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

描述(申请人提供)：年龄相关性听力损失(老年性耳聋)是最常见的神经退行性疾病，困扰着75岁以上人口的近一半。根据国家老龄委员会的说法，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。目前的治疗方案只有一小部分老年性耳聋患者接受治疗，主要局限于助听器，往往无法恢复最佳听觉功能。我们最近发现，两种阻断T型钙通道的抗癫痫药物曲美地酮和乙硫胺可以有效地改善噪声诱导的小鼠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上都会产生不良的副作用。在这里，我们提出了两个具体的目标，以将我们的发现转化为潜在的人类用途。具体目标1的研究将使我们能够确定乙琥胺及其相关化合物抗老年性耳聋的药效学特性。这些实验将提供构效关系信息，以促进这些化合物抗老年性耳聋的化学优化。这些数据还将解决乙硫胺和相关化合物是否可以在低于药物用作抗惊厥药物时的处方剂量的情况下减轻老年性耳聋。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(乙硫胺或唑尼沙胺)和一种或两种抗氧化剂(维生素C或E)。如果发现了协同效应，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在噪音中的小鼠出现与年龄相关的加速听力损失。治疗后，将使用耳蜗定量组织学分析来识别细胞靶点。一系列行为测试将被用来评估潜在的神经副作用。我们希望这个项目能产生有效缓解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已获美国食品和药物管理局批准的药物的新用途，我们的工作有可能迅速转化为临床实践。总体而言，这个项目代表着一个非同寻常的机会，它将一个多学科团队聚集在一起，以开发有效的基于药物的老年性耳聋干预措施。

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.