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

描述（由申请人提供）：人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，最终导致自发性癫痫发作的出现，即，癫痫这个过程的早期事件是血脑屏障的短暂开放，随后在血液和脑屏障之间进行细胞和蛋白质的交换。我们的假设，支持的初步证据，是神经元环氧合酶2（COX 2）诱导癫痫持续状态控制血脑屏障的破坏。具体的目的是（1）确定在两种SE啮齿动物模型中，在主要前脑神经元中COX 2的诱导是否触发神经炎级联反应，其引起血脑屏障的开放、外周白细胞浸润、小胶质细胞活化和最终癫痫;以及（2）为了验证星形胶质细胞或内皮细胞上的EP 2受体活化调节白蛋白渗漏和白细胞浸润穿过血管的假设，血脑屏障将对毛果芸香碱和红藻氨酸SE模型进行比较，以最大限度地减少模型特定的结论。通过比较野生型小鼠和限制于主要前脑神经元的COX 2基因条件性缺失的小鼠SE后炎症事件的强度来追求目标1。预期SE的广泛神经炎症后果将在COX 2 cKO小鼠中减弱。第二个目的将通过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，和B）确定目的1中所述的SE的神经炎性后果是否被全身应用的EP 2拮抗剂减弱来实现。

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.