Systemically delivered Erythropoietin transiently enhances adult hippocampal neurogenesis

Abstract

Erythropoietin is a primary regulator of erythropoiesis in the hematopoietic system. More recently erythropoietin has been shown to play a role in neurogenesis and provide neurotrophic support to injured CNS tissue. Here the effects of large systemic doses of erythropoietin on basal levels of adult hippocampal neurogenesis in mice were examined. A 7-day period of recombinant human erythropoietin (rhEPO) administration increased the number of bromodeoxyuridine [BrdU(+)] cells in the sub-granular zone (SGZ) by 30%. Analysis of cell phenotype revealed an increase in mitotically active doublecortin(+) neuronal progenitor cells and glial fibrillary acidic protein(+) SGZ radial astrocytes/stem cells but not mature S100beta(+) astrocytes. These effects appeared to be mediated, in part, by mitogen-activated protein kinase signaling and potentially regulated by suppressor of cytokine signaling-3. Hippocampal levels of phosphorylated extracellular signal-related kinase 42/44 and suppressor of cytokine signaling-3 were increased 2-6 h after a single systemic rhEPO injection. However, rhEPO had no observed effect on the long-term survival of new born cells in the SGZ, with similar numbers of BrdU(+) cells and BrdU(+)/NeuN(+) co-labeled cells after 4 weeks. Therefore, systemically delivered rhEPO transiently increased adult hippocampal neurogenesis without any apparent long-term effects.

Widespread Expression of Erythropoietin Receptor in Brain and Its Induction by Injury

“…For instance, GFAP-positive stem cells in the adult neurogenic niches showed EpoR immunoreactivity here, which is in line with reports demonstrating distinct effects of EPO on adult neural stem cells (40)(41). Also, studies identifying EPO as an inducer of oligodendrocyte precursor cell differentiation (42-43) are now further supported by the detection of specific EPOR-binding sites in culture and brain sections.…”

Adult hippocampal neurogenesis and related neurotrophic factors

“…It also increases adult hippocampal neurogenesis (72,73). The brains of EPO receptor (EPOR) knockout mice show enhanced apoptosis and the mice are highly sensitive to hypoxia (74), but it is not known if this sensitivity is because EPO has a neuroprotective effect or is a secondary effect of decreased oxygen delivery to the brain.…”

High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial

“…41 Epo exhibits antiapoptotic and antiinflammatory effects acutely after neonatal brain injury [42][43][44][45][46] and promotes neurogenesis, plasticity, and tissue remodeling after hypoxia-ischemia. 15,[47][48][49][50] In animal models of neonatal stroke, Epo increases proliferation, migration, and differentiation of neuronal precursors, resulting in increased neurogenesis in the injured basal ganglia and cortex. 47,51,52 Although therapeutic hypothermia has improved the outlook of infants with HIE, 53,54 there remains a pressing need for neuroprotective therapies that will further reduce the high rate of neurologic disabilities.…”