AMELIORATION OF PRESBYCUSIS BY BLOCKING T-TYPE CALCIUM CHANNELS WITH ANTIEPILEPT

描述（由申请人提供）：与年龄相关的听力损失（老年性耳聋）是最常见的神经退行性疾病，困扰着近一半 75 岁以上的人口。根据国家老龄化委员会的说法，老年性耳聋会导致生活质量下降，会增加悲伤和抑郁等情绪困扰，并导致远离家人、朋友和社区。目前只有一小部分患有老年性耳聋的老年人接受的治疗方案主要限于助听器，而助听器往往无法恢复最佳听觉功能。我们最近发现曲美二酮和乙舒昔亚胺这两种阻断 T 型钙通道的抗癫痫药物可以有效改善小鼠噪音引起的和与年龄相关的听力损失。不幸的是，这两种药物在用于癫痫预防的剂量下都会引起不良副作用。在这里，我们提出了两个具体目标，将我们的发现转化为人类的潜在用途。具体目标 1 的研究将使我们能够确定乙磺酰亚胺和相关化合物对抗老年性耳聋的药效学特性。这些实验将提供结构-活性关系信息，以促进这些化合物针对老年性耳聋的化学优化。该数据还将说明乙舒酰亚胺和相关化合物在低于药物用作抗惊厥药时的处方剂量时是否可以减轻老年性耳聋。在具体目标 2 中，我们将开发针对钙和自由基途径的联合疗法。联合疗法将包括一种 T 型钙通道抑制剂（乙磺酰亚胺或唑尼沙胺）加上一种或两种抗氧化剂（维生素 C 或 E）。如果发现协同效应，则每种药物的剂量 化合物可以被还原。我们还将测试相同的组合是否可以防止年轻时暴露于噪音的小鼠加速与年龄相关的听力损失。治疗后，将使用耳蜗的定量组织学分析来识别细胞靶点。一系列行为测试将用于评估潜在的神经副作用。我们预计该项目将产生有效减轻老年性耳聋的新药或药物组合。重要的是，由于我们专注于发现美国食品和药物管理局已批准的药物的新用途，因此我们的工作有可能快速转化为临床实践。总体而言，该项目代表了一个非凡的机会，它将多学科团队聚集在一起，旨在开发有效的老年性耳聋药物干预措施。

DESCRIPTION (provided by applicant): Age-related hearing loss (presbycusis) is the most common neurodegenerative disease, afflicting nearly half of the population over 75 years of age. According to the National Council on Aging, presbycusis leads to decreased quality of life, can increase emotional distress such as sadness and depression, and leads to withdrawal from family, friends, and community. Current treatment options, which only a fraction of older adults with presbycusis receive, are primarily limited to hearing aids, which often fail to restore optima auditory function. We recently discovered that trimethadione and ethosuximide, two antiepileptic drugs that block T-type calcium channels, can effectively ameliorate noise-induced and age-related hearing loss in mice. Unfortunately, both drugs cause undesirable side effects at dosages used for epilepsy prophylaxis. Here, we propose two specific aims to translate our findings for potential use in humans. The studies in specific aim 1 will allow us to determine the pharmacodynamic properties of ethosuximide and related compounds against presbycusis. These experiments will provide structure-activity relationship information to facilitate chemical optimization of these compounds against presbycusis. The data will also address whether ethosuximide and related compounds can attenuate presbycusis at dosages lower than those prescribed when the drugs are used as anticonvulsants. In specific aim 2, we will develop combination therapies targeting both calcium and free radical pathways. Combination therapies will include one inhibitor of T-type calcium channels (either ethosuximide or zonisamide) plus one or two antioxidants (vitamin C or E). If a synergistic effect is discovered, the dosage of each compound can be reduced. We will also test whether the same combinations can prevent accelerated age-related hearing loss in mice exposed to noise at a young age. After treatment, quantitative histological analysis of cochleae will be used to identify cellular targets. A batteryof behavioral tests will be used to evaluate potential neurological side effects. We expect this project to result in new drugs or drug combinations that effectively mitigate presbycusis. Importantly, because we focus on the discovery of new uses for drugs already approved by the U.S. Food and Drug Administration, our work has the potential for rapid translation into clinical practice. Overall, this project represents an extraordinary opportunity that brings a multidisciplinary team together for the purpose of developing an effective drug-based intervention for presbycusis.