Targeting multiple signaling pathways for tinnitus prevention and treatment

主观耳鸣是对幻音的感知，这会对听觉产生负面影响 全球数百万人的生活质量。尽管对补救措施的需求很大，但 不是 FDA 批准的预防或治疗耳鸣的药物。耳鸣的可能原因有 复杂。目前的观点是中枢听觉神经系统的过度活跃 导致大多数耳鸣病例。这种异常的电活动，包括 δ带活性的增加，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 针对炎症和钙信号通路可能会协同作用 预防和治疗耳鸣。中国批准使用的药物粉防己碱（TET）展出 具有抗炎和钙通道阻断特性。使用新的耳鸣 通过在小鼠中进行检测，我们发现水杨酸盐诱导的和噪音诱导的 TET 可以有效治疗耳鸣，且呈剂量依赖性。我们的假设 TET或其化学类似物可以开发为药物来预防和治疗 耳鸣。在我们提出的实验中，我们有两个并行的目标：（1）获得 TET 的研究性新药 (IND) 毒性和药代动力学数据（目标 1) 和 (2) 通过构效关系研究优化第二代产品 TET 及其化学类似物（目标 2）。目标 1 的成功实现将使 TET 进入临床开发。此外，目标 2 的研究将使我们能够 以确定其他候选人，以防 TET 在临床阶段失败。通过瞄准多个 影响耳鸣的细胞信号通路，我们的研究将为耳鸣开辟新领域 耳鸣的治疗和预防。公开可用的大量数据 TET 及其类似物将帮助我们显着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.