Photothrombotic Brain Infarction and Epileptogenesis

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。相反，由于动物模型的发展有限，对脑损伤导致卒中后癫痫发生的病理生理学事件还不清楚（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.，2001年a）。我们实验室的最近研究已经表明，皮质光血栓形成和脑梗塞的技术可以导致年轻成年大鼠的中风后癫痫，其特征在于起源于梗塞周围区域的电癫痫发作和动物运动停止的行为（Kelly等人，2001 a，Kharlamov等人，提交）。相比之下，中年和老年动物表现出以与病灶特征相关的短暂但相对强烈的节律性身体抽搐为特征的行为癫痫发作（Kelly等人，2001年a）。我们假设，中风后癫痫的差异表达与年龄相关的方式，并提出更适当的模型中风后癫痫在老年人中使用光血栓和老化的范例。具体目标#1将表征、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的皮质过度兴奋有关，这可能导致癫痫发作的发生。我们假设，限制谷氨酸介导的兴奋性毒性与光血栓形成的神经保护将防止中风后癫痫发生。具体目标#2将确定MK-801（一种非竞争性NMDA受体拮抗剂）是否能够预防卒中后癫痫发生，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一个可靠的老年中风后癫痫动物模型，并开始旨在预防或限制中风后癫痫发生的神经保护研究。这些研究的长期目标是进一步了解中风后癫痫发生过程中老年脑的渐进性解剖和生理变化，以便治疗策略的重点可以从控制症状（癫痫发作）转移到预防和治疗。

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.