DOI QR코드

DOI QR Code

Systemic injection of recombinant human erythropoietin after focal cerebral ischemia enhances oligodendroglial and endothelial progenitor cells in rat brain

  • Kim, Young-Jae (Department of Laboratory Medicine, Masansamsung Medical Center, School of Medicine, Sungkyunkwan University) ;
  • Jung, Yong-Wook (Department of Anatomy, College of Medicine, Dongguk University)
  • Received : 2010.02.05
  • Accepted : 2010.05.03
  • Published : 2010.06.30

Abstract

Erythropoietin (EPO) has been demonstrated the ability of recombinant human erythropoietin (r-Hu-EPO), when administered intracerebro-ventricularly, to improve stroke outcome through the reduction of stroke damage. In a brain ischemic model, however, systemic administration of r-Hu-EPO has not been intensely investigated given that in general, large glycosylated molecules have been deemed incapable of crossing the blood-brain barrier. In this study, administration of r-Hu-EPO for 4 days, intraperitoneally aft er ischemia-reperfusion (I-R) increased the number of bromodeoxyuridine (BrdU)-positive cells in the penumbra ($10.1{\pm}1.4$, n=5, P<0.05) and in the subventricular zone (SVZ) of the lateral ventricle (LV) ($25{\pm}2.7$, n=5, P<0.05) as compared with those of I-R (penumbra: $2.5{\pm}0.7$; SVZ of LV: $3.8{\pm}1.5$). A significant increase of BrdU-positive cells in these areas was coincident with a strong immunoreactivity of oligodendrocyte progenitor cell marker (2', 3'-cyclic nucleotide 3'-phosphodiesterase). Furthermore, r-Hu-EPO administration increased the number of BrdU-positive cells in the choroid plexus ($7.8{\pm}2.3$, n=5, P<0.05) and in cerebral blood vessels ($3.5{\pm}1.3$, n=5, P<0.05) when compared with those of I-R (choroid plexus: $1.2{\pm}0.5$; cerebral blood vessels: $0.6{\pm}0.1$). These results suggest that, even when systemically administered, r-Hu-EPO may have therapeutic potential for stroke via the proliferation of oligodendroglial and endothelial progenitor cells.

