Magnesium Sulfate Prevents Placental Ischemia-Induced Increases in Brain Water Content and Cerebrospinal Fluid Cytokines in Pregnant Rats

Abstract

Magnesium sulfate (MgSO4) is the most widely used therapy in the clinic to prevent the progression of preeclampsia, a hypertensive disorder of pregnancy, to eclampsia. Eclampsia, manifested as unexplained seizures and/or coma during pregnancy or postpartum, accounts for ~13% of maternal deaths worldwide. While MgSO4 continues to be used in the clinic, the mechanisms by which it exerts its protective actions are not well understood. In this study, we tested the hypothesis that MgSO4 protects against placental ischemia-induced increases in brain water content and cerebrospinal fluid cytokines. To test this hypothesis, MgSO4 was administered via mini-osmotic pump (60 mg/day, i.p.) to pregnant and placental ischemic rats, induced by mechanical reduction of uterine perfusion pressure, from gestational day 14–19. This treatment regimen of MgSO4 led to therapeutic level of 2.8 ± 0.6 mmol/L Mg in plasma. MgSO4 had no effect on improving placental ischemia-induced changes in mean arterial pressure, number of live fetuses, or fetal and placental weight. Placental ischemia increased, while MgSO4 prevented the increase in water content in the anterior cerebrum. Cytokine and chemokine levels were measured in the cerebrospinal fluid using a multi-plex assay. Results demonstrate that cerebrospinal fluid, obtained via the cisterna magna, had reduced protein, albumin, interleukin (IL)-17A, IL-18, IL-2, eotaxin, fractalkine, interferon gamma, vascular endothelial growth factor (VEGF), and macrophage inflammatory protein (MIP)-2 following MgSO4 treatment. These data support the hypothesis that MgSO4 offers neuroprotection by preventing placental ischemia-induced cerebral edema and reducing levels of cytokines/chemokines in the cerebrospinal fluid.

Perinatal Micro-Bleeds and Neuroinflammation in E19 Rat Fetuses Exposed to Utero-Placental Ischemia

“…Previously, we reported that eotaxin (CCL11) is increased in the cerebrospinal fluid of placental ischemic dams [42,49]. In the current study, we found increased levels of eotaxin in the brains of fetuses exposed to placental ischemia.…”

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

“…Both preeclampsia patients and the rat model of placental ischemia are characterized by increased levels of circulating and placental inflammatory cytokines during pregnancy. Importantly, we recently showed that cerebrospinal fluid levels of the cytokines/chemokines eotaxin, IL-2, IL-17, and IL-18 are increased in the placental ischemic rat (Warrington, 2015; Zhang and Warrington, 2016). In this study, we show that 2 months after delivery, rats exposed to placental ischemia have increased levels of the anti-inflammatory cytokines IL-4 and IL-10, and a significant increase in the pro-inflammatory cytokines, IL-17, IL-1α, IL-1β, Leptin, and MIP-2 in the posterior cortex where water content was significantly increased.…”

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

“…The mechanism of action by which magnesium sulfate exerts its effects is unknown, but despite this limitation, it is widely considered a neuroprotective agent capable of reducing BBB permeability in animal models of brain injury ( Li et al, 2017 ). Furthermore, a recent study demonstrated that magnesium sulfate reduced the water content in the anterior cerebrum, as well protein, cytokine, chemokine and VEGF levels in cerebrospinal fluid of rats subjected to the RUPP procedure ( Zhang and Warrington, 2016 ). The above findings are important since the transport of drugs and endogenous mediators across the choroid plexus, which constitutes the blood-cerebrospinal fluid barrier, is a subject that is receiving increasing interest.…”