Evidence that erythropoietin modulates neuroinflammation through differential action on neurons, astrocytes, and microglia

Frontiers in Immunology

Volumn 5, Issue OCT, 2014, Pages

  Bond, Wesley S ^a   Rex, Tonia S ^b  

^a VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^b VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Astrocytes; Erythropoietin; Microglia; Neuroinflammation; Signaling pathways

Indexed keywords

ERYTHROPOIETIN; REACTIVE NITROGEN SPECIES; REACTIVE OXYGEN METABOLITE;

APOPTOSIS; ASTROCYTE; CELL DEATH; CELL INFILTRATION; CELL INTERACTION; CELL PROLIFERATION; CELL SURVIVAL; CELL TYPE; GLIA CELL; HYPERTROPHY; IMMUNOCOMPETENT CELL; MACROPHAGE; MICROGLIA; NERVE CELL; NERVOUS SYSTEM INFLAMMATION; NEUROMODULATION; NONHUMAN; OXIDATIVE STRESS; PHAGOCYTOSIS; REVIEW; SIGNAL TRANSDUCTION;

EID: 84919435787     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2014.00523     Document Type: Review

References (107)

1. Streit WJ, Mrak RE, Griffin WST. Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation (2004) 1:14. doi: 10.1186/1742-2094-1-14
2. Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG. Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener (2009) 4:47. doi:10.1186/1750-1326-4-47
3. Palis J. Primitive and definitive erythropoiesis in mammals. Front Physiol (2014) 5:3. doi:10.3389/fphys.2014.00003
4. Ghezzi P, Brines M. Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ (2004) 11(Suppl 1):S37-44. doi:10.1038/sj.cdd.4401450
5. Ingley E. Integrating novel signaling pathways involved in erythropoiesis. IUBMB Life (2012) 64:402-10. doi:10.1002/iub.1024
6. Broxmeyer HE. Erythropoietin: multiple targets, actions, and modifying influences for biological and clinical consideration. J Exp Med (2013) 210:205-8. doi:10.1084/jem.20122760
7. Genc S, Koroglu TF, Genc K. Erythropoietin and the nervous system. Brain Res (2004) 1000:19-31. doi:10.1016/j.brainres.2003.12.037
8. Noguchi CT, Asavaritikrai P, Teng R, Jia Y. Role of erythropoietin in the brain. Crit Rev Oncol Hematol (2007) 64:159-71. doi:10.1016/j.critrevonc.2007.03.001
9. Maiese K, Chong ZZ, Shang YC, Wang S. Erythropoietin: new directions for the nervous system. Int J Mol Sci (2012) 13:11102-29. doi:10.3390/ijms130911102
10. Weishaupt JH, Rohde G, Pölking E, Siren A-L, Ehrenreich H, Bähr M. Effect of erythropoietin axotomy-induced apoptosis in rat retinal ganglion cells. Invest Ophthalmol Vis Sci (2004) 45:1514-22. doi:10.1167/iovs.03-1039
11. Tsai JC, Wu L, Worgul B, Forbes M, Cao J. Intravitreal administration of erythropoietin and preservation of retinal ganglion cells in an experimental rat model of glaucoma. Curr Eye Res (2005) 30:1025-31. doi:10.1080/02713680500320729
12. Zhong L, Bradley J, Schubert W, Ahmed E, Adamis AP, Shima DT, et al. Erythropoietin promotes survival of retinal ganglion cells in DBA/2J glaucoma mice. Invest Ophthalmol Vis Sci (2007) 48:1212-8. doi:10.1167/iovs.06-0757
13. Sullivan TA, Geisert EE, Hines-Beard J, Rex TS. Systemic adeno-associated virus-mediated gene therapy preserves retinal ganglion cells and visual function in DBA/2J glaucomatous mice. Hum Gene Ther (2011) 22:1191-200. doi:10.1089/hum.2011.052
14. Sullivan T, Kodali K, Rex TS. Systemic gene delivery protects the photoreceptors in the retinal degeneration slow mouse. Neurochem Res (2011) 36:613-8. doi:10.1007/s11064-010-0272-6
15. Sullivan TA, Geisert EE, Templeton JP, Rex TS. Dose-dependent treatment of optic nerve crush by exogenous systemic mutant erythropoietin. Exp Eye Res (2012) 96:36-41. doi:10.1016/j.exer.2012.01.006
