Pathogenic substantiation of application of erythropoietin modified forms and peptide analogues as cytotprotectors

  • Authors: Ivanov I.1, Nikiforov A.1, Vengerovich N.2,3, Perelygin V.V.4, Proshina Y.1
  • Affiliations:
    1. Institute of Military Medicine, Russian Federation of Ministry of Defense, Saint-Petersburg, Russia
    2. State Research Institute of Military Medicine, Russian Federation of Ministry of Defense
    3. Saint Petersburg State Chemical Pharmaceutical Universit of Ministry of health, St.-Petersburg
    4. Saint-Petersburg, Russia State Chemical Pharmaceutical University, Saint-Petersburg, Russia
  • Issue: Vol 2, No 1 (2020)
  • Pages: 70-81
  • Section: Biological sciences
  • URL: https://journals.eco-vector.com/PharmForm/article/view/21382
  • DOI: https://doi.org/10.17816/phf21382
  • Cite item

Abstract


Provides a review of the evidence from experimental and clinical studies on the blood-forming and non-blood-forming tissue protective effects of erythropoietin. Information on its side effects (stimulation of tumor growth, autoimmune reactions, arterial hypertension, etc.), limiting the clinical use as a cytoprotector, is summarized. Well-known modifications of the erythropoietin molecule with a tissue protective effect are considered, in particular, desialylated (asialoEPO), carboxylated (CEPO) and glutaraldehyde (GEPO) cytokine analogues.

The results of biomedical studies describing the tissue protective effects of these compounds, as well as possible mechanisms of their receptor action, are presented. The article discusses the main short-chain erythropoietin mimetics that reproduce individual active regions of cytokine amino acid sequence and contain from 11 to 25 amino acids: Helix B, ARA290, Eportis, Epopeptide-ab, MK-X, Epobis, NL100.

The biochemical mechanisms of cytoprotective action of erythropoietin and its derivatives are considered, including binding to the heterodimeric receptor of non-blood-forming tissues and activation of intracellular signaling molecules possessing properties of apopotosis inhibitors.

It was noted that the tissue protective effect of erythropoietin in vivo is observed in hemostimulating doses and is accompanied by side effects. At the same time, the use of modified forms of erythropoietin and its short-chain peptide analogues, which have a high affinity for the isoform of the erythropoietin receptor of non-blood-forming tissues and do not have hematopoietic properties, allows avoiding the development of side effects and reducing effective doses by 10-20 times.


About the authors

Igor Ivanov

Institute of Military Medicine, Russian Federation of Ministry of Defense, Saint-Petersburg, Russia

Email: gniiivm_15@mil.ru

Ph.D. in Medicine, Deputy Head of Department State Research

Aleksandr Nikiforov

Institute of Military Medicine, Russian Federation of Ministry of Defense, Saint-Petersburg, Russia

Email: gniiivm_15@mil.ru

доктор биологических наук, ведущий научный сотрудник

Nikolai Vengerovich

State Research Institute of Military Medicine, Russian Federation of Ministry of Defense; Saint Petersburg State Chemical Pharmaceutical Universit of Ministry of health, St.-Petersburg

Author for correspondence.
Email: nikolai.vengerovich@pharminnotech.com
ORCID iD: 0000-0003-3219-341X

Russian Federation, 195043, г. Санкт-Петербург, ул. Лесопарковая, д.4;, 197376, г. Санкт-Петербург, ул. Профессора Попова, д. 14,литер.А

Doctor of Medical Science, Deputy Head of Department; Professor at the Industrial Ecology Department

Vladimir V. Perelygin

Saint-Petersburg, Russia State Chemical Pharmaceutical University, Saint-Petersburg, Russia

Email: vladimir.pereligin@pharminnotech.com
ORCID iD: 0000-0002-0999-5644
ResearcherId: AAV-6556-2020

Russian Federation, 197376, г. Санкт-Петербург, ул. Профессора Попова, д. 14,литер.А;

профессор, доктор медицинских наук, заведующий кафедрой промышленной экологии

Ylia Proshina

Institute of Military Medicine, Russian Federation of Ministry of Defense, Saint-Petersburg, Russia

Email: gniiivm_15@mil.ru
195043, Россия, Санкт-Петербург, Лесопарковая, дом 4.

