Epileptogenicity in the Developing Brain

大脑发育中的致癫痫性

• 批准号: 6847749
• 负责人: RAMAN SANKAR
• 金额: $ 32.07万
• 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/6847749
• 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）：癫痫的儿童比患有其他慢性疾病的儿童具有更多的认知和精神病困难。小儿神经科医生敏锐地意识到，未成熟大脑对各种侮辱以及治疗干预的独特方式。 2000年3月，Ninds协调了一次关于“治愈癫痫”的白宫发起的会议，该会议确定中断癫痫发生的过程是第一议程。在该会议上，将发现与癫痫发作相关的解剖，生理和分子底物以及定义明确的癫痫发作标记的需求是该会议的主要优先事项。 这里提出的研究有两个目标，其主题是癫痫发作对发育中的大脑的后果。具体而言，这项研究将集中于（1）癫痫发作引起的脑损伤，以及（2）癫痫发育中发育中的大脑结构和功能的改变。在研究癫痫发作引起的脑损伤时，拟议的工作旨在确定（a）动物的发育阶段和（b）癫痫持续时间的持续时间，这可能构成损伤的阈值。细胞死亡的机制（坏死与程序性细胞死亡）将作为这些变量的函数进行研究。该研究将寻求隔离在癫痫持续状态下可能显而易见的神经元损伤至关重要的不同过程。为了确定癫痫癫痫病的阈值阈值，将观察到几个月的慢性自发癫痫发育，即癫痫发作，即癫痫病，以及如何通过大脑的发育阶段来修饰。将研究这些动物的解剖学（在海马中发芽的苔藓纤维发芽的证据）和生理学（种群尖峰振幅和EPSP斜率）改变，这些变化伴随着发育过程中癫痫发作后的癫痫发作和癫痫发作后的发作和进展。我们的发现将为未来的神经保护干预措施提供基础，该干预措施针对癫痫持续状态的不同阶段发育型大脑，以中断癫痫发作过程。