Effect of cerebral hypothermia and asphyxia on the subventricular zone and white matter tracts in preterm fetal sheep

Prolonged, moderate cerebral hypothermia is consistently neuroprotective after experimental hypoxia–ischemia. We have previously shown that hypothermia is also protective after profound asphyxia in the preterm brain. However, there is a concern whether hypothermia could suppress the proliferative response to injury in the white matter or subventricular zone (SVZ). Preterm (0.7 gestation) fetal sheep received complete umbilical cord occlusion for 25 min followed by cerebral hypothermia (extradural temperature reduced from 39.4±0.3 to 29.5±2.6 °C) from 90 min to 70 h after the end of occlusion or sham cooling. Occlusion-normothermia was associated with no effect on CNPase+ cells, but loss of O4+ oligodendrocytes, induction of cleaved caspase-3, and IB4+ microglia in the gyral and periventricular white matter compared to sham-occlusion (p < 0.05), with a significant increase in KI67+ cells in the periventricular white matter (p < 0.05). Hypothermia was associated with significant protection of O4+ cells, with suppression of IB4+ microglia and KI67+ cells in the periventricular white matter. There was no significant change in astrocytes, microglia, KI67+, or caspase-3+ cells in the SVZ after asphyxia. In conclusion, this study provides strong support for the selective vulnerability of immature oligodendrocytes to a highly relevant insult in the fetal sheep. Although white matter protection with cerebral hypothermia was associated with reduced proliferation in the white matter tracts, it did not impair proliferation in the SVZ.

► Selective white matter injury was induced in a translational model of profound hypoxia in preterm fetal sheep.
► Mild therapeutic hypothermia was induced from 90 min to 70 h after hypoxia.
► There was marked loss of preoligogendrocytes, but not immature and mature cells in the white matter tracts.
► Therapeutic hypothermia protected the periventricular white matter but suppressed proliferation after 3 days recovery.
► Reassuringly, cerebral hypothermia did not impair proliferation in the SVZ.