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

描述（申请人提供）：老年性听力损失（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。根据美国老龄问题全国委员会的说法，老年性痴呆会导致生活质量下降，会增加悲伤和抑郁等情绪困扰，并导致远离家庭、朋友和社区。目前的治疗方案，只有一小部分老年人老年性耳聋接受，主要局限于助听器，这往往不能恢复最佳的听觉功能。我们最近发现，阻断t型钙通道的两种抗癫痫药物——甲美二酮和乙砜胺，可以有效改善小鼠噪声性和年龄相关性听力损失。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的副作用。在这里，我们提出了两个具体的目标，将我们的发现转化为人类的潜在应用。具体目标1的研究将使我们能够确定乙氧亚胺和相关化合物对老年性痴呆的药效学特性。这些实验将为这些抗老年性衰老化合物的化学优化提供构效关系信息。数据还将说明乙氧亚胺和相关化合物是否可以在低于处方剂量的情况下减轻老年性痴呆，当这些药物被用作抗惊厥药时。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）。如果发现有协同作用，则各剂量

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.