Hamers Frank P T, Wijbenga Jeroen, Wolters Francisca L C, Klis Sjaak F L, Sluyter Steven, Smoorenburg Guido F
Hearing Research Laboratories, Department of Oto-Rhino-Laryngology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
Audiol Neurootol. 2003 Nov-Dec;8(6):305-15. doi: 10.1159/000073515.
It has been shown that alphaMSH and the nonmelanotropic ACTH/MSH(4-9) analog ORG 2766 can ameliorate cisplatin-induced neurotoxicity and ototoxicity. Here, we investigated whether these peptides delay the occurrence of the cisplatin-induced shift in auditory threshold, and whether they affect the subsequent recovery of cochlear potentials. Chronically implanted round window electrodes were used to obtain daily recordings of auditory nerve compound action potentials (CAP) and cochlear microphonics at frequencies ranging from 2 to 16 kHz. Cisplatin (1.5 mg/kg i.p.) plus alphaMSH, ORG 2766 (75 mug/kg s.c.), or saline were injected daily until the 40-dB CAP threshold shift at 8 kHz was reached. Endocochlear potential (EP) was measured either 1-2 days or 28 days later, followed by morphometric analysis of the cochlea. Peptide cotreatment did not consistently delay the threshold shift; however, the CAP threshold recovered faster and to a greater extent, with the potency order being alphaMSH > ORG 2766 > saline. Significant recovery at the 2 highest frequencies was seen in the alphaMSH-treated animals only. CAP amplitude at high sound pressures, which depends more on nerve function than on outer hair cell (OHC) function, decreased severely in all groups but recovered significantly in the alphaMSH- and completely in the ORG-2766-cotreated group. EP was significantly lower in the first days after the threshold shift but had completely recovered at 28 days. Morphometric analysis of the spiral ganglion also indicated involvement of ganglion cells. OHC loss was most severe in the basal turn of saline-cotreated animals. These data suggest that the cisplatin-induced acute threshold shift might be due to reversible strial failure, whereas subsequent OHC survival determines the final degree of functional recovery. Both OHC loss and neuronal function were ameliorated by peptide cotreatment.
已表明α - 促黑素（alphaMSH）和非促黑素皮质激素/促黑素（4 - 9）类似物ORG 2766可改善顺铂诱导的神经毒性和耳毒性。在此，我们研究了这些肽是否能延迟顺铂诱导的听觉阈值变化的发生，以及它们是否影响随后耳蜗电位的恢复。使用长期植入的圆窗电极，每天记录2至16 kHz频率范围内的听神经复合动作电位（CAP）和耳蜗微音电位。每天腹腔注射顺铂（1.5 mg/kg）加α - 促黑素、ORG 2766（75 μg/kg皮下注射）或生理盐水，直至达到8 kHz处40 dB的CAP阈值变化。在1 - 2天或28天后测量内淋巴电位（EP），随后对耳蜗进行形态计量分析。肽联合治疗并未始终延迟阈值变化；然而，CAP阈值恢复得更快且程度更大，效力顺序为α - 促黑素> ORG 2766>生理盐水。仅在α - 促黑素治疗的动物中，在2个最高频率处观察到显著恢复。高声压下的CAP幅度在所有组中均严重降低，其更多依赖于神经功能而非外毛细胞（OHC）功能，但在α - 促黑素联合治疗组中显著恢复，在ORG - 2766联合治疗组中完全恢复。阈值变化后的头几天，EP显著降低，但在28天时已完全恢复。螺旋神经节的形态计量分析也表明神经节细胞受累。在生理盐水联合治疗的动物中，OHC损失在蜗底最为严重。这些数据表明，顺铂诱导的急性阈值变化可能是由于可逆的血管纹功能衰竭，而随后的OHC存活决定了功能恢复的最终程度。肽联合治疗改善了OHC损失和神经元功能。
