The ischemic newborn brain: Endogenous response, functional deficits, and transplantation repair following stroke in the neonatal rat

In the clinical setting, ischemic stroke within the neonatal period may result in significant morbidity and mortality immediately following the event or go unrecognized until developmental delays present themselves much later; smaller cortical insults in particular frequently manifest with mild delay or attention or learning deficits. This dissertation explores the mechanisms by which the ischemic newborn rat brain attempts to self-repair following insult, the degree of functional deficit that is observed in our new rat model of neonatal ischemia, and a novel strategy for therapeutic stem cell transplantation. Here, we report a novel pro-migratory mechanism for subventricular zone neuroblast migration toward the ischemic boundary via the VEGF-VEGFR-2 pathway using an ischemia-only rat model. We further assess the degree and extent of functional deficits generated by our ischemia-only neonatal model with regard to developmental milestones and sensory and motor development. We report that ischemic stroke induces significant effects on sensory and motor function in addition to delaying certain developmental milestones in the rat pup. We also report that stroke results in gender-dependent effects for certain functional measurements. Finally, we introduce the utility of transplanted of hypoxically-preconditioned bone marrow stromal cells to further support the endogenous repair process that we have shown occurs after neonatal ischemic stroke. We demonstrate that hypoxic preconditioning up-regulates pro-angiogenic trophic, adhesion, support, and signaling mediators in vitro. Further, when these cells are transplanted in the ischemic neonatal rat, we show that these cells maintain an up-regulated pro-angiogenic expression profile that likely forms an improved support structure and a trophic foundation for enhanced endogenous neurogenesis and structural repair.