The protective effect of melanocortins on cisplatin-induced hearing loss

Abstract

Cisplatin is widely used for the treatment of a variety of tumors. Unfortunately, the therapeutic effect of cisplatin is limited because patients can develop a high frequency hearing loss in both ears. Recovery of this hearing loss is observed sporadically. Animal studies have shown that chronic cisplatin administration leads to loss of outer hair cells (OHCs) in the inner ear (cochlea), with those in the basal turn most severely affected. Furthermore, cisplatin also damages the cells of the stria vascularis and the spiral ganglion. Nowadays several groups of protective compounds have been found that have beneficial effects upon cisplatin-induced hearing loss. Melanocortins, which include the endogenous peptide ?-melanocyte stimulating hormone (?-MSH) and the synthetic analogue ORG2766, have shown to be able to partially prevent cisplatin-induced ototoxicity. However, the exact mechanism of the protective effect of the melanocortins is still unclear. The aim of my thesis was to characterize the protective effect of the melanocortins ?-MSH, ORG 2766 and a new synthetic melanocortin melanotan-II (MT-II). First guinea pigs were implanted with a permanent electrode for measuring the electrocochleograms and injected with cisplatin and one of the melanocortins or saline (control) until a threshold loss of 40 dB at 8 kHz was observed. Next both treatments were terminated but the electrocochleography measurements were continued for another 14 days to study the recovery. These experiments showed that both ?-MSH and ORG 2766 are able to protect the inner ear from cisplatin-induced hearing loss. MT-II did not show an effect. Furthermore it was shown that treatment with the melanocortins partly prevented the damage to the OHCs. Unfortunately, these experiments showed large variations between the treated animals. Therefore we introduced a new animal model in which both an electrode and a mini-osmotic pump were attached to the cochlea. First cisplatin was applied directly into the cochlea by means of the osmotic pump system and ?-MSH was administered systemically. Subsequently an experiment with a mirrored experimental design was executed, in which ?-MSH was applied directly into the cochlea and cisplatin systemically. Also in both these experiments a protective effect of ?-MSH was observed. Since cisplatin was administered through a different route than ?-MSH (local versus systemic) it can be assumed that the protective effect of ?-MSH is not caused through a direct interaction of ?-MSH with cisplatin, but that ?-MSH induces its effects directly in the inner ear. If ?-MSH would have had a direct interaction with cisplatin or a systemic effect, such as induced clearance, it would decrease the antineoplastic effect of cisplatin and thereby undermine the clinical relevance. The results in this thesis also show that the protective effects of ?-MSH and other melanocortins are rather small and vary considerably between individuals. This hampers the introduction of melanocortins as an otoprotective agent in patients. However, improvement of the effect of melanocortins by optimizing the treatment cannot be excluded. Summarizing, the research performed in this thesis brought us a step closer to the prevention of cisplatin-induced ototoxicity. Furthermore we learned more about the apparently very complex mechanism of the toxic effects of cisplatin in the inner ear