Developing a rat model of posttraumatic epilepsy

建立创伤后癫痫大鼠模型

• 批准号: 6756357
• 负责人: PHILIP A SCHWARTZKROIN
• 金额: $ 20.67万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6756357
• 关键词: brain injury; cerebral ischemia /hypoxia; chronic brain damage; disease /disorder model; electroencephalography; epilepsy; genetic susceptibility; hippocampus; histology; laboratory rat; model design /development; neuropathology; telemetry; trauma

The goal of the current application is to develop a rodent model of post-traumatic epilepsy. The importance of such a model arises from two related but separate observations: 1) Post-traumatic epilepsy is of considerable clinical concern. The population of individuals with traumatic head injury has a significantly higher risk of developing epilepsy than the uninjured population. 2) Post-traumatic epilepsy is often associated with a variable "latent" period between injury and appearance of a clinical seizure disorder. This latent period provides an important window into potential epileptogenic processes that can be targeted with new anti-epileptogenic therapies. While there is a large body of research focusing on traumatic brain injury (TBI), there has been surprisingly little experimental/animal model work on post-traumatic epilepsy. This gap is likely due, at least in part, to the difficulty in demonstrating a chronic epileptic condition in rodents (rats or mice) following experimental manipulations that produce traumatic brain injury (e.g., fluid percussion, weight drop, controlled cortical impact). Investigators have produced chronic seizure states in rats following status epilepticus, but at best have produced a more seizure-prone animal (lower seizure threshold) following TBI. We propose to develop a rat model of TBI in which a latent period is followed by a chronic seizure state. We will approach this goal initially by manipulating key variables of controlled cortical impact (CCI) (e.g., position of impact, degree of penetration), Based on the neuropathology mostoften associated with status epilepticus models, we hypothesize that TBI insults that result in s!gnificant damage to ventral hippocampus, and/or in bilateral hippocampal injury and reorganization, will result in chronic seizure activity - especially if the injury is associated with significant post-trauma hypoxia. Once a reliable model has been developed, we will begin to assess the contributions of predisposing factors (e.g., genetics, early insult) to the establishment of a post-traumatic epileptic condition. Determination of seizure activity in animals with TBI will be carried': out using long-term video/EEG telemetric monitoring. In addition, animals will be tested for seizure threshold (latency to flurothyl-induced seizures). Treated and tested animals will be sacrificed for histological analysis of damage.

本申请的目标是开发创伤后癫痫的啮齿动物模型。的 这种模型的重要性来自两个相关但独立的观察：1）创伤后癫痫是相当重要的临床问题。与未受伤的人群相比，患有创伤性头部损伤的人群患癫痫的风险明显更高。2)创伤后癫痫通常与损伤和临床癫痫发作障碍的出现之间的可变“潜伏”期相关。这个潜伏期为了解潜在的致癫痫过程提供了一个重要的窗口，可以通过新的抗癫痫疗法来针对这些过程。 虽然有大量的研究集中在创伤性脑损伤（TBI），但令人惊讶的是，关于创伤后癫痫的实验/动物模型工作很少。这一差距可能是由于，至少部分是由于，在产生创伤性脑损伤的实验操作（例如，流体冲击、重量下降、受控皮质撞击）。研究人员已经在癫痫持续状态后的大鼠中产生了慢性癫痫发作状态，但最多在TBI后产生了更容易癫痫发作的动物（较低的癫痫发作阈值）。 我们建议建立一种大鼠TBI模型，其中潜伏期之后是慢性癫痫发作状态。我们将通过操纵受控皮质影响（CCI）的关键变量（例如，根据癫痫持续状态模型的神经病理学，我们假设TBI损伤导致癫痫持续状态的发生是由于TBI损伤引起的。腹侧海马体的显著损伤和/或双侧海马体损伤和重组将导致慢性癫痫发作活动-特别是如果损伤与显著的创伤后缺氧相关。一旦开发出可靠的模型，我们 将开始评估诱发因素的作用（例如，遗传学，早期损伤）建立创伤后癫痫状态。 将使用长期视频/EEG遥测监测确定TBI动物的癫痫发作活动。此外，还将检测动物的癫痫发作阈值（至氟乙烯诱导癫痫发作的潜伏期）。将处死处理和试验动物，以进行损伤的组织学分析。