Elsevier

Brain Research

Volume 1000, Issues 1–2, 12 March 2004, Pages 19-31
Brain Research

Review
Erythropoietin and the nervous system

https://doi.org/10.1016/j.brainres.2003.12.037Get rights and content

Abstract

Erythropoietin (Epo) is a hematopoietic growth factor and cytokine which stimulates erythropoiesis. In recent years, Epo has been shown to have important nonhematopoietic functions in the nervous system. Nonerythropoietic actions of Epo include a critical role in the development, maintenance, protection and repair of the nervous system. A wide variety of experimental studies have shown that Epo and its receptor are expressed in the nervous system and Epo exerts remarkable neuroprotection in cell culture and animal models of nervous system disorders. In this review, we summarize the current knowledge on the neurotrophic and neuroprotective properties of Epo, the mechanisms by which Epo produces neuroprotection and the signal transduction systems regulated by Epo in the nervous system.

Introduction

Erythropoietin (Epo) was first identified as a hematopoietic cytokine acting as a survival and differentiation factor [43]. It is a 34-kDa glycoprotein that functions as a main regulator of erythropoiesis. During fetal development, Epo is initially produced in the liver, but shortly after birth, Epo production is subsequently shifted to the kidney [43]. Circulating Epo binds to its receptor expressed on erythroid precursor cells in bone marrow and results in the stimulation of erythropoiesis. The role of Epo in hematopoiesis is inhibiting apoptosis of erythroid precursor cells and supporting their proliferation and differentiation into normoblasts [43]. The induction of erythropoiesis results in a progressive improvement in the supply of oxygen to tissue. In addition, tissue oxygen supply functions as a critical hormonal feedback mechanism and a significant modulator of oxygen-dependent Epo production and erythropoiesis.

Epo was isolated from the urine of patients with aplastic anemia and Epo DNA probes were constructed from tryptic fragments of the isolate and the gene cloned in 1985 [43]. Soon, recombinant Epo became available and underwent evaluation in clinical trials for patients with end-stage renal disease. The US Food and Drug Administration approved Epo use in 1989, and it is now widely used for the treatment of anemia associated with renal failure, cancer, prematurity, chronic inflammatory disease and human immunodeficiency virus infection [43].

Epo was thought to be exclusively produced in fetal liver and adult kidney. However, several lines of evidences suggest that Epo and erythropoietin receptor (EpoR) are expressed by other tissues, including the nervous system. Different cell types (neurons, glial cells and endothelial cells) in the nervous system produce Epo and express EpoR. Epo has tissue-specific regulation and multiple actions in the nervous system. Epo and EpoR expression change significantly during brain development, thus indicating the importance of Epo in neurodevelopment. The cytokine Epo has been shown to possess neuroprotective characteristics following ischemic, hypoxic, metabolic, neurotoxic and excitotoxic stress in the nervous system. Epo acts in a coordinated fashion at multiple levels in the nervous system, including limiting the production of tissue-injuring molecules such as reactive oxygen species and glutamate, modulation of neurotransmission, reversal of vasospasm, stimulation of angiogenesis, attenuation of apoptosis, modulation of inflammation and recruitment of stem cells. In this respect, the present review focuses on evidence that suggests Epo has neurotrophic and neuroprotective properties in the nervous system. Several mechanisms by which Epo produces neuroprotection and signal transduction systems regulated by Epo in the nervous system are also outlined.

Section snippets

Role of erythropoietin in neurodevelopment

Epo and its receptor have been identified in specific areas of the embryonic, fetal and adult brain of rodents, nonhuman primates and humans. The presence of Epo and its receptor in the developing brain suggests that these molecules play a role in neurodevelopment. Epo is a general morphogen and inducer of neurogenesis during early development [103], [109]. During development, Epo is produced primarily in the fetal liver and is necessary for embryonic survival. Embryos that have deleted or

Expression of erythropoietin and erythropoietin receptor in the nervous system

It was previously thought that Epo function was unique to the hematopoietic system; however, recent studies have located functional EpoRs in a wide variety of organs, tissues and cells in animal models and in the human. These nonhematopoietic cells include endothelial cells [4], [79], enterocytes [46], [75], muscle (skeletal, smooth and cardiac) [68], [74], [99], [103], placental tissues [84], insulin-producing cells [35] and neuronal and nonneuronal cells of the nervous system. Because Epo

Developmental changes

Epo and EpoR expression change significantly during brain development, thus indicating the importance of the Epo/EpoR system in neurodevelopment. High EpoR expression has been found in embryonic mouse neural tissue and brain, reaching levels similar to that observed in adult bone marrow [61]. This expression decreases significantly during development and maturation of the brain, by up to 100-fold after birth [60]. The level of Epo in the human nervous system is also variable, with elevated

Neuroprotective effect of erythropoietin in the nervous system

Recombinant human Epo (rhEpo) treatment has a beneficial effect on brain function, as demonstrated by findings from neuropsychological tests and electrophysiological evaluation [73]. This improvement is correlated with a progressive increase in the hematocrit level and therefore with the correction of the hypoxic state of the brain. If anemia is corrected, and the hematocrit levels return to normal, a further improvement in neurocognitive function has been reported [76]. However, several

Mechanisms of erythropoietin neuroprotection

Questions about the mechanisms by which Epo is neuroprotective have not been fully answered. Epo may act in a coordinated fashion at multiple levels, including limiting the production of tissue-injuring molecules such as reactive oxygen species and glutamate, reversal of vasospasm, stimulation of angiogenesis, attenuation of apoptosis, modulation of inflammation and recruitment of stem cells. Thus, Epo may protect neurons by a combination of these mechanisms.

The EpoR belongs to the cytokine

Use of erythropoietin as a neurotherapeutic agent in humans

Evidence from cell culture and animal experiments systematically reviewed above indicates a neuroprotective function for Epo. Neuroprotection as a tool to prevent or oppose neuronal loss in CNS disorders with various pathophysiological origins, such as cerebral ischemia, hypoxia, trauma and inflammatory and neurodegenerative diseases, represents a novel therapeutic approach. This approach is supported by a large body of experimental evidence on cell culture and experimental animal studies

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