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Gentamicin, acting as an iron chelator, activates membrane lipid peroxidation (MPL) and induces free radical formation, as observed in vitro and in vivo. Antioxidants, such as alpha-tocopherol, are able to suppress MLP, thus attenuating tissue damage. The present study was designed to investigate the possible protective effects of alpha-tocopherol on gentamicin ototoxicity. The study was carried out on albino guinea pigs (250-350 g). The animals were divided into four groups: group A (n = 4), injected with corn oil daily at a dose of 100 mg/kg body weight intramuscularly (IM); group B (n = 10), treated with corn oil at a dose of 100 mg/kg body weight and gentamicin base at a dose of 100 mg/kg body weight (IM); group C (n = 10). treated with gentamicin alone at a dose of 100 mg/kg body weight (IM); and group D (n = 10), treated with gentamicin at the same dose plus alpha-tocopherol acetate at dose of 100 mg/kg body weight (IM). Electrocochleographic recordings were made from an implanted round-window electrode. All animals were treated for 14 days. The compound action potentials (CAPs) were measured at 2-16 kHz at days 0, 10, 14 and 18 after treatment. Changes in cochlear function were characterized as CAP threshold shifts. Morphological changes were analysed by scanning electron microscopy. Gentamicin induced progressive high-frequency hearing loss of 50-60 dB SPL. alpha-Tocopherol co-therapy slowed the progression of hearing loss. The significant loss of outer hair cells (OHCs) in the cochlear basal turn in gentamicin-treated animals was not observed in the cochleas of animals protected with alpha-tocopherol. This study supports the hypothesis that alpha-tocopherol interferes with gentamicin-induced free radical formation, and suggests that this drug may be useful in protecting OHC function from aminoglycoside ototoxicity, thus reducing hearing loss.

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.

The purpose of this study was to evaluate cisplatin-induced ototoxicity and the protective effects of tiopronin. Twenty-four adult Wistar rats served as subjects and were divided into three groups. Eight rats receiving only saline (group A) were used as controls. Eight rats received cisplatin (2 mg/kg) injections (group B) and eight rats received cisplatin and tiopronin (300 mg/kg) (group C) for 8 consecutive days. Both ears of all animals were tested by DPOAE before treatment and on the 4th and 9th days. Seventy-two hours after the final recording session, all animals were killed, and the left cochleas were prepared for electron microscopy and analysed. DPOAE responses were significantly reduced in group B compared to controls (p

The aim of the present study was to investigate both vestibular and cochlear cisplatin toxicity. Twelve albino guinea pigs were divided into an experimental (n=8) and a control saline group (n=4) and were treated with cisplatin at a daily dose of 2.5 mg/kg for 6 consecutive days. Vestibular dysfunction was evaluated by computing the gain of the vestibular ocular reflex (VOR) evoked by stimulation in the horizontal (HVOR) and vertical (VVOR) planes. Changes in cochlear function were characterised as compound action potential threshold shifts. After the functional testing, tympanic bullae were removed and processed for morphological examination of the sensorineural epithelium. The onset of vestibular functional impairment was observed on the third day, although the VOR gain decrease was not significant. The impairment of the vestibular function progressed until the sixth day becoming statistically significant particularly at VVOR mid frequencies of stimulation. At these frequencies both macula and crista ampullaris functions are involved. Concomitantly a progressive auditory threshold shift was observed at all stimulus frequencies. The decline of the auditory function was statistically significant from the third day of treatment and it was more evident at high frequencies. Morphological observations showed a massive loss of outer hair cells and a degeneration of the organ of Corti in the basal/middle turns and only a slight loss of hair cells of the cristae ampullares and maculae. In conclusion, functional and morphological data provide evidence that the toxic effect of cisplatin is more pronounced in the organ of Corti than in the vestibular epithelium.