Intranasal administration of NeuroEPO does not affect the structure of respiratory mucosa in Wistar rats

Authors

  • Ketty Suárez Borrás Universidad de Ciencias Médicas de la Habana, Instituto de Ciencias Básicas y Preclínicas “Victoria de Girón”. La Habana. https://orcid.org/0000-0002-3998-1657
  • Gisselle Fernández Peña Universidad de Ciencias Médicas de la Habana, Instituto de Ciencias Básicas y Preclínicas “Victoria de Girón”. La Habana. https://orcid.org/0000-0002-5339-8118
  • Yamila Rodríguez Cruz Universidad de Ciencias Médicas de la Habana, Instituto de Ciencias Básicas y Preclínicas “Victoria de Girón”. La Habana. https://orcid.org/0000-0001-8492-9797
  • Giselle Puldón Seguí Universidad de Ciencias Médicas de la Habana, Instituto de Ciencias Básicas y Preclínicas “Victoria de Girón”. La Habana.

Keywords:

NeuroEPO, respiratory mucosa, neurodegenerative diseases, neuroprotection

Abstract

Introduction: Diseases associated with the Central Nervous System represent a group of conditions with important social and economic repercussions.  New treatment strategies with NeuroEPO offer new opportunities to prevent the onset and progression of these disorders. NeuroEPO administered intranasally can reach the Central Nervous System through various mechanisms involving the olfactory and trigeminal nerves, respiratory and olfactory mucosa, nasal vasculature, cerebrospinal fluid, and the lymphatic system.

Objective: To determine the effect of intranasal administration of NeuroEPO on the histologic structure of the respiratory mucosa and its associated lymphatic tissue in Wistar rats.

Material and Methods: An experimental, descriptive, longitudinal, prospective study was conducted, using the Wistar rat as a biological model.  Ten healthy animals were randomly distributed in two groups of five animals each. One of the groups received intranasal NeuroEPO for 28 days at doses of 300 μg/kg. The other group was given a vehicle at a rate of 0,3μl/g. The histological characteristics of the respiratory mucosa were studied. The Mann-Whitney test was used to compare the means.

Results: No alterations in the histological characteristics of the respiratory mucosa and the lymphatic tissue associated with the nasal mucosa were observed in Wistar rats after the administration of NeuroEPO.

Conclusion: Intranasal administration of NeuroEPO does not cause pathological changes in the histological structure of the respiratory mucosa or the lymphatic tissue associated with the nasal mucosa of Wistar rats in our experimental conditions.

Downloads

Download data is not yet available.

References

1. Garzón F, Rodríguez Y, García JC, Rama R. Neuroprotective Effects of neuroEPO Using an In Vitro Model of Stroke. Behav Sci.2018;8(2):26.

2. Rama R, Garzón F, Rodríguez Cruz Y, Maurice T, García Rodríguez JC. Neuroprotective effect of Neuro-EPO in neurodegenerative diseases: “Aleajacta est.” Neural Regen Res [Online]. 2019 Sep [Cited 04/02/2022];14(9):1519. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557108/

3. Rey F, Balsari A, Giallongo T. Erythropoietin as a Neuroprotective Molecule: An Overview of Its Therapeutic Potential in Neurodegenerative Diseases. ASN Neuro [Online]. 2019 [Cited 04/02/2022];11:1759091419871420. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712762/

4. Zucchella C, Sinforiani E, Tamburin S, Federico A, Mantovani E, Bernini S, et al. The Multidisciplinary Approach to Alzheimer'sDisease and Dementia. A Narrative Review of Non-Pharmacological Treatment. Front Neurol [Online]. 2018 Dec [Cited 04/02/2022];9:1058. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300511/

5. 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 17/04/2022];21(1):e4617. Disponible en: http://www.revhabanera.sld.cu/index.php/rhab/article/view/4617

