Inhibition of nitric oxide synthesis promotes increased mortality despite the reduction of parasitemia in Plasmodium berghei-infected mice

Authors

DOI:

https://doi.org/10.33448/rsd-v10i1.11805

Keywords:

Nitric oxide; Malaria; Nitric oxide synthase; Oxidative stress.

Abstract

Nitric oxide (NO) is an important mediator molecule in inflammatory processes, but its role in the pathophysiology of malaria is still uncertain. To investigate the NO synthesis inhibition on the oxidative changes induced by Plasmodium berghei infection in mice, malaria was induced in 150 animals, of which 75 animals were treated with the NO inhibitor L-NAME; the remaining animals were sham controls. All animals underwent euthanasia 1, 5, 10, 15, or 20 days after infection for the collection of lungs, brain, and blood. Parasitemia was determined, and the survival of the animals was evaluated. Tissue samples were assayed for nitrites and nitrates (NN), thiobarbituric acid reactive substances (TBARS), and total Trolox equivalent antioxidant capacity (TEAC). A histopathological study was performed. Mortality rates in the L-NAME group were always higher than those in the controls. In the brain, NN was lower in the L-NAME group. Parasitemia and its progression rate were greater in the control group. By the 5th day of infection, mice treated with L-NAME showed cerebral edema and interstitial pneumonia of greater intensity than controls. In conclusion, the anti-inflammatory and hemodynamic effects of NO surpass its pro-oxidant role in murine malaria.

Author Biographies

Aline da Silva Barbosa, Federal University of Pará

PhD student, Oxidative Stress Research Lab, Institute of Biological Sciences

Mayani Costa Ribeiro Temple, Federal University of Pará

MD, Oxidative Stress Research Lab, Institute of Biological Sciences

 

Everton Luiz Pompeu Varela, Federal University of Pará

PhD student, Oxidative Stress Research Lab, Institute of Biological Sciences

 

Antonio Rafael Quadros Gomes, Federal University of Pará

PhD student, Oxidative Stress Research Lab, Institute of Biological Sciences

Edvaldo Lima Silveira, Federal University of Pará

Professor, Oxidative Stress Research Lab, Institute of Biological Sciences

Eliete Pereira de Carvalho, Federal University of Pará

PhD student, Oxidative Stress Research Lab, Institute of Biological Sciences

Maria Fani Dolabela, Federal University of Pará

Professor, Institute of Health Sciences

 

References

Anstey, N. M., Granger, D. L., Hassanali, M. Y., Mwaikambo, E. D., Duffy, P. E., & Weinberg, J. B. (1999). Nitric oxide, malaria, and anemia: inverse relationship between nitric oxide production and hemoglobin concentration in asymptomatic, malaria-exposed children. The American journal of tropical medicine and hygiene, 61(2), 249-252. https://doi.org/10.4269/ajtmh.1999.61.249

Anstey, N. M., Weinberg, J. B., Hassanali, M. Y., Mwaikambo, E. D., Manyenga, D., Misukonis, M. A., Arnelle, D. R., Hollis, D., McDonald, M. I., & Granger, D. L. (1996). Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. Journal of Experimental Medicine, 184(2), 557-567. https://doi.org/10.1084/jem.184.2.557

Aviado, D. M., & Cambar, P. J. (1969). Pathologic physiology and chemotherapy of Plasmodium berghei: X. Pulmonary edema and naphthoquinones. Experimental Parasitology, 26(3), 354-368. https://doi.org/10.1016/0014-4894(69)90129-5

Balmer, P., Phillips, H. M., Maestre, A. E., McMonagle, F. A., & Phillips, R. S. (2000). The effect of nitric oxide on the growth of Plasmodium falciparum, P. chabaudi and P. berghei in vitro. Parasite Immunology, 22(2), 97-106. https://doi.org/10.1046/j.1365-3024.2000.00281.x

Barreto, R. L., Correia, C. R. D., & Muscará, M. N. (2005). Óxido nítrico: propriedades e potenciais usos terapêuticos. Química Nova, 28(6), 1046-1054. https://doi.org/10.1590/S0100-40422005000600020

