Volume 27, Issue 4 (December 2023)                   Physiol Pharmacol 2023, 27(4): 345-356 | Back to browse issues page

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Maghsoudi A, Zaringhalam J, Moosavi M, Eidi A. The therapeutic effects of erythropoietin and carbamylated erythropoietin derivatives in neurological and other disorders. Physiol Pharmacol 2023; 27 (4) : 2
URL: http://ppj.phypha.ir/article-1-2037-en.html
Abstract:   (888 Views)

Erythropoietin (EPO) has been considered in several studies as a significant factor in the development of erythroid cells, the inhibition of neuronal cell death, and neurogenesis. Fortunately, a modified version of EPO called carbamylated erythropoietin (CEPO) possesses tissue-protective properties without eliciting erythropoietic effects. CEPO is a derivative of EPO that results in an alpha-amino derivative group with less biological hematopoiesis than EPO. In neurological diseases, CEPO and its carbamylated erythropoietin Fc fusion protein (CEPO-Fc) has been shown to play a better role than EPO. In this study, the effects of EPO and its derivatives on neurological diseases and their role in treatment have been reviewed.

Article number: 2
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Type of Manuscript: Review | Subject: Neurophysiology/Pharmacology

1. Adembri C, Massagrande A, Tani A, Miranda M, Margheri M, De Gaudio R, et al. Carbamylated erythropoietin is neuroprotective in an experimental model of traumatic brain injury. Crit Care Med 2008; 36: 975-8. [DOI:10.1097/CCM.0B013E3181644343.]
2. Armand-Ugón M, Aso E, Moreno J, Riera-Codina M, Sánchez A, Vegas E, et al. Memory improvement in the AβPP/PS1 mouse model of familial alzheimer’s disease induced by carbamylated-erythropoietin is accompanied by modulation of synaptic genes. J Alzheimers Dis 2015; 45: 407-21. [DOI:10.3233/JAD-150002]
3. Cevik B, Solmaz V, Yigitturk G, Cavusoğlu T, Peker G, Erbas O. Neuroprotective effects of erythropoietin on Alzheimer’s dementia model in rats. Adv Clin Exp Med 2017; 26: 23-9. [DOI:0.17219/acem/61044]
4. Chamorro ME, Wenker SD, Vota DM, Vittori DC, Nesse AB. Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative. Biochim Biophys Acta 2013; 1833: 1960-8. [DOI:10.1016/j.bbamcr.2013.04.006]
5. Chen J, Yang Z, Zhang X. Carbamylated Erythropoietin: A Prospective Drug Candidate for Neuroprotection. Biochem Insights 2016; 8: 25-9. [DOI:10.4137/BCI.S30753]
6. Choi M, Ko SY, Lee IY, Wang SE, Lee SH, Oh DH, et al. Carbamylated erythropoietin promotes neurite outgrowth and neuronal spine formation in association with CBP/p300. Biochem Biophys Res Commun 2014; 446: 79-84. [DOI:10.1016/j.bbrc.2014.02.066]
7. Dang JZ, Tu YF, Wang J, Yang YJ. Carbamylated Erythropoietin Alleviates Kidney Damage in Diabetic Rats by Suppressing Oxidative Stress. Curr Med Sci 2021; 41: 513-21. [DOI:10.1007/s11596-021-2370-x]
8. Ding J, Wang J, Li QY, Yu JZ, Ma CG, Wang X, et al. Neuroprotection and CD131/GDNF/AKT pathway of carbamylated erythropoietin in hypoxic neurons. Mol Neurobiol 2017; 54: 5051-60. [DOI:10.1007/s12035-016-0022-0]
