Protective effect of NeuroEPO on the reproduction of diabetic rats
Keywords:
pre-gestational diabetes, streptozotocin-induced diabetes, NeuroEPO, reproduction, reproductive variables in rats.Abstract
Introduction: Pregestational diabetes constitutes a reproductive risk which requires new treatment strategies. NeuroEPO, a variant of the recombinant human erythropoietin produced in Cuba, has neuroprotective and hypoglycemic effects which can be considered for the treatment of this entity.
Objective: To evaluate the protective effect of NeuroEPO on the reproduction of diabetic rats.
Material and Methods: Four groups of adult female Wistar rats with streptozotocin-induced diabetes were used. During pregnancy, one group received the vehicle and the rest of the groups received different doses of NeuroEPO (0,5 mg/kg, 0,75 mg/kg, and 1 mg/kg) subcutaneously, on alternate days, for a total of six applications. A group of non-diabetic rats was used as a control group. Glycemia and reproductive variables were evaluated. For comparisons, Analysis of Variance and Fisher's Exact Test were used. There were significant differences with p-values less than 0,05.
Results: The group with vehicle presented maintained hyperglycemia, fewer implantations, and embryos, and increased gestational losses. In the group receiving 0,5 mg/kg of NeuroEPO, glycemia decreased significantly and the results of the reproductive variables were similar to the group of non-diabetic rats. With higher doses of NeuroEPO, gestational losses were increased. No congenital malformations were identified in either group.
Conclusions: The repeated administration of 0,5 mg/kg of NeuroEPO has a beneficial effect on the reproduction of diabetic rats, which may be associated with the reduction of hyperglycemia. Other cytoprotective mechanisms of NeuroEPO should be evaluated in future studies.
Downloads
References
1. Licea ME, Acosta A, Álvarez VA, Aldana D, Arnold Y, Álvarez Y, et al. Diabetes mellitus. Una mirada integral [Online]. La Habana: Editorial Ciencias Médicas; 2021 [Cited 21/01/2022]. Available from: http://www.bvscuba.sld.cu/libro/diabetes-mellitus-una-mirada-integral//
2. Dirección de Registros Médicos y Estadísticas de Salud. Anuario estadístico de salud 2019 [Online]. La Habana: Ministerio de Salud Pública; 2020 [Cited 21/01/2022]. Available from: http://files.sld.cu/bvscuba/files/2020/05/Anuario-Electrónico-Español-2019-ed-2020.pdf
3. Yu L, Zeng XL, Cheng ML, Yang GZ, Wang B, Xiao ZW, et al. Quantitative assessment of the effect of pre-gestational diabetes and risk of adverse maternal, perinatal and neonatal outcomes. Oncotarget [Online]. 2017;8(37):61048-56. Available from: http://doi.org/10.18632/oncotarget.17824
4. Ornoy A, Reece EA, Pavlinkova G, Kappen C, Kermit R. Effect of maternal diabetes on the embryo, fetus, and children: congenital anomalies, genetic and epigenetic changes and developmental outcomes. Birth Defects Research (Part C) [Online]. 2015;105:53-72. Available from: http://doi.org/10.1002/bdrc.21090
5. Eriksson UJ, Wentzel P. The status of diabetic embryopathyUpsala Journal of Medical Sciences [Online]. 2015;121(2):96-112. Available from: http://doi.org/10.3109/03009734.2016.1165317
6. Loeken MR. Mechanisms of congenital malformations in pregnancies with pre-existing diabetes. Curr Diab Rep [Online]. 2020;20(10):54. Available from: http://doi.org/10.1007/s11892-020-01338-4
7. Suresh S, Rajvanshi PK , Noguchi CT. The many facets of erythropoietin physiologic and metabolic response. Front Physiol [Online]. 2020;10:1534. Available from: http://doi.org/10.3389/fphys.2019.01534
8. Chen ZY, Asavaritikrai P, Prchal JT, Noguchi CT. Endogenous
erythropoietin signaling is required for normal neural progenitor cell
proliferation. J Biol Chem [Online]. 2007;282(35):25875-83. Available from: http://doi.org/10.1074/jbc.M701988200
9. Ji YQ, Zhang YQ, Li MQ, Du MR, Wei WW, Li DJ. EPO improves the
proliferation and inhibits apoptosis of trophoblast and decidual stromal
cells through activating STAT-5 and inactivating p38 signal in human
early pregnancy. Int J Clin Exp Pathol. 2011;4(8):765-74.
