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Stroke during the perinatal or early postnatal period affects brain development and leads to lifelong neurological morbidity. Emerging evidence suggests that there is selective vulnerability in the immature brain, and mechanisms of acute neonatal cerebral ischemic injury differ from those seen in the mature central nervous system. Recently completed developmental corticogenesis and enhanced migratory activity of cells during the early postnatal period could result in a more prominent role for precursor cells in regeneration and repair after neonatal stroke. We showed that HIF1a induction occurs after ischemia and that this induction is associated with upregulation of survival genes resulting in neuroprotection in the developing nervous system . In particular in a focal transient middle cerebral ischemia model (MCAO), we showed that erythropoietin (Epo) and vascular endothelial growth factor (VEGF) were upregulated in neurons early and in astrocytes after one week . We are now investigating the role of the HIF 1a regulated downstream targets, VEGF and Epo, in protection and recovery from an ischemic insult to the newborn brain. VEGF has been reported to both enhance angiogenesis and blood brain barrier integrity . In the newborn brain, astrocyte derived VEGF has been reported to mediate stabilization of hypoxic brain microvascular endothelial cells. In addition to its effects on endothelial cells, VEGF has also been shown to stimulate neurite outgrowth and neurogenesis . It is well established that neural stem cells are concentrated around blood vessels that provide a “niche” for proliferation. High levels of VEGF and its receptor, VEGFR2, are found in these regions, consistent with a role for VEGF in coupling angiogenesis with neurogenesis .Our hypothesis is that VEGF signaling plays a critical role in these processes after injury. A continuing search for factors that can increase neurogenesis show that erythropoietin (Epo) is a promising candidate capable of regulating the production of neuronal progenitors by neural stem cells. The upregulation of Epo in the brain after hypoxia supports a role for Epo in the brain's response to injury not only acutely after injury but in repopulating injured areas as well. The expression of the Epo receptor in the developing mouse and human central nervous system (CNS) also supports a role for Epo in CNS regeneration after injury during early development. We propose that erythropoietin enhances ischemic brain repair through increased precursor cell proliferation and neural cell fate commitment, migration and integration in damaged areas.
Selected Publications
Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM. (2002) Focal cerebral ischemia increases adult rat forebrain subventricular zone neuroblast proliferation and induces neostriatal neurogenesis. Ann Neurol 52(6):802-813.
Ferriero DM. (2004) Neonatal Brain Injury- Invited review- Medical Progress Series, NEJM 351: 1985-95.
Mu D, Chang Y, Vexler Z, Ferriero DM. (2005) Hypoxia-Inducible Factor 1α and Erythropoietin Upregulation with Deferoxamine Salvage after Neonatal Stroke. Exp Neurol 195(2):407-15.
Gonzalez FF, Mu D, Chang Y, McQuillen P, Wendland M, Vexler Z, Ferriero DM. Erythropoietin Enhances Long-Term Neuroprotection and Neurogenesis in Neonatal Stroke, Dev Neurosci, in press.
Information last updated April 2007
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