Becker, K., Tilley, L., Vennerstrom, J. L., Roberts, D., Rogerson, S., & Ginsburg, H. (2004). Oxidative stress in malaria parasite-infected erythrocytes: host-parasite interactions. International Journal for Parasitology, 34(2), 163-189. https://doi.org/10.1016/j.ijpara.2003.09.011

Beleslin-Čokić, B. B., Čokić, V. P., Wang, L., Piknova, B., Teng, R., Schechter, A. N., & Noguchi, C. T. (2011) Erythropoietin and hypoxia increase erythropoietin receptor and nitric oxide levels in lung microvascular endothelial cells. Cytokine, 54(2), 129-135. https://doi.org/10.1016/j.cyto.2011.01.015

Cabrales, P., Zanini, G. M., Meays, D., Frangos, J. A., & Carvalho, L. J. M. (2011). Nitric Oxide protection against murine cerebral malaria is associated with improved cerebral microcirculatory physiology. The Journal of Infectious Diseases, 203(10), 1454-1463. https://doi.org/10.1093/infdis/jir058

Dusse, L. M. S., Vieira, L. M., & Carvalho, M. G. (2003). Revisão sobre óxido nítrico. Jornal Brasileiro de Patologia e Medicina Laboratorial, 39(4), 343-350. https://doi.org/10.1590/S1676-24442003000400012

Erel, O., Kocyigit, A., Avci, S., Aktepe, N., & Bulut, V. (1997). Oxidative stress and antioxidative status of plasma and erythrocytes in patients with vivax malaria. Clinical Biochemistry, 30(8), 631-639. https://doi.org/10.1016/s0009-9120(97)00119-7

Favre, N., Ryffel, B., & Rudin, W. (1999). Parasite killing in murine malaria does not require nitric oxide production. Parasitology, 118(2), 139-143. https://doi.org/10.1017/S0031182098003618

Förstermann, U., & Sessa, W. C. (2012). Nitric oxide synthases: regulation and function. European Heart Journal, 33(7), 829-837. https://doi.org/10.1093/eurheartj/ehr304

Fritsche, G., Larcher, C., Schennach, H., & Weiss, G. (2001). Regulatory interactions between iron and nitric oxide metabolism for immune defense against Plasmodium falciparum infection. The Journal of Infectious Diseases, 183(9), 1388-1394. https://doi.org/10.1086/319860

Gaston, B., Drazen, J. M., Loscalzo, J., & Stamler, J. S. (1994). The biology of nitrogen oxides in the airways. American Journal of Respiratory and Critical Care Medicine, 149(2), 538-551. https://doi.org/10.1164/ajrccm.149.2.7508323

Gomes, B. A. Q., Silva, L. F. D., Gomes, A. R. Q., Moreira, D. R., Dolabela, M. F., Santos, R. S., Green, M. D., Carvalho, E. P., & Percário, S. (2015). N-acetyl cysteine and mushroom Agaricus sylvaticus supplementation decreased parasitemia and pulmonary oxidative stress in a mice model of malaria. Malaria Journal, 14(202), 1-12. https://doi.org/10.1186/s12936-015-0717-0

Green, S. J., Scheller, L. F., Marletta, M. A., Seguin, M. C., Klotz, F. W., Slayter, M., Nelson, B. J., & Nacy, C. A. (1994). Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens. Immunology Letters, 43(1-2), 87-94. https://doi.org/10.1016/0165-2478(94)00158-8

Halliwell, B. & Gutteridge, J. M. C. (2007). Free Radicals in Biology and Medicine. (4th ed.) Oxford University Press.

Hawkes, M., Opoka, R. O., Namasopo, S., Miller, C., Conroy, A. L., Serghides, L., Kim, H., Thampi, N., Liles, W. C., John, C. C., & Kain, K. C. (2011). Nitric oxide for the adjunctive treatment of severe malaria: Hypothesis and rationale. Medical Hypotheses, 77(3), 437-444. https://doi.org/10.1016/j.mehy.2011.06.003

Lacerda, M. V. G., Mourão, M. P. G., Santos, P. J. T., & Alecrim, M. G. C. (2009). Malária álgida: um diagnóstico sindrômico. Revista da Sociedade Brasileira de Medicina Tropical, 42(1), 79-81. https://doi.org/10.1590/S0037-86822009000100017