Researcher State Research

References

  1. Jelkmann W, Bohlius J, Hallek M, Sytkowski AJ. The erythropoietin receptor in normal and cancer tissues. Crit. Rev. Oncol. Hematol. 2008; 67: 39–61. doi: 10.1016/j.critrevonc.2008.03.006.
  2. Brines M, Cerami A. Erythropoietin mediated tissue protection: reducing collateral damage from the primary injury response. J. Intern. Med. 2008; 264: 405–32.
  3. Noguchi CT, Asavaritikrai P, Teng R. Role of erythropoietin in the brain. Crit. Rev. Oncol. Hematol. 2007; 64 (2): 159–71. doi: 10.1016/j.critrevonc.2007.03.001.
  4. Brines M. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc. Natl. Acad. Sci. 2004; 101: 14907–12.
  5. Buemi M, Galeano M, Sturiale A, et al. Recombinant human erythropoietin stimulates angiogenesis and healing of ischemic skin wounds. Shock. 2004; 22: 169-73. doi: 10.1097/01.shk.0000133591.47776.bd.
  6. Harder Y, Amon M, Schramm R. Erythropoietin reduces necrosis in critically ischemic myocutaneous tissue by protecting nutritive perfusion in a dose-dependent manner. Surgery. 2009; 145: 372–83. doi: 10.1016/j.surg.2008.12.001.
  7. Erbayraktar Z, Erbayraktar S, Yilmaz O, et al. Nonerythropoietic Tissue Protective Compounds Are Highly Effective Facilitators of Wound Healing. Mol. Med. 2009; 15 (7–8): 235-41. doi: 10.2119/molmed.2009.00051.
  8. Haroon ZA, Amin K, Jiang X. A novel role for erythropoietin during fibrin-induced wound-healing response. Am. J. Pathol. 2003; 163: 993–1000. doi: 10.1016/S0002-9440(10)63459-1.
  9. Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature. 2001; 412: 641–7. doi: 10.1038/35088074.
  10. Genc S, Koroglu TF, Genc K. Erythropoietin and the nervous system. Brain research. 2004; 1000 (1–2): 19–31. doi: 10.1016/j.brainres.2003.12.037.
  11. Lee ST, Chu K, Sinn DI, et al. Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage. Journal of neurochemistry. 2006; 96 (6): 1728–39. doi: 10.1111/j.1471-4159.2006.03697.x.
  12. Souvenir R, Doycheva D, Zhang J, Tang J. Erythropoietin in Stroke Therapy: Friend or Foe. Current Medicinal Chemistry. 2015; 22:10.
  13. Sytkowski AJ. Does erythropoietin have a dark side? Epo signaling and cancer cells. Sci. STKE. 2007; 395: 38. doi: 10.1126/stke.3952007pe38
  14. Yasuda Y, Fujita Y, Matsuo T, et al. Erythropoietin regulates tumor growth of human malignancies. Carcinogenesis. 2003; 6: 1009–21. doi: 10.1093/carcin/bgg060.
  15. Ikeda Y, Taveira-Dasilva AM, Pacheco-Rodriguez G, et al. Erythropoietin-driven proliferation of cells with mutations in the tumor suppressor gene TSC2. Am. J. Physiol. Lung. Cell. Mol. Physiol. 2010; 300: 64–72. doi: 10.1152/ajplung.00095.2010.
  16. Macdougall IC. Epoetin-induced pure red cell aplasia: diagnosis and treatment. Curr. Opin. Nephrol. Hypertens. 2007; 6: 585–8. doi: 10.1097/MNH.0b013e3282f0c4bf.
  17. Woodburn KW, Schatz PJ, Fong KL. Erythropoiesis equivalence, pharmacokinetics and immune response following repeat hematide administration in cynomolgus monkeys. Int. J. Immunopathol. Pharmacol. 2010; 1: 121–9. doi: 10.1177/039463201002300111.
  18. Mennini T, De Paola M, Bigini P. Nonhematopoietic Erythropoietin Derivatives Prevent Motoneuron Degeneration In Vitro and In Vivo. Mol. Med. 2006; 12 (7–8): 153–60. doi: 10.2119/2006-00045.Mennini.
  19. Nissenson AR, Nimer SD, Wolcott DL. Recombinant human erythropoietin and renal anemia: molecular biology, clinical efficacy, and nervous system effects. Ann. Intern. Med. 1991; 114 (5): 402–16. doi: 10.7326/0003-4819-114-5-402.
