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(申请人提供)：癫痫儿童比其他慢性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和治疗干预做出不同反应的独特方式。2000年3月，NINDS协调了一次由白宫发起的关于“治愈癫痫”的会议，该会议将中断癫痫发生的过程确定为首要议程。需要发现与癫痫相关的解剖、生理和分子底物的范围，并定义明确的致痫标志物，这是该会议的主要优先事项。 这里提出的这项研究有两个目标，由癫痫发作对发育中的大脑的后果这一主题联系在一起。具体地说，这项研究将集中在(1)癫痫诱发的脑损伤，以及(2)导致癫痫的发育中大脑的结构和功能的变化。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)癫痫持续时间的影响，这可能构成损伤的阈值。细胞死亡的机制(坏死性和程序性细胞死亡)将作为这些变量的函数进行研究。这项研究将寻求分离在产生神经元损伤过程中至关重要的不同过程，这些损伤可能在癫痫持续状态过程中变得明显。将在几个月的时间里观察动物在首次癫痫持续状态后出现慢性自发性癫痫发作的情况，以确定致痫的癫痫持续状态的阈值持续时间，以及大脑的发育阶段如何改变这一点。将对这些动物进行研究，以了解在发育期癫痫持续状态后伴随癫痫发生和发展的解剖学变化(海马区苔藓纤维发芽的证据)和生理学变化(群体棘波幅度和EPSP斜率)。我们的发现将为未来针对癫痫持续状态不同阶段发育中的大脑进行神经保护干预，以中断癫痫形成过程的过程提供基础。