Monoamine-Mediated Arousal to Prevent Seizure-Induced Sudden Death

单胺介导的唤醒可预防癫痫引起的猝死

• 批准号: 9297506
• 负责人: Huajun Feng
• 金额: $ 21.91万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9297506
• 关键词: Address; Adenosine; Adrenergic Agents; Agonist; Animal Model; Animals; Arousal; Brain; Breathing; Cause of Death; Cell Nucleus; Cessation of life; Clinical; Complication; DBA/1 Mouse; Data; Development; Disease; Dopamine; Dopamine D1 Receptor; Dopamine Uptake Inhibitors; Dorsal; Drug usage; Epilepsy; Event; Exhibits; Fluoxetine; Fostering; Functional disorder; Generalized seizures; Goals; Grant; HTR2A gene; Human; Injection of therapeutic agent; Intervention; Knowledge; Laboratories; Lead; Mediating; Methodology; Modeling; Mus; Neurons; Neurotransmitters; Norepinephrine; Pathway interactions; Patients; Pharmacology; Prevention; Prevention strategy; Prevention therapy; Preventive treatment; Prosencephalon; Public Health; Publishing; Receptor Activation; Research; Role; Seizures; Serotonin; Serotonin Receptors 5-HT-3; Structure; Sudden Death; Syndrome; Testing; Transgenic Mice; Transgenic Organisms; Ventral Tegmental Area; Viral; atomoxetine; dopaminergic neuron; effective therapy; high risk; inhibitor/antagonist; innovation; locus ceruleus structure; monoamine; mortality; mouse model; nervous system disorder; neuronal circuitry; novel; optogenetics; prevent; receptor; respiratory; response; reuptake; selective expression; sudden unexpected death in epilepsy; tool

PROJECT SUMMARY/ABSTRACT Sudden unexpected death in epilepsy (SUDEP) is the major cause of deaths associated with generalized seizures, and there are currently no effective therapies for this devastating disorder. Clinical observations and animal studies suggest that seizure-induced respiratory arrest (S-IRA) is the primary event leading to SUDEP. Although current studies implicate serotonin (5-HT) (also adenosine) in S-IRA, it is unclear if other neurotransmitters contribute to S-IRA, and how these neurotransmitters modulate S-IRA. These gaps in knowledge have significantly hindered the development of effective prevention strategies against SUDEP. Monoamine neurotransmitters in the brain, such as 5-HT, norepinephrine (NE) and dopamine (DA), are arousal-promoting and may stimulate breathing. In our preliminary and published studies in the DBA/1 mouse model, we determined that pharmacologic elevation of 5-HT or NE levels, and optogenetic stimulation of 5-HT- mediated arousal suppress S-IRA. Thus, in this high risk and high impact proposal, we hypothesize that enhanced monoamine-mediated arousal prevents seizure-induced sudden death in mice. We will test this hypothesis in two separate SUDEP mouse models, the DBA/1 mouse and the Dravet mouse that exhibits the salient features of Dravet syndrome (a type of epilepsy) in humans, including spontaneous seizures. In specific aim 1, we will determine if pharmacologic enhancement of monoamine function reduces S-IRA and/or sudden death in both DBA/1 and Dravet mice. We will examine if 5-HT, NE and DA are implicated in seizure- related mortality using monoamine reuptake inhibitors, and identify the specific serotonergic, adrenergic and dopaminergic receptors that are involved in prevention of seizure-related mortality. In specific aim 2, we will determine if selective stimulation of the dorsal raphe, locus coeruleus or ventral tegmental area reduces S-IRA in both DBA/1 and Dravet mice. We will use optogenetics to activate the monoaminergic brain nuclei that are known to mediate arousal response, and examine if enhancing arousal mediated by each monoamine suppresses S-IRA. If successful, the proposed studies could lead to significant conceptual advance in the mechanisms of SUDEP, and foster development of novel pharmacologic and neurostimulatory strategies against SUDEP. Completion of the proposed studies will establish animal models and methodology for further dissecting the neuronal circuitry, investigating the interaction, and elucidating the cellular mechanisms of monoamines involved in seizure-related mortality.

项目总结/摘要 癫痫猝死（SUDEP）是与全身性癫痫相关的死亡的主要原因。 癫痫发作，目前还没有有效的治疗这种毁灭性的疾病。临床观察和 动物研究表明，尿素诱导的呼吸停止（S-IRA）是导致SUDEP的主要事件。 虽然目前的研究表明血清素（5-HT）（也是腺苷）在S-IRA中，但尚不清楚其他因素是否会影响S-IRA。 神经递质参与S-IRA，以及这些神经递质如何调节S-IRA。这些差距在 知识严重阻碍了针对SUDEP的有效预防策略的制定。 脑中的单胺类神经递质，如5-HT、去甲肾上腺素（NE）和多巴胺（DA）， 促进觉醒并可能刺激呼吸。在我们对DBA/1小鼠的初步和已发表的研究中， 模型中，我们确定了5-HT或NE水平的药理学升高以及5-HT-的光遗传学刺激 介导的唤醒抑制S-IRA。因此，在这个高风险和高影响的提案中，我们假设， 增强的单胺介导的唤醒防止小鼠中的惊厥诱导的猝死。我们将测试 在两个独立的SUDEP小鼠模型，DBA/1小鼠和Dravet小鼠中， 人类Dravet综合征（一种癫痫）的显著特征，包括自发性癫痫发作。在 具体目标1，我们将确定单胺功能的药理学增强是否会减少S-IRA和/或 DBA/1和Dravet小鼠均发生猝死。我们将检查5-HT、NE和DA是否与癫痫发作有关- 相关死亡率使用单胺再摄取抑制剂，并确定具体的肾上腺素能，肾上腺素能和 多巴胺能受体参与预防糖尿病相关死亡。具体目标2： 确定选择性刺激中缝背核、蓝斑或腹侧被盖区是否会减少S-IRA 在DBA/1和Dravet小鼠中。我们将使用光遗传学来激活大脑中的单胺能核团， 已知介导唤醒反应，并检查是否增强唤醒介导的每一个单胺 抑制S-IRA如果成功，拟议的研究可能会带来重大的概念进步 机制，并促进新的药理学和神经刺激策略的发展 针对SUDEP。完成拟议的研究将建立进一步研究的动物模型和方法。 解剖神经元回路，研究相互作用，并阐明细胞机制， 单胺参与糖尿病相关死亡率。