Mechanisms of Seizure in Pregnancy and Preeclampsia

项目总结： 在经历新的癫痫发作的妇女(怀孕和产后早期)被诊断为子痫，可能是 对母亲和胎儿都是致命的。而很大比例的子痫病例会影响有诊断的妇女 先兆子痫，一种妊娠高血压疾病，一些怀孕其他方面健康的妇女 出现子痫。导致怀孕期间癫痫发作的机制尚不完全清楚。目前， 硫酸镁用于有严重症状的先兆子痫患者，对 及早开始预防癫痫发作。然而，硫酸镁预防癫痫发作的机制 活动尚不完全清楚，还很难预测哪些女性会出现癫痫发作。我们的初步数据 结果表明，在先兆子痫大鼠模型中，通过手术降低子宫-胎盘灌注压 (RUPP)，癫痫敏感度增加。我们还表明，RUPP小鼠的癫痫发作持续时间更长，并具有 与妊娠相比，海马酸感受离子通道(ASIC2a)的表达减少 接受假手术的小鼠。ASIC对于维持动态平衡PH值很重要，尤其是在 癫痫发作时出现的神经元活动增加。ASIC2a基因敲除导致癫痫发作增加 妊娠小鼠的严重程度和寿命表明ASIC2a对于终止癫痫非常重要。在这 应用，我们建议检验这一假设，即硫酸镁通过减少炎症(IL-17水平)而起作用 允许ASIC正常工作，以恢复体内平衡组织的pH值。我们将重点介绍ASIC2a在 在我们的子痫前期小鼠RUPP模型中调节癫痫发作活动的增加。我们将利用具有基因的小鼠 抑制ASIC2a和IL-17ra(IL-17受体)并在药理上诱导癫痫发作 戊四唑。我们将使用急性给予硫酸镁来评估预防的行动机制 或减少接受假手术或RUPP手术的小鼠的癫痫发作活动。我们建议回答以下问题 问题：1)ASIC2a基因的敲除是否加剧了RUPP诱导的癫痫敏感性的增加？2)是 在我们的先兆子痫小鼠模型中，硫酸镁具有抗癫痫作用所需的ASIC2a增加了 IL-17与RUPP诱导的癫痫敏感性增加有关，IL-17是否调节ASIC2a的表达？ 通过回答这些问题，我们将找到治疗子痫的新靶点，并将有更好的 对代表神经学领域重大进展的硫酸镁作用机制的理解 还有产科。

PROJECT SUMMARY: Eclampsia, diagnosed in women (pregnant and early postpartum) who experience new onset seizures, can be deadly to both the mother and fetus. While a large proportion of eclampsia cases affect women with a diagnosis of preeclampsia, a hypertensive disorder of pregnancy, some women with otherwise healthy pregnancies develop eclampsia. The mechanisms contributing to seizures during pregnancy are not fully known. Currently, magnesium sulfate (MgSO4) is administered to preeclampsia patients with severe symptoms and is effective in preventing seizures when started early. However, the mechanisms by which MgSO4 protects against seizure activity is not fully known and it is still difficult to predict which women will develop seizures. Our preliminary data show that in a rat model of preeclampsia, induced by surgical reduction of utero-placental perfusion pressure (RUPP), seizure sensitivity is increased. We also show that RUPP mice have higher seizure duration and have decreased acid sensing ion channels (ASIC2a) expression in the hippocampus when compared to pregnant mice that underwent sham surgery. ASICs are important for maintaining homeostatic pH especially after increased neuronal activity as occurs in seizures. Genetic knockdown of ASIC2a led to increased seizure severity and longevity in pregnant mice indicating that ASIC2a is important for seizure termination. In this application, we propose to test the hypothesis that MgSO4 acts by reducing inflammation (IL-17 levels) which allows ASICs to function normally to restore homeostatic tissue pH. We will focus on the role of ASIC2a in mediating increased seizure activity in our mouse RUPP model of preeclampsia. We will utilize mice with genetic knockdown of ASIC2a and IL-17ra (the IL-17 receptor) and induce seizures pharmacologically using pentylenetetrazol. We will use acute administration of MgSO4 to assess the mechanisms of action in preventing or reducing seizure activity in mice subjected to sham or RUPP surgery. We propose to answer the following questions: 1) Does knockdown of ASIC2a exacerbate RUPP-induced increases in seizure sensitivity? 2) Is ASIC2a required for MgSO4 to have anti-seizure effects in our mouse model of preeclampsia? 3) Is increased IL-17 responsible for RUPP-induced increases in seizure sensitivity and does IL-17 regulate ASIC2a expression? By answering these questions, we will identify new therapeutic targets for eclampsia and will have a better understanding of the mechanisms of action of MgSO4 which represents major advances in the field of neurology and obstetrics.