PERINATAL HYPOXIA/ISCHEMIA MODEL OF MR AND EPILEPSY

因缺氧/缺血引起的围产期脑病可导致永久性 神经缺陷，如智力低下、癫痫和脑部 瘫痪。围产期缺氧/缺血常合并急性 癫痫发作。该研究计划的长期目标是：1)使用 动物模型以确定急性癫痫发作活动与长时间的关系 术语神经行为缺陷，以及2)确定成熟的 短期和长期癫痫发生的潜在机制 可以设计出针对年龄的预防性治疗方法。在活体大鼠体内 围产期低氧模型，一个惊人的发现是低氧导致 未成熟大鼠的脑电和行为发作，但不是 在成人身上。围产期缺氧大鼠的表现 增加了长期癫痫的易感性。不会有长期影响 关于成人低氧后癫痫发作的研究。的发展之窗 缺氧的急性和长期致痫作用都在 出生后(P)5-17天。以确定癫痫发作的程度 围产期急性缺氧期的活动影响长期 结果：大鼠表现出不同程度的癫痫样活动 低氧会伴随到成年。氟乙基诱发癫痫 这些成年大鼠的易感性将与它们的行为相关 在围产期缺氧期间。以确定大脑中哪些部位是 主要参与了低氧诱导癫痫的产生， 对早期反应基因c-fos蛋白产物的免疫反应性， 将被用作功能图。人的相对免疫反应性 新皮质区域将与边缘结构的区域进行比较， 包括在低氧后牺牲的未成熟动物的海马体。 因为有证据表明，在此期间的发展窗口 低氧诱导的癫痫发作是一段兴奋机制可能 压倒那些抑制性、兴奋性的功效 氨基酸(EAA)拮抗剂将与劳拉西潘进行比较，劳拉西潘是一种 抑制的促进者，因为他们有能力抑制急性 低氧所致癫痫发作及其长期后果。海马区和 新皮质脑片将在体外进行研究，在从 低氧未成熟大鼠隔离检查这些结构 有先天癫痫样活动的证据。这些体外实验 允许对单独的大脑区域进行研究，这在 活体，其中传入连接可能改变自发和诱发 神经元活动。动物将在体内接受药物治疗，然后 缺氧，缺氧后取出切片，以确定是否在 体外活性揭示体内药物的特定区域相关性 功效。总体目标是使用这些体内和体外模型 系统结合在一起，以确定导致 在整个动物身上观察到的独特反应。他们的基础 可以研究分子、生理和生化机制。

Perinatal encephalopathy due to hypoxia/ischemia can result in permanent neurologic deficits such as mental retardation, epilepsy and cerebral palsy. Perinatal hypoxia/ischemia is frequently complicated by acute seizures. The long term goals of this research program are 1) to use animal models to define how the acute seizure activity relates to long term neurobehavioral deficits, and 2) to determine the maturational mechanisms underlying the short and long term epileptogenesis so that age-specific preventative therapies can be devised. In an in vivo rat model of perinatal hypoxia, a striking finding is that hypoxia results in electrographic (EEG) and behavioral seizures in the immature rat, but not in the adult. Rats rendered hypoxic in the perinatal period exhibit increased long term seizure susceptibility. There is no long term effect on seizures after hypoxia at adult ages. The window of development for both the acute and long term epileptogenicity of hypoxia is between postnatal days (P) 5-17 in the rat. To determine if the level of seizure activity during acute hypoxia in the perinatal period affects long term outcome, rats exhibiting varying levels of epileptiform activity during hypoxia will be followed to adulthood. Flurothyl induced seizure susceptibility of these adult rats will be correlated to their behavior during perinatal hypoxia. To identify sites in the brain which are predominantly involved in the generation of hypoxia induced seizures, immunoreactivity to the protein product of an early response gene, c-fos, will be used as a functional map. Relative immunoreactivity in neocortical regions will be compared to that of limbic structures, including the hippocampus, in immature animals sacrificed after hypoxia. Since evidence suggests that the window of development during which hypoxia-induced seizures occur is a period when excitatory mechanisms may predominate over those which are inhibitory, the efficacy of excitatory amino acid (EAA) antagonists will be compared to lorazepam, which is a facilitator of inhibition, for their ability to suppress both the acute hypoxia-induced seizures and the long term consequences. Hippocampal and neocortical brain slices will be studied in vitro after removal from hypoxic immature rats to examine these structures in isolation for evidence of inherent epileptiform activity. These in vitro experiments allow the study of individual brain regions, which is not possible in vivo, where afferent connectivity may alter spontaneous and evoked neuronal activity. Animals will be treated with drugs in vivo prior to hypoxia, and slices will be removed after hypoxia to determine if in vitro activity reveals specific regional correlates to in vivo drug efficacy. The overall goal is to use these in vivo and in vitro model systems together to identify maturational factors responsible for the unique responses observed in the whole animal so that. their underlying Molecular, physiological, and biochemical mechanisms may be studied.