16. Grimm C, Wenzel A, Groszer M, Mayser H, Seeliger M, Samardzija M, et al. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med (2002) 8:718-24. doi:10.1038/nm723
17. Grimm C, Wenzel A, Stanescu D, Samardzija M, Hotop S, Groszer M, et al. Constitutive overexpression of human erythropoietin protects the mouse retina against induced but not inherited retinal degeneration. J Neurosci (2004) 24:5651-8. doi:10.1523/JNEUROSCI.1288-04.2004
18. Rex TS, Allocca M, Domenici L, Surace EM, Maguire AM, Lyubarsky A, et al. Systemic but not intraocular Epo gene transfer protects the retina from light-and genetic-induced degeneration. Mol Ther (2004) 10:855-61. doi:10.1016/j.ymthe.2004.07.027
19. Rex TS, Wong Y, Kodali K, Merry S. Neuroprotection of photoreceptors by direct delivery of erythropoietin to the retina of the retinal degeneration slow mouse. Exp Eye Res (2009) 89:735-40. doi:10.1016/j.exer.2009.06.017
20. Shen J, Wu Y, Xu J-Y, Zhang J, Sinclair SH, YanoffM, et al. ERK- and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-AGEs via modulation of Bcl-xL, Bax, and BAD. Invest Ophthalmol Vis Sci (2010) 51:35-46. doi:10.1167/iovs.09-3544
21. Zhang J, Wu Y, Jin Y, Ji F, Sinclair SH, Luo Y, et al. Intravitreal injection of erythropoietin protects both retinal vascular and neuronal cells in early diabetes. Invest Ophthalmol Vis Sci (2008) 49:732-42. doi:10.1167/iovs.07-0721
22. Villa P, Bigini P, Mennini T, Agnello D, Laragione T, Cagnotto A, et al. Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med (2003) 198:971-5. doi:10.1084/jem.20021067
23. Yatsiv I, Grigoriadis N, Simeonidou C, Stahel PF, Schmidt OI, Alexandrovitch AG, et al. Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury. FASEB J (2005) 19:1701-3. doi:10.1096/fj.05-3907fje
24. Duchen MR. Roles of mitochondria in health and disease. Diabetes (2004) 53(Suppl 1):S96-102. doi:10.2337/diabetes.53.2007.S96
25. Block ML, Zecca L, Hong J-S. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci (2007) 8:57-69. doi:10.1038/nrn2038
26. Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, Radi E. Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci (2012) 322:254-62. doi:10.1016/j.jns.2012.05.030
27. Chrysostomou V, Rezania F, Trounce IA, Crowston JG. Oxidative stress and mitochondrial dysfunction in glaucoma. Curr Opin Pharmacol (2013) 13:12-5. doi:10.1016/j.coph.2012.09.008
28. Al-Qahtani JM, Abdel-Wahab BA, El-Aziz SMA. Long-term moderate dose exogenous erythropoietin treatment protects from intermittent hypoxia-induced spatial learning deficits and hippocampal oxidative stress in young rats. Neurochem Res (2014) 39:161-71. doi:10.1007/s11064-013-1201-2
29. Yazihan N, Uzuner K, Salman B, Vural M, Koken T, Arslantas A. Erythropoietin improves oxidative stress following spinal cord trauma in rats. Injury (2008) 39:1408-13. doi:10.1016/j.injury.2008.03.010
30. Barichello T, Simões LR, Generoso JS, Sangiogo G, Danielski LG, Florentino D, et al. Erythropoietin prevents cognitive impairment and oxidative parameters in Wistar rats subjected to pneumococcal meningitis. Transl Res (2014) 163:503-13. doi:10.1016/j.trsl.2013.12.008
31. Lu M-J, Chen Y-S, Huang H-S, Ma M-C. Erythropoietin alleviates post-ischemic injury of rat hearts by attenuating nitrosative stress. Life Sci (2012) 90:776-84. doi:10.1016/j.lfs.2012.04.012
32. Li G, Ma R, Huang C, Tang Q, Fu Q, Liu H, et al. Protective effect of erythropoietin on ß-amyloid-induced PC12 cell death through antioxidant mechanisms. Neurosci Lett (2008) 442:143-7. doi:10.1016/j.neulet.2008.07.007
