Introduction: Incidence of perinatal arterial ischemic stroke (PAIS) is surprisingly high, approaching that of the elderly. It has been postulated that the developing brain has a greater degree of plasticity and capacity for repair compared to the adult, thereby enhancing functional recovery. To address this issue, we utilized the recently developed intraluminal filament mouse model of ischemic stroke in postnatal day 10 mice. The aim of this study was to examine the cellular responses to ischemic stroke in the neonatal brain that contribute to the enhanced functional recovery.
Method: Middle cerebral artery occlusion (45 minutes) was performed on adult and p10 mice using the intraluminal filament method. Immunohistochemistry was performed to identify oligodendrocyte precursors (PDGFRα/Olig2+), mature oligodendrocytes (CC1/Olig2+), vascular endothelial cells (Glut-1) and pericytes (CD13), and TUNEL to identify injured cells. Blood brain barrier integrity was examined by staining for fibrinogen. A protein array was conducted to examine extracellular protein levels. In situ hybridization was used to confirm source of IGF-1.
Results: Oligodendrocytes were remarkably resistant to ischemic insult in the neonatal brain up to 7 days after injury; no change in oligodendrocyte precursor or mature oligodendrocyte cell count following neonatal stroke, compared to the significant loss of oligodendrocytes following adult stroke. In contrast, large numbers of TUNEL+ neurons were observed in both groups following stroke. In contrast to well-established vascular injury in adult stroke, no change in vascular integrity (Glut-1 positive vessel length/number or fibrinogen leakage) was detected following neonatal stroke. Unbiased analysis of extracellular protein levels in the adult and neonatal brain following stroke identified IGF-1 as a protein uniquely up-regulated following neonatal stroke. In situ hybridization revealed increased IGF-1 mRNA levels in oligodendrocytes following neonatal stroke.
Conclusion: These results suggest that ischemia-resistant developing oligodendrocytes provide trophic support (IGF-1) to the vasculature following neonatal stroke.