Abstract
Background
In the last two decades, there has been considerable evolution in understanding the
role of erythropoietin in neuroprotection. Erythropoietin has both paracrine and autocrine
functions in the brain. Erythropoietin binding results in neurogenesis, oligodendrogenesis,
and angiogenesis. Erythropoietin and its receptor are upregulated by exposure to hypoxia
and proinflammatory cytokines after brain injury. While erythropoietin aids in recovery
of locally injured neuronal cells, it provides negative feedback to glial cells in
the penumbra, thereby limiting extension of injury. This forms the rationale for use
of recombinant erythropoietin and erythropoietin mimetics in neonatal and adult injury
models of stroke, traumatic brain injury, spinal cord injury, intracerebral hemorrhage,
and neonatal hypoxic ischemia.
Method
Review of published literature (Pubmed, Medline, and Google scholar).
Results
Preclinical neuroprotective data are reviewed, and the rationale for proceeding to
clinical trials is discussed. Results from phase I/II trials are presented, as are
updates on ongoing and upcoming clinical trials of erythropoietin neuroprotection
in neonatal populations.
Conclusions
The scientific rationale and preclinical data for erythropoietin neuroprotection are
promising. Phase II and III clinical trials are currently in process to determine
the safety and efficacy of neuroprotective dosing of erythropoietin for extreme prematurity
and hypoxic-ischemic encephalopathy in neonates.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Pediatric NeurologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Sur l'activite hematopoietique des differents organes au cours de la regeneration du sang.Comt Rend Acad Sci. 1906; 143: 432-435
- Localization of specific erythropoietin binding sites in defined areas of the mouse brain.Proc Natl Acad Sci U S A. 1995; 92: 3717-3720
- Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture.Journal of neuropathology and experimental neurology. 2001; 60 (PubMed PMID: 11305874. Epub 2001/04/18. eng): 386-392
- Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death.Neuroscience. 1997; 76 (PubMed PMID: 8971763): 105-116
- Brain capillary endothelial cells express two forms of erythropoietin receptor mRNA.Eur J Biochem. 1996; 239: 494-500
- Neuroprotection and angiogenesis: dual role of erythropoietin in brain ischemia.News Physiol Sci. 2000; 15: 225-229
- In vivo evidence that erythropoietin protects neurons from ischemic damage.Proc Natl Acad Sci U S A. 1998; 95 (PubMed PMID: 9539790): 4635-4640
- Erythropoietin: a hormone with multiple functions.Pathobiology. 2011; 78 (PubMed PMID: 21474975): 41-53
- Erythropoietin: molecular and cellular biology.Prog Clin Biol Res. 1990; 338: 19-26
- Erythropoietin structure-function relationships.Prog Clin Biol Res. 1990; 352 (PubMed PMID: 2402516): 227-232
- Tissue distribution of erythropoietin and erythropoietin receptor in the developing human fetus.Early Hum Dev. 1998; 52: 235-249
- Erythropoietin gene expression in human, monkey and murine brain.Eur J Neurosci. 1996; 8 (PubMed PMID: 0009081618): 666-676
- Immunohistochemical localization of erythropoietin and its receptor in the developing human brain.Pediatr Dev Pathol. 1999; 2 (PubMed PMID: 9949221): 148-158
- Effects of erythropoietin on glial cell development; oligodendrocyte maturation and astrocyte proliferation.Neurosci Res. 2002; 44 (PubMed PMID: 12445627. Epub 2002/11/26. eng): 391-403
- Erythropoietin-receptor gene regulation in neuronal cells.Pediatr Res. 2009; 65 (PubMed PMID: 19218878. Epub 2009/02/17. eng): 619-624
- Erythropoietin increases neurogenesis and oligodendrogliosis of subventricular zone precursor cells after neonatal stroke.Stroke. 2013; 44 (PubMed PMID: 23391775. Pubmed Central PMCID: 3689426): 753-758
