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

通过抗癫痫药阻断 T 型钙通道来改善老年性耳聋

• 批准号: 8675828
• 负责人: Jianxin Bao
• 金额: $ 32.22万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675828
• 关键词: Address; Adverse effects; Affect; Aftercare; Age; Age-Years; Aging; Anticonvulsants; Antiepileptic Agents; Antioxidants; Arthritis; Ascorbic Acid; Attenuated; Auditory; Behavior; Behavioral; CBA/CaJ Mouse; Calcium; Calcium Channel Blockers; Cavia; Centers for Disease Control and Prevention (U.S.); Chemical Structure; Chemicals; Cochlea; Combined Modality Therapy; Communities; Complex; Data; Depressed mood; Development; Disease; Dose; Drug Combinations; Drug Kinetics; Drug usage; Ear; Elderly; Epilepsy; Equation; Ethosuximide; Family; Free Radicals; Friends; Future; Genetic; Hearing Aids; Human; Incidence; Intervention; Investigational New Drug Application; Link; Medical; Mental Depression; Methods; Modeling; Molecular; Mus; Neurodegenerative Disorders; Neurologic; New Agents; Noise; Noise-Induced Hearing Loss; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Population; Presbycusis; Prevalence; Prevention strategy; Property; Prophylactic treatment; Publishing; Quality of life; Research; Scientist; Severities; Societies; Structure; Structure-Activity Relationship; Succinimides; T-Type Calcium Channels; Testing; Therapeutic; Translating; Translations; Trimethadione; United States Food and Drug Administration; Vitamin E; Withdrawal; Work; anti aging; base; behavior test; cellular targeting; clinical practice; dosage; effective therapy; emotional distress; indexing; inhibitor/antagonist; mouse model; multidisciplinary; novel; pre-clinical; prevent; prophylactic; research study

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.

描述（由申请人提供）：听力损失（老年性耳聋）是最常见的神经退行性疾病，困扰着近一半的75岁以上的人口。根据全国老龄问题理事会的说法，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，并导致远离家庭、朋友和社区。目前的治疗选择，只有一小部分老年人接受，主要限于助听器，这往往无法恢复最佳的听觉功能。我们最近发现，曲美双酮和乙琥胺，两种抗癫痫药物，阻断T型钙通道，可以有效地改善小鼠噪声诱导的和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的目标，将我们的发现转化为人类的潜在用途。具体目标1中的研究将使我们能够确定乙琥胺和相关化合物对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聋的化学优化。数据还将说明乙琥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耳聋，当这些药物用作抗惊厥药时。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。联合治疗将包括一种T型钙通道抑制剂（乙琥胺或唑尼沙胺）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 化合物可以减少。我们还将测试相同的组合是否可以防止在年轻时暴露于噪音的小鼠中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鉴定细胞靶点。一系列的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新的药物或药物组合，有效地减轻老年性耳聋。重要的是，由于我们专注于发现美国食品和药物管理局已经批准的药物的新用途，我们的工作有可能快速转化为临床实践。总的来说，这个项目代表了一个非凡的机会，它将一个多学科团队聚集在一起，以开发一种有效的基于药物的老年性耳聋干预措施。