NEUROPROTECTIVE EFFECT OF ERYTHROPOIETIN AT EXPERIMENTAL SPINAL CORD ISCHEMIA
Keywords:
Erythropoietin, spinal stroke, neurons, morphology, ethological status
Abstract
Aim. To study dynamics of the ethological status and morphological changes in neurons at experimental spinal cord ischemia influenced by erythropoietin (EPO) administration. Materials and Methods. The research was conducted on 54 outbred white rats. Spinal cord ischemia was modeled via total intravasal occlusion of abdominal aorta and its branches. EPO was administered intraperitoneally at a dose of 5000 IU per kg of body weight three times in 3, 24 and 48 hours after induction of lumbar spinal cord ischemia. The ethological status in animals was assessed using the 6-point scale based on the integral indicator of behavioral responses (IIBR). Morphological methods were used to estimate numbers of unchanged neurons, chromatolytic cells, ghost cells, glial cells, and blood vessels in the spinal cord. Results. Experimental spinal cord ischemia induced by total intravasal occlusion of the abdominal aorta and its branches was followed by progressive (from day 3 to day 14) and partially recovering (by day 30) changes in the ethological status manifested by symmetric peripheral paraplegia, apselaphesia of the hind limbs and lumbar spine, fecal and urinary incontinence. Morphological changes of the lumbar spine at spinal ischemia included progressive (from day 3 to day 30) increase in numbers of chromatolytic neurons, ghost cells, glial cells, and small blood vessels; the number of intact neurons was maximally decreased on days 3 and 7 and started recovering on day 30. Conclusion. EPO administration at a total dose of 15000 IU/kg at experimental spinal cord ischemia results in a partial (on day 3) and complete (on days 7-14-30) recovery of animals’ behavioral activity. After EPO has been administered, numbers of normal neurons, glial cells, and small blood vessels in the spinal cord are progressively increasing from day 3 do day 30 of observation while the percentage of chromatolytic neurons and ghost cells is progressively decreasing.References
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2. Ezdakova M.I., Andreeva E.R., Gur'eva T.S., Dadasheva O.A., Orlova V.S., Buravkova L.B. [Influence of Hypoxia and Growth Factors on the Angiogenic Activity of Multipatent Mesenchymal Stromal Cells]. Aviakosmicheskaya i ekologicheskaya meditsina [Aerospace and Ecological Medicine], 2015, vol. 49, no. 5, pp. 29–35. (in Russ.)
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7. Osikov M.V., Akhmatov K.V., Krivokhizhina L.V. [Pathophysiological Analysis of the Effect of Erythropoietin on Psychological Status in Patients with Chronic Renal Failure who are on Hemodialysis]. Bulletin of the South Ural State University. Ser. Education, Healthcare Service, Physical Education, 2010, no. 19 (195), pp. 110–116. (in Russ.)
8. Osikov M.V., Grigor'ev T.A., Ageev Yu.I. [Efferent and Antioxidant Properties of Erythropoietin in Chronic Renal Failure]. Efferentnaya terapiya [Efferent Therapy], 2011, vol. 17, no. 4, pp. 7–13. (in Russ.)
9. Osikov M.V. [On the Mechanism of the Influence of Erythropoietin on the Affective Status in Patients with Chronic Renal Failure who are on Hemodialysis]. Fundamental'nye issledovaniya [Fundamental Research], 2012, no. 7–1, pp. 140–145. (in Russ.)
10. Osikov M.V., Akhmatov K.V., Fedosov A.A. [Differentiation of the Role of Erythropoietin and the Procedure of Hemodialysis in the Correction of Affective Disorders in Patients with Chronic Renal Failure]. Fundamental'nye issledovaniya [Fundamental Research], 2013, no. 3–1, pp. 138–142. (in Russ.)
11. Osikov M.V. [Effect of Erythropoietin on the Processes of Free Radical Oxidation and Expression of Glycoproteins in Platelets in Chronic Renal Failure]. Byulleten' eksperimental'noy biologii i meditsiny [Bulletin of Experimental Biology and Medicine], 2014, vol. 157, no. 1, pp. 30–33. (in Russ.) DOI: 10.1007/s10517-014-2483-3
12. Osikov M.V., Telesheva L.F., Ageev Yu.I. [Influence of Erythropoietin on Apoptosis of Lymphocytes in Experimental Chronic Renal Failure]. Byulleten' eksperimental'noy biologii i meditsiny [Bulletin of Experimental Biology and Medicine], 2015, no. 3, pp. 326–329. (in Russ.)