Keywords

Acknowledgement

Supported by : Dongguk Research Fund, Dongguk University

References

  1. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. (2002). Neuronal replacement from endogenous precursors in the adult brain aft er stroke. Nat Med 8: 963-970 https://doi.org/10.1038/nm747
  2. Asahara T, Masuda H, Takahashi T, et al. (1999). Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85: 221-228 https://doi.org/10.1161/01.RES.85.3.221
  3. Bernaudin M, Marti HH, Roussel S, et al. (1999). A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19: 643-651
  4. Brines ML, Ghezzi P, Keenan S, et al. (2000). Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97: 10526-10531 https://doi.org/10.1073/pnas.97.19.10526
  5. Bu J, Banki A, Wu Q, Nishiyama A. (2004). Increased $NG2^+$ glial cell proliferation and oligodendrocyte generation in the hypomyelinating mutant shiverer. Glia 48: 51-63 https://doi.org/10.1002/glia.20055
  6. Calvillo L, Latini R, Kajstura J, et al. (2003). Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci U S A 100: 4802-4806 https://doi.org/10.1073/pnas.0630444100
  7. Carlini RG, Reyes AA, Rothstein M. (1995). Recombinant human erythropoietin stimulates angiogenesis in vitro. Kidney Int 47: 740-745 https://doi.org/10.1038/ki.1995.113
  8. Chong ZZ, Kang JQ, Maiese K. (2002). Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation 106: 2973-2979 https://doi.org/10.1161/01.CIR.0000039103.58920.1F
  9. Crawford LE, Milliken EE, Irani K, et al. (1996). Superoxide-mediated actin response in post-hypoxic endothelial cells. J Biol Chem 271: 26863-26867 https://doi.org/10.1074/jbc.271.43.26863
  10. Digicaylioglu M, Bichet S, Marti HH, et al. (1995). Localization of specific erythropoietin binding sites in defi ned areas of the mouse brain. Proc Natl Acad Sci U S A 92: 3717-3720 https://doi.org/10.1073/pnas.92.9.3717
  11. Egrie JC, Strickland TW, Lane J, et al. (1986). Characterization and biological effects of recombinant human erythropoietin. Immunobiology 172: 213-224 https://doi.org/10.1016/S0171-2985(86)80101-2
  12. Gage FH, Kempermann G, Palmer TD, Peterson DA, Ray J. (1998). Multipotent progenitor cells in the adult dentate gyrus. J Neurobiol 36: 249-266 https://doi.org/10.1002/(SICI)1097-4695(199808)36:2<249::AID-NEU11>3.0.CO;2-9
  13. Girard C, Bemelmans AP, Dufour N, et al. (2005). Grafts of brain-derived neurotrophic factor and neurotrophin 3-transduced primate Schwann cells lead to functional recovery of the demyelinated mouse spinal cord. J Neurosci 25: 7924-7933 https://doi.org/10.1523/JNEUROSCI.4890-04.2005
  14. Gottlieb M, Domercq M, Matute C. (2000). Altered expression of the glutamate transporter EAAC1 in neurons and immature oligodendrocytes aft er transient forebrain ischemia. J Cereb Blood Flow Metab 20: 678-687 https://doi.org/10.1097/00004647-200004000-00005
  15. Grasso G, Buemi M, Alafaci C, et al. (2002). Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage. Proc Natl Acad Sci U S A 99: 5627-5631 https://doi.org/10.1073/pnas.082097299
  16. Hasegawa H, Ma T, Skach W, Matthay MA, Verkman AS. (1994). Molecular cloning of a mercurial-insensitive water channel expressed in selected water-transporting tissues. J Biol Chem 269: 5497-5500
  17. Kadota T, Shingo T, Yasuhara T, et al. (2009). Continuous intraventricular infusion of erythropoietin exerts neuroprotective/ rescue eff ects upon Parkinson's disease model of rats with enhanced neurogenesis. Brain Res 1254: 120-127 https://doi.org/10.1016/j.brainres.2008.11.094
  18. Kim HM, Hwang DH, Lee JE, Kim SU, Kim BG. (2009). Ex vivo VEGF delivery by neural stem cells enhances proliferation of glial progenitors, angiogenesis, and tissue sparing aft er spinal cord injury. PLoS One 4: e4987 https://doi.org/10.1371/journal.pone.0004987
  19. Kuhn HG, Dickinson-Anson H, Gage FH. (1996). Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16: 2027-2033
  20. Leventhal C, Rafi i S, Rafi i D, Shahar A, Goldman SA. (1999). Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol Cell Neurosci 13: 450-464 https://doi.org/10.1006/mcne.1999.0762
  21. Levison SW, Rothstein RP, Romanko MJ, Snyder MJ, Meyers RL, Vannucci SJ. (2001). Hypoxia/ischemia depletes the rat perinatal subventricular zone of oligodendrocyte progenitors and neural stem cells. Dev Neurosci 23: 234-247 https://doi.org/10.1159/000046149
  22. Liu J, Solway K, Messing RO, Sharp FR. (1998). Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci 18: 7768-7778
  23. Marti HH, Bernaudin M, Petit E, Bauer C. (2000). Neuro-protection and Angiogenesis: Dual Role of Erythropoietin in Brain Ischemia. News Physiol Sci 15: 225-229
  24. Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R. (1997). Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 76: 105-116
  25. Moritz KM, Lim GB, Wintour EM. (1997). Developmental regulation of erythropoietin and erythropoiesis. Am J Physiol 273: R1829-R1844
  26. Ness JK, Valentino M, McIver SR, Goldberg MP. (2005). Identification of oligodendrocytes in experimental disease models. Glia 50: 321-328 https://doi.org/10.1002/glia.20206
  27. Palmer TD, Willhoite AR, Gage FH. (2000). Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425: 479-494 https://doi.org/10.1002/1096-9861(20001002)425:4<479::AID-CNE2>3.0.CO;2-3
  28. Pardridge WM. (1997). Drug delivery to the brain. J Cereb Blood Flow Metab 17: 713-731
  29. Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM. (2002). Rat forebrain neurogenesis and striatal neuron replacement aft er focal stroke. Ann Neurol 52: 802-813 https://doi.org/10.1002/ana.10393
  30. Pincus DW, Keyoung HM, Harrison-Restelli C, et al. (1998). Fibroblast growth factor-2/brain-derived neurotrophic factor-associated maturation of new neurons generated from adult human subependymal cells. Ann Neurol 43: 576-585 https://doi.org/10.1002/ana.410430505
  31. Potten CS, Loeffler M. (1990). Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110: 1001-1020
  32. Profyris C, Cheema SS, Zang D, Azari MF, Boyle K, Petratos S. (2004). Degenerative and regenerative mechanisms governing spinal cord injury. Neurobiol Dis 15: 415-436 https://doi.org/10.1016/j.nbd.2003.11.015
  33. Ribatti D, Presta M, Vacca A, et al. (1999). Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood 93: 2627-2636
  34. Sakanaka M, Wen TC, Matsuda S, et al. (1998). In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci U S A 95: 4635-4640 https://doi.org/10.1073/pnas.95.8.4635
  35. Shi J, Marinovich A, Barres BA. (1998). Purification and characterization of adult oligodendrocyte precursor cells from the rat optic nerve. J Neurosci 18: 4627-4636
  36. Shingo T, Sorokan ST, Shimazaki T, 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
  37. Siren AL, Fratelli M, Brines M, et al. (2001). Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A 98: 4044-4049 https://doi.org/10.1073/pnas.051606598
  38. Skoff RP, Bessert DA, Barks JD, Song D, Cerghet M, Silverstein FS. (2001). Hypoxic-ischemic injury results in acute disruption of myelin gene expression and death of oligodendroglial precursors in neonatal mice. Int J Dev Neurosci 19: 197-208 https://doi.org/10.1016/S0736-5748(00)00075-7
  39. Sugawa M, Sakurai Y, Ishikawa-Ieda Y, Suzuki H, Asou H. (2002). Effects of erythropoietin on glial cell development; oligodendrocyte maturation and astrocyte proliferation. Neurosci Res 44: 391-403 https://doi.org/10.1016/S0168-0102(02)00161-X
  40. Takahashi T, Kalka C, Masuda H, et al. (1999). Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5: 434-438 https://doi.org/10.1038/7434
  41. Vitellaro-Zuccarello L, Mazzetti S, Madaschi L, et al. (2008). Chronic erythropoietin-mediated eff ects on the expression of astrocyte markers in a rat model of contusive spinal cord injury. Neuroscience 151: 452-466 https://doi.org/10.1016/j.neuroscience.2007.11.004
  42. Vogel V, Kramer HJ, Backer A, Meyer-Lehnert H, Jelkmann W, Fandrey J. (1997). Effects of erythropoietin on endothelin-1 synthesis and the cellular calcium messenger system in vascular endothelial cells. Am J Hypertens 10: 289-296 https://doi.org/10.1016/S0895-7061(96)00410-4
  43. Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. (2004). Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35: 1732-1737 https://doi.org/10.1161/01.STR.0000132196.49028.a4
  44. Weiss S, Reynolds BA, Vescovi AL, Morshead C, Craig CG, van der Kooy D. (1996). Is there a neural stem cell in the mammalian forebrain? Trends Neurosci 19: 387-393 https://doi.org/10.1016/S0166-2236(96)10035-7
  45. Yan Y, Dempsey RJ, Sun D. (2001). Na+-K+-Cl- cotransporter in rat focal cerebral ischemia. J Cereb Blood Flow Metab 21: 711-721 https://doi.org/10.1097/00004647-200106000-00009
  46. Zhang F, Signore AP, Zhou Z, Wang S, Cao G, Chen J. (2006). Erythropoietin protects CA1 neurons against global cerebral ischemia in rat: potential signaling mechanisms. J Neurosci Res 83: 1241-1251 https://doi.org/10.1002/jnr.20816
  47. Zhang J, Li Y, Cui Y, et al. (2005). Erythropoietin treatment improves neurological functional recovery in EAE mice. Brain Res 1034: 34-39 https://doi.org/10.1016/j.brainres.2004.11.036
  48. Zhang ZG, Zhang L, Jiang Q, et al. (2000). VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 106: 829-838 https://doi.org/10.1172/JCI9369

