Recombinant human erythropoietin: Novel strategies for neuroprotective/neuroregenerative treatment of multiple sclerosis

Therapeutic Advances in Neurological Disorders

Volumn 1, Issue 3, 2008, Pages 193-206

  Bartels, Claudia ^a   Späte, Kira ^a   Krampe, Henning ^a   Ehrenreich, Hannelore ^a  

^a MAX PLANCK INSTITUTE OF EXPERIMENTAL MEDICINE   (Germany)

Author keywords

Chronic progressive multiple sclerosis (MS); Clinical trial; Cognition; Erythropoietin receptor (EPOR); Experimental autoimmune encephalomyelitis (EAE); Hematopoietic growth factor; Motor function; Neurodegeneration

Indexed keywords

EID: 84993790552     PISSN: 17562856     EISSN: None     Source Type: Journal    
DOI: 10.1177/1756285608098422     Document Type: Review

References (105)

1. Adamcio, B., Sargin, D., Stradomska, A., Medrihan, L., Gertler, C., Theis, F. et al. (2008) Erythropoietin enhances hippocampal long-term potentiation and memory. BMC Biol 6: 37.
2. Agnello, D., Bigini, P., Villa, P., Mennini, T., Cerami, A., Brines, M.L. et al. (2002) Erythropoietin exerts an anti-inflammatory effect on the CNS in a model of experimental autoimmune encephalomyelitis. Brain Res 952: 128-134.
3. Banks, W.A., Jumbe, N.L., Farrell, C.L., Niehoff, M.L. and Heatherington, A.C. (2004) passage of erythropoietic agents across the blood-brain barrier: a comparison of human and murine erythropoietin and the analog darbepoetin alfa. Eur J Pharmacol 505: 93-101.
4. Bauer, C. and Kurtz, A. (1989) Oxygen sensing in the kidney and its relation to erythropoietin production. Annu Rev Physiol 51: 845-856.
5. Beleslin-Cokic, B.B., Cokic, V.P., Yu, X., Weksler, B.B., Schechter, A.N. and Noguchi, C.T. (2004) Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood 104: 2073-2080.
6. Bernaudin, M., Marti, H.H., Roussel, S., Divoux, D., Nouvelot, A., Mackenzie, E.T. et al. (1999) A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19: 643- 651.
7. Bianchi, R., Buyukakilli, B., Brines, M., Savino, C., Cavaletti, G., Oggioni, N. et al. (2004) Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proc Natl Acad Sci USA 101: 823-828.
8. Bocker-Meffert, S., Rosenstiel, P., Rohl, C., Warneke, N., Held-Feindt, J., Sievers, J. et al. (2002) Erythropoietin and VEGF promote neural outgrowth from retinal explants in postnatal rats. Invest Ophthalmol Vis Sci 43: 2021-2026.
9. Brettschneider, J., Widl, K., Ehrenreich, H., Riepe, M. and Tumani, H. (2006) Erythropoietin in the cerebrospinal fluid in neurodegenerative diseases. Neurosci Lett 404: 347-351.
10. Brines, M., Grasso, G., Fiordaliso, F., Sfacteria, A., Ghezzi, P., Fratelli, M. et al. (2004) Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci USA 101: 14907-14912.
11. Brines, M.L., Ghezzi, P., Keenan, S., Agnello, D., de Lanerolle, N.C., Cerami, C. et al. (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 97: 10526-10531.
12. Brück, W. (2005) Clinical implications of neuro-pathological findings in multiple sclerosis. J Neurol 252(Suppl. 3): iii10-iii14.
13. Byts, N., Samoylenko, A., Fasshauer, T., Ivanisevic, M., Hennighausen, L., Ehrenreich, H. et al. (2008) Essential role for Stat 5 in the neurotrophic but not in the neuroprotective effect of erythropoietin. Cell Death Differ 15: 783-792.
14. Byts, N., Samoylenko, A., Woldt, H., Ehrenreich, H. and Siren, A.L. (2006) Cell type specific signalling by hematopoietic growth factors in neural cells. Neurochem Res 31: 1219-1230.
