Mechanisms of Seizure in Pregnancy and Preeclampsia

妊娠期癫痫发作和先兆子痫的机制

基本信息

批准号：
10279955
负责人：
Junie Paula Warrington
金额：
$ 38.95万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10279955
关键词：
ASIC channel Acute Affect Astrocytes Behavior Behavioral Blood Circulation Cations Cerebrospinal Fluid Cerebrovascular Circulation Cerebrum Chemicals Chronic Clinic Coma Data Dendritic Spines Diagnosis Discipline of obstetrics Eclampsia Epilepsy Fetal Death Fetus Genetic Healthcare Hippocampus (Brain)Homeostasis Infant Mortality Inflammation Inflammatory Infusion procedures Interleukin-17 Ion Channel Protein Ischemia Knockout Mice Laboratories Laser Speckle Imaging Longevity Magnesium Sulfate Maternal Mortality Measures Mediating Modeling Molecular Mothers Mus Neurology Neurons Operative Surgical Procedures Pathologic Patients Pentylenetetrazole Perfusion Peripheral Nervous System Pharmacology Physiological Placenta Positioning Attribute Postpartum Period Pre-Eclampsia Predisposition Pregnancy Premature Birth Prevention strategy Proteins Protons Rattus Recombinants Role Seizures Severities Smooth Muscle Myocytes Symptoms Synapses Synaptosomes Testing Tissues Vascular Smooth Muscle Vasodilation Woman Work attenuation cytokine experience healthy pregnancy improved infant morbidity knock-down mortality risk mouse model neurotransmission new therapeutic target normotensive novel pregnancy disorder pregnancy hypertension pregnant pressure prevent protective effect receptor sham surgery treatment strategy voltage

项目摘要

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.

项目概要：子痫是在经历新发癫痫发作的女性（怀孕期和产后早期）中诊断出来的。对母亲和胎儿都是致命的。虽然很大一部分子痫病例影响已诊断的女性先兆子痫（一种妊娠期高血压疾病），一些妊娠期健康的女性发展子痫。妊娠期间癫痫发作的机制尚不完全清楚。现在，硫酸镁（MgSO4）用于症状严重的先兆子痫患者，可有效治疗尽早开始预防癫痫发作。然而，MgSO4 防止癫痫发作的机制活动尚不完全清楚，并且仍然很难预测哪些女性会出现癫痫发作。我们的初步数据研究表明，在先兆子痫大鼠模型中，通过手术降低子宫胎盘灌注压诱发（RUPP），癫痫发作敏感性增加。我们还表明 RUPP 小鼠的癫痫发作持续时间更长并且具有与怀孕时相比，海马中的酸感应离子通道 (ASIC2a) 表达减少接受假手术的小鼠。 ASIC 对于维持 pH 值稳态非常重要，尤其是在癫痫发作时神经元活动增加。 ASIC2a 基因敲除导致癫痫发作增加怀孕小鼠的严重程度和寿命表明 ASIC2a 对于癫痫发作终止很重要。在这个应用中，我们建议检验 MgSO4 通过减少炎症（IL-17 水平）发挥作用的假设，允许 ASIC 正常运行以恢复组织 pH 值稳态。我们将重点关注 ASIC2a 在以下方面的作用：在我们的先兆子痫小鼠 RUPP 模型中介导癫痫发作活动增加。我们将利用具有遗传基因的小鼠敲低 ASIC2a 和 IL-17ra（IL-17 受体）并使用药物诱导癫痫发作戊四唑。我们将使用 MgSO4 的急性给药来评估预防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 的敲低是否会加剧 RUPP 诱导的癫痫敏感性增加？ 2) 是在我们的先兆子痫小鼠模型中，MgSO4 需要 ASIC2a 才能发挥抗癫痫作用吗？ 3）增加 IL-17 负责 RUPP 诱导的癫痫敏感性增加，IL-17 是否调节 ASIC2a 表达？通过回答这些问题，我们将确定子痫的新治疗靶点，并有更好的治疗方案。了解 MgSO4 的作用机制，这代表了神经病学领域的重大进展和产科。