Stroke Outcome in Pregnancy and Preeclampsia

妊娠期和先兆子痫的中风结果

基本信息

批准号：
10228815
负责人：
Marilyn J Cipolla
金额：
$ 42.9万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
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：
2021-04-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228815
关键词：
Acute Affect Age Alteplase Blood Vessels Brain Brain Injuries CASP3 gene Calcium Channel Blockers Case Fatality Rates Case Study Cell Death Cerebrovascular Circulation Cessation of life Child Child Care Clinical Data Data Disease Dose Edema Estrogens Experimental Models Female Fetal Development Glutamates Goals Gonadal Steroid Hormones Growth and Development function Health Hemorrhage Hour Hypertension Immunohistochemistry In Situ Nick-End Labeling Incidence Infarction Inflammation Inflammatory Injury Ischemia Ischemic Stroke Life Magnesium Sulfate Maternal Mortality Measurement Measures Microglia Middle Cerebral Artery Occlusion Modeling N-Methyl-D-Aspartate Receptors Neurologic Deficit Neurotransmitter Receptor Outcome Oxidative Stress Perfusion Peripheral Physiological Adaptation Placenta Placentation Population Postpartum Women Pre-Eclampsia Predisposition Pregnancy Pregnant Women Prevention Progesterone Proteins Public Health Publishing Randomized Rattus Reperfusion Injury Reperfusion Therapy Safety Seizures Stroke Stroke prevention TNF gene Therapeutic Tight Junctions Treatment outcome United States Up-Regulation Vascular resistance Vulnerable Populations Woman base blood-brain barrier permeabilization cell injury clinically relevant comorbidity cresyl violet effective therapy endothelial dysfunction excitotoxicity high risk improved outcome ischemic injury maternal morbidity mortality neuroinflammation neuronal excitability oxidized low density lipoprotein pregnancy disorder pregnant prevent reproductive hormone response standard of care stroke clinical trials stroke outcome stroke patient stroke risk stroke therapy young adult young woman

项目摘要

PROJECT SUMMARY Stroke in pregnancy is a major health problem in the US, with an incidence that is 3-fold higher than stroke rates in comparable nonpregnant women. Pregnancy-related stroke has a profound and devastating impact on a women’s life and her ability to care for her child or children. Complicating the public health concerns even more is the fact pregnancy-related strokes in the United States is on the rise. The increased risk of stroke in pregnancy is largely driven by the comorbidity of preeclampsia (PE), a hypertensive disorder that complicates up to 10% of all pregnancies. In fact, greater than 1/3 of women with pregnancy-related stroke have comorbid PE, increasing the risk of stroke 6-fold vs. women without PE. Relevant to this proposal, stroke in pregnancy is largely unstudied. Pregnant women have been excluded from randomized stroke clinical trials and therefore nothing is known about treatment and outcome in this population. This R21 proposal is to provide critically needed information on stroke injury and outcome in pregnancy and PE. Our overall hypothesis is that the maternal brain is more susceptible to ischemia and reperfusion injury than age-matched nonpregnant females and that this susceptibility is further exacerbated by PE. This hypothesis is based on our published and preliminary data demonstrating increased neuronal excitability and brain injury in a rat model of normal pregnancy that is further increased in a model of PE. In addition, PE is a state of high oxidative stress and neuroinflammation that could exacerbate stroke injury. Remarkably, it is unknown how pregnancy and PE affect stroke outcome. Aim 1 will use a model of transient focal ischemia in nonpregnant, normal pregnant and PE rats to determine stroke outcome (infarct, cellular injury, neurologic deficit and mortality) as well as contributors to injury, including perfusion deficit, collateral flow and reperfusion injury (edema and hemorrhagic transformation). Aim 2 will acutely treat with clinically relevant doses of magnesium sulfate (MgSO4), a safe and effective treatment in pregnancy that has been used for decades to prevent brain hyperexcitability and seizure. MgSO4 is a calcium antagonist that prevents glutamate-induced excitotoxic injury and may be beneficial in preventing stroke injury in pregnancy and PE, an excitotoxic state. Importantly, we will use MgSO4 in combination with tissue plasminogen activator (tPA) since tPA has been shown to interfere with stroke treatment. tPA alone will also be studied since it is standard of care yet the safety and therapeutic window is not known in pregnancy or PE. It is our hope that the results of this project will lead to better treatment of stroke in pregnancy.

项目概要妊娠期中风是美国的一个主要健康问题，其发病率比中风发生率高 3 倍与怀孕相关的中风对类似的非怀孕女性具有深远的破坏性影响。妇女的生活及其照顾孩子的能力使公共卫生问题变得更加复杂。事实上，在美国，与怀孕相关的中风正在增加。怀孕期间中风的风险增加。很大程度上是由先兆子痫 (PE) 的合并症引起的，先兆子痫是一种高血压疾病，可使高达 10% 的患者复杂化事实上，超过 1/3 的妊娠相关中风女性患有 PE，并且这一数字正在增加。与没有 PE 的女性相比，妊娠期中风的风险是其 6 倍。孕妇已被排除在随机卒中临床试验之外，因此对此一无所知该 R21 提案旨在提供有关中风的急需信息。我们的总体假设是，母亲的大脑更容易受到影响。与年龄匹配的非妊娠女性相比，其对缺血和再灌注损伤的敏感性更高这一假设是基于我们公布的初步数据，证明了 PE 的增加。正常妊娠大鼠模型中的神经元兴奋性和脑损伤在妊娠模型中进一步增加此外，PE 是一种高氧化应激和神经炎症状态，可能会加剧中风损伤。值得注意的是，尚不清楚妊娠和 PE 如何影响中风结果。目标 1 将使用短暂模型。对非妊娠大鼠、正常妊娠大鼠和 PE 大鼠进行局灶性缺血，以确定中风结果（梗死、细胞损伤、神经功能缺损和死亡率）以及损伤的影响因素，包括灌注缺损、侧支血流和再灌注损伤（水肿和出血性转化）。目标 2 将使用临床相关剂量进行急性治疗。硫酸镁 (MgSO4) 是一种安全有效的妊娠治疗方法，已使用数十年防止大脑过度兴奋和癫痫发作。 MgSO4 是一种钙拮抗剂，可防止谷氨酸诱导的癫痫发作。兴奋性毒性损伤，可能有益于预防妊娠期中风损伤和 PE（一种兴奋性毒性状态）。重要的是，我们将使用 MgSO4 与组织纤溶酶原激活剂 (tPA) 结合使用，因为 tPA 已被证明单独使用 tPA 来干扰中风治疗也将被研究，因为它是标准护理，但其安全性和有效性也受到关注。妊娠期或 PE 中的治疗窗口尚不清楚，我们希望该项目的结果能够导致这一结果。更好地治疗妊娠期中风。