15. Campana, W.M. and Myers, R.R. (2001) Erythropoietin and erythropoietin receptors in the peripheral nervous system: changes after nerve injury. Faseb J 15: 1804-1806.
16. Carlini, R., Obialo, C.I. and Rothstein, M. (1993 a) Intravenous erythropoietin (rhuepo) administration increases plasma endothelin and blood pressure in hemodialysis patients. Am J Hypertens 6: 103-107.
17. Carlini, R.G., Dusso, A.S., Obialo, C.I., Alvarez, U.M. and Rothstein, M. (1993 b) Recombinant human erythropoietin (rhuepo) increases endothelin-1 release by endothelial cells. Kidney Int 43: 1010-1014.
18. Casals-Pascual, C., Idro, R., Gicheru, N., Gwer, S., Kitsao, B., Gitau, E. et al. (2008) High levels of erythropoietin are associated with protection against neurological sequelae in african children with cerebral malaria. Proc Natl Acad Sci USA 105: 2634-2639.
19. Celik, M., Gokmen, N., Erbayraktar, S., Akhisaroglu, M., Konakc, S., Ulukus, C. et al. (2002) Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci USA 99: 2258-2263.
20. Chang, K.H., Tam, M. and Stevenson, M.M. (2004) Modulation of the course and outcome of blood-stage malaria by erythropoietin-induced reticulocytosis. J Infect Dis 189: 735-743.
21. Chikuma, M., Masuda, S., Kobayashi, T., Nagao, M. and Sasaki, R. (2000) Tissue-specific regulation of erythropoietin production in the murine kidney, brain, and uterus. Am J Physiol Endocrinol Metab 279: 1242-1248.
22. Chopp, M., Li, Y. and Zhang, J. (2008) Plasticity and remodeling of brain. J Neurol Sci 265: 97-101.
23. Chung, Y.H., Joo, K.M., Kim, Y.S., Lee, K.H., Lee, W.B. and Cha, C.I. (2004) Enhanced Expression of erythropoietin in the central nervous system of Sod1(G93a) transgenic mice. Brain Res 1016: 272-280.
24. Compston, A. and Coles, A. (2002) Multiple sclerosis. Lancet 359: 1221-1231.
25. Confavreux, C. and Vukusic, S. (2006) Accumulation of irreversible disability in multiple sclerosis: from epidemiology to treatment. Clin Neurol Neurosurg 108: 327-332.
26. Csete, M., Rodriguez, L., Wilcox, M. and Chadalavada, S. (2004) Erythropoietin receptor is expressed on adult rat dopaminergic neurons and erythropoietin is neurotrophic in cultured dopaminergic neuroblasts. Neurosci Lett 359: 124-126.
27. Diem, R., Sattler, M.B., Merkler, D., Demmer, I., Maier, K., Stadelmann, C. et al. (2005) Combined therapy with methylprednisolone and erythropoietin in a model of multiple sclerosis. Brain 128: 375-385.
28. Digicaylioglu, M. and Lipton, S.A. (2001) Erythropoietin-mediated neuroprotection involves cross-talk between JAK2 and NF-kappab signalling cascades. Nature 412: 641-647.
29. Ehrenreich, H., Degner, D., Meller, J., Brines, M., Behe, M., Hasselblatt, M. et al. (2004) Erythropoietin: a candidate compound for neuroprotection in schizophrenia. Molecular Psychiatry 9: 42-54.
30. Ehrenreich, H., Fischer, B., Norra, C., Schellenberger, F., Stender, N., Stiefel, M. et al. (2007 a) Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 130: 2577-2588.
31. Ehrenreich, H., Hasselblatt, M., Dembowski, C., Cepek, L., Lewczuk, P., Stiefel, M. et al. (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. Molecular Medicine 8: 495-505.
32. Ehrenreich, H., Hasselblatt, M., Knerlich, F., von Ahsen, N., Jacob, S., Sperling, S. et al. (2005) A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain. Proc Natl Acad Sci USA 102: 862-867.