33. Zhang J, Zhu Y, Zhou D, Wang Z, Chen G. Recombinant human erythropoietin (rhEPO) alleviates early brain injury following subarachnoid hemorrhage in rats: possible involvement of Nrf2-ARE pathway. Cytokine (2010) 52:252-7. doi:10.1016/j.cyto.2010.08.011
34. Jin W, Wu J, Wang H, Kong J, Ni H, Liang W. Erythropoietin administration modulates pulmonary Nrf2 signaling pathway after traumatic brain injury in mice. J Trauma (2011) 71:680-6. doi:10.1097/TA.0b013e3181f6b984
35. Jin W, Ming X, Hou X, Zhu T, Yuan B, Wang J, et al. Protective effects of erythropoietin in traumatic spinal cord injury by inducing the Nrf2 signaling pathway activation. J Trauma Acute Care Surg (2014) 76:1228-34. doi:10.1097/TA.0000000000000211
36. Genc K, Egrilmez MY, Genc S. Erythropoietin induces nuclear translocation of Nrf2 and heme oxygenase-1 expression in SH-SY5Y cells. Cell Biochem Funct (2010) 28:197-201. doi:10.1002/cbf.1639
37. Meloni BP, Tilbrook PA, Boulos S, Arthur PG, Knuckey NW. Erythropoietin preconditioning in neuronal cultures: signaling, protection from in vitro ischemia, and proteomic analysis. J Neurosci Res (2006) 83:584-93. doi:10.1002/jnr.20755
38. Kumral A, Gonenc S, Acikgoz O, Sonmez A, Genc K, Yilmaz O, et al. Erythropoietin increases glutathione peroxidase enzyme activity and decreases lipid peroxidation levels in hypoxic-ischemic brain injury in neonatal rats. Biol Neonate (2005) 87:15-8. doi:10.1159/000080490
39. Kumral A, Tugyan K, Gonenc S, Genc K, Genc S, Sonmez U, et al. Protective effects of erythropoietin against ethanol-induced apoptotic neurodegeneration and oxidative stress in the developing C57BL/6 mouse brain. Brain Res Dev Brain Res (2005) 160:146-56. doi:10.1016/j.devbrainres.2005.08.006
40. Comim CM, Cassol OJ Jr., Abreu I, Moraz T, Constantino LS, Vuolo F, et al. Erythropoietin reverts cognitive impairment and alters the oxidative parameters and energetic metabolism in sepsis animal model. J Neural Transm (2012) 119:1267-74. doi:10.1007/s00702-012-0774-2
41. Wenker SD, Chamorro ME, Vittori DC, Nesse AB. Protective action of erythropoietin on neuronal damage induced by activated microglia. FEBS J (2013) 280:1630-42. doi:10.1111/febs.12172
42. Gui D-M, Yang Y, Li X, Gao D-W. Effect of erythropoietin on the expression of HIF-1 and iNOS in retina in chronic ocular hypertension rats. Int J Ophthalmol (2011) 4:40-3. doi:10.3980/j.issn.2222-3959.2011.01.09
43. Bailey DM, Lundby C, Berg RM, Taudorf S, Rahmouni H, Gutowski M, et al. On the antioxidant properties of erythropoietin and its association with the oxidative-nitrosative stress response to hypoxia in humans. Acta Physiol (2014) 212:175-87. doi:10.1111/apha.12313
44. Liu J, Narasimhan P, Song YS, Nishi T, Yu F, Lee Y-S, et al. Epo protects SOD2-deficient mouse astrocytes from damage by oxidative stress. Glia (2006) 53:360-5. doi:10.1002/glia.20289
45. Weinreb O, Mandel S, Youdim MBH, Amit T. Targeting dysregulation of brain iron homeostasis in Parkinson's disease by iron chelators. Free Radic Biol Med (2013) 62:52-64. doi:10.1016/j.freeradbiomed.2013.01.017
46. Goodnough LT. Erythropoietin and iron-restricted erythropoiesis. Exp Hematol (2007) 35:167-72. doi:10.1016/j.exphem.2007.01.026
47. Rezai-Zadeh K, Gate D, Town T. CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J Neuroimmune Pharmacol (2009) 4:462-75. doi:10.1007/s11481-009-9166-2
48. Mengozzi M, Cervellini I, Villa P, Erbayraktar Z, Gökmen N, Yilmaz O, et al. Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke. Proc Natl Acad Sci U S A (2012) 109:9617-22. doi:10.1073/pnas.1200554109