6. Ul Islam S, Shehzad A, Bilal Ahmed M, Lee YS. Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders. Molecules [Online]. 2020 Apr [Cited 04/02/2022];25(8):[Aprox. 2 p.]. Available from: https://pubmed.ncbi.nlm.nih.gov/32326318/

7. Fernández Romero T, Clapés Hernández S, Pérez CL, Núñez López N, Suárez Román G, Fernández G. Protective effect of NeuroEPO in the reproduction of diabetic rats. Rev haban cienc méd [Online]. 2022 [Cited 08/08/2022];21(4):[Aprox. 6 p.]. Available from : http://www.revhabanera.sld.cu/index.php/rhab/article/view/4797

8. 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: https://www.doi.org/10.3233/JAD-160500

9. Vega MLB, Shengnan L, Leon YR, Rodríguez AM, Fernández EC, Llano MG, et al. NeuroEPO improves cognition in Parkinson’s disease. Preliminary report. medRxiv [Online]. New York: medRxiv; 2022 [Cited 17/04/2022]. Available from: https://www.medrxiv.org/content/10.1101/2022.02.24.22271444v2

10. Pérez L, Sosa S, Valenzuela C, Bringas G, Urrutia N, Peñalver AI, et al. Clinical trial of neuroEPO in mild-to-moderate Alzheimer’s disease. Alzheimer's Dement [Online]. 2021;17:e050212. Available from: https://doi.org/10.1002/alz.050212

11. McCormick-Ell J, Connell N. Laboratory safety, biosecurity, and responsible animal use. ILAR journal [Online]. 2019;60(1):24-33. Available from: https://doi.org/10.1093/ilar/ilz012

12. Muñoz Cernada A, García Rodríguez JC, Núñez Figueredo Y, Pardo Ruiz Z, García Selman JD, Sosa Testé I, et al. Formulaciones nasales de EPOrh con bajo contenido de ácido siálico para el tratamiento de enfermedades del sistema nervioso central [Online]. La Habana; WO2007009404, 2007 [Cited 17/04/2022]. Available from: https://patentscope.wipo.int/search/es/detail.jsf?docId=WO2007009404

13. Tveden Nyborg P, Lykkesfeldt J. Animal Models in Pharmacology and Toxicology. In: Handbook of Laboratory Animal Science [Online]. Florida: CRC Press; 2021 [Cited 25/07/2022]. p. 665–94. Available from: https://www.taylorfrancis.com/chapters/edit/10.1201/9780429439964-30/animal-models-pharmacology-toxicology-pernille-tveden-nyborg-jens-lykkesfeldt

14. Uraih LC, Maronpot RR. Normal histology of the nasal cavity and application of special techniques. Environ Health Perspect [Online]. 1990;85:187-208. Available from: https://www.doi.org/10.1289/ehp.85-1568325

15. Young JT. Histopathologic examination of the rat nasal cavity. Fundam Appl Toxicol [Online]. 1981;1(4):309-12. Available from: https://www.doi.org/10.1016/s0272-0590(81)80037-1

16. Grada A, Mervis J, Falanga V. Research techniques made simple: animal models of wound healing. Journal of Investigative Dermatology [Online].2018;138(10):2095-105.e1. Available from: https://doi.org/10.1016/j.jid.2018.08.005

17. Verma A, Verma M, Singh A. Animal tissue culture principles and applications. Animal Biotechnology [Online]. 2020:269-93. Available from: http://www.doi.org/10.1016/B978-0-12-811710-1.00012-4

18. Abbas KA, Lichtman HA, Pillai S. Células y tejidos del sistema inmunitario. In: Inmunología celular y molecular. 7 ed. Barcelona: Elsevier Saunders; 2012.p.15-32.

