Epileptogenesis after febrile status epilepticus: a role of hyperthermia

发热性癫痫持续状态后的癫痫发生：热疗的作用

• 批准号: 7472188
• 负责人: CLAUDE G WASTERLAIN
• 金额: $ 16.66万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472188
• 关键词: Acute; Adverse effects; Affect; Alcohol consumption; Alcohols; Amygdaloid structure; Animals; Back; Bathing; Behavior monitoring; Behavioral; Body Temperature; Brain; Brain Injuries; Cessation of life; Childhood; Chronic; Control Groups; Count; Country; Data; Development; Diazepam; Elderly; Electroencephalography; Electrographic Status Epilepticus; Epilepsy; Epileptogenesis; Experimental Models; Febrile Convulsions; Fever; Frequencies; Goals; Hippocampus (Brain); Hour; Human; Incidence; Intractable Epilepsy; Lead; Lithium; Location; Measures; Modeling; Monitor; Motor Seizures; Necrosis; Neuronal Injury; Neurons; Numbers; Physiological; Pilocarpine; Population; Porifera; Public Health; Range; Rattus; Recurrence; Role; Score; Seizures; Severities; Status Epilepticus; Telemetry; Temperature; Testing; Therapeutic; Therapeutic Effect; Time; Translating; Week; Weight; base; caspase-3; day; digital; experience; human study; hyperthermia treatment; immunocytochemistry; induced hypothermia; mind control; natural hypothermia; neuron loss; prevent; pup; rectal; sex

DESCRIPTION (provided by applicant): The goal of this project is to develop a model which will tell us if correcting hyperthermia after the first seizure reduces the long-term consequences of febrile status epilepticus (epileptogenesis and brain damage). The long-term goal is to understand the relationship between seizures in early life and the later development of chronic epilepsy. This project studies the role of temperature in the epileptogenic effects of febrile status epilepticus. We have begun to develop a model in which status epilepticus of similar severity can be triggered in 10-day-old rat pups maintained at a body temperature of either 39 or 35 degrees Celsius (35 degrees C being close to the physiological temperature of pups in the nest). Animals subjected to status epilepticus at 39 degrees Celsius develop spontaneous recurrent behavioral and EEG seizures within 4 months, while the 35 degree C group develops no behavioral seizures and few EEG seizures. Brain damage is also more extensive and affects more brain locations in the 39 degree group than in the 35 degree group. We want to fully develop this model to study the role of brain and body temperature in the long-term consequences of status epilepticus. We will follow the physiological and anatomical consequences of status epilepticus in those 2 groups and in several control groups, using telemetry-video monitoring of seizures, and using several anatomical markers of neuronal injury and death. These include immunocytochemistry for active caspase-3, and quantitative unbiased stereology. We will also correct the hyperthermia with alcohol sponges after the first seizure, and expect this to prevent the epileptogenic effects of hyperthermia. We also expect this treatment to reduce brain damage, to prevent caspase-3 activation and to reduce the amount of neuronal necrosis of hippocampal neurons.Epileptogenesis after febrile status epilepticus: role of hyperthermia. PUBLIC HEALTH RELEVANCE There is a strong association between the occurrence of febrile status epilepticus (FSE) in childhood and the later development of intractable epilepsy. Recent evidence suggests that experimental prolonged febrile convulsions are epileptogenic, but we do not know whether the presence of hyperthermia has any effect on epileptogenesis. Our preliminary data suggest that hyperthermia acts as a `second hit which enhances status epilepticus- induced epileptogenesis. This project will determine the role of hyperthermia in FSE- induced epileptogenesis in experimental animals, in a way which will be easily translated into human studies and treatments.

描述（由申请人提供）：本项目的目标是开发一种模型，该模型将告诉我们，在首次癫痫发作后纠正体温过高是否会减少发热性癫痫持续状态（癫痫发生和脑损伤）的长期后果。长期目标是了解早期癫痫发作与慢性癫痫后期发展之间的关系。本项目研究温度在发热性癫痫持续状态致痫效应中的作用。我们已经开始开发一种模型，在该模型中，在保持体温为39或35摄氏度（35摄氏度接近巢中幼崽的生理温度）的10天大的大鼠幼崽中可以触发类似严重程度的癫痫持续状态。在39摄氏度下经受癫痫持续状态的动物在4个月内发展自发的复发性行为和EEG癫痫发作，而35摄氏度组没有发展行为癫痫发作和很少的EEG癫痫发作。脑损伤也更广泛，39度组比35度组影响更多的大脑部位。我们希望充分开发这个模型，以研究大脑和体温在癫痫持续状态长期后果中的作用。我们将使用遥测视频监测癫痫发作，并使用神经元损伤和死亡的几个解剖标志物，跟踪这两组和几个对照组中癫痫持续状态的生理和解剖后果。这些包括活性caspase-3的免疫细胞化学和定量无偏体视学。我们还将在第一次癫痫发作后用酒精海绵纠正高热，并期望这能防止高热的致癫痫作用。我们还希望这种治疗，以减少脑损伤，防止半胱天冬酶-3激活，并减少海马神经元的神经元坏死量。公共卫生相关性儿童期发热性癫痫持续状态（FSE）的发生与后来难治性癫痫的发展之间有很强的关联。最近的证据表明，实验性长期热性惊厥是致癫痫的，但我们不知道是否存在高温对癫痫发生有任何影响。我们的初步数据表明，高温作为一个'二次打击，加强癫痫持续状态诱导癫痫发生。该项目将确定高温在FSE诱导的实验动物癫痫发生中的作用，以一种易于转化为人类研究和治疗的方式。