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.

项目摘要：经历新发作性癫痫发作的女性（孕妇和早期产后）被诊断出的eClampsia可能是对母亲和胎儿都致命。虽然大部分子痫病例会影响有诊断的妇女先兆子痫，一种怀孕的高血压障碍，一些其他健康怀孕的妇女发展子痫。在怀孕期间导致癫痫发作的机制尚不清楚。现在，将硫酸镁（MGSO4）施用针对患有严重症状的先兆子痫患者，并且有效早点开始时防止癫痫发作。但是，MGSO4防止癫痫发作的机制活动尚不清楚，仍然很难预测哪些女性会出现癫痫发作。我们的初步数据表明，在先兆子痫的大鼠模型中，通过手术降低子宫置换压力引起的（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高，并且具有与孕妇相比接受假手术的小鼠。 ASIC对于维持稳态pH非常重要癫痫发作中的神经元活性增加。 ASIC2A的遗传敲低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，我们建议检验以下假设：MGSO4通过减少炎症（IL-17水平）起作用，该假设允许ASIC正常运作以恢复稳态组织pH。我们将专注于ASIC2A在介导我们的小鼠前启示性小鼠RUPP模型中的癫痫发作活性增加。我们将利用遗传的小鼠敲低ASIC2A和IL-17RA（IL-17受体），并使用药理诱导癫痫发作甲基苯甲酸。我们将使用MGSO4的急性给药来评估防止的作用机制或减少接受假手术或RUPP手术的小鼠的癫痫发作活性。我们建议回答以下内容问题：1）ASIC2A的敲低是否加剧了Rupp诱导的癫痫发作敏感性的增加？ 2）是 MGSO4是否需要在我们的小鼠前启示性模型中具有抗塞菌作用？ 3）增加了 IL-17负责RUPP诱导的癫痫发作敏感性增加，IL-17是否调节ASIC2A表达？通过回答这些问题，我们将确定Eclampsia的新治疗靶标的理解MGSO4的作用机理，该机制代表神经病学领域的重大进步和妇产科。