33. Ehrenreich, H., Hinze-Selch, D., Stawick, S., Aust, C., Knolle-Veentjer, S., Wilms, S. et al. (2007 b) Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Molecular Psychiatry 12: 206-220.
34. Eid, T., Brines, M.L., Cerami, A., Spencer, D.D., Kim, J.H., Schweitzer, J.S. et al. (2004) Increased expression of erythropoietin receptor on blood vessels in the human epileptogenic hippocampus with sclerosis. J Neuropathol Exp Neurol 63: 73-83.
35. Erbayraktar, S., de Lanerolle, N., de Lotbiniere, A., Knisely, J.P., Erbayraktar, Z., Yilmaz, O. et al. (2006) Carbamylated erythropoietin reduces radiosurgicallyinduced brain injury. Mol Med 12: 74-80.
36. Erbayraktar, S., Grasso, G., Sfacteria, A., Xie, Q.W., Coleman, T., Kreilgaard, M. et al. (2003) Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci USA 100: 6741-6746.
37. Feldmann, M. and Steinman, L. (2005) Design of effective immunotherapy for human autoimmunity. Nature 435: 612-619.
38. Fisher, J.W. (2003) Erythropoietin: physiology and pharmacology update. Exp Biol Med 228: 1-14.
39. Flachenecker, P., Stuke, K., Elias, W., Freidel, M., Haas, J., Pitschnau-Michel, D. et al. (2008) Multiple-Sklerose-Register in Deutschland: Ausweitung des Projektes 2005 / 2006. Deutsches Ärzteblatt Ä 105: 113-119.
40. Flachenecker, P., Zettl, U.K., Gotze, U., Haas, J., Schimrigk, S., Elias, W. et al. (2005) [Ms registry in Germany - design and first results of the pilot phase]. Nervenarzt 76: 967-975.
41. Genc, S., Akhisaroglu, M., Kuralay, F. and Genc, K. (2002) Erythropoietin restores glutathione peroxidase activity in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced neurotoxicity in C57bl mice and stimulates murine astroglial glutathione peroxidase production in vitro. Neurosci Lett 321: 73-76.
42. Genc, S., Kuralay, F., Genc, K., Akhisaroglu, M., Fadiloglu, S., Yorukoglu, K. et al. (2001) Erythropoietin exerts neuroprotection in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated C57/Bl mice via increasing nitric oxide production. Neurosci Lett 298: 139-141.
43. Giovannoni, G. (2004) Management of secondary-progressive multiple sclerosis. CNS Drugs 18: 653-669.
44. Gold, R., Linington, C. and Lassmann, H. (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129: 1953-1971.
45. Gorio, A., Gokmen, N., Erbayraktar, S., Yilmaz, O., Madaschi, L., Cichetti, C. et al. (2002) Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci USA 99: 9450-9455.
46. Grant, S.M., Wiesinger, J.A., Beard, J.L. and Cantorna, M.T. (2003) Iron-deficient mice fail to develop autoimmune encephalomyelitis. J Nutr 133: 2635-2638.
47. Grasso, G., Buemi, M., Alafaci, C., Sfacteria, A., Passalacqua, M., Sturiale, A. et al. (2002) Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage. Proc Natl Acad Sci USA 99: 5627-5631.
48. Grignaschi, G., Zennaro, E., Tortarolo, M., Calvaresi, N. and Bendotti, C. (2007) Erythropoietin does not preserve motor neurons in a mouse model of familial ALS. Amyotroph Lateral Scler 8: 31-35.
49. Grimm, C., Wenzel, A., Groszer, M., Mayser, H., Seeliger, M., Samardzija, M. et al. (2002) HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med 8: 718-724.
50. Grunfeld, J.F., Barhum, Y., Blondheim, N., Rabey, J.M., Melamed, E. and Offen, D. (2007) Erythropoietin delays disease onset in an amyotrophic lateral sclerosis model. Exp Neurol 204: 260-263.
