The Pleiotropic Effects of Erythropoietin in the Central Nervous System

Abstract

Erythropoietin (Epo) is a hydrophobic sialoglycoproteic hormone produced by the kidney and responsible for the proliferation, maturation, and differentiation of the precursors of the erythroid cell line. Human recombinant erythropoietin (rHuEpo) is used to treat different types of anemia, not only in uremic patients but also in newborns with anemia of prematurity, in patients with cancer-related anemia or myeloproliferative disease, thalassemias, bone marrow transplants, or those with chronic infectious diseases. The pleiotropic functions of Epo are well known. It has been shown that this hormone can modulate the inflammatory and immune response, has direct hemodynamic and vasoactive effects, could be considered a proangiogenic factor because of its interaction with vascular endothelial growth factor, and its ability to stimulate mitosis and motility of endothelial cells. The multifunctional role of Epo has further been confirmed by the discovery in the central nervous system of a specific Epo/Epo receptor (EpoR) system. Both Epo and EpoR are expressed by astrocytes and neurons and Epo is present in the cerebrospinal fluid (CSF). Therefore, novel functions of Epo, tissue-specific regulation, and the mechanisms of action have been investigated. In this review we have tried to summarize the current data on the role of Epo on brain function. We discuss the different sites of cerebral expression and mechanisms of regulation of Epo and its receptor and its role in the development and maturation of the brain. Second, we discuss the neurotrophic and neuroprotective function of Epo in different conditions of neuronal damage, such as hypoxia, cerebral ischemia, and subarachnoid hemorrhage, and the consequent possibility that rHuEpo therapy could soon be used in clinical practice to limit neuronal damage induced by these diseases.

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

“…The detection of EPO-Rs in cells other than erythroid progenitors, such as polymorphonuclear leukocytes, megakaryocytes, endothelial, myocardial and neural cells (Anagnostou et al, 1994;Brines and Cerami, 2005;Buemi et al, 2003;Fraser et al, 1989;Jaquet et al, 2002;Sela et al, 2001) showed that besides its role in erythropoiesis, EPO has additional biological functions. It should be noted that alongside the beneficial effects of EPO, a concern that EPO treatment for anemia might adversely affect the prognosis in certain cases of solid tumor cancers (Aapro et al, 2008;Henke et al, 2006;Longmore, 2007) has been raised.…”

Parsing Physiological Functions of Erythropoietin One Domain at a Time

“…Experimental autoimmune encephalomyelitis Although erythropoietin (EPO) is best known for its role in hematopoiesis, there are other functions that are instigated via this protein. EPO is effective as a neuroprotective molecule in various animal models of neuroinflammation and ischemia, including experimental autoimmune encephalomyelitis (EAE), brain trauma, and stroke [1][2][3][4][5][6]. Fortunately, proteins are often divided into discrete domains with different functional activities residing in different regions of the molecule.…”

New Insights Into Erythropoietin and Epoetin Alfa: Mechanisms of Action, Target Tissues, and Clinical Applications

“…Based on these observations, EPO signaling has been suggested to have various nonerythroid functions. The EPO-R is present in nonerythroid blood lines including myeloid cells, lymphocytes, and megakaryocytes, as well as in multiple nonhematopoietic cells, such as endothelial cells; mesangial, myocardial, and smooth muscle fiber cells; neural cells; prostate cells, and renal cells (Table 1) [65][66][67][68][69][70][71][72][73]. Moreover, many of these cell types exhibit active EPO signaling pathways and biologic responses.…”

“…Both EPO and the EPO-R are present in the central nervous system [65,[76][77][78][79], including the retina [80,81]. Epoetin alfa has been shown to actively cross the blood-brain barrier in animals (although at significantly higher doses than are conventionally used in the treatment of anemia in humans) [82] and in human subjects at doses of 40,000 U or 1,500 U/kg administered intravenously [83].…”

“…Epoetin alfa has been shown to actively cross the blood-brain barrier in animals (although at significantly higher doses than are conventionally used in the treatment of anemia in humans) [82] and in human subjects at doses of 40,000 U or 1,500 U/kg administered intravenously [83]. In vitro, EPO protects neurons against ischemia-induced glutamate toxicity, the primary factor responsible for neuronal cell death related to hypoxia [65,84].…”