19. Dan Wilcox, Brent Dove. UTHSCSA image tool (3.0) [Online]. USA: Informer Technologies, Inc; 2022 [Cited 25/07/2022]. Available from: https://imagetool.software.informer.com/Descargar-gratis/

20. Motulsky H, Chistopoulos A, Miller JR. Graphpad Prism Version 5.0 Software Inc, USA [Online]. San Diego: GraphPad; 2022 [Cited 25/07/2022]. Available from: http://www.graphpad.com

21. Suarez K, Fernández G, Rodriguez Y, Puldon G (2022), “Administration of intranasal NeuroEPO does not affect the structure of the respiratory mucosa in Wistar rats” [Online]. Amsterdam: Mendeley Data; 2022. Available from: http://doi.org/10.17632/c5zhgv532g.1

22. Jiang XZ, Buckley LA, Morgan KT. Pathology of toxic responses to the RD50 concentration of chlorine gas in the nasal passages of rats and mice. Toxicol Appl Pharmacol [Online]. 1983;71(2):225-36. Available from: http://www.doi.org/10.1016/0041-008x(83)90339-3

23. Harkema JR, Wagner JG. Innate Lymphoid Cell-Dependent Airway Epithelial and Inflammatory Responses to Inhaled Ozone: A New Paradigm in Pathogenesis. Toxicol Pathol [Online]. 2019;47(8):993-1003. Available from: http://www.doi.org/10.1177/0192623319873872

24. Edrissi B, Taghizadeh K, Moeller BC, Yu R, Kracko D, Doyle Eisele M, et al. N6-Formyllysine as a Biomarker of Formaldehyde Exposure: Formation and Loss of N6-Formyllysine in Nasal Epithelium in Long-Term, Low-Dose Inhalation Studies in Rats. Chem Res Toxicol [Online]. 2017;30(8):1572-6. Available from: http://www.doi.org/10.1021/acs.chemrestox.7b00075

25. Tesfaye S, Hamba N, Gerbi A, Negeri Z. Oxidative Stress and Carcinogenic Effect of Formaldehyde Exposure: Systematic Review & Analysis. Endocrinol Metab Syndr [Online]. 2020 Sep [Cited 04/02/2022];9(6):1-11. Available from: https://www.longdom.org/open-access/oxidative-stress-and-carcinogenic-effect-of-formaldehyde-exposure-systematic-review-analysis-58212.html

26. Eda A, Baver S, Seyla SB, Hüseyin Ö, Deveci E. Effects of Xylene on Respiratory Mucosa in Rats. Int J Morphol [Online]. 2016 Sep [Cited 04/02/2022];34(3):934-8. Available from: http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0717-95022016000300019&lng=en&nrm=iso&tlng=en

27. Horak F, Zieglmayer UP, Zieglmayer R, Kavina A, Marschall K, Munzel U, et al. Azelastine nasal spray and desloratadine tablets in pollen-induced seasonal allergic rhinitis: a pharmacodynamic study of onset of action and efficacy. Curr Med Res Opin [Online]. 2006;22(1):151-7. Available from: http://www.doi.org/10.1185/030079906X80305

28. Small P, Keith PK, Kim H. Allergic rhinitis. Allergy Asthma Clin Immunol [Online]. 2018 [Cited 04/02/2022];14(2):1-11. Available from: https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0280-7

29. Lagarto A, Bueno V, Guerra I, Valdés O, Couret M, López R, et al. Absence of hematological side effects in acute and subacute nasal dosing of erythropoietin with a low content of sialic acid. Exp Toxicol Pathol [Online]. 2011 [Cited 04/02/2022];63(6):563-7. Available from: https://pubmed.ncbi.nlm.nih.gov/20488687/

30. Rodríguez Cruz Y, Suárez Borrás K, Fernández Peña G, Puldón Seguí G. Efectos de la NeuroEPO sobre las características histológicas de la mucosa olfatoria en ratas wistar. En: Congreso MorfoVirtual 2020 [Online]. La Habana: Sociedad Cuabana de Ciencias Morfológicas; 2020 [Cited 25/07/2022]. Available from: http://www.morfovirtual2020.sld.cu/index.php/morfovirtual/morfovirtual2020/paper/view/25/

