Early axonal and glial pathology in fetal sheep brains with leukomalacia induced by repeated umbilical cord occlusion.
We conducted a chronic preparation experiment involving near term fetal sheep to evaluate the contribution of umbilical cord occlusion to fetal brain injury. In experimental groups (n = 11), complete cord occlusion for 3 min followed by 5 min release, repeated 5 times were performed at 3 days after initial surgery. Instrumental cases without cord occlusion (n = 3) and uninstrumental twins (n = 6) were also examined as controls. Multiple necrotic foci predominantly in the periventricular white matter were found in the fetal brains examined at 1-3 days after cord occlusion. To estimate the contribution of early axonal and glial reaction to brain injury the following immunohistochemical study was performed. In the lesions, coagulation necrosis, axonal swelling and microglial activation were demonstrated with amyloid precursor protein or ionized calcium binding adapter molecule 1 immunohistochemistry. The induction of tumor necrosis factor alpha and inducible nitric oxide synthase were also detected immunohistochemically in the microglia at 1 and 3 days after cord occlusion. In contrast, the reaction of glial fibrillary acidic protein positive astrocytes was faint at 1 day after occlusion, but the induction of cyclooxygenase-2 was observed. These findings suggest the glial reaction of cytokines and free radicals induced by fetal hypoxia may contribute to the occurrence of brain injury.
Ohyu
J
J
Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan. ohyu@ncnaxp.ncnp.go.jp
Marumo
G
G
Ozawa
H
H
Takashima
S
S
Nakajima
K
K
Kohsaka
S
S
Hamai
Y
Y
Machida
Y
Y
Kobayashi
K
K
Ryo
E
E
Baba
K
K
Kozuma
S
S
Okai
T
T
Taketani
Y
Y
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism; D001369:Axons / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007527:Isoenzymes / Q000378:metabolism; D007969:Leukomalacia, Periventricular / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins; D008840:Microfilament Proteins; D017628:Microglia / Q000201:enzymology / Q000378:metabolism; D009336:Necrosis; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012756:Sheep; D013788:Thalamus / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C112986:AIF1 protein, human; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D007527:Isoenzymes; D008565:Membrane Proteins; D008840:Microfilament Proteins; D014409:Tumor Necrosis Factor-alpha; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases