances and an increased lipid peroxidation. The authors summarize the results obtained evaluating the auditory and vestibular functions and the inner ear hair cell morphology and survival after administration of antioxidant agents against cisplatin and gentamicin. In the first experiment, albino guinea pigs were treated with gentamicin (100 mg/kg per day, i.m.) alone or gentamicin (100 mg/kg per day, i.m.) plus alpha-tocopherol (100 mg/kg per day, i.m.) for 2 weeks. In a second experiment, albino guinea pigs were injected with cisplatin (2.5 mg/kg per day) or cisplatin (2.5 mg/kg per day) plus tiopronin (300 mg/kg) for 6 days. Electrocochleographic recordings were made from an implanted round window electrode. In all experiments compound action potentials (CAPs) were measured at 2-16 kHz. Changes in cochlear function were characterized as CAP threshold shifts. To evaluate vestibular function, the animals underwent sinusoidal oscillations in the dark about their vertical and longitudinal axes to evoke horizontal and vertical vestibulo-ocular reflexes (VOR). Frequency stimulation parameters ranged from 0.02 to 0.4 Hz and peak-to-peak amplitude was 20 degrees. Morphological changes were analysed by light microscopy and scanning electron microscopy. Both hearing loss and vestibular dysfunction induced by gentamicin were significantly attenuated by alpha-tocopherol. However, tiopronin co-therapy slowed the progression of hearing loss in cisplatin-treated animals and significantly attenuated the final threshold shifts. Cisplatin had little effect on the hair cells of cristae ampullares and maculae. Vestibular function was completely preserved in tiopronin co-treated animals. In conclusion, antioxidants such as alpha-tocopherol or tiopronin interfere with gentamicin and cisplatin damage and this suggests that they may be useful in preventing oto-vestibulotoxicity. Therefore, it is important to develop protective strategies that permit the avoidance of the toxic side effects of these drugs without interfering with their therapeutic effects.
Sergi
B
B
Institute of Otolaryngology, Catholic University of Rome, Italy. carosergi@yahoo.com
Fetoni
A R
AR
Ferraresi
A
A
Troiani
D
D
Azzena
G B
GB
Paludetti
G
G
Maurizi
M
M
D000200:Action Potentials; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000975:Antioxidants / Q000494:pharmacology*; D001300:Audiometry, Evoked Response; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects*; D003051:Cochlea / Q000187:drug effects / Q000473:pathology; D005260:Female; D005839:Gentamicins / Q000008:administration & dosage / Q000009:adverse effects*; D006168:Guinea Pigs; D034381:Hearing Loss / Q000139:chemically induced / Q000517:prevention & control*; D008853:Microscopy; D012027:Reflex, Vestibulo-Ocular / Q000187:drug effects; D008625:Tiopronin / Q000494:pharmacology; D014722:Vestibule, Labyrinth / Q000187:drug effects / Q000473:pathology; D024502:alpha-Tocopherol / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D000975:Antioxidants; D005839:Gentamicins; D008625:Tiopronin; D024502:alpha-Tocopherol; D002945:Cisplatin