51. Hauser, S.L. and Oksenberg, J.R. (2006) The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52: 61-76.
52. Hohlfeld, R. and Wekerle, H. (2004) Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: from pipe dreams to (therapeutic) pipelines. Proc Natl Acad Sci USA 101(Suppl. 2): 14599-14606.
53. Jelkmann, W. (1992) Erythropoietin: structure, control of production, and function. Physiol Rev 72: 449-489.
54. Jelkmann, W. (2007) Erythropoietin after a century of research: younger than ever. Eur J Haematol 78: 183-205.
55. Jelkmann, W. (2008) Developments in the therapeutic use of erythropoiesis stimulating agents. Br J Haematol 141: 287-297.
56. Jelkmann, W., Bohlius, J., Hallek, M. and Sytkowski, A.J. (2008) The erythropoietin receptor in normal and cancer tissues. Crit Rev Oncol Hematol 67: 39-61.
57. Jubinsky, P.T., Krijanovski, O.I., Nathan, D.G., Tavernier, J. and Sieff, C.A. (1997) The beta chain of the interleukin-3 receptor functionally associates with the erythropoietin receptor. Blood 90: 1867-1873.
58. Juul, S.E., Anderson, D.K., Li, Y. and Christensen, R.D. (1998) Erythropoietin and erythropoietin receptor in the developing human central nervous system. Pediatr Res 43: 40-49.
59. Kaiser, K., Texier, A., Ferrandiz, J., Buguet, A., Meiller, A., Latour, C. et al. (2006) Recombinant human erythropoietin prevents the death of mice during cerebral malaria. J Infect Dis 193: 987-995.
60. Kertesz, N., Wu, J., Chen, T.H., Sucov, H.M. and Wu, H. (2004) The role of erythropoietin in regulating angiogenesis. Dev Biol 276: 101-110.
61. Keswani, S.C., Buldanlioglu, U., Fischer, A., Reed, N., Polley, M., Liang, H. et al. (2004) A novel endogenous erythropoietin mediated pathway prevents axonal degeneration. Ann Neurol 56: 815-826.
62. Kilic, E., Kilic, U., Soliz, J., Bassetti, C.L., Gassmann, M. and Hermann, D.M. (2005) Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and AKT pathways. Faseb J 19: 2026-2028.
63. Knabe, W., Knerlich, F., Washausen, S., Kietzmann, T., Siren, A.L., Brunnett, G. et al. (2004) Expression patterns of erythropoietin and its receptor in the developing midbrain. Anat Embryol ( Berl) 207: 503-512.
64. Knabe, W., Siren, A.L., Ehrenreich, H. and Kuhn, H.J. (2005) Expression patterns of erythropoietin and its receptor in the developing spinal cord and dorsal root ganglia. Anat Embryol (Berl) 210: 209-219.
65. Koh, S.H., Kim, Y., Kim, H.Y., Cho, G.W., Kim, K.S. and Kim, S.H. (2007) Recombinant human erythropoietin suppresses symptom onset and progression of G93a-Sod1 mouse model of ALS by preventing motor neuron death and inflammation. Eur J Neurosci 25: 1923-1930.
66. Konishi, Y., Chui, D.H., Hirose, H., Kunishita, T. and Tabira, T. (1993) Trophic effect of erythropoietin and other hematopoietic factors on central cholinergic neurons in vitro and in vivo. Brain Res 609: 29-35.
67. Kwack, C. and Balakrishnan, V.S. (2006) Managing erythropoietin hyporesponsiveness. Semin Dial 19: 146-151.
68. Leist, M., Ghezzi, P., Grasso, G., Bianchi, R., Villa, P., Fratelli, M. et al. (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305: 239-242.
69. Lewczuk, P., Hasselblatt, M., Kamrowski-Kruck, H., Heyer, A., Unzicker, C., Siren, A.L. et al. (2000) Survival of hippocampal neurons in culture upon hypoxia: effect of erythropoietin. Neuroreport 11: 3485-3488.
