Targeting multiple signaling pathways for tinnitus prevention and treatment

耳鸣是一种常见的耳鸣现象，也是耳鸣的一种表现形式。 全世界数百万人的生活质量。尽管对补救措施的需求很大， 没有FDA批准的药物来预防或治疗耳鸣。耳鸣的原因有哪些 复杂目前的观点是中枢听觉神经系统的过度活跃 耳鸣的症状有哪些？这种异常的电活动，包括 δ-带活动增加，可能是T-型钙增加的直接结果。 渠道活动。其他研究表明，大脑内的炎症反应可能 参与耳鸣的发展和持续;因此，候选药物 同时靶向炎症和钙信号传导途径可能协同作用， 预防和治疗耳鸣。汉防己甲素（泰特）是一种在中国获批使用的药物， 抗炎和钙通道阻断特性。使用新的耳鸣 检测方法在小鼠中，我们已经表明，无论是水杨酸诱导和噪声诱导 泰特可以以剂量依赖性方式有效治疗耳鸣。我们的假设 是泰特或其化学类似物可以被开发为预防和治疗 耳鸣在我们提出的实验中，我们有两个平行的目标：（1）获得 泰特（Aim）的研究性新药（IND）毒性和药代动力学数据 1)（2）通过构效关系研究优化第二代产品 泰特及其化学类似物（目的2）。目标1的成功实现将使 泰特进入临床开发阶段。此外，目标2的研究将使我们能够 在临床阶段泰特失败的情况下，确定其他候选药物。通过瞄准多个 细胞信号通路的影响耳鸣，我们的研究将开辟新的领域， 耳鸣的治疗和预防公开的大量数据， 泰特及其类似物将帮助我们显著减少开发时间和成本。

Subjective tinnitus is the perception of a phantom sound, which negatively impacts the quality of life for millions of people worldwide. Despite the great demand for remedy, there are no FDA-approved drugs to prevent or treat tinnitus. Possible causes of tinnitus are complicated. The current view is that hyperactivity in the central auditory nervous system contributes to the majority of tinnitus cases. This abnormal electrical activity, including an increase in delta-band activity, may be the direct result of an increase in T-type calcium channel activity. Other studies suggest that inflammatory responses within the brain may be involved in the development and persistence of tinnitus; therefore, drug candidates targeting both inflammatory and calcium signaling pathways may act synergistically to prevent and treat tinnitus. Tetrandrine (TET), an approved drug used in China, exhibits both anti-inflammatory and calcium channel-blocking properties. Using a new tinnitus detection method in mice, we have shown that both salicylate-induced and noise-induced tinnitus can be effectively treated by TET in a dose-dependent manner. Our hypothesis is that TET or its chemical analogs can be developed as drugs to prevent and treat tinnitus. In our proposed experiments, we have two parallel goals: (1) obtain investigational new drug (IND)-enabling toxicity and pharmacokinetics data for TET (Aim 1) and (2) optimize second-generation products with structure-activity relationship studies of TET and its chemical analogs (Aim 2). Successful accomplishment of Aim 1 will enable TET to advance into clinical development. In addition, the studies of Aim 2 will enable us to identify additional candidates in case TET fails at clinical stages. By targeting multiple cellular signaling pathways that impinge upon tinnitus, our study will open new areas for the treatment and prevention of tinnitus. The extensive body of data publicly available for TET and its analogs will help us significantly reduce development time and costs.