Division of Otolaryngology-Head and Neck Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania Health System, Philadelphia, Pennsylvania.
Otol Neurotol. 2020 Jan;41(1):115-122. doi: 10.1097/MAO.0000000000002417.
Local administration of the calcium-channel blocker (CCB), diltiazem, via intratympanic (IT) chitosan-glycerophosphate (CGP) hydrogel will protect against cisplatin-induced ototoxicity.
Cisplatin induces calcium-mediated apoptosis of cochlear outer hair cells (OHCs). Previous work demonstrated otoprotection and reduced auditory brainstem response (ABR) threshold shifts in a cisplatin-induced ototoxicity mouse model treated with multiple doses of IT diltiazem given in solution. Here, we evaluated the role of a single dose of IT CGP-diltiazem as a novel otoprotectant against cisplatin-induced ototoxicity.
Baseline pure-tone and click-evoked ABRs were performed in control (IT CGP-saline, n = 13) and treatment (IT CGP-diltiazem 2 mg/kg, n = 9) groups of female CBA/J mice. A single dose of IT CGP hydrogel was administered just before intraperitoneal injection of cisplatin (14 mg/kg). On Day 7 posttreatment, ABRs were performed and cochleae were harvested. Hair cells were quantified using anti-myosin VIIa immunostaining and inner hair cell ribbon synapses were quantified using Ctbp2 immunostaining.
There was a statistically significant effect of treatment on click- and tone-evoked ABRs between groups. The mean threshold shifts were significantly reduced in both click- and tone-evoked ABRs on Day 7 in IT CGP-diltiazem treated mice compared with CGP-saline control mice. There were no significant differences in OHC counting between groups, but there appears to be an otoprotection against loss of synapses in the apical turn from IT CGP-diltiazem treated mice (p < 0.05).
This preliminary work suggests that IT CGP-diltiazem reduces ABR threshold shifts with possible mechanisms of protecting ribbon synapses in the setting of cisplatin-induced ototoxicity. More work is necessary to determine the mechanism underlying this otoprotection.
通过鼓室内（IT）壳聚糖-甘油磷酸（CGP）水凝胶局部给予钙通道阻滞剂（CCB）地尔硫卓，将预防顺铂引起的耳毒性。
顺铂诱导耳蜗外毛细胞（OHC）的钙介导凋亡。以前的工作表明，在顺铂诱导的耳毒性小鼠模型中，多次给予 IT 地尔硫卓溶液可减轻耳毒性并降低听脑干反应（ABR）阈值变化。在这里，我们评估了单次 IT CGP-地尔硫卓给药作为一种新型顺铂诱导耳毒性保护剂的作用。
在雌性 CBA/J 小鼠的对照组（IT CGP-生理盐水，n=13）和治疗组（IT CGP-地尔硫卓 2mg/kg，n=9）中进行了纯音和 click-evoked ABR 基线测试。在腹腔注射顺铂（14mg/kg）之前，给予单次 IT CGP 水凝胶。在治疗后第 7 天，进行 ABR 测试并收获耳蜗。使用抗肌球蛋白 VIIa 免疫染色来量化毛细胞，使用 Ctbp2 免疫染色来量化内毛细胞带状突触。
治疗组之间在 click 和 tone-evoked ABR 上有统计学上显著的影响。与 CGP 生理盐水对照组相比，在 IT CGP-地尔硫卓治疗组的 click 和 tone-evoked ABR 中，第 7 天的平均阈值变化明显降低。各组之间的毛细胞计数没有显著差异，但 IT CGP-地尔硫卓治疗组的顶端 turn 中似乎存在对突触丢失的保护作用（p<0.05）。
这项初步工作表明，IT CGP-地尔硫卓降低了 ABR 阈值变化，其机制可能是在顺铂诱导的耳毒性中保护带状突触。需要进一步的工作来确定这种耳保护作用的机制。
