Developing a rat model of posttraumatic epilepsy

建立创伤后癫痫大鼠模型

• 批准号: 6846023
• 负责人: PHILIP A SCHWARTZKROIN
• 金额: $ 13.74万
• 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/6846023
• 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.

目前应用的目标是开发一种创伤后癫痫的啮齿动物模型。这个 这种模型的重要性来自两个相互关联但又相互独立的观察：1)创伤后癫痫具有相当大的临床意义。与未受伤的人群相比，头部创伤患者患癫痫的风险明显更高。2)创伤后癫痫通常与从受伤到出现临床癫痫障碍之间有一段可变的“潜伏期”。这一潜伏期为了解潜在的致痫过程提供了一个重要的窗口，这些致痫过程可以通过新的抗癫痫疗法进行靶向治疗。 虽然有大量关于创伤性脑损伤(TBI)的研究，但令人惊讶的是，关于创伤性癫痫的实验/动物模型工作很少。这一差距可能至少部分是由于在实验操作后难以证明啮齿动物(大鼠或小鼠)的慢性癫痫状态，这些操作会造成创伤性脑损伤(例如，液体冲击、体重下降、受控皮质撞击)。研究人员在癫痫持续状态后产生了大鼠的慢性癫痫状态，但充其量也就是在脑外伤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脑创伤模型，在这种模型中，潜伏期之后是慢性癫痫状态。我们首先将通过控制皮质冲击的关键变量(例如，影响位置、穿透程度)来实现这一目标，基于最常见的与癫痫持续状态模型相关的神经病理学，我们假设，脑损伤导致S！腹侧海马区严重损害，和/或双侧海马区损伤和重组，将导致慢性癫痫发作活动--特别是当损伤与严重的缺氧后创伤相关时。一旦开发出可靠的模型，我们 将开始评估诱因(例如，遗传、早期侮辱)对建立创伤后癫痫状态的作用。 将使用长期视频/脑电遥测监测来确定脑外伤动物的癫痫发作活动。此外，还将测试动物的癫痫阈值(对氟乙基诱发癫痫的潜伏期)。经过处理和测试的动物将被牺牲以进行损伤的组织学分析。