Postpartum increases in cerebral edema and inflammation in response to placental ischemia during pregnancy

Abstract

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.

Drug Transport at the Brain and Endothelial Dysfunction in Preeclampsia: Implications and Perspectives

“…The increased BBB permeability reported by both Warrington et al (2014) and Clayton et al (2018) , is partly supported by clinical studies which demonstrated that in women developing preeclampsia, blood levels of S100B, neuronal specific enolase (NSE) and neurofilament light chain (NfL), three markers of cerebral injury, were higher than those observed in women with normal pregnancies ( Bergman et al, 2018 ). Indeed, another report showed that in preeclamptic women, the levels of S100B and NSE were still high 1-year post-partum, suggesting that the alterations in the integrity of the BBB are manifest for a substantial period of time following delivery ( Bergman et al, 2016 ).…”

“…When RUPP was performed in pregnant rats at gestational day 14, edema and increased maternal BBB permeability in the anterior cerebrum were observed, with increased expression of the protein aquaporin 4 and no changes in the expression of TJ proteins ( Warrington et al, 2014 ). However, it has been reported the same procedure led to post-partum edema and increased maternal BBB permeability in the posterior cortex, probably due to reduced expression of the TJ protein occludin ( Clayton et al, 2018 ).…”

Preeclampsia and Cerebrovascular Disease

“…44 Placental-ischemic rats had evidence of cerebral edema and neuroinflammation 2 months postpartum, suggesting that the deleterious effects of PE on the NVU persist after delivery. 51 The same rats had decreased expression of occludin, a tight junction protein, in the posterior cortex; however, other tight junction proteins in the BBB were unchanged. 51 Magnesium, the standard treatment for prevention of eclamptic seizures in women with severe PE, has been shown to reduce brain edema and neuroinflammation in a rat model of eclampsia.…”

“…51 The same rats had decreased expression of occludin, a tight junction protein, in the posterior cortex; however, other tight junction proteins in the BBB were unchanged. 51 Magnesium, the standard treatment for prevention of eclamptic seizures in women with severe PE, has been shown to reduce brain edema and neuroinflammation in a rat model of eclampsia. 52 Neuronal biomarkers were elevated in serum from women with PE during pregnancy and up to a year postpartum, suggesting persistent BBB dysfunction.…”

Investigating Maternal Brain Alterations in Preeclampsia: the Need for a Multidisciplinary Effort

“…The increased BBB permeability in this model may be associated with tight junction disruption, but no direct evidence has yet been reported. Furthermore, rat studies investigating the effect of preeclampsia on brain physiology postpartum report that decreased expression of the tight junction protein occludin in the posterior cortex was associated with edema [49].…”