Stroke Outcome in Pregnancy and Preeclampsia

项目总结 在美国，妊娠期中风是一个主要的健康问题，其发病率是中风发病率的3倍 在可比的非怀孕妇女中。与妊娠相关的中风对 妇女的生活及其照顾子女的能力。使公众健康问题变得更加复杂 事实是，在美国，与怀孕有关的中风正在上升。怀孕期间中风风险的增加 这在很大程度上是由先兆子痫(PE)的共病引起的，这是一种高血压疾病，会使高达10%的 所有怀孕的人。事实上，超过三分之一患有妊娠相关中风的女性患有并存的PE，增加了 中风的风险是没有体育锻炼的女性的6倍。与这一建议相关的是，妊娠期中风在很大程度上没有研究。 孕妇被排除在随机中风临床试验之外，因此对此一无所知 这一人群的治疗和结果。本R21提案旨在提供有关中风的迫切需要的信息 妊娠和PE中的损伤和结局。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，这种易感性更高 PE加剧了这一现象。这一假设是基于我们公布的初步数据表明 正常妊娠大鼠模型中神经元兴奋性和脑损伤的研究 佩。此外，PE是一种高度氧化应激和神经炎症的状态，可能会加剧中风损伤。 值得注意的是，怀孕和PE是如何影响中风结局的尚不清楚。目标1将使用瞬变模型 未妊娠、正常妊娠和PE大鼠的局灶性缺血以确定卒中结果(脑梗塞，细胞损伤， 神经功能缺陷和死亡率)以及造成损伤的因素，包括灌流缺陷、侧支循环和 再灌注损伤(水肿和出血性转化)。目标2将用临床相关的剂量进行尖锐的治疗 硫酸镁(镁)，一种安全有效的妊娠治疗方法，几十年来一直用于 防止大脑过度兴奋和癫痫发作。硫酸镁是一种钙拮抗剂，可防止谷氨酸诱导 兴奋性毒性损伤，可能有益于预防妊娠和PE期间的中风损伤，PE是一种兴奋性毒性状态。 重要的是，我们将联合使用硫酸镁和组织型纤溶酶原激活剂(TPA)，因为tPA已经显示出来 干扰中风的治疗。还将单独研究TPA，因为它是护理的标准，但其安全性和 妊娠期或PE的治疗窗口尚不清楚。我们希望这个项目的结果将导致 更好地治疗妊娠期中风。

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.