Lovegrove, F. E., Gharib, S. A., Peña-Castillo, L., Patel, S. N., Ruzinski, J. T., Hughes, T. R., Liles, W. C., & Kain, K. C. (2008). Parasite burden and CD36-mediated sequestration are determinants of acute lung injury in an experimental malaria model. PLoS Pathogens, 4(5), e1000068. https://doi.org/10.1371/journal.ppat.1000068

Martins, Y. C., Smith, M. J., Pelajo-Machado, M., Werneck, G. L., Lenzi, H. L., Daniel-Ribeiro, C. T., & Carvalho, L. J. M. (2009). Characterization of cerebral malaria in the outbred Swiss Webster mouse infected by Plasmodium berghei ANKA. International Journal of Experimental Pathology, 90(2), 119-130. https://doi.org/10.1111/j.1365-2613.2008.00622.x

Martins, Y. C., Zanini, G. M., Frangos, J. A., & Carvalho, L. J. M. (2012). Efficacy of different nitric oxide-based strategies in preventing experimental cerebral malaria by Plasmodium berghei ANKA. PLoS ONE, 7(2), e32048. https://doi.org/10.1371/journal.pone.0032048

Miller, N. J., Rice-Evans, C., Davies, M. J., Gopinathan, V., & Milner, A. (1993). A novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates. Clinical Sciense, 84(4), 407-12. https://doi.org/10.1042/cs0840407

Moore, B. R., Jago, J. D., & Batty, K. T. (2008). Plasmodium berghei: Parasite clearance after treatment with dihydroartemisinin in an asplenic murine malaria model. Experimental Parasitology ,118(4), 458-467. https://doi.org/10.1016/j.exppara.2007.10.011

Moreira, D. R, Uberti, A. C. M. G., Gomes, A. R. Q., Ferreira. M. E. S., Ferrari, C. K. B., Santos, R. S., et al. Inhibition of nitric oxide synthesis by dexamethasone increases survival rate in Plasmodium berghei-infected mice. In press.

Nussler, A. K., Eling, W., & Kremsher, P. G. (1994). Patients with Plasmodium falciparum malaria and Plasmodium vivax malaria show increased nitrite and nitrate plasma levels. The Journal of Infectious Diseases, 169(6), 1418-1419. https://doi.org/10.1093/infdis/169.6.1418

Pablón, A., Carmona, J., Burgos, L. C., & Blair, S. (2002). Oxidative stress in patients with non-complicated malaria. Clinical Biochemistry, 36(1), 71-78. https://doi.org/10.1016/S0009-9120(02)00423-X

Percário, S., Moreira, D. R., Gomes, B. A. Q., Ferreira, M. E. S., Gonçalves, A. C. M., Laurindo, P. S. O. C., Vilhena, T. C., Dolabela, M. F., & Green, M. D. (2012). Oxidative stress in malaria. International Journal of Molecular Sciences, 13(12), 16346-16372. https://doi.org/10.3390/ijms131216346

Percario, S., Vital, A. C. C., & Jablonka, F. (1994). Dosagem do malondialdeido. Newslab, 2(6), 46-50.

Pino, P., Vouldoukis, I., Dugas, N., Hassani-Loppion, G., Dugas, B., & Mazier, D. (2003). Redox-dependent apoptosis in human endothelial cells after adhesion of Plasmodium falciparum-infected erythrocytes. Annals of the New York Academy of Sciences, 1010 (1), 582-586. https://doi.org/10.1196/annals.1299.109

Re, R., Pellegrini, N., Proteggente, A., Pannala, A., Yang, M., & Rice-Evans, C. (1999). Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radical Biology and Medicine, 26(9-10), 1231-1237. https://doi.org/10.1016/S0891-5849(98)00315-3

Reis, P. A., Comim, C. M., Hermani, F., Silva, B., Barichello. T., Portella, A. C., Gomes, F. C. A., Sab, I. M., Frutuoso, V. S., Oliveira, M. F., Bozza, P. T., Bozza, F. A., Dal-Pizzol, F., Zimmerman, G. A., Quevedo, J., & Castro-Faria-Neto, H. C. (2010). Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy. PLoS Pathogens, 6(6), e.1000963. https://doi.org/10.1371/journal.ppat.1000963

