Photothrombotic Brain Infarction and Epileptogenesis

光血栓性脑梗死和癫痫发生

• 批准号: 6739605
• 负责人: KEVIN M KELLY
• 金额: $ 33.46万
• 依托单位: ALLEGHENY-SINGER RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6739605
• 关键词: NMDA receptors; aging; brain injury; cerebral cortex; electroencephalography; epilepsy; glutamates; immunocytochemistry; inhibitor /antagonist; laboratory rat; stroke; thrombosis

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 animal modelinq has had limited development (Kelly, 2002). In the elderly, stroke is the dominant cause of epilepsy yet the modeling of poststroke epilepsy in aged animals has had only preliminary study (Kelly et al., 2001a). Recent studies in our laboratory have indicated that the technique of cortical photothrombosis and brain infarction can result in poststroke epilepsy in young adult rats characterized electrically by seizures originating in the peri-infarct area and behaviorally by motor arrest of the animal (Kelly et al., 2001a, Kharlamov et al., submitted). In contrast, mid-aged and aged animals demonstrated behavioral seizures characterized by brief but relatively intense rhythmic body jerking associated with focal features (Kelly et al., 2001a). We hypothesize that poststroke epileptogenesis is expressed differentially in an aging-related manner and propose to more appropriately model poststroke epilepsy in the elderly by using photothrombosis and an aging paradigm. Specific Aim #1 will characterize, compare, and contrast the electroencephalographic, behavioral, and neuroanatomical properties of 4 and 20 mo old F344 rats during epileptogenesis and the epileptic state. During photothrombosis, NMDA receptor-mediated events have been implicated in establishing subsequent cortical hyperexcitability, which could lead to the development of epileptic seizures. We hypothesize that neuroprotection limiting glutamate-mediated excitotoxicity associated with photothrombosis will prevent poststroke epileptogenesis. Specific Aim #2 will determine whether MK-801, a non-competitive NMDA receptor antagonist, is capable of preventing poststroke epileptogenesis and whether animal age is a critical variable. The short-term goals of these studies are to establish a reliable animal model of poststroke epilepsy in the elderly and to begin neuroprotection studies designed to prevent or limit poststroke epileptogenesis. The long-term goal of these studies is to advance understanding of the progressive anatomic and physiologic changes of aged brain during poststroke epileptogenesis so that the focus of therapeutic strategies can shift from control of symptoms (seizures) to prevention and cure.

描述（由申请人提供）：大量临床和人群研究中已经描述了中风后癫痫发作和癫痫。相比之下，由于动物模型的发展有限，导致中风后癫痫发生的受损大脑的病理生理学事件尚不清楚（Kelly，2002）。在老年人中，中风是癫痫的主要原因，但老年动物中风后癫痫的建模仅进行了初步研究（Kelly 等人，2001a）。我们实验室最近的研究表明，皮质光血栓形成和脑梗塞技术可导致年轻成年大鼠中风后癫痫，其特征为电学上源自梗塞周围区域的癫痫发作和行为上的动物运动停止（Kelly等人，2001a，Kharlamov等人提交）。相比之下，中年和老年动物表现出行为性癫痫发作，其特征是短暂但相对强烈的有节奏的身体抽搐，与局灶性特征相关（Kelly等人，2001a）。我们假设中风后癫痫发生以与衰老相关的方式差异表达，并建议通过使用光血栓形成和衰老范式更合适地模拟老年人中风后癫痫。具体目标#1 将描述、比较和对比 4 月龄和 20 月龄 F344 大鼠在癫痫发生和癫痫状态期间的脑电图、行为和神经解剖学特性。在光血栓形成过程中，NMDA 受体介导的事件与随后皮质过度兴奋的建立有关，这可能导致癫痫发作。我们假设限制谷氨酸介导的与光血栓形成相关的兴奋性毒性的神经保护将预防中风后癫痫的发生。具体目标#2 将确定 MK-801（一种非竞争性 NMDA 受体拮抗剂）是否能够预防中风后癫痫发生，以及动物年龄是否是一个关键变量。这些研究的短期目标是建立可靠的老年人卒中后癫痫动物模型，并开始旨在预防或限制卒中后癫痫发生的神经保护研究。这些研究的长期目标是加深对中风后癫痫发生过程中老年大脑的渐进性解剖和生理变化的了解，以便治疗策略的重点可以从控制症状（癫痫发作）转向预防和治疗。