Epileptogenicity in the Developing Brain

大脑发育中的致癫痫性

• 批准号: 7010643
• 负责人: RAMAN SANKAR
• 金额: $ 31.4万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010643
• 关键词: anticonvulsants; brain; brain electrical activity; brain injury; brain morphology; cell death; cysteine endopeptidases; developmental neurobiology; diazepam; disease /disorder onset; disease /disorder proneness /risk; disease /therapy duration; electroencephalography; electron microscopy; epilepsy; generalized seizures; hippocampus; immunocytochemistry; laboratory rat; mossy fiber; neurons; neuropathology; neuropharmacology; pathologic process; phenobarbital; pilocarpine; terminal nick end labeling

DESCRIPTION (provided by applicant): Children with epilepsy have more cognitive and psychiatric difficulties than children with other chronic illnesses. Pediatric neurologists are acutely aware of the distinctive manner in which the immature brain responds differently to a variety of insults as well as to therapeutic interventions. In March of 2000, NINDS coordinated a White House-initiated conference on "Curing Epilepsy" that identified interrupting the process of epileptogenesis as the number one agenda. The need for discovering the range of anatomic, physiological, and molecular substrates associated with the epilepsies and defining unambiguous markers of epileptogenicity was set as a major priority at that conference. The research proposed here has two goals, linked by the theme of the consequences of seizures on the developing brain. Specifically, this study will focus on (1) seizure-induced brain injury, and (2) the resulting alterations in structure and function of the developing brain that are epileptogenic. In studying seizure induced brain injury, the proposed work aims to determine the influence of (a) the developmental stage of the animals and (b) the duration of status epilepticus, that may constitute a threshold for injury. Mechanisms of cell-death (necrotic versus programmed cell death) will be studied as a function of these variables. The study will seek to isolate distinct processes critical in producing neuronal injury that may become evident during the course of status epilepticus. Animals will be observed over several months for the development of chronic spontaneous seizures, i.e. epilepsy, after the initial bout of status epilepticus, in order to determine the threshold duration of status epilepticus that is epileptogenic, and how this is modified by the developmental stage of the brain. These animals will be studied for anatomic (evidence of mossy fiber sprouting in the hippocampus) and physiologic (population spike amplitude and EPSP slope) alterations that accompany the onset and progression of epilepsy after a bout of status epilepticus during development. Our findings will provide the basis for future neuroprotective interventions targeting the developing brain at different stages of status epilepticus in order to interrupt the course of the epileptogenic process.

描述（由申请人提供）：癫痫儿童比其他慢性疾病儿童有更多的认知和精神障碍。儿科神经学家敏锐地意识到，未成熟的大脑对各种侮辱以及治疗干预的反应是不同的。2000年3月，NINDS协调了一个由白色议院发起的关于“治疗癫痫”的会议，该会议将中断癫痫发生过程确定为首要议程。需要发现与癫痫相关的解剖学、生理学和分子底物的范围，并定义明确的致癫痫性标记物，这在那次会议上被定为一个主要优先事项。 这里提出的研究有两个目标，由癫痫发作对发育中的大脑的后果这一主题联系起来。具体而言，本研究将重点关注（1）癫痫引起的脑损伤，以及（2）发育中大脑结构和功能的变化，这些变化是致癫痫的。在研究癫痫引起的脑损伤时，拟议的工作旨在确定（a）动物的发育阶段和（B）癫痫持续状态的持续时间的影响，这可能构成损伤的阈值。细胞死亡机制（坏死性与程序性细胞死亡）将作为这些变量的函数进行研究。这项研究将寻求分离不同的过程中产生神经元损伤，可能成为癫痫持续状态的过程中明显的关键。在癫痫持续状态的初始发作后，将观察动物几个月的慢性自发性癫痫发作（即癫痫）的发展，以确定致癫痫性癫痫持续状态的阈值持续时间，以及大脑发育阶段如何改变癫痫持续状态。将研究这些动物在发育期间癫痫持续状态发作后伴随癫痫发作和进展的解剖学（海马中苔藓纤维发芽的证据）和生理学（群体尖峰振幅和EPSP斜率）变化。我们的研究结果将为未来针对癫痫持续状态不同阶段发育中大脑的神经保护干预提供基础，以中断癫痫发生过程。