Abstract:
Background: Many cases of cerebral palsy and impaired neurodevelopment are associated with hypoxia-ischaemia (HI) well before birth, during preterm development. HI leads to longterm impairment of myelination and neuroinflammation, both of which would likely contribute to poor connectivity. My objective was to determine the evolution of neuroinflammation, myelination and brain injury after an acute HI insult in preterm fetal sheep. 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=2, sham n=2) 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 and 21 days. A significant decrease in Olig2 and CC1 (P<0.05) at 3 days and 21 days (P<0.05). 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 SMI-312 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, my 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. My thesis therefore, highlights a potential new window of opportunity for treatment in the tertiary phase.
