Prenatal ischemia and white matter damage in rats.
Ischemia/reperfusion injury to the developing brain is a major cause of neurologic abnormalities in preterm infants. To investigate the underlying mechanisms, we modified a previously described rat model of unilateral uterine-artery ligation on the 17th embryonic day (E17). Growth retardation was taken as an index of in utero ischemia, and pups born with a birth weight more than 2 standard deviations below that of controls were compared with the same-litter, normal-growth control pups born from the nonligated horn. Prenatal ischemia probably associated with hypoxia and followed by reperfusion at birth induced white matter damage at a developmental stage corresponding to extreme prematurity in humans. On P0 (day of birth), growth-retarded pups exhibited lesions in the cingular white matter and internal capsule with increased counts of activated microglial cells for 2 weeks compared with controls. Astrogliosis was detected in the injured white matter. On P3, increased apoptotic cell death was seen in O4-positive preoligodendrocytes, which were abnormally scarce on P7. Defective myelination, as assessed by myelin-binding-protein labeling, was detected until adulthood. The diffuse white matter damage in growth-retarded rats replicated the main features of white matter damage in human preterm infants.
Olivier
Paul
P
INSERM U676-Université Paris7, Robert Debré Pediatric Hospital, France.
Baud
Olivier
O
Evrard
Philippe
P
Gressens
Pierre
P
Verney
Catherine
C
D000818:Animals; D000831:Animals, Newborn; D001927:Brain Diseases / Q000378:metabolism / Q000473:pathology*; D039481:CD11b Antigen / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D016923:Cell Death; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D004676:Myelin Basic Protein / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D019081:O Antigens / Q000378:metabolism; D037121:Plant Lectins / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric
D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D051273:Glucose Transporter Type 2; D004676:Myelin Basic Protein; D019081:O Antigens; D037121:Plant Lectins; C034981:tomato lectin; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases