It is widely believed that
rewarming slowly after
therapeutic hypothermia for hypoxic-ischemic (HI)
encephalopathy can improve outcomes, but its impact on white matter injury after HI is unclear. Fetal sheep (0.85 gestation) received 30 min
ischemia-normothermia (n = 8), or
hypothermia from 3-48 h with rapid spontaneous
rewarming over 1 h (
ischemia-48 h
hypothermia, n = 8), or 48 h with slow
rewarming over 24 h (
ischemia-slow
rewarming, n = 7) or 72 h with rapid
rewarming (
ischemia-72 h
hypothermia, n = 8).
Ischemia was associated with loss of total and mature oligodendrocytes and reduced area fraction of
myelin basic protein (MBP) and
2',3'-cyclic nucleotide 3'-phosphodiesterase (
CNPase; immature/mature oligodendrocytes) and increased microglia and astrocytes. Total numbers of oligodendrocytes were increased by all
hypothermia protocols but only ischemia-72 h
hypothermia attenuated loss of mature oligodendrocytes. All
hypothermia protocols similarly increased the area fraction of MBP, whereas there was only an intermediate effect on the area fraction of
CNPase. Microglia were suppressed by all
hypothermia protocols, with the greatest reduction after ischemia-72 h
hypothermia, and an intermediate effect after
ischemia-slow
rewarming. By contrast, induction of astrocytes was significantly reduced only after
ischemia-slow
rewarming. In conclusion, slow
rewarming after
hypothermia did not improve oligodendrocyte survival or myelination or suppression of microgliosis compared to fast
rewarming, but modestly reduced
astrocytosis.