13. Osikov M.V., Telesheva L.F., Ageev Yu.I. [Antioxidant Effect of Erythropoietin in Experimental Chronic Renal Failure]. Byulleten' eksperimental'noy biologii i meditsiny [Bulletin of Experimental Biology and Medicine], 2015, vol. 160, no. 8, pp. 162–165. (in Russ.)
14. Gold M. Primenenie eritropoetina v vosstanovlenii posle insul'ta [Use of Erythropoietin in Recovery After a Stroke]. Patent RF, no. 2341284, 2008.
15. Pashin S.S., Viktorov I.V. [Morphofunctional Changes in the Spinal Cord of Rats in the Field of Focal Phlebothrombosis]. Morfologiya [Morphology], 2008, vol. 133, no. 1, pp. 35–38. (in Russ.)
16. Skoromets A.A., Skoromets A.P., Skoromets T.A., Tissen T.P. Spinal'naya angionevrologiya. Rukovodstvo dlya vrachey [Spinal Angioneurology. Manual for Doctors]. Moscow, MEDPRESS INFORM Publ., 2003. 608 p.
17. Charriaut-Marlangue C., Margaill I., Represa A. Apoptosis and Necrosis After Reversible Focal Ischemia. An in Situ DNA Fragmentation Analysis. J Cereb Blood Flow Metab., 1996, vol. 16(2), pp. 186–194. DOI: 10.1097/00004647-199603000-00002
18. Astrup J., Siesjo B.K., Symon L. Thresholds in Cerebral Ischemia the Ischemic Penumbra. Stroke, 1981, vol. 12, pp. 723–725. DOI: 10.1161/01.STR.12.6.723
19. Byts N., Siren A.L. Erythropoietin. A Multimodal Neuroprotective Agent. Exp. Transl. Stroke. Med., 2009, vol. 1, 4 р.
20. Charriaut-Marlangue C., Margaill I., Plotkine M., Ben-Ari Y. Early Endonuclease Activation Following Reversible Focal Ischemia in the Rat Brain. J Cereb Blood Flow Metab., 1995, vol. 15(3), pp. 385–388. DOI: 10.1038/jcbfm.1995.48
21. Celik M., Gokmen N., Erbayraktar S. Erythropoietin Prevents Motor Neuron Apoptosis and Neurologic Disability in Experimental Spinal Cord Ischemic Injury. Proc Natl Acad Sci USA, 2002, vol. 99, pp. 2258–2263. DOI: 10.1073/pnas.042693799
22. Xiong Y., Mahmood A., Qu C. Erythropoietin Improves Histological and Functional Outcomes After Traumatic Brain Injury in Mice in the Absence of the Neural Erythropoietin Receptor. J. Neurotrauma, 2010, vol. 27, no. 1, pp. 205–215. DOI: 10.1089/neu.2009.1001
23. Siren A.L., Fratelli M., Brines M. Erythropoietin Prevent Neuronal Apoptosis After Cerebral Ischemia and Metabolic Stress. Proc Natl Acad Sci USA, 2001, vol. 98, pp. 4044–4049. DOI: 10.1073/pnas.051606598
24. Fisher M., Takano K., Hachinski V. Ballierie's Clinical Neurology, Cerebrovascular Disease. London, 1995, pp. 279–296.
25. Hossmann K.A. Disturbances of Cerebral Protein Synthesis and Ischemic Cell Death. Prog Brain Res., 1993, vol. 96, pp. 161–177. DOI: 10.1016/S0079-6123(08)63265-3
26. Hossmann K.A. Viability Thresholds and the Penumbra of Focal Ischemia. Ann Neurol., 1994, vol. 36, pp. 557–565. DOI: 10.1002/ana.410360404
27. Li Y., Chopp M., Jiang N. Induction of DNA Fragmentation after 10 to 120 Minutes of Focal Cerebral Ischemia in Rats. Stroke, 1995, vol. 26(7), pp. 1252–1257. DOI: 10.1161/01.STR.26.7.1252
28. Jacewicz M., Kiessling M., Pulsinelli W.A. Selective Gene Expression in Focal Cerebral Ischemia. J Cereb Blood Flow Metab., 1986, vol. 6(3), pp. 263–272. DOI: 10.1038/jcbfm.1986.48
29. Kim Y.J., Jung Y.W. Systemic Injection of Recombinant Human Erythropoietin after Focal Cerebral Ischemia Enhances Oligodendroglial and Endothelial Progenitor Cells in Rat Brain. Anat. Cell. Biol., 2010, vol. 43, no. 2, pp. 140–149. DOI: 10.5115/acb.2010.43.2.140
30. Lawler P.R., Filion K.B., Eisenberg M.J. Correcting Anemia in Heart Failure. The Efficacy and Safety of Erythropoiesis–Stimulating Agents. J. Card. Fail., 2010, vol. 16, pp. 649–658. DOI: 10.1016/j.cardfail.2010.03.013
31. Linnik M.D., Zobrist R.H., Hatfield M.D. Evidence Supporting a Role for Programmed Cell Death in Focal Cerebral Ischemia in Rats. Stroke, 1993, vol. 24 (12), pp. 2002–2008. DOI: 10.1161/01.STR.24.12.2002
32. Mies G., Ishimaru S., Xie Y. Ischemic Thresholds of Cerebral Protein Synthesis and Energy State Following Middle Cerebral Artery Occlusion in Rat. J Cereb Blood Flow Metab., 1991, vol. 11 (5), pp. 753–761. DOI: 10.1038/jcbfm.1991.132
33. Milano M., Collomp R. Erythropoietin and Neuroprotection. A Therapeutic Perspective. J. Oncol. Pharm. Pract., 2005, vol. 11, no. 4, pp. 145–149. DOI: 10.1191/1078155205jp162oa
34. Sadoul R., Dubois–Dauphin M., Fernandez P.A. Mechanisms of Neuronal Cell Death. Adv Neurol., 1996, vol. 71, pp. 419–423.
