Co-treatment with melanotan-II,a potent melanocortin,does not protect against cisplatin ototoxicity

Cisplatin, an important chemotherapeutic agent, has severe dose-limiting side effects including peripheral neurotoxicity and ototoxicity. Peripheral neurotoxicity can be delayed or prevented by simultaneous treatment with a class of neuropeptides known as melanocortins. Examples are ORG 2766, alpha-melanocyte stimulating hormone (alpha-MSH) and melanotan-II (MT-II). In albino guinea pigs, our group has found that ORG 2766 and alpha-MSH can also reduce cisplatin-induced ototoxicity. In this study we investigated the possibly protective effects of MT-II upon cisplatin ototoxicity. Guinea pigs, equipped with a permanent round-window electrode for electrocochleography, were treated with cisplatin (1.5 mg/kg/day intraperitoneal) and simultaneously with MT-II (30 or 3 microg/kg/day subcutaneous) or saline until a 40 dB suppression of the compound action potential (CAP) threshold (3 microV criterion) at 8 kHz occurred. This -40 dB criterion was reached after 5-18 days. Thereafter, the treatment was stopped, but electrocochleography was continued for another 4 weeks. The number of days in which the -40 dB criterion was reached in the MT-II co-treated group did not differ from the period in the saline group. Ten days after the end of the treatment a spontaneous recovery of the CAP was observed in all groups and at all frequencies, although it was more pronounced at lower frequencies. Also with respect to recovery, no differences were found between the saline and the MT-II co-treated group. Thus, in contrast with the otoprotective properties of other melanocortins, MT-II has no protective properties against cisplatin-induced ototoxicity, at least not with the doses applied here.