49. Rizzo MT, Leaver HA. Brain endothelial cell death: modes, signaling pathways, and relevance to neural development, homeostasis, and disease. Mol Neurobiol (2010) 42:52-63. doi:10.1007/s12035-010-8132-6
50. Luissint A-C, Artus C, Glacial F, Ganeshamoorthy K, Couraud P-O. Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation. Fluids Barriers CNS (2012) 9:23. doi:10.1186/2045-8118-9-23
51. Alvarez JI, Katayama T, Prat A. Glial influence on the blood brain barrier. Glia (2013) 61:1939-58. doi:10.1002/glia.22575
52. Weiss N, Miller F, Cazaubon S, Couraud P-O. The blood-brain barrier in brain homeostasis and neurological diseases. Biochim Biophys Acta (2009) 1788:842-57. doi:10.1016/j.bbamem.2008.10.022
53. Chu H, Ding H, Tang Y, Dong Q. Erythropoietin protects against hemorrhagic blood-brain barrier disruption through the effects of aquaporin-4. Lab Invest (2014) 94:1042-53. doi:10.1038/labinvest.2014.84
54. Li Y, Ogle ME, Wallace GC, Lu ZY, Yu SP, Wei L. Erythropoietin attenuates intracerebral hemorrhage by diminishing matrix metalloproteinases and maintaining blood-brain barrier integrity in mice. Acta Neurochir Suppl (2008) 105:105-12. doi:10.1007/978-3-211-09469-3_22
55. Zhou J, Kong H, Hua X, Xiao M, Ding J, Hu G. Altered blood-brain barrier integrity in adult aquaporin-4 knockout mice. Neuroreport (2008) 19:1-5. doi:10.1097/WNR.0b013e3282f2b4eb
56. Eilert-Olsen M, Haj-Yasein NN, Vindedal GF, Enger R, Gundersen GA, Hoddevik EH, et al. Deletion of aquaporin-4 changes the perivascular glial protein scaffold without disrupting the brain endothelial barrier. Glia (2012) 60:432-40. doi:10.1002/glia.22277
57. Mitsuma T, Tani K, Hiroaki Y, Kamegawa A, Suzuki H, Hibino H, et al. Influence of the cytoplasmic domains of aquaporin-4 on water conduction and array formation. J Mol Biol (2010) 402:669-81. doi:10.1016/j.jmb.2010.07.060
58. Tang Z, Sun X, Huo G, Xie Y, Shi Q, Chen S, et al. Protective effects of erythropoietin on astrocytic swelling after oxygen-glucose deprivation and reoxygenation: mediation through AQP4 expression and MAPK pathway. Neuropharmacology (2013) 67:8-15. doi:10.1016/j.neuropharm.2012.10.017
59. Gunnarson E, Song Y, Kowalewski JM, Brismar H, Brines M, Cerami A, et al. Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection. Proc Natl Acad Sci U S A (2009) 106:1602-7. doi:10.1073/pnas.0812708106
60. Vitellaro-Zuccarello L, Mazzetti S, Madaschi L, Bosisio P, Fontana E, Gorio A, et al. Chronic erythropoietin-mediated effects on the expression of astrocyte markers in a rat model of contusive spinal cord injury. Neuroscience (2008) 151:452-66. doi:10.1016/j.neuroscience.2007.11.004
61. Gonzalez FF, Larpthaveesarp A, McQuillen P, Derugin N, Wendland M, Spadafora R, et al. Erythropoietin increases neurogenesis and oligodendrogliosis of subventricular zone precursor cells after neonatal stroke. Stroke (2013) 44:753-8. doi:10.1161/STROKEAHA.111.000104
62. Diaz Z, Assaraf MI, Miller WH, Schipper HM. Astroglial cytoprotection by erythropoietin pre-conditioning: implications for ischemic and degenerative CNS disorders. J Neurochem (2005) 93:392-402. doi:10.1111/j.1471-4159.2005.03038.x
63. Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol (2013) 39:3-18. doi:10.1111/nan.12011
64. Streit WJ. Microglia as neuroprotective, immunocompetent cells of the CNS. Glia (2002) 40:133-9. doi:10.1002/glia.10154
65. De SR, Ajmone-Cat MA, Nicolini A, Minghetti L. Expression of phosphatidylserine receptor and down-regulation of pro-inflammatory molecule production by its natural ligand in rat microglial cultures. J Neuropathol Exp Neurol (2002) 61:237-44.
