Eshraghi Adrien A, Roell Jonathan, Shaikh Noah, Telischi Fred F, Bauer Blake, Guardiola Mateo, Bas Esperanza, Van De Water Thomas, Rivera Ileana, Mittal Jeenu
a Department of Otolaryngology , University of Miami Miller School of Medicine , Miami , FL , USA.
Acta Otolaryngol. 2016;136(4):420-4. doi: 10.3109/00016489.2015.1134809. Epub 2016 Feb 6.
Conclusions A cocktail combining NAC, Mannitol, and Dexamethasone may be used to prevent loss of residual hearing post-implantation. There is a window of opportunity to treat the cochlea before the onset of cell death in HCs. Objective Inner ear trauma caused by cochlear implant electrode insertion trauma (EIT) initiates multiple molecular mechanisms in hair cells (HCs) or support cells (SCs), resulting in initiation of programmed cell death within the damaged tissues of the cochlea, which leads to loss of residual hearing. In earlier studies L-N-acetylcysteine (L-NAC), Mannitol, and dexamethasone have been shown independently to protect the HCs loss against different types of inner ear trauma. These three molecules have different otoprotective effects. The goal of this preliminary study is to test the efficacy of a combination of these molecules to enhance the otoprotection of HCs against EIT. Methods OC explants were dissected from P-3 rats and placed in serum-free media. Explants were divided into control and experimental groups.
(1) untreated controls; (2) EIT. Experimental group: (1) EIT + L-NAC (5, 2, or 1 mM); (2) EIT + Mannitol (100, 50, or 10 mM); (3) EIT + Dex (20, 10, or 5 μg/mL); (4) EIT + L-NAC + Mannitol + Dex. After EIT was caused in an in-vitro model of CI, explants were cultured in media containing L-NAC alone, Mannitol alone, or Dex alone at decreasing concentrations. Concentrations of L-NAC, Mannitol, and Dex that showed 50% protection of hair cell loss individually were used as a combination in experimental group 4. Results There was an increase of total hair cell (THC) loss in the EIT OC explants when compared with control group HC counts or the tri-therapy cochlea. This study defined the dosage of L-NAC, Mannitol, and Dex for the survival of 50% protection of hair cells in vitro. Their combination provided close to 96% protection, demonstrating an additive effect.
结论 一种由N-乙酰半胱氨酸（NAC）、甘露醇和地塞米松组成的鸡尾酒疗法可用于预防植入后残余听力丧失。在毛细胞（HCs）发生细胞死亡之前，存在一个治疗耳蜗的时机窗口。目的 人工耳蜗电极插入创伤（EIT）导致的内耳创伤会在毛细胞（HCs）或支持细胞（SCs）中引发多种分子机制，从而在耳蜗受损组织内启动程序性细胞死亡，进而导致残余听力丧失。在早期研究中，已分别证明L-N-乙酰半胱氨酸（L-NAC）、甘露醇和地塞米松可保护HCs免受不同类型内耳创伤的损失。这三种分子具有不同的耳保护作用。本初步研究的目的是测试这些分子组合增强HCs对EIT耳保护作用的疗效。方法 从出生后3天（P-3）的大鼠中解剖出听泡外植体，置于无血清培养基中。将外植体分为对照组和实验组。
（1）未处理的对照组；（2）EIT。实验组：（1）EIT + L-NAC（5、2或1 mM）；（2）EIT + 甘露醇（100、50或10 mM）；（3）EIT + 地塞米松（Dex，20、10或5 μg/mL）；（4）EIT + L-NAC + 甘露醇 + 地塞米松。在人工耳蜗体外模型中造成EIT后，将外植体在分别含有浓度逐渐降低的单独L-NAC、单独甘露醇或单独地塞米松的培养基中培养。在实验组4中，将单独显示对毛细胞损失有50%保护作用的L-NAC、甘露醇和地塞米松浓度用作组合。结果 与对照组毛细胞计数或三联疗法耳蜗相比，EIT听泡外植体中的总毛细胞（THC）损失增加。本研究确定了L-NAC、甘露醇和地塞米松在体外对50%毛细胞存活保护的剂量。它们的组合提供了接近96%的保护，显示出相加效应。