  20. Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008; 299: 914–24. doi: 10.1001/jama.299.8.914.
  21. Leist M, Ghezzi P, Grasso G, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 2004; 305 (5681): 239–42.
  22. Coleman TR, Westenfelder C, Tögel FE, et al. Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities. Proc. Natl. Acad. Sci. 2006; 103: 5965–70. doi: 10.1073/pnas.0601377103.
  23. Kittur FS, Lin Y, Arthur E, et al. Recombinant asialoerythropoetin protects HL-1 cardiomyocytes from injury via suppression of Mst1 activation. Biochem. Biophys. Rep. 2019; 17: 157-68. doi: 10.1016/j.bbrep.2019.01.004.
  24. Sonoda A, Nitta N, Tsuchiya K, et al. Asialoerythropoietin ameliorates bleomycin-induced acute lung injury in rabbits by reducing inflammation. Exp. Ther. Med. 2014; 8 (5): 1443–46. doi: 10.3892/etm.2014.1960.
  25. Fiordaliso F, Chimenti S, Staszewsky L, et al. A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury. Proc. Natl. Acad. Sci. 2005; 102 (6): 2046-51. doi: 10.1073/pnas.0409329102.
  26. Nakazawa J, Isshiki K, Sugimoto T, et al. Renoprotective effects of asialoerythropoietin in diabetic mice against ischaemia-reperfusion-induced acute kidney injury. Nephrology (Carlton). 2010; 15 (1): 93–101. doi: 10.1111/j.1440-1797.2009.01170.x.
  27. Ishii T, Asai T, Fukuta T. A single injection of liposomal asialo-erythropoietin improves motor function deficit caused by cerebral ischemia/reperfusion. Int. J. Pharm. 2012; 15 (439):269–74. doi: 10.1016/j.ijpharm.2012.09.026.
  28. Yamashita T, Nonoguchi N, Ikemoto T, et al. Asialoerythropoietin attenuates neuronal cell death in the hippocampal CA1 region after transient forebrain ischemia in a gerbil model. Neurol Res. 2010; 32 (9): 957–62. doi: 10.1179/016164110X12700393823336.
  29. Takeyama T, Takemura G, Kanamori H, et al. Asialoerythropoietin, a nonerythropoietic derivative of erythropoietin, displays broad anti-heart failure activity. Circ. Heart Fail. 2012; 1 (5): 274–85. doi: 10.1161/CIRCHEARTFAILURE.111.965061.
  30. Sasaki N, Sekiguchi M, Kikuchi S, et al. Effects of asialo-erythropoietin on pain-related behavior and expression of phosphorylated-p38 map kinase and tumor necrosis factor-alpha induced by application of autologous nucleus pulposus on nerve root in rat. Spine (Phila Pa 1976). 2011; 15 (36): 86–94. doi: 10.1097/BRS.0b013e3181f137a8.
  31. Mori S, Sawada T, Okada T, et al. Erythropoietin and its derivative protect the intestine from severe ischemia/reperfusion injury in the rat. Surgery. 2008; 143 (4): 556–65. doi: 10.1016/j.surg.2007.12.013.
  32. Adembri C, Massagrande A, Tani A. Carbamylated erythropoietin is neuroprotective in an experimental model of traumatic brain injury. Crit Care Med. 2008. 36 (3): 975–8. doi: 10.1097/CCM.0B013E3181644343.
  33. King VR, Averill SA, Hewazy D, et al. Erythropoietin and carbamylated erythropoietin are neuroprotective following spinal cord hemisection in the rat. Eur J Neurosci. 2007; 26 (1): 90–100. doi: 10.1111/j.1460-9568.2007.05635.x.
  34. Simon F, Scheuerle A, Gröger M, 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 (9): 1525–33. doi: 10.1007/s00134-011-2303-4.
  35. Lapchak PA, Kirkeby A, Zivin JA, et al. Therapeutic window for nonerythropoietic carbamylated-erythropoietin to improve motor function following multiple infarct ischemic strokes in New Zealand white rabbits. Brain Res. 2008; 1238: 208–14. doi: 10.4137/BCI.S30753.