66. Chong ZZ, Kang J-Q, Maiese K. Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways. Br J Pharmacol (2003) 138:1107-18. doi:10.1038/sj.bjp.0705161
67. Hellewell SC, Yan EB, Alwis DS, Bye N, Morganti-Kossmann MC. 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. J Neuroinflammation (2013) 10:156. doi:10.1186/1742-2094-10-156
68. Hagemeyer N, Boretius S, Ott C, Von Streitberg A, Welpinghus H, Sperling S, et al. Erythropoietin attenuates neurological and histological consequences of toxic demyelination in mice. Mol Med (2012) 18:628-35. doi:10.2119/molmed.2011.00457
69. Wang Y, Zhang ZG, Rhodes K, Renzi M, Zhang RL, Kapke A, et al. Post-ischemic treatment with erythropoietin or carbamylated erythropoietin reduces infarction and improves neurological outcome in a rat model of focal cerebral ischemia. Br J Pharmacol (2007) 151:1377-84. doi:10.1038/sj.bjp.0707285
70. Wilms H, Schwabedissen B, Sievers J, Lucius R. Erythropoietin does not attenuate cytokine production and inflammation in microglia - Implications for the neuroprotective effect of erythropoietin in neurological diseases. J Neuroimmunol (2009) 212:106-11. doi:10.1016/j.jneuroim.2009.04.018
71. Shang YC, Chong ZZ, Wang S, Maiese K. Erythropoietin and Wnt1 govern pathways of mTOR, Apaf-1, and XIAP in inflammatory microglia. Curr Neurovasc Res (2011) 8:270-85. doi:10.2174/156720211798120990
72. Shang YC, Chong ZZ, Wang S, Maiese K. Prevention of ß-amyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL. Aging (2012) 4:187-201.
73. Li F, Chong ZZ, Maiese K. Microglial integrity is maintained by erythropoietin through integration of Akt and its substrates of glycogen synthase kinase-3beta, beta-catenin, and nuclear factor-kappaB. Curr Neurovasc Res (2006) 3:187-201. doi:10.2174/156720206778018758
74. Lifshitz L, Tabak G, Gassmann M, Mittelman M, Neumann D. Macrophages as novel target cells for erythropoietin. Haematologica (2010) 95:1823-31. doi:10.3324/haematol.2010.025015
75. Deng J, Miller SA, Wang H-Y, Xia W, Wen Y, Zhou BP, et al. ß-catenin interacts with and inhibits NF-?B in human colon and breast cancer. Cancer Cell (2002) 2:323-34. doi:10.1016/S1535-6108(02)00154-X
76. Xu F, Kang Y, Zhang H, Piao Z, Yin H, Diao R, et al. Akt1-mediated regulation of macrophage polarization in a murine model of Staphylococcus aureus pulmonary infection. J Infect Dis (2013) 208:528-38. doi:10.1093/infdis/jit177
77. Liu Y, Luo B, Han F, Li X, Xiong J, Jiang M, et al. Erythropoietin-derived nonerythropoietic peptide ameliorates experimental autoimmune neuritis by inflammation suppression and tissue protection. PLoS One (2014) 9:e90942. doi:10.1371/journal.pone.0090942
78. Nairz M, Schroll A, Moschen AR, Sonnweber T, Theurl M, Theurl I, et al. Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-?B-inducible immune pathways. Immunity (2011) 34:61-74. doi:10.1016/j.immuni.2011.01.002
79. Monick MM, Carter AB, RobeffPK, Flaherty DM, Peterson MW, Hunninghake GW. Lipopolysaccharide activates Akt in human alveolar macrophages resulting in nuclear accumulation and transcriptional activity of ß-catenin. J Immunol (2001) 166:4713-20. doi:10.4049/jimmunol.166.7.4713
