Middle Cerebral and Common Artery Occlusion and Poststroke Epilepsy

描述（由申请人提供）：在许多临床和人群研究中描述了卒中后癫痫发作和癫痫。与此相反，脑损伤的病理生理学事件，建立中风后癫痫的理解并不充分，因为没有标准的动物模型中风后癫痫。在老年人中，脑卒中是癫痫的主要原因，但在老年动物中建立脑卒中后癫痫模型的研究还很有限。我们实验室最近的初步研究表明，短暂的（3小时）单侧（左侧）大脑中动脉（MCA）和颈总动脉（CCA）闭塞（MCA/CCAO）导致中风后癫痫发生率低于4月龄雄性Fischer 344（F344）大鼠比20月龄动物在2个月内的损害。基于这些发现，我们的中心假设是MCA/CCAO可以导致癫痫发作，并且随着年龄的增长而更频繁地表达。将通过将我们的初步研究扩展至4、12和20月龄雄性F344大鼠并进行短暂的（具体目标#1）或永久（具体目标#2）单侧MCA/CCAO，随后进行4个月的间歇性视频脑电图（EEG）监测，梗死核心的形态测定，以及使用体视学技术评估半影区和远端区域内的神经元和神经胶质。这些特定目的将表征缺血/梗死（有或无再灌注损伤）与动物年龄增长和长期监测期间卒中后癫痫发生的表达之间的关系。本提案的短期目标是建立老年人卒中后癫痫的生理相关模型的关键实验组成部分。这些研究的长期目标是提供卒中后癫痫发生的机制描述，从而能够转化为旨在预防或阻止老年人卒中后癫痫发展的临床试验。 拟议的研究项目旨在建立一个动物模型，以研究中风如何导致老年人癫痫发作。通过开发一个可靠的中风后癫痫模型，可以更好地了解和理解为什么中风会导致某些患者的癫痫发作和癫痫，而不是在其他患者中-大约15-20%的老年患者会在中风后发生癫痫。具体来说，这项研究的重点是描述和分析一些重要的电和解剖学变化发生在年轻，中年和老年人的大脑中风后，可能导致癫痫发作的发展在短期内和/或癫痫在长期。通过识别中风后大脑中发生的关键变化，有可能开发新的和明显改善的药物来预防或限制癫痫发作的发展。拟议的研究旨在最终将治疗的重点从控制症状，即，癫痫发作一旦确立，就要治疗，要防治。中风后立即使用标准抗癫痫（抗癫痫）药物可能会在短期内防止癫痫发作，但它们在防止其他癫痫发作方面无效。希望拟议的研究可以产生一个可靠的老年人中风后癫痫模型，最终将发展成新的和有效的药物，可以给中风后的患者，以防止或限制癫痫发作的发展。

DESCRIPTION (provided by applicant): Poststroke seizures and epilepsy have been described in numerous clinical and population studies. In contrast, the pathophysiological events of injured brain that establish poststroke epileptogenesis are not well understood because there is no standard animal model of poststroke epilepsy. In the elderly, stroke is the dominant cause of epilepsy yet the modeling of poststroke epilepsy in aged animals has had only limited study. Recent pilot studies in our laboratory indicate that transient (3 hr) unilateral (left-sided) middle cerebral artery (MCA) and common carotid artery (CCA) occlusion (MCA/CCAO) results in poststroke epilepsy less frequently in 4 mo old male Fischer 344 (F344) rats than in 20 mo old animals within 2 months of lesioning. Based on these findings, our central hypothesis is that MCA/CCAO can result in epileptic seizures that are more frequently expressed with advancing age. This hypothesis will be tested by extending our pilot studies to 4, 12, and 20 mo old male F344 rats and performing either transient (Specific Aim #1) or permanent (Specific Aim #2) unilateral MCA/CCAO followed by 4 months of intermittent video-electroencephalogram (EEG) monitoring, morphometry of the infarct core, and assessment of neurons and glia within penumbral and remote areas using stereological techniques. These Specific Aims will characterize the relationship of ischemia/infarction, with or without reperfusion injury, to advancing animal age and the expression of poststroke epileptogenesis during long-term monitoring. The short-term goal of this proposal is to establish the critical experimental components of a physiologically relevant model of poststroke epilepsy in the elderly. The long-term goal of these studies is to provide a mechanistic delineation of poststroke epileptogenesis that can enable translation to clinical trials designed to prevent or halt the development of poststroke epilepsy in the elderly. The proposed research project is intended to establish an animal model to study how stroke can result in epileptic seizures in the elderly. By developing a reliable model of poststroke epilepsy, improved insight and understanding can be gained in knowing why stroke can result in seizures and epilepsy in some patients but not in others - approximately 15-20% of elderly patients will develop epilepsy following a stroke. Specifically, this study is focused on describing and analyzing some of the important electrical and anatomical changes that occur in the young, mid-aged, and aged brain following a stroke that potentially lead to the development of seizures in the short term and/or epilepsy in the long term. By identifying critical changes that occur in the brain after stroke, it may be possible to develop new and markedly improved medications to prevent or limit the development of epileptic seizures. The proposed studies are designed to ultimately shift the focus of therapies from the control of symptoms, i.e., treating seizures once epilepsy has been established, to prevention and cure. Use of standard antiepileptic (antiseizure) medications immediately following a stroke may prevent seizures in the short term, but they are ineffective in preventing the establishment of epilepsy in others. It is hoped that the proposed research can produce a reliable model of poststroke epilepsy in the elderly that will ultimately evolve into the development of new and effective medications that can be given to patients following stroke to prevent or limit the development of epileptic seizures.