Window of opportunity of cerebral hypothermia for postischemic white matter injury in the near-term fetal sheep.
Postresuscitation cerebral hypothermia is consistently neuroprotective in experimental preparations; however, its effects on white matter injury are poorly understood. Using a model of reversible cerebral ischemia in unanesthetized near-term fetal sheep, we examined the effects of cerebral hypothermia (fetal extradural temperature reduced from 39.4 +/- 0.1 degrees C to between 30 and 33 degrees C), induced at different times after reperfusion and continued for 72 hours after ischemia, on injury in the parasagittal white matter 5 days after ischemia. Cooling started within 90 minutes of reperfusion was associated with a significant increase in bioactive oligodendrocytes in the intragyral white matter compared with sham cooling (41 +/- 20 vs 18 +/- 11 per field, P < 0.05), increased myelin basic protein density and reduced expression of activated caspase-3 (14 +/- 12 vs 91 +/- 51, P < 0.05). Reactive microglia were profoundly suppressed compared with sham cooling (4 +/- 6 vs 38 +/- 18 per field, P < 0.05) with no effect on numbers of astrocytes. When cooling was delayed until 5.5 hours after reperfusion there was no significant effect on loss of oligodendrocytes (24 +/- 12 per field). In conclusion, hypothermia can effectively protect white matter after ischemia, but only if initiated early after the insult. Protection was closely associated with reduced expression of both activated caspase-3 and of reactive microglia.
Roelfsema
Vincent
V
The Liggins Institute, University of Auckland, Auckland, New Zealand.
Bennet
Laura
L
George
Sherly
S
Wu
David
D
Guan
Jian
J
Veerman
Marije
M
Gunn
Alistair Jan
AJ
D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D003711:Demyelinating Diseases; D004789:Enzyme Activation; D005260:Female; D005333:Fetus; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D004676:Myelin Basic Protein / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger / Q000032:analysis; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D012756:Sheep; D013997:Time Factors
D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D053148:Caspase 3; D020169:Caspases