Role of COX2 of Neuronal Origin in Blood-Brain Communication after status epilept

描述(申请人提供)：人类和啮齿动物的癫痫持续状态(SE)可产生认知缺陷，并触发一系列分子和细胞事件，最终导致自发癫痫的出现，即癫痫。这一过程中的一个早期事件是血脑屏障的短暂开放，从而导致血液和脑间质之间的细胞和蛋白质交换。我们的假设得到了初步证据的支持，即癫痫持续状态诱导的神经元环氧合酶2(COX2)控制着血脑屏障的破坏。具体目的是(1)确定在两种SE啮齿动物模型中，COX2在主要前脑神经元中的诱导是否触发了神经炎性级联反应，导致血脑屏障的开放、外周血白细胞的渗透、小胶质细胞的激活，最终导致癫痫；以及(2)验证星形胶质细胞或内皮细胞上的EP2受体激活调节白蛋白渗出和白细胞跨血脑屏障渗透的假说。将对匹罗卡品和海人藻酸盐SE模型进行比较，以最小化特定于模型的结论。目的1通过比较野生型小鼠和条件缺失COX2基因仅限于主要前脑神经元的小鼠在SE后炎症事件的强度。预期SE的广泛神经炎性后果将在COX2 CKO小鼠中得到缓解。第二个目标将通过a)测量前列腺素受体激动剂和拮抗剂对体外血脑屏障渗漏的影响，以及b)确定目标1中描述的SE的神经炎症后果是否被系统应用的EP2拮抗剂减弱。 公共卫生相关性：癫痫持续30分钟或更长时间的癫痫持续状态具有很高的死亡率，是一个主要的健康问题。癫痫持续状态在大脑中触发了大规模的炎症反应，这在一定程度上是导致发病率的原因。该项目旨在识别能够预防与癫痫持续状态相关的脑损伤的新型类药物化学物质。

DESCRIPTION (provided by applicant): Status epilepticus (SE) in man and rodents can produce cognitive deficits and trigger a series of molecular and cellular events that eventually culminate in the appearance of spontaneous seizures, i.e., epilepsy. An early event in this process is the transient opening of the blood-brain barrier with consequent exchange of cells and proteins between blood and brain interstitium. Our hypothesis, supported by preliminary evidence, is that neuronal cyclooxygenase 2 (COX2) induction by status epilepticus controls the breakdown of the blood-brain barrier. Specific aims are (1) to determine whether the induction of COX2 in principal forebrain neurons in both rodent models of SE triggers a neuroinflammatory cascade that causes opening of the blood-brain barrier, peripheral leukocyte infiltration, microglial activation, and eventually epilepsy; and (2) To test the hypothesis that EP2 receptor activation on astrocytes or endothelial cells regulates albumin leakage and leukocyte infiltration across the blood-brain barrier. A comparison of the pilocarpine and kainate SE models will be done to minimize model-specific conclusions. Aim 1 will be pursued by comparing the intensity of inflammatory events following SE in wildtype mice and mice with conditional deletion of the COX2 gene limited to principal forebrain neurons. The expectation is that the broad neuroinflammatory consequences of SE will be attenuated in the COX2 cKO mouse. The second aim will be pursued by a) measuring the effect of prostaglandin receptor agonists and antagonists on the leakiness of an in vitro blood-brain barrier, and b) determining whether the neuroinflammatory consequences of SE described in aim 1 are attenuated by systemically applied EP2 antagonists. PUBLIC HEALTH RELEVANCE: Status epilepticus, defined as seizures with duration 30 minutes or longer, has high mortality and is a major health concern. Status epilepticus triggers a massive inflammatory reaction in the brain that is partly responsible for morbidity. This project is designed to identify novel drug-like chemicals that can prevent the brain damage associated with status epilepticus.