Targeting TRPC3 Channels for Epileptic Seizures

针对癫痫发作的 TRPC3 通道

• 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
• 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

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.

项目总结 癫痫是最常见的脑部疾病之一，约占世界人口的1%。尽管最近 在癫痫治疗方面取得了显著进展，仍有超过30%的患者对 目前的抗癫痫药物(ASD)可能会引起广泛的副作用，通常是无法承受的副作用。它是 另一个非常不幸的事实是，目前的ASD只提供症状缓解，而没有FDA批准的 药物已被证明可以防止高危人群癫痫的发展，或者改变 被诊断为癫痫的人的疾病进展。开发更安全、更有效的抗癫痫和/或 抗癫痫治疗的需求迫切，尚未得到满足。 瞬时受体电位规范3(TRPC3)是色氨酸受体家族控制钙离子通道的成员 大量涌入。TRPC3在大脑皮层和海马体中含量丰富，与脑源性成分共存。 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信号转导- 锥体神经元中介导的树突重塑。最近研究的越来越多的证据表明， 脑源性神经营养因子/TrkB活性过高导致癫痫持续状态后自发性反复发作 (Se)，表明TRPC3在癫痫发作中的作用。基因消融TRPC3可降低匹罗卡品- 诱导小鼠癫痫发作，提示TRPC3抑制可能代表了一种新的抗癫痫和/或抗癫痫 致痫策略。 在过去十年出现的TRPC3抑制剂中，Pyr3是最具选择性的，因此被广泛用于 研究不同病理条件下TRPC3介导的钙内流。然而，PYR3的化学结构 造成了一些主要的责任，包括其酯的快速水解所引起的低代谢稳定性 部分，导致不活跃的羧酸代谢产物。我们的首要目标是--利用基本设计原理-- 开发一种高代谢稳定性、低毒、有利的先导型TRPC3抑制剂 药效学和药代动力学性质(R61期)。然后我们将确定它压制的能力 急性癫痫发作，预防自发性癫痫(癫痫发生)，和/或改善认知结果(R33阶段)。 在成功完成后，我们将建立TRPC3抑制作为一种新型抗肿瘤药物的概念验证 典型癫痫小鼠模型和专利铅分子的癫痫发作和/或抗癫痫策略 为了进一步的发展。预期的结果将证明未来关于安全性、有效性和更广泛的研究是正确的。 如果需要，在开发预防和/或抑制获得性癫痫患者的新疗法时进行导联优化 患有可能导致癫痫发作的事件，如自发性癫痫发作、创伤性脑损伤等。