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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：在经历新发癫痫发作的女性（妊娠和产后早期）中诊断出的子痫，对母亲和胎儿都是致命的虽然很大一部分子痫病例影响诊断为先兆子痫是一种妊娠期高血压疾病，出现子痫导致妊娠期间癫痫发作的机制尚不完全清楚。目前，将硫酸镁（MgSO 4）给予具有严重症状的先兆子痫患者，预防癫痫发作时，开始早。然而，MgSO 4防止癫痫发作的机制活动尚不完全清楚，仍然难以预测哪些妇女会发生癫痫。我们的初步数据显示在通过手术降低子宫-胎盘灌注压诱导先兆子痫大鼠模型中（RUPP），癫痫敏感性增加。我们还发现RUPP小鼠具有更长的癫痫发作持续时间，与妊娠组相比，海马酸敏感离子通道（ASIC 2a）表达降低接受假手术的小鼠。ASIC对于维持稳态pH是重要的，特别是在癫痫发作时神经元活动增加。ASIC 2a基因敲低导致癫痫发作增加严重性和寿命，表明ASIC 2a对于癫痫发作终止是重要的。在这应用中，我们建议测试MgSO 4通过减少炎症（IL-17水平）起作用的假设，允许ASICs正常发挥功能，恢复稳态组织pH值。我们将重点关注ASIC 2a在在我们的先兆子痫小鼠RUPP模型中介导增加的癫痫发作活性。我们将利用具有遗传基因的老鼠 ASIC 2a和IL-17 ra（IL-17受体）的敲低并诱导癫痫发作戊四氮我们将使用硫酸镁的急性管理，以评估预防的作用机制，或减少经受假手术或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）ASIC 2a的敲低是否会加剧RIPP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，MgSO 4需要ASIC 2a才能具有抗癫痫作用？3)增加 IL-17导致RIPP诱导的癫痫敏感性增加，IL-17调节ASIC 2a表达吗？通过回答这些问题，我们将确定子痫的新治疗靶点，了解硫酸镁的作用机制，这代表了神经学领域的重大进展和产科