  36. Armand-Ugon M., Aso E., Moreno J, et al. Memory improvement in the AbetaPP/PS1 mouse model of familial Alzheimer’s disease induced by carbamylated-erythropoietin is accompanied by modulation of synaptic genes. J. Alzheimers. Dis. 2015; 45 (2): 407–21. doi: 10.3233/JAD-150002.
  37. Thomas Tayra J, Kameda M, Yasuhara T, 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.
  38. Liu W, Shen Y, Plane JM, et al. Neuroprotective potential of erythropoietin and its derivative carbamylatederythropoietin in periventricular leukomalacia. Exp Neurol. 2011; 230 (2): 227–39. doi: 10.1016/j.expneurol.2011.04.021.
  39. Huang Z, Xu W, Wu J, et al. The role of PI3-K/Akt signal pathway in the antagonist effect of CEPO on CHF rats. Exp Ther Med. 2018; 16 (6): 5161–5. doi: 10.3892/etm.2018.6822.
  40. Tögel FE, Ahlstrom JD, Yang Y, et al. Carbamylated Erythropoietin Outperforms Erythropoietin in the Treatment of AKI-on-CKD and Other AKI Models. J. Am. Soc. Nephrol. 2016; 27 (11): 3394–404.
  41. Hooshmandi E, Motamedi F, Moosavi M, 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; 15 (388): 405–417. doi: 10.1016/j.neuroscience.2018.08.001.
  42. He H, Qiao X, Wu S, et al. Carbamylated erythropoietin attenuates cardiomyopathy via PI3K/Akt activation in rats with diabetic cardiomyopathy. Exp Ther Med. 2013; 6 (2): 567–73. doi: 10.3892/etm.2013.1134.
  43. Liu X, Zhu B, Zou H, et al. Carbamylated erythropoietin mediates retinal neuroprotection in streptozotocin-induced early-stage diabetic rats. Graefes Arch Clin Exp Ophthalmol. 2015; 253 (8): 1263–72. doi: 10.1007/s00417-015-2969-3.
  44. Millet A, Bouzat P, Trouve-Buisson T, et al. Erythropoietin and Its Derivates Modulate Mitochondrial Dysfunction after Diffuse Traumatic Brain Injury. J. Neurotrauma. 2016; 33 (17): 1625–33. doi: 10.1089/neu.2015.4160.
  45. Diao M, Qu Y, Liu H, et al. Effect of carbamylated erythropoietin on neuronal apoptosis in fetal rats during intrauterine hypoxic-ischemic encephalopathy. Biol Res. 2019; 13 (52): 28. doi: 10.1186/s40659-019-0234-7.
  46. Woodburn KW, Schatz PJ, Fong KL. Erythropoiesis equivalence, pharmacokinetics and immune response following repeat hematide administration in cynomolgus monkeys. Int. J. Immunopathol. Pharmacol. 2010; 1: 121–9. doi: 10.1177/039463201002300111.
  47. Osato K, Sato Y, Osato A, et al. Carbamylated Erythropoietin Decreased Proliferation and Neurogenesis in the Subventricular Zone, but Not the Dentate Gyrus, After Irradiation to the Developing Rat Brain. Front Neurol. 2018; 9: 738. doi: 10.3389/fneur.2018.00738.
  48. Gomez-De la Riva Á, Isla-Guerrero A, García-Grande A. Erythropoietin as a protective factor in rat CNS cells receiving radiotherapy -an in vitro study. Rev. Neurol. 2014; 58 (5): 199–206.
  49. Ding J, Wang J, Li WY, et al. Neuroprotection and CD131/GDNF/AKT Pathway of Carbamylated Erythropoietin in Hypoxic Neurons. Mol. Neurobiol. 2017; 54 (7): 5051–60. doi: 10.1007/s12035-016-0022-0.
  50. Murphy JM, Young IG. IL-3, IL-5, and GM-CSF signaling: crystal structure of the human beta-common receptor. Vitam Horm. 2006; 74: 1–30. doi: 10.1016/S0083-6729(06)74001-8.
  51. Um MA, Gross AW, Lodish HF. “Classical” homodimeric erythropoietin receptor is essential for the antiapoptotic effects of erythropoietin on differentiated neuroblastoma SH-SY5Y and pheochromocytoma PC-12 cells. Cell Signal. 2007; 19 (3): 634–45. doi: 10.1016/j.cellsig.2006.08.014.