80. Zhao J, Li G, Zhang Y, Su X, Hang C. The potential role of JAK2/STAT3 pathway on the anti-apoptotic effect of recombinant human erythropoietin (rhEPO) after experimental traumatic brain injury of rats. Cytokine (2011) 56:343-50. doi:10.1016/j.cyto.2011.07.018
81. Wang G-B, Ni Y-L, Zhou X-P, Zhang W-F. The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis. Mol Cell Biochem (2014) 385:125-32. doi:10.1007/s11010-013-1821-5
82. Zhou T-F, Yu J-G. Recombinant human erythropoietin attenuates neuronal apoptosis and cognitive defects via JAK2/STAT3 signaling in experimental endotoxemia. J Surg Res (2013) 183:304-12. doi:10.1016/j.jss.2012.11.035
83. Kilic U, Kilic E, Soliz J, Bassetti CI, Gassmann M, Hermann DM. Erythropoietin protects from axotomy-induced degeneration of retinal ganglion cells by activating ERK-1/-2. FASEB J (2005) 19:249-51. doi:10.1096/fj.04-2493fje
84. Kretz A, Happold CJ, Marticke JK, Isenmann S. Erythropoietin promotes regeneration of adult CNS neurons via Jak2/Stat3 and PI3K/AKT pathway activation. Mol Cell Neurosci (2005) 29:569-79. doi:10.1016/j.mcn.2005.04.009
85. Xie Z, Chen F, Wu X, Zhuang C, Zhu J, Wang J, et al. Effects of supplemental erythropoietin on its receptor expression and signal transduction pathways in rat model of retinal detachment. Curr Eye Res (2012) 37:138-44. doi:10.3109/02713683.2011.647225
86. Jia Y, Mo S-J, Feng Q-Q, Zhan M-L, Ouyang L-S, Chen J-C, et al. EPO-dependent activation of PI3K/Akt/FOXO3A signalling mediates neuroprotection in in vitro and in vivo models of Parkinson's disease. J Mol Neurosci (2014) 53:117-24. doi:10.1007/s12031-013-0208-0
87. Sättler MB, Merkler D, Maier K, Stadelmann C, Ehrenreich H, Bähr M, et al. Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis. Cell Death Differ (2004) 11(Suppl 2):S181-92. doi:10.1038/sj.cdd.4401504
88. Sawyer ST, Penta K. Association of JAK2 and STAT5 with erythropoietin receptors. Role of receptor phosphorylation in erythropoietin signal transduction. J Biol Chem (1996) 271:32430-7. doi:10.1074/jbc.271.50.32430
89. Chin H, Arai A, Wakao H, Kamiyama R, Miyasaka N, Miura O. Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway. Blood (1998) 91:3734-45.
90. Okutani Y, Kitanaka A, Tanaka T, Kamano H, Ohnishi H, Kubota Y, et al. Src directly tyrosine-phosphorylates STAT5 on its activation site and is involved in erythropoietin-induced signaling pathway. Oncogene (2001) 20:6643-50. doi:10.1038/sj.onc.1204807
91. Myklebust JH, BlomhoffHK, Rusten LS, Stokke T, Smeland EB. Activation of phosphatidylinositol 3-kinase is important for erythropoietin-induced erythropoiesis from CD34(+) hematopoietic progenitor cells. Exp Hematol (2002) 30:990-1000. doi:10.1016/S0301-472X(02)00868-8
92. Chen C, Sytkowski AJ. Erythropoietin regulation of Raf-1 and MEK: evidence for a Ras-independent mechanism. Blood (2004) 104:73-80. doi:10.1182/blood-2003-04-1340
93. Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M, et al. Erythropoietin mediates tissue protection through an erythropoietin and common ß-subunit heteroreceptor. Proc Natl Acad Sci U S A (2004) 101:14907-12. doi:10.1073/pnas.0406491101
94. Jubinsky PT, Krijanovski OI, Nathan DG, Tavernier J, SieffCA. The beta chain of the interleukin-3 receptor functionally associates with the erythropoietin receptor. Blood (1997) 90:1867-73.
