Heijmen P S, Klis S F, De Groot J C, Smoorenburg G F
Department of Otorhinolaryngology, University Hospital Utrecht, The Netherlands.
Hear Res. 1999 Feb;128(1-2):27-39. doi: 10.1016/s0378-5955(98)00194-4.
It is known that adrenocorticotrophic hormone (ACTH)-derived peptides, the so-called melanocortins, can reduce cisplatin-induced neurotoxicity. Recently, our group has found that cisplatin-induced ototoxicity can also be reduced or prevented by treatment with the synthetic melanocortin-like peptide, ORG 2766 (Hamers et al., 1994; De Groot et al., 1997). The present study was designed to investigate the possibly ameliorating effects of the physiologically more relevant naturally occurring neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) upon cisplatin ototoxicity and to compare its protective effects to those of ORG 2766. For eight consecutive days guinea pigs were treated with cisplatin at a concentration of either 1.5 mg/kg/day or 2 mg/kg/day. Animals were co-treated with either alpha-MSH (75 microg/kg/day), ORG 2766 (75 microg/kg/day), or a sham injection containing physiological saline. Electrocochleography and hair cell counts were performed. Treatment with 1.5 mg/kg/day cisplatin resulted in a large variability of the morphological and electrophysiological data, a variability that might have masked possible effects of ORG 2766 and alpha-MSH. Treatment with 2 mg/kg/day cisplatin caused less variable, severe reductions in the compound action potentials and cochlear microphonics combined with basal and middle-turn outer hair cell loss in five out of six animals. However, in the alpha-MSH co-treated groups, two out of six animals could be classified as normal, two animals as moderately affected and two animals as severely affected. In the ORG 2766 co-treated group we found three animals that were not affected and three animals that were severely affected. We conclude that the protective effects of alpha-MSH and ORG 2766 co-treatment are comparable and that alpha-MSH might be clinically useful in protecting against cisplatin-induced ototoxicity.
已知促肾上腺皮质激素（ACTH）衍生肽，即所谓的促黑素细胞激素，可降低顺铂诱导的神经毒性。最近，我们小组发现，用合成的促黑素细胞激素样肽ORG 2766治疗也可降低或预防顺铂诱导的耳毒性（哈默斯等人，1994年；德格鲁特等人，1997年）。本研究旨在调查生理上更相关的天然存在的神经肽α-黑素细胞刺激素（α-MSH）对顺铂耳毒性可能的改善作用，并将其保护作用与ORG 2766的保护作用进行比较。连续八天，豚鼠以1.5毫克/千克/天或2毫克/千克/天的浓度接受顺铂治疗。动物同时接受α-MSH（75微克/千克/天）、ORG 2766（75微克/千克/天）或含有生理盐水的假注射治疗。进行了耳蜗电图和毛细胞计数。以1.5毫克/千克/天的顺铂治疗导致形态学和电生理学数据的巨大变异性，这种变异性可能掩盖了ORG 2766和α-MSH的可能作用。以2毫克/千克/天的顺铂治疗导致复合动作电位和耳蜗微音电位的变异性较小，但严重降低，并且六只动物中有五只出现基底和中回外毛细胞损失。然而，在α-MSH联合治疗组中，六只动物中有两只可归类为正常，两只动物为中度受影响，两只动物为重度受影响。在ORG 2766联合治疗组中，我们发现三只动物未受影响，三只动物重度受影响。我们得出结论，α-MSH和ORG 2766联合治疗的保护作用相当，并且α-MSH在预防顺铂诱导的耳毒性方面可能具有临床应用价值。