9. Erbayraktar S, de Lanerolle N, de Lotbinière A, Knisely JPS, Erbayraktar Z, Yilmaz O, et al. Carbamylated erythropoietin reduces radiosurgically-induced brain injury. Mol Med 2006; 12: 74-80. [DOI:10.2119/2006-00042]
10. Fantacci M, Bianciardi P, Caretti A, Coleman TR, Cerami A, Brines M, et al. Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia. Proc Natl Acad Sci U S A 2006; 103: 17531-6. [DOI:10.1073/pnas.0608814103]
11. Gadhave K, Kumar D, Uversky VN, Giri R. A multitude of signaling pathways associated with Alzheimer’s disease and their roles in AD pathogenesis and therapy. Med Res Rev 2021; 41: 2689-745. [DOI:10.1002/med.21719]
12. Gattinger P, Izadi S, Grünwald-Gruber C, Kallolimath S, Castilho A. The instability of dimeric Fc-fusions expressed in plants can be solved by monomeric Fc technology. Front Plant Sci 2021; 12: 671728. [DOI:10.3389/fpls.2021.671728]
13. Godoy JA, Rios JA, Zolezzi JM, Braidy N, Inestrosa NC. Signaling pathway cross talk in Alzheimer’s disease. Cell Commun Signal 2014; 12: 23. [DOI:10.1186/1478-811X-12-23]
14. He H, Qiao X, Wu S. Carbamylated erythropoietin attenuates cardiomyopathy via PI3K/Akt activation in rats with diabetic cardiomyopathy. Exp Ther Med 2013; 6: 567-73. https://doi.org/ 10.3892/etm.2013.1134 [DOI:10.3892/etm.2013.1134]
15. Hooshmandi E, Moosavi M, Katinger H, Sardab S, Ghasemi R, Maghsoudi N. CEPO (carbamylated erythropoietin)-Fc protects hippocampal cells in culture against beta amyloid-induced apoptosis: considering Akt/GSK-3β and ERK signaling pathways. Mol Biol Rep 2020; 47: 2097-108. [DOI:10.1007/s11033-020-05309-6]
16. Hooshmandi E, Motamedi F, Moosavi M, Katinger H, Zakeri Z, Zaringhalam J, et al. CEPO-Fc (An EPO Derivative) protects hippocampus against Aβ-induced memory deterioration: A behavioral and molecular study in a rat model of Aβ toxicity. Neuroscience 2018; 388: 405-17. [DOI:10.1016/j.neuroscience.2018.08.001]
17. Kimáková P, Solár P, Solárová Z, Komel R, Debeljak N. Erythropoietin and its angiogenic activity. Int J Mol Sci 2017; 18: 1519. [DOI:10.3390/ijms18071519]
18. King VR, Averill SA, Hewazy D, Priestley JV, Torup L, Michael-Titus AT. Erythropoietin and carbamylated erythropoietin are neuroprotective following spinal cord hemisection in the rat. Eur J Neurosci 2007; 26: 90-100. [DOI:10.1111/j.1460-9568.2007.05635.x]
19. Kontermann RE. Strategies for extended serum half-life of protein therapeutics. Curr Opin Biotechnol 2011; 22: 868-76. [DOI:10.1016/j.copbio.2011.06.012]
20. Li H, Diao M, Yu-Shan M, Xue-Mei L. Carbamylated erythropoietin and its role of tissue protection. JAPM 2017; 4: 123. [DOI:10.24015/JAPM.2017.0027]
21. Liu W, Shen Y, Plane JM, Pleasure DE, Deng W. Neuroprotective potential of erythropoietin and its derivative carbamylated erythropoietin in periventricular leukomalacia. Exp Neurol 2011; 230: 227-39. [DOI:10.1016/j.expneurol.2011.04.021]
22. Liu X, Zhu B, Zou H, Hu D, Gu Q, Liu K, et al. Carbamylated erythropoietin mediates retinal neuroprotection in streptozotocin-induced early-stage diabetic rats. Graefes Arch Clin Exp Ophthalmol 2015; 253: 1263-72. [DOI:10.1007/s00417-015-2969-3]
23. Ma Y, Zhou Z, Yang GY, Ding J, Wang X. The effect of erythropoietin and its derivatives on ischemic stroke therapy: A comprehensive review. Front Pharmacol 2022; 13: 743926. [DOI:10.3389/fphar.2022.743926]
