Many infants with mild hypoxic–ischemic encephalopathy (HIE) are treated with therapeutic hypothermia despite the lack of robust preclinical and clinical data that hypothermia is safe and effective. The aim of this study was to determine if hypothermia is neuroprotective after mild hypoxia–ischemia (HI). Chronically instrumented near-term fetal sheep (0.85 gestation) were randomized to sham control (n = 8) or to HI induced by 10 min of bilateral carotid artery occlusion followed by normothermia (HI-normothermia, n = 8) or 72 h of hypothermia started 6 h after the end of HI (HI-hypothermia, n = 8) and recovered for 7 days. Mild HI was associated with reduced electroencephalographic power compared with sham controls until 78 h after HI. HI was associated with a loss of neurons and an increase in microglia within the hippocampus, while HI-hypothermia restored numbers of neurons and microglia back to sham control. There was no difference in the number of total oligodendrocytes between groups. HI-hypothermia was associated with a significant decrease in mature oligodendrocyte number and myelin basic protein area fraction compared with sham control, despite no change in HI-normothermia. Hypothermia for 72 h is significantly neuroprotective within the hippocampus but potentially delays white matter maturation when started 6 h after mild HI.
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