70. Li, W., Maeda, Y., Yuan, R.R., Elkabes, S., Cook, S. and Dowling, P. (2004) Beneficial effect of erythropoietin on experimental allergic encephalomyelitis. Ann Neurol 56: 767-777.
71. Livnah, O., Stura, E.A., Middleton, S.A., Johnson, D.L., Jolliffe, L.K. and Wilson, I.A. (1999) Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science 283: 987-990.
72. Lynch, S.G., Fonseca, T. and Levine, S.M. (2000) A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis. Cell Mol Biol ( Noisy-le-grand) 46: 865-869.
73. Marti, H.H., Wenger, R.H., Rivas, L.A., Straumann, U., Digicaylioglu, M., Henn, V. et al. (1996) Erythropoietin gene expression in human, monkey and murine brain. Eur J Neurosci 8: 666-676.
74. Martinez-Estrada, O.M., Rodriguez-Millan, E., Gonzalez-De Vicente, E., Reina, M., Vilaro, S. and Fabre, M. (2003) Erythropoietin protects the in vitro blood-brain barrier against vegf-induced permeability. Eur J Neurosci 18: 2538-2544.
75. Masuda, S., Nagao, M., Takahata, K., Konishi, Y., Gallyas, F., Tabira, T. et al. (1993) Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J Biol Chem 268: 11208-11216.
76. Masuda, S., Okano, M., Yamagishi, K., Nagao, M., Ueda, M. and Sasaki, R. (1994) A Novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. J Biol Chem 269: 19488-19493.
77. Miyashita, K., Tojo, A., Kimura, K., Goto, A., Omata, M., Nishiyama, K. et al. (2004) Blood pressure response to erythropoietin injection in hemodialysis and predialysis patients. Hypertens Res 27: 79-84.
78. Noseworthy, J.H. (2003) Management of multiple sclerosis: current trials and future options. Curr Opin Neurol 16: 289-297.
79. Park, M.H., Lee, S.M., Lee, J.W., Son, D.J., Moon, D.C., Yoon, D.Y. et al. (2006) ERK-mediated production of neurotrophic factors by astrocytes promotes neuronal stem cell differentiation by erythropoietin. Biochem Biophys Res Commun 339: 1021-1028.
80. Pugliatti, M., Rosati, G., Carton, H., Riise, T., Drulovic, J., Vecsei, L. et al. (2006) The epidemiology of multiple sclerosis in Europe. Eur J Neurol 13: 700-722.
81. Quaschning, T., Ruschitzka, F., Stallmach, T., Shaw, S., Morawietz, H., Goettsch, W. et al. (2003) Erythropoietin-induced excessive erythrocytosis activates the tissue endothelin system in mice. Faseb J 17: 259-261.
82. Rovaris, M., Confavreux, C., Furlan, R., Kappos, L., Comi, G. and Filippi, M. (2006) Secondary progressive multiple sclerosis: current knowledge and future challenges. Lancet Neurol 5: 343-354.
83. Sadamoto, Y., Igase, K., Sakanaka, M., Sato, K., Otsuka, H., Sakaki, S. et al. (1998) Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem Biophys Res Commun 253: 26-32.
84. Sakanaka, M., Wen, T.C., Matsuda, S., Masuda, S., Morishita, E., Nagao, M. et al. (1998) In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA 95: 4635-4640.
85. Sättler, M.B., Merkler, D., Maier, K., Stadelmann, C., Ehrenreich, H., Bahr, M. et al. (2004) Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis. Cell Death Differ 11(Suppl. 2): S181-S192
86. Savino, C., Pedotti, R., Baggi, F., Ubiali, F., Gallo, B., Nava, S. et al. (2006) Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitis. J Neuroimmunol 172: 27-37.
87. Sfagos, C., Makis, A.C., Chaidos, A., Hatzimichael, E.C., Dalamaga, A., Kosma, K. et al. (2005) Serum ferritin, transferrin and soluble transferrin receptor levels in multiple sclerosis patients. Mult Scler 11: 272-275.