24. Maghsoudi A, Zaringhalam J, Moosavi M, Eidi A. Carbamylated Erythropoietin-Fc (CEPO-Fc) ameliorates Aβ25-35 induced neurotoxicity by modulating autophagy, apoptosis, and necroptosis in alzheimer’s disease model rats. Physiology and Pharmacology 2021. [DOI:10.52547/phypha.26.3.3]
25. Maghsoudi A, Zaringhalam J, Moosavi M, Eidi A. Intraperitoneal Carbamylated erythropoietin improves memory and hippocampal apoptosis in beta amyloid rat model of Alzheimer’s disease through stimulating autophagy and inhibiting necroptosis. Physiology and Pharmacology 2021. [DOI:10.52547/phypha.26.4.1]
26. Mahmood A, Lu D, Qu C, Goussev A, Zhang ZG, Lu C, et al. Treatment of traumatic brain injury in rats with erythropoietin and carbamylated erythropoietin. J Neurosurg 2007; 107: 392-7. [DOI:10.3171/JNS-07/08/0392]
27. Matějková Š, Scheuerle A, Wagner F, McCook O, Matallo J, Gröger M, et al. Carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine kidney ischemia/reperfusion injury. Intensive Care Med 2013; 39: 497-510. [DOI:10.1007/s00134-012-2766-y]
28. McCook O, Georgieff M, Scheuerle A, Möller P, Thiemermann C, Radermacher P. Erythropoietin in the critically ill: do we ask the right questions? Crit Care 2012; 16: 319. [DOI:10.1186/cc11430]
29. Mesonzhnik NV, Postnikov PV, Appolonova SA, Krotov GI. Characterization and detection of erythropoietin fc fusion proteins using liquid chromatography-mass spectrometry. J Proteome Res 2018; 17: 689-97. [DOI:10.1021/acs.jproteome.7b00739]
30. Moosavi M, Hooshmandi E, Javadpour P, Maghsoudi N, Katinger H, Ghasemi R. Effect of carbamylated erythropoietin Fc fusion protein (CEPO-Fc) on learning and memory impairment and hippocampal apoptosis induced by intracerebroventricular administration of streptozotocin in rats. Behav Brain Res 2020; 384: 112554. [DOI:10.1016/j.bbr.2020.112554]
31. Na N, Zhao D, Zhang J, Wu J, Miao B, Li H, et al. Carbamylated erythropoietin regulates immune responses and promotes long-term kidney allograft survival through activation of PI3K/AKT signaling. Signal Transduct Target Ther 2020; 5: 194. [DOI:10.1038/s41392-020-00232-5]
32. Nijboer WN, Ottens PJ, van Dijk A, van Goor H, Ploeg RJ, Leuvenink HG. Donor pretreatment with carbamylated erythropoietin in a brain death model reduces inflammation more effectively than erythropoietin while preserving renal function. Crit Care Med 2010; 38: 1155-61. [DOI:10.1097/CCM.0b013e3181cf6e78]
33. Pavenski K, Hare GM, Mazer CD. Erythropoietic neuroprotection: Holy Grail or potential to fail?. Intensive Care Med 2011; 37: 1403-5. [DOI:10.3390/10.1007/s00134-011-2305-2]
34. Pezeshkian Z, Nobili S, Peyravian N, Shojaee B, Nazari H, Soleimani H, et al. Insights into the role of matrix metalloproteinases in precancerous conditions and in colorectal cancer. Cancers 2021; 13: 6226. [DOI:10.3390/cancers13246226]
35. Rahmani N, Mohammadi M, Manaheji H, Maghsoudi N, Katinger H, Baniasadi M, et al. Carbamylated erythropoietin improves recognition memory by modulating microglia in a rat model of pain. Behav Brain Res 2022; 416: 113576. [DOI:10.1016/j.bbr.2021.113576]
