Erythropoietin Regulates theIn VitroandIn VivoProduction of Neuronal Progenitors by Mammalian Forebrain Neural Stem Cells

Abstract

Recent studies have shown that neurogenesis is enhanced after hypoxia and that erythropoietin (EPO), an inducible cytokine, is produced in the brain as part of the intrinsic hypoxia response. Thus, we asked whether EPO might regulate neurogenesis by forebrain neural stem cells (NSCs). We found that EPO receptors are expressed in the embryonic germinal zone during neurogenesis as well as in the adult subventricular zone, which continues to generate neurons throughout adulthood. Cultured NSCs exposed to a modest hypoxia produced two-to threefold more neurons, which was associated with an elevation in EPO gene expression. The enhanced neuron production attributable to hypoxia was mimicked by EPO and blocked by coadministration of an EPO neutralizing antibody. EPO appears to act directly on NSCs, promoting the production of neuronal progenitors at the expense of multipotent progenitors. EPO infusion into the adult lateral ventricles resulted in a decrease in the numbers of NSCs in the subventricular zone, an increase in newly generated cells migrating to the olfactory bulb, and an increase in new olfactory bulb interneurons. Infusion of anti-EPO antibodies had the opposite effect: an increase in the number of NSCs in the subventricular zone and a decrease in the number of newly generated cells migrating to the bulb. These findings suggest that EPO is an autocrine-paracrine factor, capable of regulating the production of neuronal progenitor cells by forebrain NSCs.

Atorvastatin Induction of VEGF and BDNF Promotes Brain Plasticity after Stroke in Mice

“…Neurogenesis and synaptic reorganization are important for functional improvement after stroke (Gomez-Fernandez, 2000;Hallett, 2001;Shingo et al, 2001). Our data show that atorvastatin treatment after stroke induces the expression of BDNF and synaptic proteins, and neuronal migration in the ischemic border, and some neuronal migrating cells are localized to blood vessels.…”

Targeting Astrocytes for Stroke Therapy

“…2D). [101][102][103] To harness the restorative power of EPO in stroke, it is important to examine the mechanisms by which the temporal expression of endogenous EPO may be enhanced in astrocytes after stroke. Instead of direct administration of EPO, it may be more beneficial to avoid its potential systemic side effects by administering small molecules that can induce endogenous EPO …”

Neurorestorative treatment of stroke: Cell and pharmacological approaches

“…EPO infusion into the adult lateral ventricles increases the number of newly generated cells migrating to the olfactory bulb, and thereby increases new olfactory bulb interneurons. 80 The JAK2-STAT3 and PI3K-AKT pathways activated by EPO may also underlie the EPO-mediated neuronal regeneration. 81 Thus, multiple signaling pathways may regulate the EPO-induced angiogenesis and neurogenesis that promote neurorestorative effects after stroke.…”