Chronic ischemia preferentially causes white matter injury in the neonatal rat brain

Chronic ischemic brain injuries were studied in 7- and 14-day-old rat pups, which were subjected to bilateral carotid artery occlusion (BCAO) on postnatal day 1. BCAO preferentially injured white matter in the corpus callosum, subcortex and internal capsule areas while largely spared cortical neurons. White matter rarefaction in the corpus callosum was observed in 12 out of the 17 BCAO rat brains and significantly enlarged lateral ventricles were found in five out of seven P14 BCAO rat brains. These white matter changes were similar to injuries found in newborn infants with periventricular leukomalacia (PVL). White matter injuries in the 7-day-old BCAO rat brain were accompanied with increased activation of microglia/macrophages, as indicated by ED1 and OX42 positive immunostaining. Immature oligodendrocytes in the 7-day-old BCAO rat brain, as indicated by O4+/O1+ staining, were much fewer than in the sham-operated rat brain. Immunostaining for myelin basic protein (MBP) at the fimbria hippocampus and the internal capsule areas in the 7-day-old BACO rat brain was also much less than in the control rat brain. Consistent with the immunostaining data, MBP mRNA expression in the 7-day-old, but not in the 14-day-old, BCAO rat brain was significantly less than in the control rat brain. The overall results suggest that pre-oligodendrocytes and immature oligodendrocytes might be major targets for chronic ischemic insults and activated microglia/macrophages are possibly involved in the process of white matter injury.