Department of Neurology, University of Mississippi Medical Center, Jackson, MS 39216, United States.
Department of Obstetrics, Wilhelmina Children's Hospital Birth Center, University Medical Center Utrecht, Utrecht, The Netherlands.
Brain Behav Immun. 2018 May;70:376-389. doi: 10.1016/j.bbi.2018.03.028. Epub 2018 Mar 26.
Reduced placental blood flow results in placental ischemia, an initiating event in the pathophysiology of preeclampsia, a hypertensive pregnancy disorder. While studies show increased mortality risk from Alzheimer's disease, stroke, and cerebrovascular complications in women with a history of preeclampsia, the underlying mechanisms are unknown. During pregnancy, placental ischemia, induced by reducing uterine perfusion pressure (RUPP), leads to cerebral edema and increased blood-brain barrier (BBB) permeability; however whether these complications persist after delivery is not known. Therefore, we tested the hypothesis that placental ischemia contributes to postpartum cerebral edema and neuroinflammation. On gestational day 14, time-pregnant Sprague Dawley rats underwent Sham (n = 10) or RUPP (n = 9) surgery and brain tissue collected 2 months post-delivery. Water content increased in posterior cortex but not hippocampus, striatum, or anterior cerebrum following RUPP. Using a rat cytokine multi-plex kit, posterior cortical IL-17, IL-1α, IL-1β, Leptin, and MIP2 increased while hippocampal IL-4, IL-12(p70) and RANTES increased and IL-18 decreased following RUPP. Western blot analysis showed no changes in astrocyte marker, Glial Fibrillary Acidic Protein (GFAP); however, the microglia marker, ionized calcium binding adaptor molecule (Iba1) tended to increase in hippocampus of RUPP-exposed rats. Immunofluorescence staining revealed reduced number of posterior cortical microglia but increased activated (Type 4) microglia in RUPP. Astrocyte number increased in both regions but area covered by astrocytes increased only in posterior cortex following RUPP. BBB-associated proteins, Claudin-1, Aquaporin-4, and zonular occludens-1 expression were unaltered; however, posterior cortical occludin decreased. These results suggest that 2 months postpartum, neuroinflammation, along with decreased occludin expression, may partly explain posterior cortical edema in rats with history of placental ischemia.
胎盘血流减少导致胎盘缺血，这是子痫前期病理生理学的起始事件，子痫前期是一种妊娠高血压疾病。虽然研究表明，有子痫前期病史的女性患阿尔茨海默病、中风和脑血管并发症的死亡风险增加，但潜在机制尚不清楚。在怀孕期间，通过降低子宫灌注压（RUPP）引起的胎盘缺血会导致脑水肿和血脑屏障（BBB）通透性增加；然而，尚不清楚这些并发症在分娩后是否持续存在。因此，我们测试了胎盘缺血导致产后脑水肿和神经炎症的假说。在妊娠第 14 天，时间怀孕的 Sprague Dawley 大鼠接受假手术（n=10）或 RUPP 手术（n=9），并在分娩后 2 个月收集脑组织。RUPP 后，后皮质的水含量增加，但海马、纹状体或前脑没有增加。使用大鼠细胞因子多谱试剂盒，RUPP 后后皮质的 IL-17、IL-1α、IL-1β、瘦素和 MIP2 增加，而海马的 IL-4、IL-12(p70)和 RANTES 增加，IL-18 减少。Western blot 分析显示星形胶质细胞标志物胶质纤维酸性蛋白（GFAP）没有变化；然而，RUPP 暴露大鼠海马中的小胶质细胞标志物离子钙结合接头分子（Iba1）有增加的趋势。免疫荧光染色显示后皮质的小胶质细胞数量减少，但 RUPP 后激活（类型 4）小胶质细胞增加。两种区域的星形胶质细胞数量都增加，但 RUPP 后仅在后皮质的星形胶质细胞覆盖面积增加。紧密连接相关蛋白 Claudin-1、水通道蛋白-4 和紧密连接蛋白-1 的表达没有改变；然而，后皮质的闭合蛋白减少。这些结果表明，产后 2 个月，神经炎症以及闭合蛋白表达减少，可能部分解释了有胎盘缺血史的大鼠后皮质水肿的原因。
