Targeting TRPC3 Channels for Epileptic Seizures

针对癫痫发作的 TRPC3 通道

基本信息

批准号：
10353604
负责人：
Jianxiong Jiang
金额：
$ 38万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10353604
关键词：
Ablation Acute Adverse effects Affect Amides Animals Antiepileptogenic Behavioral Brain Brain Diseases Brain-Derived Neurotrophic Factor Carboxylic Acids Cations Chemical Structure Chronic Cognitive Cognitive deficits Development Diagnosis Diazepam Disease Progression Dose Drug Exposure Drug Kinetics Electroencephalography Epilepsy Epileptogenesis Esters Event FDA approved Family Frequencies Future Generations Genetic Glial Fibrillary Acidic Protein Gliosis Goals Half-Life Hippocampus (Brain)Human Hydrolysis Impairment Lead Legal patent Mediating Metabolic Modeling Molecular Conformation Mus Neocortex Outcome Pathologic Patients Penetration Persons Pharmaceutical Preparations Phase Phosphotransferases Pilocarpine Plasma Population Pre-Clinical Model Property Pyrazoles Quality of life Recurrence Research Risk Role Safety Seizures Series Severities Signal Transduction Status Epilepticus Stroke Structure TRP channel Tail Testing Time Toxic effect Traumatic Brain Injury Treatment Protocols Tropomyosin acquired epilepsy analog anxiety-like behavior base cognitive testing comorbidity design experience high risk hippocampal pyramidal neuron improved in vivo inhibitor lead optimization member mouse model nervous system disorder neuron loss novel novel therapeutics object recognition pharmacokinetics and pharmacodynamics preclinical study prevent receptor scaffold scale up side effect therapeutic target therapy outcome

项目摘要

PROJECT SUMMARY As one of the most common brain disorders, epilepsy afflicts about 1% of the world population. Despite recent marked advances in seizure management, there are still more than 30% of patients poorly responding to current anti-seizure drugs (ASDs), which can cause wide-ranging and often unbearable side effects. It is another very unfortunate fact that current ASDs merely provide symptomatic relief, and no FDA-approved medication has been demonstrated to prevent the development of epilepsy in people at risks or modify the disease progression in those diagnosed with epilepsy. Developing safer, more effective anti-seizure and/or anti-epileptogenic therapies is in urgent unmet demand. Transient receptor potential canonical 3 (TRPC3) is a member of TRP family channels that control Ca2+ influxes. TRPC3 is found abundant in neocortex and hippocampus, where it colocalizes with brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase receptor B (TrkB), regulating BDNF/TrkB signaling- mediated dendritic remodeling in pyramidal neurons. Mounting evidence from recent studies suggest that the excessive BDNF/TrkB activity contributes to spontaneous recurrent seizures (SRSs) after status epilepticus (SE), indicative of a role of TRPC3 in epileptic seizures. Genetic ablation of TRPC3 reduces pilocarpine- induced seizures in mice, suggesting that TRPC3 inhibition might represent a novel anti-seizure and/or anti- epileptogenic strategy. Among TRPC3 inhibitors that emerged during the past decade, Pyr3 is most selective and thus widely used to study TRPC3-mediated Ca2+ entry in various pathological conditions. However, the chemical structure of Pyr3 poses a number of major liabilities including low metabolic stability caused by rapid hydrolysis of its ester moiety, leading to inactive carboxylic acid metabolite. Our overarching goal is to – using rationale design – develop a lead TRPC3 inhibitor with high metabolic stability, low toxicity, as well as favorable pharmacodynamic and pharmacokinetic properties (R61 phase). We will then determine its ability to suppress acute seizures, prevent SRSs (epileptogenesis), and/or improve cognitive outcomes (R33 phase). Upon successful completion, we will have established a proof-of-concept for TRPC3 inhibition as a novel anti- seizure and/or anti-epileptogenic strategy in a classical mouse model of epilepsy and a patented lead molecule for further development. Anticipated results will justify future studies on safety, efficacy, and more extensive lead-optimization if needed to develop a new therapy to prevent and/or suppress acquired epilepsy in patients suffering from putative seizure-precipitating events, such as de novo SE, traumatic brain injuries, etc.

项目摘要作为最常见的脑部疾病之一，癫痫病大约1％的世界人口。尽管最近癫痫发作管理的明显进展，仍有30％以上的患者对当前的抗Seizure药物（ASDS），可能会引起大范围且通常难以忍受的副作用。这是另一个非常不幸的事实是，当前ASD仅提供症状缓解，也没有FDA批准已经证明了药物以防止有风险的人的癫痫发育或修改被诊断为癫痫患者的疾病进展。开发更安全，更有效的反西萨斯和/或抗癫痫发作的疗法正在紧急未满足的需求中。瞬态受体电位规范3（TRPC3）是控制Ca2+的TRP家族通道的成员影响。发现TRPC3在新皮层和海马中很丰富，它与脑衍生神经营养因子（BDNF）和tropomyosin相关激酶受体B（TRKB），调节BDNF/TRKB信号传导锥体神经元中介导的树突状重塑。最近研究的越来越多的证据表明过量的BDNF/TRKB活性导致癫痫持续状态后的赞助复发性癫痫发作（SRSS）（SE），指示TRPC3在癫痫发作中的作用。 TRPC3的遗传消融减少了毛果果- 小鼠诱导的癫痫发作，表明TRPC3抑制作用可能代表了一种新型的抗seizure和/或抗 - 癫痫发作策略。在过去十年中出现的TRPC3抑制剂中，Pyr3最有选择性，因此广泛用于在各种病理条件下，研究TRPC3介导的Ca2+进入。但是，pyr3的化学结构构成许多主要负债，包括由其酯快速水解引起的低代谢稳定性部分导致非活性羧酸代谢产物。我们的总体目标是 - 使用理由设计 - 开发具有高代谢稳定性，低毒性和有利的铅TRPC3抑制剂药物动力学特性（R61期）。然后，我们将确定其抑制的能力急性癫痫发作，预防SRSS（癫痫发生）和/或改善认知结果（R33期）。成功完成后，我们将建立一个trpc3抑制的概念证明经典的癫痫和专利铅分子的小鼠模型中的癫痫发作和/或抗癫痫策略为了进一步发展。抗衡结果将证明未来的安全性，效率和更广泛的研究铅优化（如果需要）开发新疗法以预防和/或抑制患者的发作患有假定的癫痫发作至关重事件，例如从头开始，脑损伤等。