Recombinant erythropoietin (EPO) is used to correct for anaemia caused by chronic renal failure or cancer therapy. Improvement of the quality of life of anaemic patients treated with EPO was recently demonstrated and preliminary clinical results suggest an improvement of cognitive functions in patients receiving EPO. High expression of EPO and its receptor in the brain during embryonic development has led to the investigation of not only the neurotrophic role of EPO but also its neuroprotective properties. The neuroprotective effects of EPO have various complementary actions including antagonism of the effects of glutamate, increased expression of antioxidant enzymes, changes in production of neurotransmitters and induction of neuroglobin. Convincing experimental results suggest a blood-brain transport of EPO whereas clinical pharmacokinetic data do not as yet support this. The neuroprotective effects of EPO and its therapeutic promise need to be underlined.
Ratcliffe PJ, O’Rourke JF, Maxwell PH, Pugh CW.Oxygen sensing hypoxia-inducible factor-I and the regulation of mammalian gene expression. J Exp Biol1998; 201: 1153-1162.
3.
Rizzo JD, Lichtin AE, Woolf SH, et al.Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol2002; 20: 4083-4107.
4.
Bottomley A, Thomas R, van Steen K, et al.Human recombinant erythropoietin and quality of life: a wonder drug or something to wonder about?Lancet Oncol2002; 3: 145-153.
5.
Fallowfield L, Gagnon D, Zagari M, et al.; the Epoetin Alfa Study Group. Multivariate regression analyses of data from a randomised, double-blind, placebo-controlled study confirm quality of life benefit of epoetin alfa in patients receiving non-platinum chemotherapy. Br J Cancer2002; 87: 1341-1353.
6.
Boogaerts M, Coiffier B, Kainz C;Epoetin b QOL Working Group. Impact of epoetin b on quality of life in patients with malignant disease. Br J Cancer2003; 88: 988-995.
7.
Cella D, Zagari MJ, Vandoros C, et al.Epoetin alfa treatment result in clinically significant improvements in quality of life anemic cancer patients when referenced to the general population. J Clin Oncol2003; 21: 366-373.
8.
Minisini A, Atalay G, Bottomeley A, et al.What is the effect of systemic anticancer treatment on cognitive function?Lancet Oncol2004; 5: 273-282.
9.
O’Shaughnessy JA.Effects of epoetin alfa on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant chemotherapy. Clin Breast Cancer2002; 3: 116-120.
10.
Brines M.What evidence supports use of erythropoietin as a novel neurotherapeutic?Oncology2002; 16: 79-89.
11.
Juul SE, Harcum J, Li Y, Christensen RD.Erythropoietin is present in the cerebrospinal fluid of neonates. J Pediatr1997; 130: 428-430.
12.
Liu C, Kun S, Ziyao L, Noguchi CT.Regulated human erythropoietin receptor expression in mouse brain. J Biol Chem1997; 272: 32395-32400.
13.
Juul SE, Yachnis AT, Rojiani AM.Immunohistochemical localization of erythropoietin and its receptor in the developing human brain. Pediatr Dev Pathol1999; 2: 148-158.
14.
Juul SE, Yachnis AT, Christensen RD.Tissue distribution of erythropoietin and erythropoietin receptor in developing human fetuses. Early Hum Dev1998; 52: 235-249.
15.
Yu X, Lin C-S, Costantini F, Noguchi CT.The human erythropoietin receptor gene rescues erythropoiesis and developmental defects in the erythropoietin receptor null mouse. Blood2001; 98: 475-477.
16.
Buemi M, Cavallaro E, Floccari F, et al.Erythropoietin and the brain: from neurodevelopment to neuroprotection. Clin Sci2002; 103: 275-282.
17.
Juul SE, Anderson DK, Li Y, Christensen RD.Erythropoietin and erythropoietin receptor in the developing human central nervous system. Pediatr Res1998; 43: 40-49.
18.
Bernaudin M, Bellail A, Marti HH, et al.Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. Glia2000; 30: 271-278.
19.
Morishida E, Masuda S, Nagao M, et al.Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience1997; 76: 105-116.
20.
Lewczuk P, Hasselblatt M, Kamrowski-Kruck H, et al.Survival of hippocampal neurons in culture upon hypoxia: effect of erythropoietin. Neuroport2000; 11: 3485-3488.
21.
Sadamoto Y, Igase K, Sakanaka M, et al.Erythropoietin prevents place-navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem Biophys Res Commun1998; 253: 26-32.
22.
Bernaudin M, Marti HH, Roussel S, et al.A potential role of erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab1999; 19: 643-651.
23.
Springborg JB, Ma W, Rochat P, et al.A single subcutaneous bolus of erythropoietin normalizes cerebral blood flow autoregulation after subarachnoid haemorrhage in rats. Br J Pharmacol2002; 135: 823-829.
24.
Buemi M, Cavallaro E, Flocarri F, et al.The pleiotropic effects of erythropoietin in the central nervous system. J Neuropathol Exp Neurol2003; 62: 228-236.
Digicaylioglu M, Lipton SA.Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kB signaling cascades. Nature2001; 412: 641-647.
27.
Wen TC, Sadamato Y, Tanaka J, et al.Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by up-regulating Bcl-xL expression. J Neurosci Res2002; 67: 795-803.
28.
Ehrenreich H, Hasselblatt M, Dembowski C, et al.Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med2002; 8: 495-505.
29.
Grasso G.An overview of new pharmacological treatments for cerebrovascular dysfunction after experimental subarachnoid hemorrhage. Brain Res Rev2004; 44: 49-63.
30.
Hugo HM.Erythropoietin and the hypoxic brain. J Exp Biol2004; 207: 3233-3242.
31.
Brines ML, Ghezzi P, Keenan S, et al.Erythropoietin crosses the blood -brain barrier to protect against experimental brain injury. Proc Natl Acad Sci2000; 97: 10526-10531.
32.
Juul SE, McPherson RJ, Farrell FX, et al.Erythropoietin concentrations in cerebrospinal fluid of nonhuman primates and teal sheep following high-dose recombinant erythropoietin. Biol Neonate2004; 85: 138-144.
33.
Buemi M, Allegra A, Corica F, et al.Intravenous recombinant erythropoietin does not lead to an increase in cerebrospinal fluid erythropoietin concentration. Nephrol Dial Transplant2000; 15: 422-423.
34.
Erbayaraktar S, Yilmaz O, Gökmen N, Brines M.Erythropoietin is a multifunctional tissue-protective cytokine. Curr Hematol Rep2003; 2: 465-470.
35.
Parsa CJ, Masumoto A, Kim J, et al.A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest2003; 112: 999-1007.
36.
Smith KJ, Bleyer AJ, Little WC, Sane DC.The cardiovascular effects of erythropoietin. Cardiovasc Res2003; 59: 538-548.
37.
Leist M, Ghezzi P, Grasso G, et al.Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science2004; 305: 239-242.
