Photothrombotic Brain Infarction and Epileptogenesis

描述（由申请人提供）：卒中后发作和癫痫在许多临床和人群研究中都有描述。相比之下，由于动物模型的发展有限，受伤脑的病理生理事件并不能很好地理解卒中后癫痫发生（Kelly, 2002）。在老年人中，中风是癫痫的主要原因，但对老年动物中风后癫痫的建模仅进行了初步研究（Kelly et al., 2001a）。我们实验室最近的研究表明，皮质光血栓形成和脑梗死技术可导致年轻成年大鼠中风后癫痫，其电特征是源自梗死周围区域的癫痫发作，行为特征是动物的运动停止（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癫痫，其特征是与局灶特征相关的短暂但相对强烈的有节奏的身体抽搐（Kelly et al., 2001a）。我们假设脑卒中后癫痫发生以与年龄相关的方式表达差异，并提出通过光血栓形成和衰老范式更合适地模拟老年人脑卒中后癫痫。特异性目标#1将描述、比较和对比4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受体介导的事件涉及建立随后的皮质高兴奋性，这可能导致癫痫发作的发展。我们假设限制谷氨酸介导的与光血栓相关的兴奋性毒性的神经保护将防止中风后癫痫发生。特异性目标#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脑卒中后癫痫动物模型，并开始旨在预防或限制脑卒中后癫痫发生的神经保护研究。这些研究的长期目标是促进对脑卒中后癫痫发生过程中老年脑的渐进解剖和生理变化的理解，从而使治疗策略的重点从症状控制（癫痫发作）转向预防和治疗。

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.