Effects of intrauterine inflammation on developing rat brain

Damage to the white matter in the brain during development can lead to cerebral palsy (CP), a heterogeneous group of clinical syndromes that results in life‐long disorders of movement and posture. Periventricular leukomalacia (PVL) is a pathological process within the white matter characterized by oligodendrocyte loss and is associated with the development of CP. Clinically, CP and PVL are associated with intrauterine infection and inflammation, but mechanisms involved are not well understood. We developed a model of intrauterine inflammation in Lewis and Fischer 344 rats to study the effects of intrauterine inflammation on developing glia. Pregnant rats were intracervically injected with lipopolysaccharide (LPS) at 15 days of gestation (E15) and a dose of LPS that caused low fetal mortality was determined. At E20, treated fetuses had increased TUNEL+ nuclei and tumor necrosis factor (TNF)‐α‐immunoreactive areas within the brains. In a second series of animals allowed to survive until postnatal day 21 (PND 21), immunostaining was performed against several glial markers. Staining for the oligodendrocyte‐specific proteins 2′, 3′‐cyclic nucleotide phosphodiesterase (CNP) and myelin proteolipid protein (PLP) was decreased in treated pups compared to shams within the corpus callosum, a white matter structure used as a representative area of developing white matter. Treated pups had activated astrocytes lining cerebral blood vessels, as observed by glial fibrillary acidic protein (GFAP) staining, while sham pups did not. Activated microglia were not detected using OX42 as a cell marker. Our model of intrauterine inflammation causes increased TUNEL and TNF‐α staining early after injury, suggesting increased apoptotic cell death, possibly by cytokine‐related mechanisms. © 2002 Wiley‐Liss, Inc.

[1]  D. Strauss,et al.  Life expectancy of adults with cerebral palsy. , 2008, Developmental medicine and child neurology.

[2]  Pamela L. Follett,et al.  The Toll-Like Receptor TLR4 Is Necessary for Lipopolysaccharide-Induced Oligodendrocyte Injury in the CNS , 2002, The Journal of Neuroscience.

[3]  H. Flad,et al.  The biology of endotoxin. , 2001, Molecular biotechnology.

[4]  J. Volpe,et al.  Neurobiology of Periventricular Leukomalacia in the Premature Infant , 2001, Pediatric Research.

[5]  A. Suffredini,et al.  Human models of innate immunity: local and systemic inflammatory responses , 2001, Journal of endotoxin research.

[6]  A. Riley,et al.  Effects of Cross Fostering on Open-Field Behavior, Acoustic Startle, Lipopolysaccharide-Induced Corticosterone Release, and Body Weight in Lewis and Fischer Rats , 2001, Behavior genetics.

[7]  N. Baumann,et al.  Biology of oligodendrocyte and myelin in the mammalian central nervous system. , 2001, Physiological reviews.

[8]  K. Blomgren,et al.  Bacterial endotoxin sensitizes the immature brain to hypoxic–ischaemic injury , 2001, The European journal of neuroscience.

[9]  H. Kinney,et al.  Late Oligodendrocyte Progenitors Coincide with the Developmental Window of Vulnerability for Human Perinatal White Matter Injury , 2001, The Journal of Neuroscience.

[10]  Yvonne W Wu,et al.  Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. , 2000, JAMA.

[11]  P. Gressens,et al.  Intrauterine Infection Induces Programmed Cell Death in Rabbit Periventricular White Matter , 2000, Pediatric Research.

[12]  W. Cammer.  Effects of TNFα on immature and mature oligodendrocytes and their progenitors in vitro , 2000, Brain Research.

[13]  Kazuyoshi Watanabe,et al.  Correlation between the serum level of endotoxin and periventricular leukomalacia in preterm infants , 1999, Brain and Development.

[14]  J. Nalbantoglu,et al.  p53 Induction by Tumor Necrosis Factor‐α and Involvement of p53 in Cell Death of Human Oligodendrocytes , 1999, Journal of neurochemistry.

[15]  P. Ye,et al.  Insulin-Like Growth Factor I Protects Oligodendrocytes from Tumor Necrosis Factor-α-Induced Injury. , 1999, Endocrinology.

[16]  K. Matsushima,et al.  The molecular pathogenesis of endotoxic shock and organ failure. , 1999, Molecular medicine today.