  52. Chamorro ME, Wenker SD, Vota DM, et al. Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative. Biochim Biophys Acta. 2013; 1833 (8): 1960–8. doi: 10.1016/j.bbamcr.2013.04.006.
  53. Sturm B, Helminger M, Steinkellner H, et al. Carbamylated erythropoietin increases frataxin independent from the erythropoietin receptor. Eur J Clin Invest. 2010; 40 (6): 561-5. doi: 10.1111/j.1365-2362.2010.02292.x.
  54. Choi M, Ko SY, Lee IY, et al. Carbamylated erythropoietin promotes neurite outgrowth and neuronal spine formation in association with CBP/p300. Biochem Biophys Res Commun. 2014; 446 (1): 79–84.
  55. Chattong S, Tanamai J, Kiatsomchai P, et al. Glutaraldehyde erythropoietin protects kidney in ischaemia/reperfusion injury without increasing red blood cell production. Br J Pharmacol. 2013; 168 (1): 189–99. doi: 10.1111/j.1476-5381.2012.02123.x
  56. Sooklert K, S. Chattong S, Manotham K, et al. Cytoprotective effect of glutaraldehyde erythropoietin on HEK293 kidney cells after silver nanoparticle exposure. Int. J. Nanomedicine. 2016; 11: 597–605. doi: 10.2147/IJN.S95654.
  57. Orschell C, Plett A, M. Yamin M, et al. ARA 290 is an efficacious radiomitigator of both the hematopoietic and gastrointestinal syndromes of the acute radiation syndrome. Abstracts of the 55th Annual Meeting of the Radiation Research Society. 2009: 143.
  58. Collino M, Thiemermann C, Cerami A, et al. Flipping the molecular switch for innate protection and repair of tissues: long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin. Pharmacol Ther. 2015; 151: 32–40.
  59. Nagao M, Wen TC, Okamoto M. In vivo neuroprotective activity of epopeptide ab against ischemic damage. Cytotechnology. 2005; (1-3): 139–44. doi: 10.1007/s10616-005-3758-3.
  60. Yoo SJ, Cho B, Moon C. Neuroprotective Effects of an Erythropoietin-Derived Peptide in PC1 2 Cells under Oxidative Stress. CNS Neurol Disord Drug Targets. 2016; 15 (8): 927–34.
  61. Yoo SJ, Cho B, Lee D, et al. The erythropoietin-derived peptide MK-X and erythropoietin have neuroprotective effects against ischemic brain damage. Cell Death Dis. 2017; 17 (8): 3003. doi: 10.1038/cddis.2017.381.
  62. Pankratova S, Gu B, Kiryushko D, et al. A new agonist of the erythropoietin receptor, Epobis, induces neurite outgrowth and promotes neuronal survival. J Neurochem. 2012; 121 (6): 915-23. doi: 10.1111/j.1471-4159.2012.07751.x.
  63. Dmytriyeva O, Pankratova S, Korshunova I, et al. Epobis is a Nonerythropoietic and Neuroprotective Agonist of the Erythropoietin Receptor with Anti-Inflammatory and Memory Enhancing Effects. Mediators Inflamm. 2016; 2016: 1346390. doi: 10.1155/2016/1346390.
  64. Dmytriyeva O, Belmeguenai A, Bezin L, et al. Short erythropoietin-derived peptide enhances memory, improves long-term potentiation, and counteracts amyloid beta-induced pathology. Neurobiol Aging. 2019; 81: 88-101. doi: 10.1016/j.neurobiolaging.2019.05.003.
  65. Fu Z, Huang D, Cai J, et al. Expression changes of ERK1/2, STAT3 and SHP-2 in bone marrow cells from gamma-ray induced leukemia mice. J Radiat Res. 2006; 47 (2): 121-30. doi: 10.1269/jrr.47.121.

Statistics

Views

Abstract - 207

PDF (Russian) - 83

Cited-By


Article Metrics

Metrics Loading ...

PlumX

Dimensions

Refbacks

  • There are currently no refbacks.

Copyright (c) 2020 Pharmacy Formulas

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies