Cytokines and the blood-brain barrier in the ovine fetus

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 DESCRIPTION (provided by applicant): Perinatal brain injury often results in cerebral palsy and neurodevelopmental disability. Consequently, developmental disabilities place a huge burden on society, emphasizing the paramount need for improved prevention/treatment strategies to reduce individual and societal burdens related to perinatal brain damage. Therapeutic strategies are currently not available for infants with brain damage, except for hypothermia, which can only be used in full term infants for hypoxic-ischemic encephalopathy and is only partially protective. Recent studies suggest that fetal inflammation is a strong predictor of perinatal brain injury. Inflammatory processes in utero are likely antecedents of brain damage in preterm infants as cytokine elevations predict neonatal brain damage. The blood-brain barrier (BBB)/neurovascular unit (NVU) is a privileged site consisting of brain micro- vascular endothelia, glia, and neurons that regulate the microenvironment for neural functioning. A novel ap- proach to prevent perinatal brain injury would be to target the BBB with agents to preserve its function to limit entry of toxic substances into brain. This proposal is based on the central hypothesis that cytokines cross the BBB in the fetus to damage the brain and that blockade of cytokines attenuates damage to the BBB/NVU and the brain parenchyma. Our published data show that blocking effects of pro-inflammatory cytokines with systemic infusions of cytokine neutralizing monoclonal antibodies (mAb) attenuate ischemia-related increases in BBB permeability in the ovine fetus. The novel overall goal of this continuation of an R01 is to elucidate the effects of systemic inflammation on BBB/NVU function to determine whether blocking cytokines with systemic antibody infusions attenuates inflammation-related damage to the BBB/NVU/brain parenchyma in the fetus. A multidisciplinary approach to address the specific aims includes physiological, biochemical, pathological, immunohistochemical, and molecular methods. Aim 1 tests the hypothesis that systemic inflammation (induced by LPS) results in increases in BBB permeability measured both with α-aminoisobutyric acid and radiolabeled cytokines, as a function of gestational age, and a result of changes in the NVU. Aim 2 tests the hypothesis that cytokine-specific neutralizing mAbs prevent inflammation-related increases in non- specific BBB permeability, cytokine transport into brain by attenuating damage to the NVU, and, thus, reduce parenchymal brain damage. Aim 3 tests the hypothesis that inflammation-related increases in BBB permeability are prostanoid dependent by determining whether cyclooxygenase inhibition prevents LPS-induced BBB dysfunction. Understanding how the BBB/NVU responds to inflammation and mechanism(s) responsible for damage to BBB/NVU will facilitate development of innovative therapeutic approaches. Treatment of neonates with anti-cytokine mAb would be feasible, as humanized anti-IL-1β antibody is currently in use to treat inflammatory conditions and shows beneficial effects in pediatric trials. This project could provide new insights into novel strategies to prevent brain injury in the human fetus and/or full term and premature infant.