Adenosine receptor mediated therapies for SUDEP

腺苷受体介导的 SUDEP 疗法

• 批准号: 10197236
• 负责人: Detlev Boison
• 金额: $ 34.34万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197236
• 关键词: ADORA2A gene; Acute; Address; Adenosine; Adenosine Kinase; Affect; Apnea; Astrocytes; Benefits and Risks; Biological Models; Brain; Brain Stem; Caffeine; Chronic; Consumption; Crossover Design; Data; Dissection; Dose; Drops; Enterobacteria phage P1 Cre recombinase; Epilepsy; Family; Genes; Goals; Impairment; Incidence; Intake; Limbic System; Link; LoxP-flanked allele; Mediating; Metabolic; Metabolism; Molecular; Mus; Outcome; Outcomes Research; Parkinson Disease; Pathway interactions; Patients; Persons; Physiological; Play; Predisposition; Prevention; Property; Purinergic P1 Receptors; Receptor Gene; Recommendation; Research; Respiration; Respiration Disorders; Respiratory Center; Respiratory System; Respiratory physiology; Risk; Risk Factors; Rodent Model; Role; Route; Seizures; Signal Transduction; Sleep; System; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; Traumatic Brain Injury; Viral; Wild Type Mouse; Withdrawal; adenosine receptor activation; base; clinical development; clinically relevant; design; feasibility testing; mouse model; novel; overexpression; prevent; receptor; reconstitution; respiratory; response; sudden unexpected death in epilepsy; therapy development

Project Summary/Abstract Sudden unexpected death in epilepsy (SUDEP) remains a major concern for persons with epilepsy and their families. The incidence of SUDEP is estimated at 1 to 2.5 per 1000 patient years however the underlying reasons are poorly understood. Here we will address the adenosine hypothesis of SUDEP. Epileptic seizures trigger a surge of adenosine (ADO), which is an endogenous agent required for seizure termination, but which also controls respiratory functions in the brainstem by activation of different subtypes of adenosine receptors (ARs). Our overarching hypothesis is that a seizure-induced increase in ADO in combination with insufficient metabolic clearance of ADO in the brainstem can cause fatal over-activation of ARs leading to brainstem dysregulation and respiratory dysfunction as a precipitator of SUDEP. In support of our hypothesis, we demonstrated that a non-selective AR antagonist (caffeine) reduced lethal apnea in rodent models of epilepsy and traumatic brain injury. Our preliminary data support a strong association between ADO metabolism, AR activation, and lethal apnea. For those reasons we focus our proposal on the brainstem- dependent respiratory mechanisms of SUDEP. Specifically, we will address our central hypothesis that the susceptibility to SUDEP is related to abnormal ADO metabolism and signaling in respiratory regions of the brainstem and preventable by therapeutic interventions that enhance metabolic clearance of ADO or block AR activation. Brainstem specific manipulations will allow us to test a specific role of ADO in the brainstem. Dissection of seizure-related functions of ADO metabolism and signaling in the limbic system from respiratory control functions in the brainstem will enable a translational path for ADO-manipulation for the prevention of SUDEP. Our model system is a `SUDEP-prone mouse' with impaired metabolic clearance of ADO due to a heterozygous disruption of the adenosine kinase (Adk) gene. ADK, expressed in astrocytes is the main metabolic clearance route for ADO in the brain. Our research goals will be approached in 3 Specific Aims: (1) Test hypothesis that SUDEP is associated with maladaptive changes in ADO metabolism. (2) Test hypothesis that caffeine plays a critical role in SUDEP susceptibility. (3) Test whether suppression of A2AR activation can prevent SUDEP. The expected outcome of this research is the demonstration that the capacity for the metabolic clearance of seizure-induced ADO through the brainstem determines susceptibility to SUDEP. Mechanistic studies will identify the AR subtypes involved. In addition, this research will help to clarify whether the chronic use of caffeine is of benefit or presents a risk factor for persons with epilepsy. Finally, we will test whether A2AR antagonists, which are already in clinical development for the treatment of Parkinson's disease, can prevent SUDEP.

项目概要/摘要 癫痫猝死（SUDEP）仍然是癫痫患者及其家人的主要关注点 家庭。 SUDEP 的发病率估计为每 1000 名患者年 1 至 2.5 例，但其基本情况 原因尚不清楚。在这里我们将讨论 SUDEP 的腺苷假说。癫痫发作 触发腺苷 (ADO) 激增，这是终止癫痫发作所需的内源性物质，但 还通过激活不同亚型的腺苷受体来控制脑干的呼吸功能 （AR）。我们的首要假设是癫痫发作引起的 ADO 增加与不足相结合 脑干中 ADO 的代谢清除可导致致命的 AR 过度激活，从而导致脑干 调节失调和呼吸功能障碍是 SUDEP 的促发因素。为了支持我们的假设，我们 证明非选择性 AR 拮抗剂（咖啡因）可减少啮齿动物模型中的致命性呼吸暂停 癫痫和创伤性脑损伤。我们的初步数据支持 ADO 之间的紧密关联 新陈代谢、AR 激活和致命性呼吸暂停。出于这些原因，我们将我们的建议集中在脑干上—— SUDEP 的依赖呼吸机制。 具体来说，我们将提出我们的中心假设，即对 SUDEP 的敏感性与 脑干呼吸区 ADO 代谢和信号异常，可通过以下方法预防 增强 ADO 代谢清除或阻断 AR 激活的治疗干预措施。脑干 特定的操作将使我们能够测试 ADO 在脑干中的特定作用。剖析癫痫相关的 边缘系统中 ADO 代谢和信号传导的功能来自呼吸控制功能 脑干将为 ADO 操作提供一条翻译路径，以预防 SUDEP。我们的模型 系统是“SUDEP易感小鼠”，由于杂合性破坏，ADO代谢清除受损 腺苷激酶（Adk）基因。 ADK，在星形胶质细胞中表达，是主要的代谢清除途径 ADO在大脑中。我们的研究目标将通过 3 个具体目标来实现：(1) 检验 SUDEP 的假设 与 ADO 代谢的适应不良变化有关。 (2) 检验咖啡因发挥关键作用的假设 SUDEP 敏感性。 (3)测试抑制A2AR激活是否可以预防SUDEP。预期的 这项研究的结果证明了代谢清除癫痫引起的药物的能力 ADO 通过脑干决定对 SUDEP 的易感性。机制研究将确定 AR 涉及的亚型。此外，这项研究将有助于阐明长期使用咖啡因是否有益 或为癫痫患者带来危险因素。最后，我们将测试 A2AR 拮抗剂是否 已经在临床开发中用于治疗帕金森病，可以预防 SUDEP。