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.

项目概要作为最常见的脑部疾病之一，癫痫症困扰着世界上约 1% 的人口，尽管近年来癫痫病的发病率一直居高不下。癫痫治疗取得了显着进展，但仍有超过 30% 的患者对癫痫治疗反应不佳目前的抗癫痫药物（ASD）可能会引起广泛且往往难以忍受的副作用。另一个非常不幸的事实是，目前的 ASD 只能缓解症状，并没有获得 FDA 批准药物已被证明可以预防高危人群癫痫的发展或改变开发更安全、更有效的抗癫痫药物和/或药物。抗癫痫治疗的需求亟待满足。瞬时受体电位规范 3 (TRPC3) 是控制 Ca2+ 的 TRP 家族通道的成员 TRPC3 在新皮质和海马体中含量丰富，与脑源性共定位。神经营养因子 (BDNF) 和原肌球蛋白相关激酶受体 B (TrkB)，调节 BDNF/TrkB 信号传导- 最近研究的越来越多的证据表明，锥体神经元介导的树突重塑。过度的 BDNF/TrkB 活性导致癫痫持续状态后自发性复发性癫痫发作 (SRS) (SE)，TRPC3 在癫痫发作中的作用指标。TRPC3 的基因消融可减少毛果芸香碱- 诱导小鼠癫痫发作，表明 TRPC3 抑制可能代表一种新型的抗癫痫和/或抗癫痫药物致癫痫策略。在过去十年出现的 TRPC3 抑制剂中，Pyr3 选择性最强，因此被广泛用于研究各种病理条件下 TRPC3 介导的 Ca2+ 进入然而，Pyr3 的化学结构。造成许多主要缺点，包括其酯快速水解导致代谢稳定性低部分，导致无活性的羧酸代谢物我们的总体目标是 - 使用基本原理设计 - 开发一种具有高代谢稳定性、低毒性和良好的TRPC3先导抑制剂然后我们将确定其抑制能力。急性癫痫发作、预防 SRS（癫痫发生）和/或改善认知结果（R33 期）。成功完成后，我们将建立 TRPC3 抑制作为一种新型抗肿瘤药物的概念验证。经典小鼠癫痫模型中的癫痫发作和/或抗癫痫策略以及专利先导分子进一步开发的预期结果将证明未来的安全性、有效性和更广泛的研究是合理的。如果需要开发新疗法来预防和/或抑制患者获得性癫痫，则进行先导优化患有假定的癫痫发作事件，例如新发癫痫发作、创伤性脑损伤等。