Eclampsia, the new onset of seizure in a woman with preeclampsia, is a serious complication of pregnancy with life-threatening consequences for both mother and fetus. Eclampsia remains a leading cause of maternal mortality worldwide, yet there are no reliable tests or symptoms for predicting the development of seizure because of our lack of understanding of its cause. Importantly, seizure can also occur spontaneously during normal pregnancy, suggesting that an adaptation to pregnancy may provoke seizure. The long-term goal of this project is to define changes in the brain and cerebral circulation during pregnancy that promote seizure in the absence of preeclampsia, and how the preeclamptic state, superimposed on pregnancy, predisposes the brain to seizure, leading to eclampsia. Our central hypothesis is that seizure in women with uncomplicated pregnancies is due to a failure of the blood-brain barrier (BBB) to adapt to high levels of seizure-provoking circulating factors that rise over the course of gestation and pass into the brain to cause neuronal excitability. We further hypothesize that oxidative injury to the BBB during severe preeclampsia initiates a cascade of events that include neuroinflammation that lowers the seizure threshold and promotes susceptibility to seizure. These hypotheses are based on our previous study that found circulating serum factors, present in the blood of normal pregnant rats, causes neuronal excitability when exposed to cultured brain slices, suggesting there are seizure-provoking factors in the maternal blood. However, the brain is not normally exposed to serum factors due to the highly protective nature of the BBB. In addition, our preliminary data using a rat model found that the brain is more susceptible to seizure activity during pregnancy. We hypothesize that as seizure-provoking factors rise and seizure susceptibility increases over the course of gestation, the BBB adapts to prevent passage of these factors into a hyperexcitable brain. When this adaptation fails, de novo seizure occurs. Thus, Aim 1 is to determine the role of the BBB in protecting the brain from seizure during normal pregnancy. We will measure the expression and activity of efflux transporters, seizure threshold and neuronal excitability in response to serum over the course of gestation and investigate the nature of hyperexcitable serum factors. Our preliminary studies have also shown using a rat model of severe preeclampsia that seizure susceptibility is further increased from that of normal pregnancy and associated with oxidative disruption of the BBB and microglial activation. We hypothesize that oxidative stress during severe preeclampsia causes BBB disruption that leads to neuroinflammation and a lowered seizure threshold. Thus, Aim 2 is to investigate the mechanism by which severe preeclampsia promotes seizure in the maternal brain. We will use a rat model of severe preeclampsia to probe relevant pathways involved in oxidative stress, BBB disruption and microglial activation that can influence seizure threshold. The outcome of these studies will provide critically needed information on the mechanisms of spontaneous seizure during pregnancy and preeclampsia.

Public Health Relevance

The outcome of these studies will provide critically needed information on the mechanisms by which seizure occurs during pregnancy and preeclampsia. The proposed research is aimed at better identifying women at risk of seizure during pregnancy and providing more targeted and effective treatment strategies for preventing the eclamptic seizure.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01NS045940-10
Application #
8693282
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Burlington
State
VT
Country
United States
Zip Code
05405
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