35. Marti H.H., Bernaudin M., Petit E. Neutroprotection and Angiogenesis. Dual Role of Erythropoietin in Brain Ischemia. News Physiol. Sci., 2000, vol. 15, pp. 225–229.
36. Tamura T., Aoyama M., Ukai S., Kakita H., Sobue K., Asai K. Neuroprotective Erythropoietin Attenuates Microglial Activation, Including Morphological Changes, Phagocytosis, and Cytokine Production. Brain Res., 2017, PII: S0006-8993(17)30093-8. DOI: 10.1016/j.brainres.2017.02.023
37. Morishita E., Masuda S., Nagao M. Erythropoietin Receptor is Expressed in Rat Hippocampal and Cerebral Cortical Neurons, and Erythropoietin Prevents in Vitro Glutamate–Induced Neuronal Death. Neuroscience, 1997, vol. 76, pp. 105–116. DOI: 10.1016/S0306-4522(96)00306-5
38. Paciaroni M., Caso V., Agnelli G. The Concept of Ischemic Penumbra in Acute Stroke and Therapeutic Opportunities. Eur. Neur., 2009, vol. 61, pp. 321–230. DOI: 10.1159/000210544
39. Santhanam A.V., Katusic Z.S. Erythropoietin and Cerebral Vascular Protection. Role of Nitric Oxide. Acta Pharmacol Sin., 2006, vol. 27, pp. 1389–1394. DOI: 10.1111/j.1745-7254.2006.00441.x
40. Siesjo B.K., Bengtsson F. Calcium Fluxes, Calcium Antagonists, and Calcium-Related Pathology in Brain Ischemia, Hypoglycemia, and Spreading Depression. A Unifying Hypothesis. J Cereb Blood Flow Metab., 1989, vol. 9(2), pp. 127–140. DOI: 10.1038/jcbfm.1989.20
41. Liu W.C., Wen L., Xie T., Wang H., Gong J.B., Yang X.F. Therapeutic Effect of Erythropoietin in Patients with Traumatic Brain Injury. A Meta-Analysis of Randomized Controlled Trials. J Neurosurg., 2016, pp. 1–8. DOI: 10.3171/2016.4.jns152909
42. Donnan G.A., Baron J.C., Davis S.M., Sharp F.R. (Eds.) The Ischemic Penumbra. NY: Informa Healthcare, 2007.
43. Taoufik E., Petit E., Divoux D. TNF Receptor I Sensitizes Neurons to Erythropoietin- and VEGF-Mediated Neuroprotection after Ischemic and Excitotoxic Injury. Proc Natl Acad Sci USA, 2008, vol. 105(16), pp. 6185–6190. DOI: 10.1073/pnas.0801447105
44. Wang L., Zhang Z., Wang Y. Treatment of Stroke with Erythropoietin Enhances Neurogenesis and Angiogenesis and Improves Neurological Function in Rats. Stroke, 2004, vol. 35, pp. 1732–1737. DOI: 10.1161/01.STR.0000132196.49028.a4
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Published
2017-06-01
How to Cite
Osikov, M., Volodchenko, A., & Giniatullin, R. (2017). NEUROPROTECTIVE EFFECT OF ERYTHROPOIETIN AT EXPERIMENTAL SPINAL CORD ISCHEMIA. Human. Sport. Medicine, 17(2), 40-51. https://doi.org/10.14529/hsm170204
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