95. Blake TJ, Jenkins BJ, D'Andrea RJ, Gonda TJ. Functional cross-talk between cytokine receptors revealed by activating mutations in the extracellular domain of the beta-subunit of the GM-CSF receptor. J Leukoc Biol (2002) 72:1246-55.
96. Nadam J, Navarro F, Sanchez P, Moulin C, Georges B, Laglaine A, et al. Neuroprotective effects of erythropoietin in the rat hippocampus after pilocarpine-induced status epilepticus. Neurobiol Dis (2007) 25:412-26. doi:10.1016/j.nbd.2006.10.009
97. Xiong Y, Mahmood A, Qu C, Kazmi H, Zhang ZG, Noguchi CT, et al. Erythropoietin improves histological and functional outcomes after traumatic brain injury in mice in the absence of the neural erythropoietin receptor. J Neurotrauma (2010) 27:205-15. doi:10.1089/neu.2009.1001
98. Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science (2004) 305:239-42. doi:10.1126/science.1098313
99. Hines-Beard J, Desai S, Haag R, Esumi N, D'Surney L, Parker S, et al. Identification of a therapeutic dose of continuously delivered erythropoietin in the eye using an inducible promoter system. Curr Gene Ther (2013) 13:275-81. doi:10.2174/15665232113139990024
100. Mennini T, De Paola M, Bigini P, Mastrotto C, Fumagalli E, Barbera S, et al. Nonhematopoietic erythropoietin derivatives prevent motoneuron degeneration in vitro and in vivo. Mol Med (2006) 12:153-60. doi:10.2119/2006-00045.Mennini
101. Colella P, Iodice C, Di Vicino U, Annunziata I, Surace EM, Auricchio A. Non-erythropoietic erythropoietin derivatives protect from light-induced and genetic photoreceptor degeneration. Hum Mol Genet (2011) 20:2251-62. doi:10.1093/hmg/ddr115
102. Chu X, Cheung JY, Barber DL, Birnbaumer L, Rothblum LI, Conrad K, et al. Erythropoietin modulates calcium influx through TRPC2. J Biol Chem (2002) 277:34375-82. doi:10.1074/jbc. M205541200
103. Tong Q, Hirschler-Laszkiewicz I, Zhang W, Conrad K, Neagley DW, Barber DL, et al. TRPC3 is the erythropoietin-regulated calcium channel in human erythroid cells. J Biol Chem (2008) 283:10385-95. doi:10.1074/jbc. M710231200
104. Kakihana K, Yamamoto M, Iiyama M, Miura O. Calmodulin physically interacts with the erythropoietin receptor and enhances Jak2-mediated signaling. Biochem Biophys Res Commun (2005) 335:424-31. doi:10.1016/j.bbrc.2005.07.095
105. Fusco FR, Martorana A, Giampà C, De March Z, Vacca F, Tozzi A, et al. Cellular localization of TRPC3 channel in rat brain: preferential distribution to oligodendrocytes. Neurosci Lett (2004) 365:137-42. doi:10.1016/j.neulet.2004.04.070
106. Chung YH, Sun Ahn H, Kim D, Hoon Shin D, Su Kim S, Yong Kim K, et al. Immunohistochemical study on the distribution of TRPC channels in the rat hippocampus. Brain Res (2006) 1085:132-7. doi:10.1016/j.brainres.2006.02.087
107. Chong ZZ, Hou J, Shang YC, Wang S, Maiese K. EPO relies upon novel signaling of Wnt1 that requires Akt1, FoxO3a, GSK-3ß, and ß-catenin to foster vascular integrity during experimental diabetes. Curr Neurovasc Res (2011) 8:103-20. doi:10.2174/156720211795495402