- Erythropoietin signaling promotes oligodendrocyte development following prenatal systemic hypoxic-ischemic brain injury.Pediatr Res. 2013; 74 (PubMed PMID: 24108187): 658-667
- Neural progenitor cells treated with EPO induce angiogenesis through the production of VEGF.J Cereb Blood Flow Metab. 2008; 28 (PubMed PMID: 18414495. eng): 1361-1368
- Epo and non-hematopoietic cells: what do we know?.Methods Mol Biol. 2013; 982 (PubMed PMID: 23456860): 13-41
- Delayed administration of erythropoietin reducing hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome following traumatic brain injury in rats: comparison of treatment with single and triple dose.J Neurosurg. 2009; 113 (PubMed PMID: 19817538. Pubmed Central PMCID: 2898921. Epub 2009/10/13. Eng): 598-608
- Erythropoietin: a multimodal neuroprotective agent.Exp Transl Stroke Med. 2009; 1 (PubMed PMID: 20142991. Pubmed Central PMCID: 2816866. Epub 2010/02/10. eng): 4
- Structure, function, and activation of the erythropoietin receptor.Blood. 1993; 81: 2223-2236
- Signal transducers and activators of transcription 5 contributes to erythropoietin-mediated neuroprotection against hippocampal neuronal death after transient global cerebral ischemia.Neurobiol Dis. 2007; 25 (PubMed PMID: 17008107. eng): 45-53
- Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades.Nature. 2001; 412 (PubMed PMID: 11493922): 641-647
- Erythropoietin requires NF-kappaB and its nuclear translocation to prevent early and late apoptotic neuronal injury during beta-amyloid toxicity.Curr Neurovasc Res. 2005; 2 (PubMed PMID: 16375720. Pubmed Central PMCID: 1986681): 387-399
- Binding and receptor-mediated endocytosis of erythropoietin in Friend virus-infected erythroid cells.J Biol Chem. 1987; 262: 5554-5562
- Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor.Proc Natl Acad Sci U S A. 2004; 101 (PubMed PMID: 15456912. Pubmed Central PMCID: 522054): 14907-14912
- Erythropoietin and engineered innate repair activators.Methods Mol Biol. 2013; 982 (PubMed PMID: 23456859): 1-11
- A “classical” homodimeric erythropoietin receptor is essential for the antiapoptotic effects of erythropoietin on differentiated neuroblastoma SH-SY5Y and pheochromocytoma PC-12 cells.Cell Signal. 2007; 19 (PubMed PMID: 17045782): 634-645
- Erythropoietin receptor expression is concordant with erythropoietin but not with common beta chain expression in the rat brain throughout the life span.J Comp Neurol. 2009; 514 (PubMed PMID: 19330822): 403-414
- Erythropoietin receptor (EpoR) agonism is used to treat a wide range of disease.Mol Med. 2013; 19 (PubMed PMID: 23615965. Pubmed Central PMCID: 3646093): 62-64
- Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo.Proc Natl Acad Sci U S A. 2003; 100 (PubMed PMID: 12746497): 6741-6746
- Derivatives of erythropoietin that are tissue protective but not erythropoietic.Science. 2004; 305 (PubMed PMID: 15247477): 239-242
- Reduced functional deficits, neuroinflammation, and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives.J Cereb Blood Flow Metab. 2007; 27 (PubMed PMID: 16835629. Epub 2006/07/13. eng): 552-563
- Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative.Biochim Biophys Acta. 2013; 1833 (PubMed PMID: 23602701): 1960-1968
- Therapeutic potential of erythropoietin and its structural or functional variants in the nervous system.Neurotherapeutics. 2009; 6 (PubMed PMID: 19110203. eng): 108-127
- Neuroprotective properties of a novel, non-haematopoietic agonist of the erythropoietin receptor.Brain. 2010; 133 (PubMed PMID: 20435631. Epub 2010/05/04. Eng): 2281-2294
- Erythropoietin in brain development and beyond.Anat Res Int. 2012; 2012 (PubMed PMID: 22567318. Pubmed Central PMCID: 3335485. Epub 2012/05/09. eng): 953264
- General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia.Proc Natl Acad Sci U S A. 1993; 90: 4304-4308
- Oxygen(es) and the hypoxia-inducible factor-1.Biol Chem. 1997; 378: 609-616
- Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia.Blood. 2010; 116 (PubMed PMID: 20628150. Pubmed Central PMCID: 2974609. Epub 2010/07/16. eng): 3039-3048
- Regulation of cardiovascular development and physiology by hypoxia-inducible factor 1.Ann N Y Acad Sci. 1999; 874: 262-268
- HIF-1 and HIF-2: working alone or together in hypoxia?.J Clin Invest. 2007; 117 (PubMed PMID: 17404612. eng): 862-865
- The role and regulation of hypoxia-inducible factor-1alpha expression in brain development and neonatal hypoxic-ischemic brain injury.Brain Res Rev. 2009; 62 (PubMed PMID: 19786048. Epub 2009/09/30. eng): 99-108
- Insulin-like growth factors and insulin stimulate erythropoietin production in primary cultured astrocytes.Brain Res. 1997; 746: 63-70
- Early fetal hypoxia leads to growth restriction and myocardial thinning.Am J Physiol Regul Integr Comp Physiol. 2008; 295 (PubMed PMID: 18509101. Pubmed Central PMCID: PMC2519936. Epub 2008/05/30. eng): R583-R595
- Regulation of erythropoietin production.J Physiol. 2011; 589 (PubMed PMID: 21078592. Pubmed Central PMCID: PMC3082088. Epub 2010/11/17. eng): 1251-1258
- GATA suppresses erythropoietin gene expression through GATA site in mouse erythropoietin gene promoter.Int J Hematol. 2002; 75 (PubMed PMID: 12041667. Epub 2002/06/04. eng): 376-381
- Physiology and pharmacology of erythropoietin.Transfus Med Hemother. 2013; 40 (PubMed PMID: 24273483. Pubmed Central PMCID: PMC3822280. Epub 2013/11/26. eng): 302-309
- Erythropoietin: a neuroprotective agent in cerebral hypoxia, neurodegeneration, and epilepsy.Curr Pharm Des. 2013; 19 (PubMed PMID: 23530506): 6791-6801
- Erythropoietin improves histological and functional outcomes after traumatic brain injury in mice in the absence of the neural erythropoietin receptor.J Neurotrauma. 2010; 27 (PubMed PMID: 19715391. Pubmed Central PMCID: 2824224. Epub 2009/09/01. eng): 205-215
- Microarray analysis of high-dose recombinant erythropoietin treatment of unilateral brain injury in neonatal mouse hippocampus.Pediatr Res. 2009; 65 (PubMed PMID: 19190543. Epub 2009/02/05. eng): 485-492
- Selective inhibition of nitric oxide in hypoxic-ischemic brain model in newborn rats: is it an explanation for the protective role of erythropoietin?.Biol Neonate. 2004; 85 (PubMed PMID: 14631167): 51-54
- Erythropoietin and oxidative stress.Curr Neurovasc Res. 2008; 5 (PubMed PMID: 18473829. Pubmed Central PMCID: 2570710. Epub 2008/05/14. eng): 125-142
- Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis.J Exp Med. 2003; 198 (PubMed PMID: 12975460. Pubmed Central PMCID: 2194205. Epub 2003/09/17. eng): 971-975
- Effects of posttraumatic carbamylated erythropoietin therapy on reducing lesion volume and hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome in rats following traumatic brain injury.J Neurosurg. 2011; 114 (PubMed PMID: 21073254. Pubmed Central PMCID: 3057520. Epub 2010/11/16. eng): 549-559
- Effect of intrauterine infection on brain development and injury.Int J Dev Neurosci. 2013; 31 (PubMed PMID: 23831075. Epub 2013/07/09. Eng): 543-549
- Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1.Blood. 1999; 94 (PubMed PMID: 10477681. Epub 1999/09/09. eng): 1561-1567
- Neonatal hypoxia/ischemia is associated with decreased inflammatory mediators after erythropoietin administration.Stroke. 2005; 36 (PubMed PMID: 16040592): 1672-1678
- Hypoxia-ischemia affects erythropoietin and erythropoietin receptor expression pattern in the neonatal rat brain.Brain Res. 2004; 1021 (PubMed PMID: 15342264): 167-172
- Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain.Acta Neuropathol (Berl). 2001; 101 (PubMed PMID: 11307627): 271-276
- Intrinsic and extrinsic erythropoietin enhances neuroprotection against ischemia and reperfusion injury in vitro.J Neurochem. 2006; 96 (PubMed PMID: 16417583): 1101-1110
- 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. 2002; 22 (PubMed PMID: 11919510): 393-403
- Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin.Stroke. 2003; 34 (PubMed PMID: 12829864): 1981-1986
- Ischemic preconditioning is mediated by erythropoietin through PI-3 kinase signaling in an animal model of transient ischemic attack.J Neurosci Res. 2006; 83 (PubMed PMID: 16307446): 19-27
- Protecting neurons.Epilepsia. 2005; 46 Suppl 7 (PubMed PMID: 16201995): 45-51
- Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways.Faseb J. 2005; 19 (PubMed PMID: 16207820): 2026-2028
- Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation.J Biol Chem. 2007; 282 (PubMed PMID: 17604282. eng): 25875-25883
- Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury.FASEB J. 2005; 19 (PubMed PMID: 16099948): 1701-1703
- Erythropoietin improves motor and cognitive deficit, axonal pathology, and neuroinflammation in a combined model of diffuse traumatic brain injury and hypoxia, in association with upregulation of the erythropoietin receptor.Journal of neuroinflammation. 2013; 10 (PubMed PMID: 24344874. Epub 2013/12/19. Eng): 156
- Changes in brain tissue oxygenation after treatment of diffuse traumatic brain injury by erythropoietin.Crit Care Med. 2013; 41 (PubMed PMID: 23591210): 1316-1324
- Erythropoietin improved cognitive function and decreased hippocampal caspase activity in rat pups after traumatic brain injury.J Neurotrauma. 2013; 31 (PubMed PMID: 23972011): 358-369
- Erythropoietin and VEGF promote neural outgrowth from retinal explants in postnatal rats.Invest Ophthalmol Vis Sci. 2002; 43 (PubMed PMID: 12037014): 2021-2026
- Erythropoietin as an angiogenic factor.Eur J Clin Invest. 2003; 33 (PubMed PMID: 14511361): 891-896
- Enhancement of ventricular-subventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives.Frontiers in cellular neuroscience. 2013; 7 (PubMed PMID: 24348331. Pubmed Central PMCID: PMC3842008. Epub 2013/12/19. Eng): 235
- Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration.J Neurosci. 2006; 26 (PubMed PMID: 16738242. Epub 2006/06/02. eng): 5996-6003
- A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery.J Neurosci. 2006; 26 (PubMed PMID: 16436614): 1269-1274
- Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells.J Neurosci. 2001; 21 (PubMed PMID: 11739582): 9733-9743
- Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats.Stroke. 2004; 35 (PubMed PMID: 15178821): 1732-1737
- Erythropoietin protects primary hippocampal neurons increasing the expression of brain-derived neurotrophic factor.J Neurochem. 2005; 93 (PubMed PMID: 15816864): 412-421
- Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models.Clin Perinatol. 2004; 31 (PubMed PMID: 15183662): 129-142
- Tissue-protective cytokines: structure and evolution.Methods Mol Biol. 2013; 982 (PubMed PMID: 23456861. Epub 2013/03/05. eng): 43-58
- Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury.Proc Natl Acad Sci U S A. 2000; 97 (PubMed PMID: 10984541. Pubmed Central PMCID: 27058): 10526-10531
- Erythropoietin treatment improves neurological functional recovery in EAE mice.Brain Res. 2005; 1034 (PubMed PMID: 15713257. Epub 2005/02/17. eng): 34-39
- Erythropoietin reduces brain injury after intracerebral hemorrhagic stroke in rats.Mol Med Rep. 2013; 8 (PubMed PMID: 24008820): 1315-1322
- Erythropoietin: recent developments in the treatment of spinal cord injury.Neurol Res Int. 2011; 2011 (PubMed PMID: 21766022. Pubmed Central PMCID: PMC3135044. Epub 2011/07/19. eng): 453179
- Attenuation of spinal cord ischemia and reperfusion injury by erythropoietin.J Thorac Cardiovasc Surg. 2011; 141 (PubMed PMID: 21168028. Epub 2010/12/21. eng): 256-260
- Erythropoietin improves functional and histological outcome in neonatal stroke.Pediatr Res. 2005; 58 (PubMed PMID: 15879287): 106-111
- Erythropoietin after focal cerebral ischemia activates the Janus kinase-signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats.Pediatr Res. 2005; 57 (PubMed PMID: 15718373): 481-487
- Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke.Dev Neurosci. 2007; 29: 321-330
- The effect of recombinant human erythropoietin on neurovasculature repair after focal ischemic stroke in neonatal rats.J Pharmacol Exp Ther. 2007; 322: 521-528
- A comparison of high-dose recombinant erythropoietin treatment regimens in brain-injured neonatal rats.Pediatr Res. 2007; 61 (PubMed PMID: 17515870): 451-455
- Potential for protection and repair following injury to the developing brain: a role for erythropoietin?.Pediatr Res. 2005; 57 (PubMed PMID: 15817504): 110R-117R
- Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia.Developmental neuroscience. 2013; 35 (PubMed PMID: 24192275. Pubmed Central PMCID: PMC3873854. Epub 2013/11/07. eng): 491-503
- Erythropoietin attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain.Neonatology. 2007; 92: 269-278
- Short-term effects of erythropoietin on neurodevelopment in infants with cerebral palsy: a pilot study.Brain Dev. 2013; (PubMed PMID: 24314853)
- Safety of high-dose recombinant erythropoietin in a neonatal rat model.Neonatology. 2007; 91 (PubMed PMID: 17344650): 36-43
- A phase I/II trial of high-dose erythropoietin in extremely low birth weight infants: pharmacokinetics and safety.Pediatrics. 2008; 122 (PubMed PMID: 18676557. eng): 383-391
- An approach to using recombinant erythropoietin for neuroprotection in very preterm infants.Pediatrics. 2008; 122 (PubMed PMID: 18676556. Epub 2008/08/05. eng): 375-382
- Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics.Pediatrics. 2012; 130 (PubMed PMID: 23008465. Pubmed Central PMCID: 3457622. Epub 2012/09/26. eng): 683-691
- Feasibility and safety of erythropoietin for neuroprotection after perinatal arterial ischemic stroke.J Pediatr. 2013; 162 (PubMed PMID: 24321539): 481.e1-481.e2
- Erythropoietin neuroprotection in neonatal cardiac surgery: a phase I/II safety and efficacy trial.J Thorac Cardiovasc Surg. 2013; 146 (PubMed PMID: 23102686. Pubmed Central PMCID: 3579008): 124-131
- Outcomes of extremely low birth weight infants given early high-dose erythropoietin.J Perinatol. 2013; 33 (PubMed PMID: 22722674): 226-230
- Pharmacokinetics of high-dose recombinant erythropoietin in plasma and brain of neonatal rats.Pediatr Res. 2007; 61 (PubMed PMID: 17426655): 671-675
- A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants.Pediatrics. 2013; 132 (PubMed PMID: 23776118. Pubmed Central PMCID: 3691539): e119-e127
- Erythropoietin therapy for acute stroke is both safe and beneficial.Mol Med. 2002; 8 (PubMed PMID: 12435860): 495-505
- Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled phase 2 trial.Neuropsychopharmacology. 2013; 39 (PubMed PMID: 24322509): 1399-1408
- Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia.Mol Med. 2012; 18 (PubMed PMID: 22669473. Pubmed Central PMCID: 3459483): 1029-1040
- Circulating damage marker profiles support a neuroprotective effect of erythropoietin in ischemic stroke patients.Mol Med. 2011; 17 (PubMed PMID: 21912808. Epub 2011/09/14. Eng): 1306-1310
- Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia.Mol Psychiatry. 2011; 16 (1. PubMed PMID: 20479759. Epub 2010/05/19. eng): 26-36
- Recombinant human erythropoietin: approaches to neuroprotection and neuroregeneration in schizophrenia.Schizophrenia Bulletin. 2009; 35 (PubMed PMID: ISI:000263964701039. English): 358
- Recombinant human erythropoietin: novel strategies for neuroprotective/neuro-regenerative treatment of multiple sclerosis.Ther Adv Neurol Disord. 2008; 1 (PubMed PMID: 21180577. Pubmed Central PMCID: 3002551): 193-206
Article info
Publication history
Published online: June 23, 2014
Accepted:
June 12,
2014
Received:
April 7,
2014
Identification
Copyright
© 2014 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
