title: Effects of intra-amniotic lipopolysaccharide and maternal betamethasone on brain inflammation in fetal sheep.
abstract: BACKGROUND
  Chorioamnionitis and antenatal glucocorticoids are common exposures for preterm infants and can affect the fetal brain, contributing to cognitive and motor deficits in preterm infants. The effects of antenatal glucocorticoids on the brain in the setting of chorioamnionitis are unknown. We hypothesized that antenatal glucocorticoids would modulate inflammation in the brain and prevent hippocampal and white matter injury after intra-amniotic lipopolysaccharide (LPS) exposure.
  
  
  METHODS
  Time-mated ewes received saline (control), an intra-amniotic injection of 10 mg LPS at 106d GA or 113d GA, maternal intra-muscular betamethasone (0.5 mg/kg maternal weight) alone at 113d GA, betamethasone at 106d GA before LPS or betamethasone at 113d GA after LPS. Animals were delivered at 120d GA (term=150d). Brain structure volumes were measured on T2-weighted MRI images. The subcortical white matter (SCWM), periventricular white matter (PVWM) and hippocampus were analyzed for microglia, astrocytes, apoptosis, proliferation, myelin and pre-synaptic vesicles.
  
  
  RESULTS
  LPS and/or betamethasone exposure at different time-points during gestation did not alter brain structure volumes on MRI. Betamethasone alone did not alter any of the measurements. Intra-amniotic LPS at 106d or 113d GA induced inflammation as indicated by increased microglial and astrocyte recruitment which was paralleled by increased apoptosis and hypomyelination in the SCWM and decreased synaptophysin density in the hippocampus. Betamethasone before the LPS exposure at 113d GA prevented microglial activation and the decrease in synaptophysin. Betamethasone after LPS exposure increased microglial infiltration and apoptosis.
  
  
  CONCLUSIONS
  Intra-uterine LPS exposure for 7d or 14d before delivery induced inflammation and injury in the fetal white matter and hippocampus. Antenatal glucocorticoids aggravated the inflammatory changes in the brain caused by pre-existing intra-amniotic inflammation. Antenatal glucocorticoids prior to LPS reduced the effects of intra-uterine inflammation on the brain. The timing of glucocorticoid administration in the setting of chorioamnionitis can alter outcomes for the fetal brain.
authors.affiliation: Department of Pediatrics, School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Elke
authors.initials: E
authors.lastname: Kuypers
authors.affiliation: Department of Pediatrics, School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Reint K
authors.initials: RK
authors.lastname: Jellema
authors.affiliation: Department of Pediatrics, School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Daan R M G
authors.initials: DR
authors.lastname: Ophelders
authors.affiliation: Department of Pediatrics, Erasmus Medical Center-Sophia, Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Dudink
authors.affiliation: Department of Pediatrics, School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Nikiforou
authors.affiliation: Department of Pediatrics, School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Tim G A M
authors.initials: TG
authors.lastname: Wolfs
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Australia ; The Ritchie Centre, Monash Institute of Medical Research, Melbourne, Australia.
authors.forename: Ilias
authors.initials: I
authors.lastname: Nitsos
authors.affiliation: School of Anatomy, Physiology and Human Biology, The University of Western Australia, Perth, Australia.
authors.forename: J Jane
authors.initials: JJ
authors.lastname: Pillow
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Australia ; The Ritchie Centre, Monash Institute of Medical Research, Melbourne, Australia.
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Polglase
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kemp
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Saito
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.
authors.forename: John P
authors.initials: JP
authors.lastname: Newnham
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Australia ; Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Jobe
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Australia ; Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Suhas G
authors.initials: SG
authors.lastname: Kallapur
authors.affiliation: Department of Pediatrics, School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
mesh_terms: D000653:Amniotic Fluid / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D001623:Betamethasone / Q000494:pharmacology*; D004660:Encephalitis / Q000276:immunology*; D005260:Female; D005333:Fetus / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D011247:Pregnancy; D012756:Sheep
chemical_list: D005938:Glucocorticoids; D008070:Lipopolysaccharides; D001623:Betamethasone