[17]  J. Dambrosia,et al.  Interferons and cerebral palsy. , 1999, The Journal of pediatrics.

[18]  J. Dambrosia,et al.  Neonatal cytokines and coagulation factors in children with cerebral palsy , 1998, Annals of neurology.

[19]  D. Strauss,et al.  Life expectancy of children with cerebral palsy. , 1998, Pediatric neurology.

[20]  M. Joffres,et al.  Prevalence of Cerebral Palsy in Alberta , 1998, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[21]  J. Volpe.  Brain injury in the premature infant – from pathogenesis to prevention , 1997, Brain and Development.

[22]  J. Chi,et al.  Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits. , 1997, American journal of obstetrics and gynecology.

[23]  K. Nelson,et al.  Maternal infection and cerebral palsy in infants of normal birth weight. , 1997, JAMA.

[24]  R. Romero,et al.  Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1β, and tumor necrosis factor-α), neonatal brain white matter lesions, and cerebral palsy , 1997 .

[25]  D. Felten,et al.  Corticosterone responses of adult Lewis and Fischer rats , 1997, Journal of Neuroimmunology.

[26]  M. Dehan,et al.  PERIVENTRICULAR LEUKOMALACIA: RISK FACTORS REVISITED , 1996, Developmental medicine and child neurology.

[27]  M. Platt,et al.  The changing epidemiology of cerebral palsy. , 1996, Archives of disease in childhood. Fetal and neonatal edition.

[28]  M. D. Dal Canto,et al.  Effect of Theiler's murine encephalomyelitis virus and cytokines on cultured oligodendrocytes and astrocytes , 1996, Journal of neuroscience research.

[29]  R. Romero,et al.  Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. , 1996, American journal of obstetrics and gynecology.

[30]  T. Shimosegawa,et al.  The Role of Pituitary‐Adrenal Counterregulation of Inflammation in Cerulein‐Induced Pancreatitis: A Comparison Between Fischer and Lewis Rats , 1996, Pancreas.

[31]  D. Murphy,et al.  Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies , 1995, The Lancet.

[32]  F. Stanley,et al.  SPASTIC QUADRIPLEGIA IN WESTERN AUSTRALIA: A GENETIC EPIDEMIOLOGICAL STUDY. I: CASE POPULATION AND PERINATAL RISK FACTORS , 1993, Developmental medicine and child neurology.

[33]  N. Field,et al.  Perinatal effects of Gardnerella vaginalis deciduitis in the rabbit. , 1993, American journal of obstetrics and gynecology.

[34]  K. Benirschke,et al.  Postnatal white matter necrosis in preterm infants. , 1992, Journal of perinatology : official journal of the California Perinatal Association.

[35]  G. Chrousos,et al.  Corticotropin releasing hormone related behavioral and neuroendocrine responses to stress in Lewis and Fischer rats , 1992, Brain Research.

[36]  C. Brosnan,et al.  Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced by lymphotoxin. , 1991, Journal of immunology.

[37]  D. Mason,et al.  The role of the neuroendocrine system in determining genetic susceptibility to experimental allergic encephalomyelitis in the rat. , 1990, Immunology.

[38]  Jerrald Goldman,et al.  Embryonic divergence of oligodendrocyte and astrocyte lineages in developing rat cerebrum , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[39]  J. Hobbins,et al.  Infection and labor: the detection of endotoxin in amniotic fluid. , 1987, American journal of obstetrics and gynecology.

[40]  D. Peebles,et al.  Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults. , 2002, Mental retardation and developmental disabilities research reviews.

[41]  A. Schuchat,et al.  Public health issues related to infection in pregnancy and cerebral palsy. , 2002, Mental retardation and developmental disabilities research reviews.

[42]  R. Romero,et al.  Intrauterine infection and prematurity. , 2002, Mental retardation and developmental disabilities research reviews.

[43]  Y. Pang,et al.  Cytokine Induction in Fetal Rat Brains and Brain Injury in Neonatal Rats after Maternal Lipopolysaccharide Administration , 2000, Pediatric Research.

[44]  M. Mizuguchi,et al.  Immunohistochemical expression of tumor necrosis factor α in neonatal leukomalacia , 1996 .

[45]  J. Merrill,et al.  Effects of interleukin-1 and tumor necrosis factor-alpha on astrocytes, microglia, oligodendrocytes, and glial precursors in vitro. , 1991, Developmental neuroscience.