Hypoxic-ischemic brain injury is the single most important neurologic problem in the perinatal period. In utero hemodynamic abnormalities possibly in association with elevated pro-inflammatory cytokines (cytokines) such as IL-12, IL-6, and TNF-1 predispose to brain injury, particularly in premature neonates. Systemic cytokines produced during maternal infection and/or increases in cytokines after ischemia may accentuate damage to the fetal brain. The neurovascular unit is a privileged site that consists of brain microvascular endothelium, glia, and neurons. Although cytokines are known to cross the adult blood-brain barrier (BBB), evidence to support the hypothesis that systemic cytokines cross the BBB of the fetus and premature neonate is sparse.
Our specific aims test the hypothesis that specific cytokines cross both the intact and injured BBB in the fetus to damage the brain. A consequence of this hypothesis is that blockade of these cytokines would attenuate the ischemia related damage to the neurovascular unit (BBB) and possibly the brain. A multidisciplinary approach will be used to address our hypothesis and will include physiological, biochemical, pathological, immunohistochemical, and molecular methods.
Aim 1 tests the hypothesis that cytokines such as IL-12 &IL-6 cross the BBB in a maturation-dependent manner in ovine fetuses, and that maturation-related changes in barrier permeability to cytokines are primarily related to changes in the composition of the tight junction. BBB permeability will be quantified by the integral technique with 1-aminoisobutyric acid and radiolabeled cytokines. Tight junction (TJ) proteins and mRNA will be measured by Western blot, immunohistochemistry, and Northern blot.
Aim 2 determines whether ischemic injury increases the permeability of the BBB to cytokines as a function of gestational age and tight junction maturation. Brain ischemia is induced by carotid occlusion. BBB permeability and TJ components will be measured as in Aim 1 and brain injury assessed by pathological, immunohistochemical, and molecular methods.
Aim 3 determines whether blocking the effects of cytokines with systemic infusions of neutralizing antibodies attenuates ischemic injury to the fetal neurovascular unit (BBB) and possibly the brain more in preterm than near term fetuses. IL-6 and IL-1 2 blocking antibodies will be infused before ischemia. Brain ischemia will be induced and BBB permeability, TJ components, and brain injury measured as in Aim 2. These studies will provide the first direct evidence whether systemic cytokines cross the intact or injured fetal BBB and whether blocking the effects of cytokines with neutralizing antibodies protect the fetal neurovascular unit (BBB) and brain. This project may provide new insights into novel strategies to prevent brain injury in the human fetus and/or premature infant. Perinatal hypoxic/ischemic brain injury often results in cerebral palsy (CP) and mental retardation. The incidence of CP is 40-148/1,000 in premature and 1-2/1,000 in full term infants. This project could provide new insights into novel strategies to prevent brain injury in the human fetus and/or premature infant.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Higgins, Rosemary
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Women and Infants Hospital-Rhode Island
United States
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Chen, Xiaodi; Patra, Aparna; Sadowska, Grazyna B et al. (2018) Ischemic-Reperfusion Injury Increases Matrix Metalloproteinases and Tissue Metalloproteinase Inhibitors in Fetal Sheep Brain. Dev Neurosci 40:234-245
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Patra, Aparna; Chen, Xiaodi; Sadowska, Grazyna B et al. (2017) Neutralizing anti-interleukin-1? antibodies reduce ischemia-related interleukin-1? transport across the blood-brain barrier in fetal sheep. Neuroscience 346:113-125
Spasova, Mariya S; Chen, Xiaodi; Sadowska, Grazyna B et al. (2017) Ischemia reduces inter-alpha inhibitor proteins in the brain of the ovine fetus. Dev Neurobiol 77:726-737
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