Stroke Outcome in Pregnancy and Preeclampsia

项目摘要 在美国，妊娠期中风是一个主要的健康问题，其发病率是中风率的3倍 在可比较的非妊娠女性中。妊娠相关的中风对一个人有着深远的和毁灭性的影响。 妇女的生活和照顾子女的能力。使公众健康问题更加复杂 在美国，与怀孕有关的中风正在上升。妊娠期中风风险增加 在很大程度上是由先兆子痫（PE）的合并症驱动的，PE是一种高血压疾病， 所有怀孕。事实上，超过1/3的妊娠相关性卒中患者合并PE， 中风风险是无PE女性的6倍。与这一建议相关的是，妊娠期卒中在很大程度上未被研究。 孕妇被排除在随机卒中临床试验之外，因此对 在这个人群中的治疗和结果。本R21提案旨在提供卒中方面急需的信息 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 缺血和再灌注损伤比年龄匹配的非妊娠女性，这种易感性是进一步 加剧了PE。这一假设是基于我们公布的初步数据，表明增加 正常妊娠大鼠模型中的神经元兴奋性和脑损伤， 体育课此外，PE是一种高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，尚不清楚妊娠和PE如何影响卒中结局。目标1将使用瞬态模型 在非妊娠、正常妊娠和PE大鼠中进行局灶性局部缺血以确定中风结果（梗塞，细胞损伤， 神经功能缺损和死亡率）以及损伤的促成因素，包括灌注缺损、侧支血流和 再灌注损伤（水肿和出血性转化）。Aim 2将采用临床相关剂量进行急性治疗 硫酸镁（MgSO 4）是一种安全有效的妊娠治疗方法，几十年来一直被用于 防止大脑过度兴奋和癫痫发作。MgSO 4是一种钙拮抗剂，可防止谷氨酸诱导的 这可能有助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，我们将使用硫酸镁与组织纤溶酶原激活剂（tPA）的组合，因为tPA已被证明 干扰中风治疗也将单独研究tPA，因为它是标准护理，但安全性和 妊娠或PE的治疗窗未知。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.