AMPK and cardiac dysfunction in chronic epilepsy: a prognostic indicator of SUDEP risk

慢性癫痫中的 AMPK 和心功能障碍：SUDEP 风险的预后指标

• 批准号: 10010118
• 负责人: Heidi Grabenstatter
• 金额: $ 8.19万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010118
• 关键词: 5' -AMP-activated protein kinase; Acute; Address; Adult; Agonist; Animal Model; Animals; Antiepileptic Agents; Arrhythmia; Brain; Cardiac; Cardiovascular system; Cessation of life; Chronic; Clinical; Cyclic AMP-Dependent Protein Kinases; Data; Deoxyglucose; Development; Disease Progression; Electrocardiogram; Electroencephalography; Electrophysiology (science); Energy Metabolism; Epilepsy; Epileptogenesis; Frequencies; Functional disorder; Genetic; Genetic Models; Goals; Harvest; Heart; Heart Abnormalities; Heart Atrium; Hippocampus (Brain); Human; Hypertrophy; Impairment; Injury; Intractable Epilepsy; Investigation; Measures; Mediating; Mental Depression; Metabolic stress; Metformin; Methods; Modeling; Molecular; Monitor; Morphology; Motor Seizures; Mus; Mutation; Myocardial dysfunction; PRKAG2 gene; Pathologic; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphorylation; Pilocarpine; Predisposition; Prevention strategy; Prognostic Marker; Protein Kinase; Protein Subunits; Proteins; Rattus; Refractory; Research; Risk; Risk Factors; Rodent; Rodent Model; Role; Saline; Seizures; Severities; Sterility; Temporal Lobe Epilepsy; Tissues; Tuberous Sclerosis; Ventricular; Wolff-Parkinson-White Syndrome; base; comorbidity; effective therapy; heart function; model development; mouse model; new therapeutic target; prevent; protein kinase P; protein kinase inhibitor; protein kinase modulator; response; signal processing; therapeutic target; therapy development

PROPOSAL SUMMARY The increased risk of sudden unexplained/unexpected death in epilepsy (SUDEP) is particularly high in drug- refractory patients. In fact, 40% of adult patients with pharmacoresistant epilepsy have one or more abnormalities in cardiac function3. One of the main risk factors for SUDEP is frequent, convulsive seizures in humans4-6,26. Rodents with chronic, acquired epilepsy die suddenly and unexpectedly7,8. Continuously recorded EKG in rats with pilocarpine-induced epilepsy demonstrates that alterations in QT interval, PR interval, and T- wave amplitude are associated with increased seizure burden. These data, combined with previous human and animal studies, support further investigation of a shared mechanism underlying cardiac arrhythmia development in adult acquired and genetic epilepsies that may be used as a universal prognostic biomarker of SUDEP risk. The major goal of this proposal is to characterize the role of AMP-activated protein kinase (AMPK) activation as a potential therapeutic target in chronic epilepsy and specifically, to evaluate the hypothesis that spontaneous seizures impair energy metabolism in the hearts and brains of acquired and genetic models of epilepsy contributing to increased seizure burden and SUDEP risk. Molecular methods will be used to characterize impairment in AMPK activation and altered expression of AMPK subunits. Abnormal cardiac function will be quantitatively measured in response to seizure-induced metabolic stress using simultaneous video/EEG/EKG monitoring. AMPK activity will be pharmacologically modulated to determine whether AMPK phosphorylation is preventative or pathological. We hypothesize that potential increases in seizure frequency and severity associated with longer duration postictal depression and arrhythmogenesis mediated by impaired AMPK phosphorylation can be prevented using clinically available AMPK activators in both genetic and acquired epilepsies. We expect our results to unmask a shared mechanism contributing to SUDEP risk in genetic and acquired epilepsies. Results of these studies may inspire new strategies for the prevention of SUDEP and provide more effective treatments for chronic, pharmacoresistant epilepsy. The proposal will provide valuable translational information about the role of impaired energy metabolism in epileptogenesis and acquired cardiac dysfunction contributing to SUDEP risk.

提案摘要 癫痫患者突然不明原因/意外死亡（SUDEP）的风险增加在药物治疗中尤其高， 难治性患者事实上，40%的耐药性癫痫成年患者有一个或多个 心脏功能异常3. SUDEP的主要危险因素之一是频繁的惊厥性发作， 人类4 - 6，26.患有慢性获得性癫痫的啮齿动物会突然意外死亡7，8。连续记录 匹罗卡品诱发癫痫大鼠的EKG显示，QT间期、PR间期和T-T间期的改变与癫痫发作有关。 波幅与癫痫发作负担增加有关。这些数据，结合以前的人类 和动物研究，支持进一步研究心律失常的共同机制 成人获得性和遗传性癫痫的发展，可用作癫痫的通用预后生物标志物。 SUDEP风险。本提案的主要目标是表征AMP活化蛋白激酶的作用 （AMPK）激活作为慢性癫痫的潜在治疗靶点，具体而言， 自发性癫痫发作损害后天性和后天性癫痫患者心脏和大脑的能量代谢的假说， 癫痫的遗传模型导致癫痫发作负担和SUDEP风险增加。分子方法将 用于表征AMPK活化的损伤和AMPK亚基表达的改变。异常 心脏功能将被定量测量，以响应糖尿病诱导的代谢应激， 同步视频/EEG/EKG监测。AMPK活性将被间接调节，以确定 AMPK磷酸化是预防性的还是病理性的。我们假设， 与持续时间较长的发作后抑郁和癫痫发生相关的癫痫发作频率和严重程度 通过使用临床上可获得的AMPK激活剂， 遗传性和后天性癫痫我们希望我们的结果能够揭示一种共同的机制， 遗传性和获得性癫痫的SUDEP风险。这些研究的结果可能会激发新的战略， 预防SUDEP，并为慢性耐药性癫痫提供更有效的治疗。的 该提案将提供有价值的翻译信息的作用，受损的能量代谢， 癫痫发生和获得性心功能障碍导致SUDEP风险。