Prevention of Seizure-Induced Sudden Death by Stimulating Serotonergic Signaling

通过刺激血清素信号传导预防癫痫引起的猝死

• 批准号: 10311540
• 负责人: Huajun Feng
• 金额: $ 38.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311540
• 关键词: 5-Hydroxytryptophan; Agonist; Amygdaloid structure; Animal Model; Animals; Attenuated; Brain; Cause of Death; Cessation of life; Citalopram; Clinical; Coupling; DBA/1 Mouse; Data; Development; Disease model; Dorsal; Electrocardiogram; Electroencephalography; Electrophysiology (science); Epilepsy; Event; Exhibits; Fenfluramine; Fluoxetine; Fostering; Functional disorder; General Population; Goals; HTR2A gene; Human; Intervention; Knowledge; Literature; Midbrain structure; Mission; Modeling; Monitor; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Outcome; Paroxetine; Patients; Pharmaceutical Preparations; Pharmacology; Plethysmography; Pre-Clinical Model; Prevention; Prevention strategy; Preventive; Public Health; Reducing Agents; Reporting; Research; Risk; Role; Seizures; Serotonin; Serotonin Antagonists; Signal Transduction; Sudden Death; Technology; Testing; Therapeutic; Treatment Efficacy; Work; base; cell type; designer receptors exclusively activated by designer drugs; dravet syndrome; human disease; human model; innovation; man; mortality; mouse model; nervous system disorder; neuronal circuitry; neurotransmission; novel; optogenetics; pre-clinical; prevent; protective effect; raphe nuclei; respiratory; response; reuptake; serotonin 7 receptor; serotonin receptor; sudden unexpected death in epilepsy; transmission process

PROJECT SUMMARY/ABSTRACT The risk of sudden unexpected death in epilepsy (SUDEP) in patients with epilepsy is more than 20-fold higher than that of death in the general population. Clinical and animal studies show that seizure-induced respiratory arrest is the primary event leading to death. Increased serotonin (5-HT) levels in the brain reduce seizure- induced respiratory arrest in provoked seizure models. However, it is unclear whether enhancing 5-HT neuro- transmission exerts protective effects on seizure-induced sudden death in spontaneous seizure (epilepsy) models and which 5-HT circuitry is involved in this sudden death in both provoked and spontaneous seizure models. These gaps in knowledge have significantly hindered the therapeutics to prevent SUDEP in patients. The long-term goal is to foster effective prevention strategies against SUDEP using approaches targeted to specific SUDEP mechanisms. The overall objectives of this proposal are to (1) determine the efficacy of 5-HT- enhancing agents in suppressing seizure-induced sudden death and (2) elucidate the involved 5-HT circuitry mechanisms in animal models, especially in a widely-used mouse model of human Dravet syndrome (a type of epilepsy) that displays spontaneous seizures with a high rate of seizure-induced sudden death. The central hypothesis is that enhanced 5-HT signaling prevents seizure-induced sudden death, and that the 5-HT raphe- amygdala circuitry is involved in this sudden death in DBA/1 and Dravet mice. The rationale for this proposal is that a determination of preclinical therapeutic efficacy of 5-HT-enhancing agents and 5-HT neuronal circuitry mechanisms in seizure-induced sudden death is likely to offer a strong scientific framework by which new strategies against human SUDEP can be developed. The central hypothesis will be tested in the following two specific aims: 1) Determine the protective effects of enhancing 5-HT neurotransmission on seizure-induced sudden death in DBA/1 and Dravet mice; and 2) Elucidate how 5-HT circuitry from raphe nuclei to the amygda- la modifies seizure-induced sudden death in DBA/1 and Dravet mice. We will employ a combination of simul- taneous video EEG/ECG/plethysmography monitoring, electrophysiology, pharmacology and cell-type specific technologies (optogenetics and DREADDs) to perform the work in these aims. The proposed research is inno- vative because it defines a novel 5-HT circuitry mechanism of seizure-induced sudden death using optogenet- ics and DREADDs in animal models, especially in a human disease model, which could conceptually advance the knowledge on the pathophysiological mechanisms of SUDEP. The proposed work is significant because the expected outcomes will potentially foster targeted pharmacologic and neurostimulatory interventions of SUDEP to save lives of at-risk patients.

项目摘要/摘要 癫痫患者癫痫突然死亡（SUDEP）突然出现意外死亡的风险高20倍以上 比普通人群的死亡。临床和动物研究表明，癫痫发作引起的呼吸道 逮捕是导致死亡的主要事件。大脑中的5-羟色胺（5-HT）水平降低了癫痫 引发癫痫发作模型引起的呼吸停滞。但是，尚不清楚是否增强了5-HT神经 - 传播对自发癫痫发作的癫痫发作诱发的猝死作用（癫痫） 模型以及哪个5-HT电路涉及这种突然的死亡和自发癫痫发作 型号。这些知识的差距极大地阻碍了治疗剂防止患者的SUDEP。 长期目标是使用针对的方法来促进有效的预防策略，以防止SUDEP 特定的SUDEP机制。该提案的总体目标是（1）确定5-HT-的功效 在抑制癫痫发作引起的猝死和（2）阐明所涉及的5-HT电路时增强剂 动物模型中的机制，尤其是在广泛使用的人类Dravet综合征的小鼠模型中（一种类型 癫痫病以高发作诱发的猝死率显示自发癫痫发作。中央 假设是增强的5-HT信号传导可防止癫痫发作引起的猝死，并且5-HT Raphe- 杏仁核电路参与了DBA/1和Dravet小鼠的突然死亡。该提议的理由是 确定5-HT增强剂和5-HT神经元电路的临床前治疗功效 癫痫发作引起的猝死的机制可能会提供一个强大的科学框架 可以制定针对人类SUDEP的策略。中心假设将在以下两个中进行检验 具体目的：1）确定增强5-HT神经传递对癫痫发作的保护作用 DBA/1和Dravet小鼠突然死亡； 2）阐明5-HT电路如何从raphe核到杏仁核 LA修饰DBA/1和Dravet小鼠癫痫发作诱发的猝死。我们将采用模拟的组合 Taneous Video EEG/ECG/杂质监测，电生理学，药理学和细胞类型特异性 在这些目标中执行工作的技术（光遗传学和恐惧）。拟议的研究是无知的 由于它定义了一种新型的5-HT回路机制，其癫痫发作诱导的突然死亡使用光学网 - 动物模型中的ICS和Dreadds，尤其是在人类疾病模型中，可以从概念上提高 关于SUDEP的病理生理机制的知识。拟议的工作很重要，因为 预期的结果可能会促进针对性的药理和神经刺激干预措施 Sudep挽救高危患者的生命。