31. Marcondes de Godoy M, Lopes RA, Sala MA, Vinha D, Regalo SCH. Acción del Etanol sobre el Epitelio Nasal y Glándulas Septales de Ratas, Durante la Lactancia. Int J Morphol [Online]. 2005 [Cited 04/02/2022];23(4):293-300. Available from: http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0717-95022005000400002&lng=es&nrm=iso&tlng=es

32. Alt JA, Qin X, Pulsipher A, Orb Q, Orlandi RR, Zhang J, et al. Topical cathelicidin (LL-37) an innate immune peptide induces acute olfactory epithelium inflammation in a mouse model. Int Forum Allergy Rhinol [Online]. 2015 Dec;5(12):1141-50. Available from: http://www.doi.org/10.1002/alr.21634

33. Chamanza R, Wright J. A review of the comparative anatomy, histology, physiology and pathology of the nasal cavity of rats, mice, dogs and non-human primates. Relevance to inhalation toxicology and human health risk assessment. Journal of Comparative Pathology [Online]. 2015;153(4):287-314. Available from: https://doi.org/10.1016/j.jcpa.2015.08.009

34. Elmore SA. Enhanced Histopathology Evaluation of Lymphoid Organs. Methods Mol Biol [Online]. 2018 [Cited 30/03/2022];1803:147-68. Available from: https://link.springer.com/protocol/10.1007/978-1-4939-8549-4_10

35. Elmore SA. Enhanced Histopathology of Mucosa-Associated Lymphoid Tissue. Toxicol Pathol [Online]. 2006 Jun [Cited 30/03/2022];34(5):687-96. Available from: https://journals.sagepub.com/doi/full/10.1080/01926230600939989

36. Frieke Kuper C, van Oostrum L, Ma-Hock L, Durrer S, Woutersen RA. Hyperplasia of the lymphoepithelium of NALT in rats but not in mice upon 28-day exposure to 15ppm formaldehyde vapor. Exp Toxicol Pathol [Online]. 2011;63(1):25-32. Available from: https://www.sciencedirect.com/science/article/pii/S0940299309002437

37. Marino JH, Teague TK. The Immune System as a Sensor and Regulator of Stress: Implications in Human Development and Disease. In: Biobehavioral Markers in Risk and Resilience Research [Online]. Switzerland: Springer; 2019. p. 1-11. Available from: https://doi.org/10.1007/978-3-030-05952-1_1

38. Kuper CF, Wijnands MVW, Zander SAL. Mucosa-Associated Lymphoid Tissues BT - Immunopathology in Toxicology and Drug Development. In: Parker GA, ed. Organ Systems [Online]. Switzerland: Springer International Publishing; 2017. p. 81-121. Available from: https://doi.org/10.1007/978-3-319-47385-7_4

39. Pacák K, Palkovits M. Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. Endocr Rev [Online]. 2001 Aug;22(4):502-48. Available from: http://www.doi.org/10.1210/edrv.22.4.0436

Downloads

Published

2022-09-22

How to Cite

1.
Suárez Borrás K, Fernández Peña G, Rodríguez Cruz Y, Puldón Seguí G. Intranasal administration of NeuroEPO does not affect the structure of respiratory mucosa in Wistar rats. Rev haban cienc méd [Internet]. 2022 Sep. 22 [cited 2025 Aug. 3];21(4):e4849. Available from: https://revhabanera.sld.cu/index.php/rhab/article/view/4849

Issue

Vol. 21 No. 4: July-August 2022 (Issue in Progress)

Section

Biomedical Basic Sciences

License

All the content of this magazine is in Open Access, distributed according to the terms of the Creative Commons Attribution-Noncommercial 4.0 License that allows non-commercial use, distribution and reproduction without restrictions in any medium, provided that the primary source is duly cited.