88. Sharp, F.R. and Bernaudin, M. (2004) Hif 1 and oxygen sensing in the brain. Nat Rev Neurosci 5: 437-448.
89. Shingo, T., Sorokan, S.T., Shimazaki, T. and Weiss, S. (2001) Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci 21: 9733-9743.
90. Sirén, A.L., Fratelli, M., Brines, M., Goemans, C., Casagrande, S., Lewczuk, P. et al. (2001 a) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA 98: 4044-4049.
91. Sirén, A.L., Knerlich, F., Poser, W., Gleiter, C.H., Brück, W. and Ehrenreich, H. (2001 b) Erythropoietin and erythropoietin receptor in human ischemic / hypoxic brain. Acta Neuropathol 101: 271-276.
92. Sirén, A.L., Radyushkin, K., Boretius, S., Kämmer, D., Riechers, C.-C., Natt, O. et al. (2006) Global brain atrophy after unilateral parietal lesion and its prevention by erythropoietin. Brain 129: 480-489.
93. Springborg, J.B., Ma, X., Rochat, P., Knudsen, G.M., Amtorp, O., Paulson, O.B. et al. (2002) A single subcutaneous bolus of erythropoietin normalizes cerebral blood flow autoregulation after subarachnoid haemorrhage in rats. Br J Pharmacol 135: 823-829.
94. Tsai, P.T., Ohab, J.J., Kertesz, N., Groszer, M., Matter, C., Gao, J. et al. (2006) A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. J Neurosci 26: 1269-1274.
95. Vaziri, N.D., Zhou, X.J., Smith, J., Oveisi, F., Baldwin, K. and Purdy, R.E. (1995) In vivo and in vitro pressor effects of erythropoietin in rats. Am J Physiol 269: F838-F845
96. Villa, P., Bigini, P., Mennini, T., Agnello, D., Laragione, T., Cagnotto, A. et al. (2003) Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med 198: 971-975.
97. Weilbach, F.X., Chan, A., Toyka, K.V. and Gold, R. (2004) The cardioprotector dexrazoxane augments therapeutic efficacy of mitoxantrone in experimental autoimmune encephalomyelitis. Clin Exp Immunol 135: 49-55.
98. Weimar, C., Kraywinkel, K., Maschke, M. and Diener, H.C. (2006) Intravenous thrombolysis in German stroke units before and after regulatory approval of recombinant tissue plasminogen activator. Cerebrovasc Dis 22: 429-431.
99. Weishaupt, J.H., Rohde, G., Polking, E., Siren, A.L., Ehrenreich, H. and Bahr, M. (2004) Effect of erythropoietin axotomy-induced apoptosis in rat retinal ganglion cells. Invest Ophthalmol Vis Sci 45: 1514-1522.
100. Wiese, L., Hempel, C., Penkowa, M., Kirkby, N. and Kurtzhals, J.A. (2008) Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria. Malar J 7: 3.
101. Wingerchuk, D.M. and Noseworthy, J.H. (2002) Randomized controlled trials to assess therapies for multiple sclerosis. Neurology 58: S40-S48
102. Xenocostas, A., Cheung, W.K., Farrell, F., Zakszewski, C., Kelley, M., Lutynski, A. et al. (2005) The pharmacokinetics of erythropoietin in the cerebrospinal fluid after intravenous administration of recombinant human erythropoietin. Eur J Clin Pharmacol 61: 189-195.
103. Yu, X., Shacka, J.J., Eells, J.B., Suarez-Quian, C., Przygodzki, R.M., Beleslin-Cokic, B. et al. (2002) Erythropoietin receptor signalling is required for normal brain development. Development 129: 505-516.
104. Yuan, R., Maeda, Y., Li, W., Lu, W., Cook, S. and Dowling, P. (2008) Erythropoietin: a potent inducer of peripheral immuno / inflammatory modulation in autoimmune EAE. PloS ONE 3: e1924.
105. Zhang, J., Li, Y., Cui, Y., Chen, J., Lu, M., Elias, S.B. et al. (2005) Erythropoietin Treatment Improves Neurological Functional Recovery in EAE Mice. Brain Res 1034: 34-39.