ReviewErythropoietin and 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
References (109)
- et al.
Erythropoietin exerts anti-inflammatory effect on the CNS in a model of experimental autoimmune encephalomyelitis
Brain Res.
(2002) - et al.
Effect of recombinant human erythropoietin on cerebral ischemia following experimental subarachnoid hemorrhage
Eur. J. Pharmacol.
(2000) - et al.
Exposure of endothelial cells to recombinant human erythropoietin induces nitric oxide synthase activity
Kidney Int.
(2000) - et al.
Erythropoietin protects against brain ischemic injury by inhibition of nitric oxide formation
Eur. J. Pharmacol.
(2000) - et al.
Effect of recombinant human erythropoietin on endothelial cell apoptosis
Kidney Int.
(1999) - et al.
Erythropoietin prevents cognition impairment induced by transient brain ischemia in gerbils
Eur. J. Pharmacol.
(2002) - et al.
Protective effect of erythropoietin on the oxidative damage of erythrocyte membrane by hydroxyl radical
Biochem. Pharmacol.
(2000) - et al.
Production and processing of erythropoietin receptor transcripts in brain
Mol. Brain Res.
(2000) - et al.
Erythropoietin gene expression in different areas of the developing human central nervous system
Dev. Brain Res.
(2000) - et al.
Ischemic tolerance and endogenous neuroprotection
Trends Neurosci.
(2003)
Erythropoietin exerts neuroprotection in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated C57/BL mice via increasing nitric oxide production
Neurosci. Lett.
Erythropoietin restores glutathione peroxidase activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in C57BL mice and stimulates murine astroglial glutathione peroxidase production in vitro
Neurosci. Lett.
Erythropoietin inhibits calcium-induced neurotransmitter release from clonal neuronal cells
Biochem. Biophys. Res. Commun.
Erythropoietin receptor-mediated inhibition of exocytotic glutamate release confers neuroprotection during chemical ischemia
J. Biol. Chem.
Trophic effect of erythropoietin and other hematopoietic factors on central cholinergic neurons in vitro and in vivo
Brain Res.
Regulated human erythropoietin receptor expression in mouse brain
J. Biol. Chem.
Tissue specific expression of human erythropoietin receptor in transgenic mice
Dev. Biol.
Functional erythropoietin receptor of the cells with neural characteristics: comparison with receptor properties of erythroid cells
J. Biol. Chem.
A novel site of erythropoietin production: oxygen-dependent production in cultured rat astrocytes
J. Biol. Chem.
Insulin-like growth factors and insulin stimulate erythropoietin production in primary cultured astrocytes
Brain Res.
Identification of the erythropoietin receptor domain required for calcium channel activation
J. Biol. Chem.
Anti-erythropoietin receptor monoclonal antibody: epitope mapping, quantification of the soluble receptor, and detection of the solubilized transmembrane receptor and the receptor-expressing cells
Blood
Erythropoietin stimulates proliferation and interferes with differentiation of myoblasts
J. Biol. Chem.
Normalizing hematocrit in dialysis patients improves brain function
Am. J. Kidney Dis.
Erythropoietin induces changes in gene expression in PC12 cells
Brain Res.
Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo
Blood
Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery
Biochem. Biophys. Res. Commun.
Receptors for erythropoietin in mouse and human erythroid cells and placenta
Blood
Erythropoietin protects cultured cortical neurons, but not astroglia, from hypoxia and AMPA toxicity
Neurosci. Lett.
Effects of erythropoietin on glial cell development; oligodendrocyte maturation and astrocyte proliferation
Neurosci. Res.
Neurotrophic effect of hematopoietic cytokines on cholinergic and other neurons in vitro
Int. J. Dev. Neurosci.
Erythropoietin improves synaptic transmission during and following ischemia in rat hippocampal slice cultures
Brain Res.
Role of vascular endothelial growth factor on erythropoietin-related endothelial cell proliferation
J. Am. Soc. Nephrol.
Erythropoietin receptor mRNA expression in human endothelial cells
Proc. Natl. Acad. Sci. U. S. A.
Erythropoietin modulates intracellular calcium in a human neuroblastoma cell line
J. Physiol.
A potential role for erythropoietin in focal permanent cerebral ischemia in mice
J. Cereb. Blood Flow Metab.
Neurons and astrocytes express Epo mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain
Glia
Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain
J. Cereb. Blood Flow Metab.
What evidence supports use of erythropoietin as a novel neurotherapeutic
Oncology
Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury
Proc. Natl. Acad. Sci. U. S. A.
Hemodynamic effects of recombinant human erythropoietin
Nephron
Recombinant human erythropoietin influences revascularization and healing in a random model of ischemic flaps in rat
Acta Derm. Venereol.
Erythropoietin and erythropoietin receptors in the peripheral nervous system: changes after nerve injury
FASEB J.
Identification of a neurotrophic sequence in erythropoietin
Int. J. Mol. Med.
Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury
Proc. Natl. Acad. Sci. U. S. A.
Mitochondrial reactive oxygen species trigger hypoxia-induced transcription
Proc. Natl. Acad. Sci. U. S. A.
Tissue-specific regulation of erythropoietin production in the murine kidney, brain and uterus
Am. J. Physiol. Endocrinol. Metab.
Hematopoietic factor erythropoietin fosters neuroprotection through novel signal transduction cascades
J. Cereb. Blood Flow Metab.
Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways
Br. J. Pharmacol.
Apaf-1, Bcl-xL, cytochrome, and caspase-9 form the critical elements for cerebral vascular protection by erythropoietin
J. Cereb. Blood Flow Metab.
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