Sadavongvivad, C. & Aviado, D. (1969). Pathologic physiology and chemotherapy of Plasmodium berghei. VI. Mechanichal properties and histological features of the lung. Experimental Parasitology, 24(3), 313-326. https://doi.org/10.1016/0014-4894(69)90170-2

Serghides, L., Kim, H., Lu, Z., Kain, D. C., Miller, C., Francis, R. C., Liles, W. C., Zapol, W. M., & Kain, K. C. (2011). Inhaled Nitric Oxide reduces endothelial activation and parasite accumulation in the brain, and enhances survival in experimental cerebral malaria. PLoS ONE, 6(11), e27714. https://doi.org/10.1371/journal.pone.0027714

Sobolewski, P., Gramaglia, I., Frangos, J. A., Intaglietta, M., & Van der Heyde, H. (2005). Plasmodium berghei resists killing by reactive oxygen species. Infection and Immunity, 73(10), 6704-6710. https://doi.org/10.1128/IAI.73.10.6704-6710.2005

Speyer, C. L., Neff, T. A., Warner, R. L., Guo, R-F., Sarma, J. V., Riedermann, N. C., Murphy, M. E., Murphy, H. S., & Ward, P. A. (2003). Regulatory effects of iNOS on acute lung inflammatory responses in mice. The American Journal of Pathology, 163(3), 2319-2328. https://doi.org/10.1016/S0002-9440(10)63588-2

Van Der Heyde, H. C., Gu, Y., Zhang, Q., Sun, G., & Grisham, M. B. (2000). Nitric oxide is neither necessary nor sufficient for resolution of Plasmodium chabaudi malaria in mice. The Journal of Immunology, 165(6), 3317-3323. https://doi.org/10.4049/jimmunol.165.6.3317

Van Der Heyde, H. C., Nolan, J., Combes, V., Gramaglia, I., & Grau, G. E. (2006). A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitology, 22(11), 503-508. https://doi.org/10.1016/j.pt.2006.09.002

Weiss, M. L. & Kubat, K. (1983). Plasmodium berghei: a mouse model for the “sudden death” and “malarial lung” syndromes. Experimental Parasitology, 56(1), 143-151. https://doi.org/10.1016/0014-4894(83)90105-4

WHO. World Malaria Report (2016). Geneva: World Health Organization; 2016. http://apps.who.int/iris/bitstream/10665/252038/1/9789241511711-eng.pdf?ua=1

Xia, Y., Dawson, V. L., Dawson, T. M., Snyder, S. H., & Zweier, J. L. (1996). Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proceedings of the National Academy of Sciences, 93(13), 6770-6774. https://doi.org/10.1073/pnas.93.13.6770

Xia, Y. & Zweier, J. L. (1997). Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proceedings of the National Academy of Sciences, 94(13), 6954-6958. https://doi.org/10.1073/pnas.94.13.6954

Zanini, G. M., Cabrales, P., Barkho, W., Frangos, J. A., & Carvalho, L. J. M. (2011). Exogenous nitric oxide decreases brain vascular inflammation, leakage and venular resistance during Plasmodium berghei ANKA infection in mice. Journal of Neuroinflammation, 8(66), 1-9. https://doi.org/10.1186/1742-2094-8-66

Zeidler, P. C, Millecchia, L. M., & Castranova, V. (2004). Role of inducible nitric oxide synthase-derived nitric oxide in lipopolysaccharide plus interferon-γ-induced pulmonary inflammation. Toxicology and Applied Pharmacology, 195(1), 45-54. https://doi.org/10.1016/j.taap.2003.10.005

Downloads

Published

13/01/2021

How to Cite

BARBOSA, A. da S. .; TEMPLE, M. C. R. .; VARELA, E. L. P. .; GOMES, A. R. Q. .; SILVEIRA, E. L. .; CARVALHO, E. P. de .; DOLABELA, M. F. .; PERCARIO, S. Inhibition of nitric oxide synthesis promotes increased mortality despite the reduction of parasitemia in Plasmodium berghei-infected mice. Research, Society and Development, [S. l.], v. 10, n. 1, p. e27810111805, 2021. DOI: 10.33448/rsd-v10i1.11805. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/11805. Acesso em: 16 apr. 2024.

Issue

Section

Health Sciences