Cited by

  1. Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales vol.64, pp.4, 2012, https://doi.org/10.1124/pr.112.005850
  2. Erythropoietin signaling promotes oligodendrocyte development following prenatal systemic hypoxic-ischemic brain injury vol.74, pp.6, 2013, https://doi.org/10.1038/pr.2013.155
  3. Enhancement of ventricular-subventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives vol.7, pp.None, 2013, https://doi.org/10.3389/fncel.2013.00235
  4. Outcomes of extremely low birth weight infants given early high-dose erythropoietin vol.33, pp.3, 2010, https://doi.org/10.1038/jp.2012.78
  5. Therapeutic benefit of a combined strategy using erythropoietin and endothelial progenitor cells after transient focal cerebral ischemia in rats vol.35, pp.9, 2013, https://doi.org/10.1179/1743132813y.0000000235
  6. Effect of erythropoietin on the content of lipid peroxidation products in lymphocytes in experimental thermal injury vol.96, pp.5, 2010, https://doi.org/10.17750/kmj2015-849
  7. Ursolic Acid Ameliorates Inflammation in Cerebral Ischemia and Reperfusion Injury Possibly via High Mobility Group Box 1/Toll-Like Receptor 4/NFκB Pathway vol.9, pp.None, 2010, https://doi.org/10.3389/fneur.2018.00253