Systemic co-treatment with α-melanocyte stimulating hormone delays hearing loss caused by local cisplatin administration in guinea pigs

Abstract

It has previously been demonstrated that ototoxicity induced by systemic administration of cisplatin is reduced by concomitant administration of melanocortins, like α-melanocyte stimulating hormone (α-MSH). However, these experiments were hampered by large interanimal variability. Therefore, we re-investigated the effects of systemically administered α-MSH during local (intracochlear) administration of cisplatin. Guinea pigs, implanted with a round-window electrode, allowing daily monitoring of the compound action potentials (CAPs), and a mini-osmotic pump, pumping either 0.5 μl/h physiological saline or cisplatin solution (15 μg/ml), were co-treated daily with a subcutaneous bolus injection of either α-MSH (75 μg/kg) or physiological saline for 1 week or until the electrocochleogram showed a persistent decrease in CAP amplitude (40 dB threshold shift at 8 kHz). Next, the animals were sacrificed and the cochleas were processed for histology. After 2–3 days, cisplatin alone caused a threshold shift at all frequencies (2–16 kHz). Co-administration with α-MSH consistently delayed the criterion threshold shift by 1 day. When the 40 dB criterion had been reached, similar outer hair cell losses in both the cisplatin/α-MSH- and cisplatin/saline-treated groups were observed. This experiment confirms that direct administration of cisplatin into the cochlea results in considerably less interanimal variability than systemic administration and that co-treatment with α-MSH delays cisplatin ototoxicity. Since cisplatin was delivered directly to the cochlea, the ameliorating effect of α-MSH probably involves a cochlear target.