title: Hypoxia diminishes the protective function of white-matter astrocytes in the developing brain.
abstract: OBJECTIVE
  White-matter injury after surgery is common in neonates with cerebral immaturity secondary to in utero hypoxia. Astrocytes play a central role in brain protection; however, the reaction of astrocytes to hypothermic circulatory arrest (HCA) remains unknown. We investigated the role of astrocytes in white-matter injury after HCA and determined the effects of preoperative hypoxia on this role, using a novel mouse model.
  
  
  METHODS
  Mice were exposed to hypoxia from days 3 to 11, which is equivalent to the third trimester in humans (prehypoxia, n = 49). Brain slices were transferred to a chamber perfused by cerebrospinal fluid. Oxygen-glucose deprivation (OGD) was performed to simulate ischemia-reperfusion/reoxygenation resulting from circulatory arrest under hypothermia. Astrocyte reactions were compared with preoperative normoxia (prenormoxia; n = 45).
  
  
  RESULTS
  We observed astrocyte activation after 25°C ischemia-reperfusion/reoxygenation in prenormoxia (P < .01). Astrocyte number after OGD correlated with caspase-3(+) cells (rho = .77, P = .001), confirming that astrogliosis is an important response after HCA. At 3 hours after OGD, astrocytes in prenormoxia had already proliferated and become activated (P < .05). Conversely, astrocytes that developed under hypoxia did not display these responses. At 20 hours after ischemia-reperfusion/reoxygenation, astrogliosis was not observed in prehypoxia, demonstrating that hypoxia altered the response of astrocytes to insult. In contrast to prenormoxia, caspase-3(+) cells in prehypoxia increased after ischemia reperfusion/reoxygenation, compared with control (P < .01). Caspase-3(+) cells were more common with prehypoxia than with prenormoxia (P < .001), suggesting that lack of astrogliosis permits increased white-matter injury.
  
  
  CONCLUSIONS
  Preoperative hypoxia alters the neuroprotective function of astrocytes. Restoring this function before surgery may be a therapeutic option to reduce postoperative white-matter injury in the immature brain.
authors.affiliation: Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC.
authors.forename: Kota
authors.initials: K
authors.lastname: Agematsu
authors.affiliation: Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Korotcova
authors.affiliation: Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Morton
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, Washington, DC.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Gallo
authors.affiliation: Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Jonas
authors.affiliation: Children's National Heart Institute, Children's National Medical Center, Washington, DC; Center for Neuroscience Research, Children's National Medical Center, Washington, DC. Electronic address: nishibas@childrensnational.org.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ishibashi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005311:Fetal Hypoxia / Q000378:metabolism / Q000473:pathology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D005911:Gliosis; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D066298:In Vitro Techniques; D056784:Leukoencephalopathies / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D013997:Time Factors; D066127:White Matter / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: astrocyte; hypoxia; white matter