10. Niu HS, Shan Ch, Niu Sh, Cheng J, Lee K. Erythropoietin ameliorates hyperglycemia in type 1-like diabetic rats. Drug Des Dev Ther [Online]. 2016;10:1877-84. Available from: http://doi.org/10.2147/DDDT.S1058677
11. Kuo Sh, Li Y, Cheng KcH, NiuCh, Cheng J, Niu H. Investigation of the pronounced erythropoietin-induced reduction in hyperglycemia in type 1-like diabetic rats. Endocr J [Online]. 2018;65(2):181-91. Available from: http://doi.org/10.1507/endocrj.EJ17-0353
12. EL Okela AZ, El Arbagyb AR, Yasseinb YS, Khodirc, Kasemb HE. Effect of erythropoietin treatment on hemoglobin A1c levels in diabetic patients with chronic kidney disease. J Egypt Soc Nephrol Transplant [Online]. 2019;19(3):86-94. Available from: http://doi.org/10.4103/jesnt.jesnt_2_19
13. Peng B, Kong G, Yang C, Ming Y. Erythropoietin and its derivatives: from tissue protection to immune regulation. Cell Death Dis [Online]. 2020;11(2):2-12. Available from: http://doi.org/10.1038/s41419-020-2276-8
14. Garzón F, Rodríguez Y, García JC, Rama R. Neuroprotective effects of NeuroEPO using an in vitro model of stroke. Behav Sci (Basel) [Online]. 2018;8(26):1-11. Available from: http://doi.org/10.3390/bs8020026
15. Garzón F, Coimbra D, Parcerisas A, Rodriguez Y, García JC, Soriano E, et al. NeuroEPO preserves neuronsfromglutamate-inducedexcitotoxicity. J Alzheimers Dis [Online]. 2018;65(4):1469-83. Available from: http://doi.org/10.3233/JAD-180668
16. Rama R, Garzón F, Rodríguez Cruz Y, Maurice T, García Rodríguez JC. Neuroprotective effect of Neuro-EPO in neurodegenerative diseases: “Aleajactaest”. Neural Regen Res [Online]. 2019;14(9):1519-21. Available from: http://doi.org/10.4103/1673-5374.255968
17. Rodríguez Y, Strehaiano M, Rodríguez T, García JC, Maurice T. An intranasal formulation of erythropoietin (Neuro-EPO) prevents memory deficits and amyloid toxicity in the APPSwe transgenic mouse model of Alzheimer’s disease. J Alzheimer´s Dis [Online]. 2017;55(1):231-48. Available from: http://doi.org/10.3233/JAD-160500
18. Fernández Romero T, Clapés Hernández S, Pérez Hernández CL, Barreto López JJ, Fernández Peña G. Efecto hipoglicemiante de la NeuroEPO en ratas con y sin diabetes mellitus. Rev haban cienc méd [Online]. 2022 [Cited 21/01/2022];21(1):e4617. Available from: http://www.revhabanera.sld.cu/index.php/rhab/article/view/4617
19. Yilmaz O, Lambrecht FY, Gokmen N, Erbayraktar S, Durkan K. Distribution of 131I-labeled recombinant human erythropoietin in maternal and fetal organs following intravenous administration in pregnant rats. Journal of Radioanalytical and Nuclear Chemistry [Online]. 2007;273(2):311-3. Available from: http://doi.org/10.1007/s10967-007-6859-y
20. Kaushik K, Vaswani R. Research on animals and current UGC guidelines on animal dissection and experimentation: A critical analysis. Bioethics Update [Online]. 2018;4(2):119-39. Available from: http://doi.org/10.1016/j.bioet.2018.05.001
21. McCormick Ell J, Connell N. Laboratory safety, biosecurity and responsible animal use. ILAR J [Online]. 2019;60(1):24-33. Available from: http://doi.org/10.1093/ilar/ilz012
22. Sinzato YK, Kloppel E, Miranda CA, Paula VG, Alves LF, Nascimento LLS, et al. Comparison of streptozotocin-induced diabetes at different moments of the life of female rats for translational studies. Laboratory Animals [Online]. 2021;1:1-11. Available from: http://doi.org/10.1177/00236772211001895