36. Schriebl K, Trummer E, Lattenmayer C, Weik R, Kunert R, Müller D, et al. Biochemical characterization of rhEpo-Fc fusion protein expressed in CHO cells. Protein Expr Purif 2006; 49: 265-75. [DOI:10.1016/j.pep.2006.05.018]
37. Simon F, Floros N, Ibing W, Schelzig H, Knapsis A. Neurotherapeutic potential of erythropoietin after ischemic injury of the central nervous system. Neural Regen Res 2019; 14: 1309-12. [DOI:10.4103/1673-5374.253507]
38. Simon F, Köpke L-G, Ibing W, Schelzig H. Effects of Preoperative Pharmacological Conditioning on the Clinical and Molecular Outcome of Mice after Spinal Cord Ischemia/Reperfusion Sequence. European Journal of Vascular and Endovascular Surgery 2018; 56. [DOI:10.1016/j.ejvs.2018.06.074]
39. Simon F, Scheuerle A, Gröger M, Vcelar B, McCook O, Möller P, et al. Comparison of carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury. Intensive Care Med 2011; 37: 1525-33. [DOI:10.1007/s00134-011-2303-4]
40. Sun J, Martin JM, Vanderpoel V, Sumbria RK. The promises and challenges of erythropoietin for treatment of alzheimer’s disease. Neuromolecular Med 2019; 21: 12-24. [DOI:10.1007/s12017-019-08524-y]
41. Thomas Tayra J, Kameda M, Yasuhara T, Agari T, Kadota T, Wang F, et al. The neuroprotective and neurorescue effects of carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson’s disease. Brain Res 2013; 1502: 55-70. [DOI:10.1016/j.brainres.2013.01.042]
42. Tögel FE, Ahlstrom JD, Yang Y, Hu Z, Zhang P, Westenfelder C. Carbamylated erythropoietin outperforms erythropoietin in the treatment of AKI-on-CKD and other AKI models. J Am Soc Nephrol 2016; 27: 3394-404. [DOI:10.1681/ASN.2015091059]
43. Tsiftsoglou AS. Erythropoietin (EPO) as a key regulator of erythropoiesis, bone remodeling and endothelial transdifferentiation of multipotent mesenchymal stem cells (MSCs): implications in regenerative medicine. Cells 2021; 10:2140. [DOI:10.3390/cells10082140]
44. Vittori DC, Chamorro ME, Hernández YV, Maltaneri RE, Nesse AB. Erythropoietin and derivatives: Potential beneficial effects on the brain. J Neurochem 2021; 158: 1032-57. [DOI:10.1111/jnc.15475]
45. Wang L, Zhang ZG, Zhang RL, Gregg SR, Hozeska-Solgot A, LeTourneau Y, et al. Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J Neurosci 2006; 26: 5996-6003. [DOI:10.1523/JNEUROSCI.5380-05.2006]
46. 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.]
47. Xiong Y, Mahmood A, Zhang Y, Meng Y, Zhang ZG, Qu C, et al. 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: 549-59. [DOI:10.3171/2010.10.JNS10925]
48. Xu X, Cao Z, Cao B, Li J, Guo L, Que L, et al. Carbamylated erythropoietin protects the myocardium from acute ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Surgery 2009; 146: 506-14. [DOI:10.1016/j.surg.2009.03.022]
49. Zhang K, Wang J, Xi H, Li L, Lou Z. Investigation of neuroprotective effects of erythropoietin on chronic neuropathic pain in a chronic constriction injury rat model. J Pain Res 2020; 13: 3147-55. [DOI:10.2147/JPR.S285870]
50. Zhang SJ, Luo YM, Wang RL. The effects of erythropoietin on neurogenesis after ischemic stroke. J Integr Neurosci 2020; 19: 561-70. [DOI:10.31083/j.jin.2020.03.4]

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