title: Greater hypoxia-induced cell death in prenatal brain after bacterial-endotoxin pretreatment is not because of enhanced cerebral energy depletion: a chicken embryo model of the intrapartum response to hypoxia and infection.
abstract: Infection is a risk factor for adult stroke and neonatal encephalopathy. We investigated whether exposure to bacterial endotoxin increases hypoxia-induced brain cell death and impairs cerebral metabolic compensatory responses to hypoxia. Prehatching chicken embryos (incubation day 19) were exposed to bacterial lipopolysaccharide (LPS) (3 mg Salmonella typhimurium LPS per egg) or hypoxia (4% ambient O(2) for 1 h), alone or in combination with LPS, followed 4 h later by hypoxia. Cerebral cell death and glial activation were assessed histologically. Further, chicken embryo brains were studied by magnetic resonance imaging (MRI) and spectroscopy (MRS) to assess haemodynamic and metabolic responses. In most brain areas, combined LPS/hypoxia resulted in a 30- to 100-fold increase in terminal deoxynucleotidyl transferase dUTP nick end labelling -positive cells, compared to control and single-insult groups. Glial activation correlated with the severity of cell death and was significantly greater in the combined-insult group (P<0.05). Hypoxia was associated with a 10-fold increase in lactate/N-acetyl-aspartate (NAA), an approximately 20% increase in total creatine/NAA, rapid decreases in T2 and T2(*), and a reduction in direction-averaged brain-water diffusion (D(av)) by approximately 15%. Liposaccharide pretreatment did not alter the magnitude or timing of these responses, but engendered baseline shifts (increased Cho/NAA, Cr/NAA, and Dav, and reduced T2(*)). In conclusion, LPS greatly increased hypoxia-induced brain damage in this model and induced changes in baseline haemodynamics and metabolism but did not affect the magnitude of the glycolytic response to hypoxia. The damage-enhancing effects of LPS are not because of additional energy depletion but because of a synergistic toxic component.
authors.affiliation: Centre for Perinatal Brain Research, The Institute for Women's Health, University College London, London, UK.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Wang
authors.forename: David W
authors.initials: DW
authors.lastname: Carmichael
authors.forename: Ernest B
authors.initials: EB
authors.lastname: Cady
authors.forename: Oliver
authors.initials: O
authors.lastname: Gearing
authors.forename: Alan
authors.initials: A
authors.lastname: Bainbridge
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Ordidge
authors.forename: Gena
authors.initials: G
authors.lastname: Raivich
authors.forename: Donald M
authors.initials: DM
authors.lastname: Peebles
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000196:embryology* / Q000382:microbiology / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D004734:Energy Metabolism / Q000502:physiology; D006019:Glycolysis / Q000502:physiology; D002534:Hypoxia, Brain / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D009457:Neuroglia / Q000473:pathology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010085:Oxidative Phosphorylation; D012480:Salmonella Infections / Q000378:metabolism / Q000473:pathology*; D012486:Salmonella typhimurium; D014403:Tubocurarine / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D018733:Nicotinic Antagonists; D000255:Adenosine Triphosphate; D014403:Tubocurarine