23. Karwasik Kajszczarek K, Chmiel Perzyńska I, Marcin J, Billewicz Kraczkowska A, Pedrycz A, Smoleń A, et al. Impact of experimental diabetes and chronic hypoxia on rat fetal body weight. Ginekologia Polska [Online]. 2018;89(1):20-4. Available from: http://doi.org/10.5603/GP.a2018.0004
24. Quinna NA, Badwan AA. Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats. Drug Design, Development and Therapy [Online]. 2015;9:2515-25. Available from: http://doi.org/10.2147/DDDT.S79885
25. Fernández T, Suárez G, Clapés S. Protocolo para la citología vaginal directa de ratas de laboratorio. Rev haban cienc méd [Online]. 2021 [Cited 21/01/2022];20(3): e4086. Available from: http://www.revhabanera.sld.cu/index.php/rhab/article/view/4086
26. Fernández T, Clapés S, Suárez G, Perera A, Rodríguez VM, Purón CA, et al. Embriopatía diabética en ratas y efecto de un suplemento nutricional de vitamina E durante la gestación. Rev haban cienc méd [Online]. 2013 [Cited 21/01/2022];12(2): [Aprox.1p.]. Available from: http://www.revhabanera.sld.cu/index.php/rhab/article/view/56
27. Fernández Romero T, Clapes S, Pérez CL, Núñez López N, Suárez Román G, Fernández G. Protectiveeffect of NeuroEPO onthereproduction of diabeticrats [Online]. Amsterdam: Mendeley Data; 2022 [Cited 21/01/2022]. Available from: https://www.data.mendeley.com/datasets/dvk9rtwccy/1
28. Pan Y, Hong X, Li L, Hong Y, Yan Q, Min H, et al. Erythropoietin reduces insulin resistance via regulation of its receptor-mediated signaling pathways in db/db mice skeletal muscle. Int J Biol Sci [Online]. 2017;13(10):1329-40. Available from: http://doi.org/10.7150/ijbs.19752
29. El Desouki NI, Tabl GA, Abdel Aziz KK, Salim EI, Nazeeh N. Improvement in beta-islets of Langerhans in alloxan-induced diabetic rats by erythropoietin and spirulina. The Journal of Basic and Applied Zoology [Online]. 2015;71:20-31. Available from: http://doi.org/10.1016/j.jobaz.2015.04.003
30. Chen L, Sun Q, Liu S, Hu H, Lv J, Ji W, et al. Erythropoietin improves glucose metabolism and pancreatic β-cell damage in experimental diabetic rats. Molecular Medicine Reports [Online]. 2015;12:5391-98. Available from: http://doi.org/10.3892/mmr.2015.4006
31. Goyal SN, Reddy NM, Patil KR, Nakhate KT, Ojha S, Patil CR, et al. Challenges and issues with streptozotocin-induced diabetes- A clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics. Chemico Biological Interactions [Online]. 2016;244:49-63. Available from: http://doi.org/10.1016/j.cbi.2015.11.032
32. Jawerbaum A, White V. Animal models in diabetes and pregnancy. Endocrine Reviews [Online]. 2010;31(5):680-701. Available from: http://doi.org/10.1210/er.2009-0038
33. Weishaupt JH, Rohde G, Pölking E, Siren AL, Ehrenreich H, Bähr M. Effect of Erythropoietin Axotomy-Induced Apoptosis in Rat Retinal Ganglion Cells. Invest Ophthalmol Vis Sci. 2004;45(5):1514-22.
34. Ribatti D, Presta M, Vacca A, Ria R, Giuliani R, Dell’Era P, et al. Human Erythropoietin Induces a Pro-Angiogenic Phenotype in Cultured Endothelial Cells and Stimulates Neovascularization In Vivo. Blood. 1999;93(8):2627-36.
35. Teste IS, Tamos YM, Cruz YR, Cernada AM, Rodríguez JC, Martínez NS, et al. Dose effect evaluation and therapeutic window of the neuro-EPO nasal application for the treatment of the focal ischemia model in the Mongolian gerbil. Scientific World Journal [Online]. 2012 [Cited 21/01/2022];2012:607498. Available from: http://europepmc.org/abstract/MED/22701364
36. Voss AK, Strasser A. The essentials of developmental apoptosis. F1000Research [Online]. 2020 [Cited 21/01/2022];9:[Aprox. 2 p.]. Available from: http://www.pmc/articles/PMC7047912/
Download PDF
