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（SUDEP）突然无法解释/意外死亡的风险增加的风险特别高。 难治性患者。实际上，有40％的成年患者患有癫痫患者有一个或多个 心脏功能异常3。 SUDEP的主要危险因素之一是经常出现的惊厥性癫痫发作 人类4-6,26。慢性癫痫发作的啮齿动物突然死亡，意外死亡7,8。连续记录 与毛果石诱导的癫痫大鼠中的心电图表明，QT间隔，PR间隔和T-的变化 波幅度与癫痫发作负担增加有关。这些数据与以前的人相结合 和动物研究，支持进一步研究心律不齐的共享机制 成人获得和遗传性癫痫的发展，可以用作通用的预后生物标志物 SUDEP风险。该提案的主要目标是表征AMP激活蛋白激酶的作用 （AMPK）激活作为慢性癫痫中的潜在治疗靶标，具体来说，以评估 假设自发癫痫发作会损害被收购和大脑中的能量代谢和 癫痫的遗传模型导致癫痫发作负担增加和SUDEP风险。分子方法将 用于表征AMPK激活和AMPK亚基表达的损害。异常 心脏功能将根据癫痫发作诱导的代谢应力进行定量测量 同时视频/EEG/EKG监视。 AMPK活性将在药理学上调节以确定 AMPK磷酸化是预防性还是病理。我们假设潜在的增加 癫痫发作频率和严重程度与持续时间更长有关 可以使用临床上可用的AMPK激活剂中的AMPK磷酸化介导的AMPK磷酸化介导 遗传和获得的癫痫。我们希望我们的结果能够揭示有助于的共同机制 Sudep风险在遗传和获得的癫痫病中。这些研究的结果可能会激发新的策略 预防SUDEP并为慢性药物癫痫提供更有效的治疗方法。这 提案将提供有关能量代谢受损的作用的有价值的翻译信息 癫痫发生并获得了导致SUDEP风险的心脏功能障碍。