Posttraumatic epilepsy induced by fluid percussion injury in the rat

液体冲击损伤致大鼠创伤后癫痫

• 批准号: 7772277
• 负责人: RAIMONDO D'AMBROSIO
• 金额: $ 33.74万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7772277
• 关键词: Acute; Antiepileptogenic; Behavioral; Brain; Brain Pathology; Carbamazepine; Chronic; Closed head injuries; Data; Deoxyglucose; Development; Disease; Electroconvulsive Shock; Electrocorticogram; Epilepsy; Epileptogenesis; Event; Focal Seizure; Frequencies; Genetic; Genetically Engineered Mouse; Goals; Heterogeneity; Hippocampus (Brain); Human; Injury; Investigation; Kindling (Neurology); Lead; Levetiracetam; Location; Mediating; Modeling; Molecular; Mus; Neocortex; Neurons; Parietal; Pathology; Pentylenetetrazole; Phenobarbital; Predisposing Factor; Probability; Property; Radiofrequency Interstitial Ablation; Rattus; Recurrence; Research; Research Personnel; Risk Factors; Rodent Model; Role; Sclerosis; Seizures; Severities; Site; Staging; Standardization; Synapses; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Tetrodotoxin; Time; Translational Research; Traumatic Brain Injury; Work; clinically relevant; drug discovery; fluid percussion injury; frontal lobe; improved; piriform cortex; prevent; programs; relating to nervous system; subcutaneous; therapeutic target; uptake; valproate

The overall goal of this proposal is to begin the investigation of the mechanisms responsible for the genesis and progression of posttraumatic epilepsy (PTE) induced by fluid percussion injury (FPI), a relevant model of concussive closed head injury in the rat.In our most recent work we 1) discovered and characterized different types of chronic spontaneous recurrent partial seizures (CSRPSs grade 1, 2 and 3) following rostral parasaggital FPI (rpFPI) in the rat;2) discovered that rpFPI-induced PTE is a progressive disorder that results, months after injury, in mesial-temporal lobe epilepsy (MTLE) with dual pathology. The present proposal will focus on defining the neural substrates of rpFPI-induced CSRPSs, on the mechanisms of heterogeneity of FPI-induced CSRPSs, and on their mechanisms of genesis and progression. Specific Aims: to test the following hypotheses: 1) that the frontal-parietal neocortex at the site of rpFPI develops into the early epileptic focus, responsible for grade 1 and 2 seizures, while hippocampus and piriform cortex develop epileptic foci, responsible for grade 3 seizures, at later times. 2) that the probability of developing PTE following FPI,as well as seizure type, frequency and duration, their underlying pathology, and their temporal progression, depends on the degree and location of the injury. 3) that neuronal and synaptic activity within the incipient early epileptic focus is required for posttraumatic epileptogenesis to occur. 4) that a kindling-like cellular phenomenon mediated by the early epileptic focus is responsible for hippocampal epileptogenesis. 5) that the pharmacological responsiveness of FPI-induced epilepsy changes with time, as the disease progresses, as a function of seizure type and temporal lobe sclerosis. In addition, we aim to develop a murine model of FPI-induced PTE to introduce the use of genetically engineered mice in the investigation of risk factors and basic mechanisms ofPTE. Because of the unparalleled phenotypic and etiological similarities existing between this rodent model and human PTE the data collected will lead to the elucidation of more relevant mechanisms of genesis and progression of PTE, and to a better standardization of the model to the advantage of both basic and translational research efforts.

这项建议的总体目标是开始调查的机制，负责成因 和进展的创伤后癫痫（PTE）诱导的液压冲击损伤（FPI），相关模型 在我们最近的工作中，我们1）发现并描述了 不同类型的慢性自发性复发性部分性癫痫发作（CSRPS 1级、2级和3级）， 大鼠嘴侧附性腺FPI（rpFPI）;2）发现rpFPI诱导的PTE是一种进行性疾病 结果，在损伤后数月，在内侧颞叶癫痫（MTLE）与双重病理。本 该提案将集中于定义rpFPI诱导的CSRPSs的神经底物， FPI诱导的CSRPSs的异质性及其发生和发展机制。 具体目的：检验以下假设：1）rpFPI位点的额顶叶新皮层 发展成早期癫痫灶，负责1级和2级癫痫发作，而海马和 梨状皮质发展为癫痫灶，随后导致3级癫痫发作。2)的概率 FPI后发生PTE的风险，以及癫痫发作的类型、频率和持续时间， 病理学及其时间进展取决于损伤的程度和位置。3)的 创伤后癫痫的早期发作需要神经元和突触的活动 癫痫的发生。4)由早期癫痫灶介导的类似点燃的细胞现象， 导致海马癫痫5)FPI诱导的药理学反应 癫痫随着时间的推移而变化，随着疾病的进展，作为癫痫发作类型和颞叶的函数 硬化症此外，我们的目标是建立一种FPI诱导PTE的小鼠模型，以介绍使用 基因工程小鼠在研究PTE的危险因素和基本机制中的作用。 由于该啮齿动物模型和动物模型之间存在的无与伦比的表型和病因学相似性， 收集的数据将有助于阐明更多相关的发生机制， PTE的进展，并更好地标准化模型，以利于基本和 翻译研究工作。

项目成果

Functional definition of seizure provides new insight into post-traumatic epileptogenesis.

• DOI: 10.1093/brain/awp217
• 发表时间: 2009-10
• 期刊: Brain : a journal of neurology
• 作者: D'Ambrosio R;Hakimian S;Stewart T;Verley DR;Fender JS;Eastman CL;Sheerin AH;Gupta P;Diaz-Arrastia R;Ojemann J;Miller JW
• 通讯作者: Miller JW