Epileptogenesis after febrile status epilepticus: a role of hyperthermia

描述（由申请人提供）：该项目的目标是建立一个模型，该模型将告诉我们在第一次癫痫发作后纠正热疗是否会减少热性癫痫持续状态（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后期慢性癫痫发展之间的关系。本项目研究温度在热性癫痫持续状态的致痫效应中的作用。我们已经开始开发一种模型，在体温保持在39或35摄氏度（35摄氏度接近巢中幼鼠的生理温度）的10天大的幼鼠中，可以触发类似严重程度的癫痫持续状态。在摄氏39度下处于癫痫持续状态的动物会在4个月内出现自发性反复的行为和脑电图发作，而摄氏35度组没有行为发作，脑电图发作也很少。与35度组相比，39度组的脑损伤范围更广，影响到更多的大脑部位。我们希望充分发展这一模型，以研究脑和体温在癫痫持续状态的长期后果中的作用。我们将在这两组和几个对照组中跟踪癫痫持续状态的生理和解剖学后果，使用癫痫发作的遥测视频监测，并使用几种神经元损伤和死亡的解剖学标记。这些包括免疫细胞化学活性caspase-3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热疗，并期望这可以防止热疗的致痫作用。我们还期望这种治疗可以减少脑损伤，防止caspase-3激活，减少海马神经元的神经元坏死数量。热性癫痫持续状态后的癫痫发生：热疗的作用。儿童期癫痫持续发热状态（FSE）的发生与难治性癫痫的后期发展密切相关。最近的证据表明，实验性的长时间热性惊厥是致痫性的，但我们不知道热疗的存在是否对癫痫发生有任何影响。我们的初步数据表明，热疗可作为“第二次打击”，增强癫痫持续状态诱导的癫痫发生。该项目将在实验动物中确定热疗在FSE诱导的癫痫发生中的作用，这将很容易转化为人类的研究和治疗。

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.