Targeting multiple signaling pathways for tinnitus prevention and treatment

主观性耳鸣是对幻觉声音的感觉，它会对 提高全球数百万人的生活质量。尽管对补救措施的需求很大，但有 没有FDA批准的预防或治疗耳鸣的药物。耳鸣的可能原因是 很复杂。目前的观点是，中枢听觉神经系统的多动 在大多数耳鸣病例中，耳鸣起了重要作用。这种异常的电活动，包括 增量带活性增加，可能是T型钙离子增加的直接结果 通道活动。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通路可能会协同作用 预防和治疗耳鸣。中国使用的获批药物粉防己碱(Tet)展示 具有抗炎和钙离子通道阻断的特性。使用一种新的耳鸣 在小鼠的检测方法中，我们已经证明了水杨酸盐诱导和噪声诱导 Tet能以剂量依赖的方式有效地治疗耳鸣。我们的假设 Tet或其化学类似物可以开发为预防和治疗的药物 耳鸣。在我们提出的实验中，我们有两个平行的目标：(1)获得 研究中的新药(IND)-Tet的毒性和药代动力学数据(AIM 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)。成功完成目标1将使 TET进入临床开发阶段。此外，对目标2的研究将使我们能够 以确定更多的候选者，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，我们的研究将开辟新的领域 耳鸣的治疗和预防。公开提供的大量数据 TET及其类似产品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.