Background: Many cases of cerebral palsy and impaired neurodevelopment are associated with hypoxia-ischemia (HI) before birth, during preterm development. HI leads to long-term impairment of myelination and neuroinflammation, both of which likely contribute to poor connectivity.
Methods: Chronically instrumented fetal sheep (0.7 gestation) underwent sham HI or HI induced by 25 min of umbilical cord occlusion. Fetal brains were processed for histology post-HI at 3 days (n=9, sham n=12), 7 days (n=8, sham n=8), 14 days (n=9, sham n=10) and 21 days (n=9, sham n=10).
Results: Large cystic lesions were observed in 3/9 fetuses within the temporal lobe at 21 days post-HI. Marked white matter atrophy were also observed in 4/9 fetuses by 21 days post-HI. No lesions were observed at earlier time points. HI was associated with a significant increase in Iba-1 positive microglia at 3, 7, and 21 days post-HI (P<0.05). A significant increase in Caspase-3 apoptosis at day 3 post-HI (P<0.05), but no difference to sham levels by 7 days. A significant decrease in Olig2 and CC1 (P<0.05) at 3 days and 21 days (P<0.05). And finally, a reduction in brain weight (39.5 ±0.89 vs. 32.5 ±1.7 g, day 21), CNPase area fraction (P<0.05), MBP area fraction (P<0.05), and SMI312 area fraction (P<0.05) was observed post-HI vs. shams at all post-HI time points.
Discussion: Bulk neural cell death is thought to largely occur during the first 3 days after an HI insult. However, this study has demonstrated that significant evolving injury is observed weeks after an HI insult, with diffuse white matter injury at 3 and 7 days, evolving into a spectrum of severe white matter degeneration including cystic white matter lesions, white matter atrophy, and ventriculomegaly by 21 days post-HI.