Cisplatin is a highly effective chemotherapeutic agent that is widely used to treat solid organ malignancies. However, serious side effects have been associated with its use, such as bilateral, progressive, irreversible, dose-dependent neurosensory hearing loss. Current evidence indicates that cisplatin triggers the production of reactive oxygen species in target tissues in the inner ear. A variety of agents that protect against cisplatin-induced ototoxicity have been successfully tested in cell culture and animal models. However, many of them interfere with the therapeutic effect of cisplatin, and therefore are not suitable for systemic administration in clinical practice. Consequently, local administration strategies, namely intratympanic administration, have been developed to achieve otoprotection, without reducing the antitumoral effect of cisplatin. While a considerable amount of pre-clinical information is available, clinical data on treatments to prevent cisplatin ototoxicity are only just beginning to appear. This review summarizes clinical and experimental studies of cisplatin ototoxicity, and focuses on understanding its toxicity mechanisms, clinical repercussions and prevention strategies.

Adult male Long-Evans rats (250–350 g) received control vehicles, 3,3′-iminodipropionitrile (IDPN, 400 mg kg⁻¹ day⁻¹), allylnitrile (50 mg kg⁻¹ day⁻¹), cis-crotononitrile (110 mg kg⁻¹ day⁻¹), trans-crotononitrile (250 mg kg⁻¹ day⁻¹), or 2,4-hexadienenitrile (300 mg kg⁻¹ day⁻¹), i.p., for 3 consecutive days. Rats treated with IDPN, allylnitrile, and cis-crotononitrile developed the ECC (excitation with circling and choreiform movements) syndrome, whereas those treated with trans-crotononitrile and hexadienenitrile exhibited a different syndrome, characterized by faltering movements. On quantitative analysis, IDPN, allylnitrile, and cis-crotononitrile induced high scores in a test battery for vestibular dysfunction and hyperactivity in the open field, but they did not significantly decrease stride length. Hexadienenitrile and trans-crotononitrile did not increase the vestibular scores or the locomotor activity, but they caused a marked decrease in stride length; they also decreased holding time on a vertical ladder. In brain and spinal cord tissue from rats exposed to IDPN, allylnitrile, or cis-crotononitrile, Fluoro-Jade B, a selective stain for degenerating neurons, did not reveal any labeling other than that of nerve terminals in the glomeruli of the olfactory bulbs, indicating degeneration of the olfactory mucosa. With the same stain, rats exposed to trans-crotononitrile or hexadienenitrile showed a common pattern of selective neurotoxicity; major targets were the inferior olive and the piriform cortex. Hexadienenitrile did not cause hair cell degeneration in the vestibular and auditory sensory epithelia. Present and previous data indicate that neurotoxic nitriles induce one or the other of two different motor syndromes, through either vestibular hair cell degeneration or neuronal degeneration of the inferior olive.

Several nitriles have been demonstrated to cause hair cell loss in the inner ear of the rat, but the susceptibility of other species to this toxic effect has not been investigated. Adult male Swiss mice were administered (po) control vehicle, cis-crotononitrile (2.75 mmol/kg), or 3,3'-iminodipropionitrile (IDPN, at 8, 16, and 24 mmol/kg), and the changes in vestibular function were assessed by behavioral endpoints. In addition, surface preparations of the vestibular sensory epithelia were examined for hair cell loss using scanning electron microscopy (SEM). IDPN, in a dose-dependent manner, and cis-crotononitrile induced both vestibular dysfunction and loss of hair bundles. Male Dunkin Hartley guinea pigs were administered IDPN (0, 1.6, 2.4, or 3.2 mmol/kg, ip), and their vestibular and auditory sensory epithelia were examined by SEM. The guinea pigs developed behavioral abnormalities indicative of vestibular dysfunction, with more overt effects observed in the animals treated with larger doses, and displayed a dose-dependent loss of hair bundles in both the vestibular and the auditory epithelia. Frogs (Rana perezi) were administered IDPN (0, 16, 24, or 32 mmol/kg, ip), and their sensory epithelia in the inner ear were examined by SEM. IDPN caused behavioral abnormalities indicative of vestibular dysfunction and loss of hair bundles. We conclude that some nitriles are thorough ototoxic compounds affecting hair cells in a wide range of species. This conclusion highlights the potential interest of this toxic effect and offers new animal models in which to decipher its basis.

In the rat utricle, synaptic contacts between hair cells and the nerve fibers arising from the vestibular primary neurons form during the first week after birth. During that period, the sodium-based excitability that characterizes neonate utricle sensory cells is switched off. To investigate whether the establishment of synaptic contacts was responsible for the modulation of the hair cell excitability, we used an organotypic culture of rat utricle in which the setting of synapses was prevented. Under this condition, the voltage-gated sodium current and the underlying action potentials persisted in a large proportion of nonafferented hair cells. We then studied whether impairment of nerve terminals in the utricle of adult rats may also affect hair cell excitability. We induced selective and transient damages of afferent terminals using glutamate excitotoxicityin vivo. The efficiency of the excitotoxic injury was attested by selective swellings of the terminals and underlying altered vestibular behavior. Under this condition, the sodium-based excitability transiently recovered in hair cells. These results indicate that the modulation of hair cell excitability depends on the state of the afferent terminals. In adult utricle hair cells, this property may be essential to set the conditions required for restoration of the sensory network after damage. This is achieved via re-expression of a biological process that occurs during synaptogenesis.