title: Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats.
abstract: Encephalopathy of prematurity (EoP) is a term that encompasses the central nervous system (CNS) abnormalities associated with preterm birth. To best advance translational objectives and uncover new therapeutic strategies for brain injury associated with preterm birth, preclinical models of EoP must include similar mechanisms of prenatal global injury observed in humans and involve multiple components of the maternal-placental-fetal system. Ideally, models should produce a similar spectrum of functional deficits in the mature animal and recapitulate multiple aspects of the pathophysiology. To mimic human systemic placental perfusion defects, placental underperfusion and/or chorioamnionitis associated with pathogen-induced inflammation in early preterm birth, we developed a model of prenatal transient systemic hypoxia-ischemia (TSHI) combined with intra-amniotic lipopolysaccharide (LPS). In pregnant Sprague Dawley rats, TSHI via uterine artery occlusion on embryonic day 18 (E18) induces a graded placental underperfusion defect associated with increasing CNS damage in the fetus. When combined with intra-amniotic LPS injections, placental inflammation is increased and CNS damage is compounded with associated white matter, gait and imaging abnormalities. Prenatal TSHI and TSHI+LPS prenatal insults meet several of the criteria of an EoP model including recapitulating the intrauterine insult, causing loss of neurons, oligodendrocytes and axons, loss of subplate, and functional deficits in adult animals that mimic those observed in children born extremely preterm. Moreover, this model allows for the dissection of inflammation induced by divergent injury types.
authors.affiliation: Department of Pediatrics, University of New Mexico; Department of Neurosciences, University of New Mexico.
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Jantzie
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital.
authors.forename: Jesse L
authors.initials: JL
authors.lastname: Winer
authors.affiliation: Department of Pediatrics, University of New Mexico.
authors.forename: Jessie R
authors.initials: JR
authors.lastname: Maxwell
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital.
authors.forename: Lindsay A S
authors.initials: LA
authors.lastname: Chan
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital; Department of Neurology, Harvard Medical School; Shenandoah.Robinson@childrens.harvard.edu.
authors.forename: Shenandoah
authors.initials: S
authors.lastname: Robinson