Skip to main content Accessibility help

Nonsteroidal anti-inflammatory is more effective than anti-oxidant therapy in counteracting oxidative/nitrosative stress and heart disease in T. cruzi-infected mice



We compared the relevance of ibuprofen, vitamins C and E to control oxidative/nitrosative stress and heart disease in mice infected by Trypanosoma cruzi. Swiss mice were randomized into five groups: control, uninfected; infected without treatment; and infected treated with vitamins C, E or ibuprofen. Animals were inoculated with 2000 trypomastigote forms of T. cruzi. After 20 days, infected mice presented reduced vitamin C and E tissue levels, high cytokines (interferon gamma, tumour necrosis factor-α, interleukin 10 and chemokine ligand 2), prostaglandin F2α (PGF2α ) and nitric oxide (NO) cardiac production, intense myocarditis and reactive tissue damage, which was directly correlated with the intensity of the inflammatory infiltrate and the degree of pathological cardiac remodelling. Vitamins C and E supplementation were irrelevant to counteract reactive tissue damage and myocarditis in infected animals. Conversely, ibuprofen reduced tissue levels of cytokines, PGF2α and NO, as well as lipid and protein oxidation, antioxidant enzyme activity and the cardiac damage, without interfering with heart parasitism. Our results do not support the applicability of vitamin C and E supplementation in the management of acute Chagas cardiomyopathy. By controlling the inflammatory infiltrate, anti-inflammatory-based therapy proved to be a more rational strategy than a direct antioxidant therapy in attenuating oxidative/nitrosative stress and cardiac damage.


Corresponding author

*Corresponding author. Department of Structural Biology, Federal University of Alfenas, Rua Gabriel Monteiro da Silva, 700, Alfenas, 37130-000 Minas Gerais, Brazil. E-mail:


Hide All
Aebi, H. (1984). Catalase in vitro. Methods in Enzymology 105, 121–6.
Basile, D. R. S., Novaes, R. D., Marques, D. C., Fialho, M. C., Neves, C. A. and Fonseca, C. C. (2012). Analysis of the morphology and distribution of argentaffin, argyrophil and insulin-immunoreactive endocrine cells in the small intestine of the adult opossum Didelphis aurita (Wied-Neuwied, 1826). Tissue and Cell 44(5), 301–7.
Bern, C. (2015). Chagas’ disease. The New England journal of medicine 373(5), 456–66.
Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry 72, 248–54.
Budni, P., Pedrosa, R. C., Garlet, T. R., Dalmarco, E. M., Dalmarco, J. B., Lino, M. R., Simionato, E. L., Amara, J. A., Frode, T. S. and Wilhelm Filho, D. (2012). Carvedilol attenuates oxidative stress in chronic chagasic cardiomyopathy. Arquivos Brasileiros de Cardiologia, 98(3), 218–24.
Budni, P., Pedrosa, R. C., Dalmarco, E. M., Dalmarco, J. B., Frode, T. S. and Wilhelm Filho, D. (2013). Carvedilol enhances the antioxidant effect of vitamins E and C in chronic Chagas heart disease. Arquivos Brasileiros de Cardiologia 101(4), 304–10.
Buege, J. A. and Aust, S. D. (1978). Microsomal lipid peroxidation. Methods in Enzymology, 52, 302–10.
Carvalho, L. S. C., Camargos, E. R., Almeida, C. T., Peluzio Mdo, C., Alvarez-Leite, J. I., Chiari, E. and Reis, D. d. (2006). Vitamin E deficiency enhances pathology in acute Trypanosoma cruzi-infected rats. Transactions of the Royal Society of Tropical Medicine and Hygiene 100(11), 1025–31.
Coombs, N. J., Gough, A. C. and Primrose, J. N. (1999). Optimisation of DNA and RNA extraction from archival formalin-fixed tissue. Nucleic Acids Research 27(16), e12.
Dhiman, M., Wan, X., Popov, V. L., Vargas, G. and Garg, N. J. (2013). MnSODtg mice control myocardial inflammatory and oxidative stress and remodeling responses elicited in chronic Chagas disease. Journal of the American Heart Association 2(5), e000302.
Dutra, W. O., Menezes, C. A., Magalhães, L. M. and Gollob, K. J. (2014). Immunoregulatory networks in human Chagas disease. Parasite Immunology 36(8), 377–87.
Gupta, S., Bhatia, V., Wen, J. J., Wu, Y., Huang, M. H. and Garg, N. J. (2009 a). Trypanosoma cruzi infection disturbs mitochondrial membrane potential and ROS production rate in cardiomyocytes. Free Radical Biology and Medicine 47(10), 1414–21.
Gupta, S., Wen, J.-J. and Garg, N. J. (2009 b). Oxidative stress in Chagas disease. Interdisciplinary Perspectives on Infectious Diseases 2009, 18.
Gusmão, A. S., Castanho, R. E., Andrade, R. F., Farsetti, C. M., Mathias, A. B., Therezo, A. L. and Martins, L. P. (2012). Vitamin C effects in mice experimentally infected with Trypanosoma cruzi QM2 strain. Revista da Sociedade Brasileira de Medicina Tropical 45(1), 5154.
Habig, W. H., Pabst, M. J. and Jakoby, W. B. (1974). Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. The Journal of Biological Chemistry 249(22), 7130–9.
Hotez, P. J., Dumonteil, E., Woc-Colburn, L., Serpa, J. A., Bezek, S., Edwards, M. S., Hallmark, C. J., Musselwhite, L. W., Flink, B. J. and Bottazzi, M. E. (2012). Chagas disease: the new HIV/AIDS of the Americas. PLoS Neglected Tropical Diseases 6(5), e1498.
Kakimoto, M., Inoguchi, T., Sonta, T., Yu, H. Y., Imamura, M., Etoh, T., Hashimoto, T. and Nawata, H. (2002). Accumulation of 8-hydroxy-2'-deoxyguanosine and mitochondrial DNA deletion in kidney of diabetic rats. Diabetes 51(5), 1588–95.
Knight, J. A. (2000). Review: Free radicals, antioxidants, and the immune system. Annals of Clinical and Laboratory Science 30(2), 145–58.
Kondo, M., Oya-Ito, T., Kumagai, T., Osawa, T. and Uchida, K. (2001). Cyclopentenone prostaglandins as potential inducers of intracellular oxidative stress. Journal of Biological Chemistry 276(15), 12076–83.
Korbecki, J., Baranowska-Bosiacka, I., Gutowska, I. and Chlubek, D. (2013). The effect of reactive oxygen species on the synthesis of prostanoids from arachidonic acid. Journal of Physiology and Pharmacology 64(4), 409–21.
Kusmic, C., Basta, G., Lazzerini, G., Vesentini, N. and Barsacchi, R. (2004). The effect of Ginkgo biloba in isolated ischemic/reperfused rat heart: a link between vitamin E preservation and prostaglandin biosynthesis. Journal of Cardiovascular Pharmacology 44(3), 356–62.
Levine, R. L., Garland, D., Oliver, C. N., Amici, A., Climent, I., Lenz, A. G., Ahn, B. W., Shaltiel, S. and Stadtman, E. R. (1990). Determination of carbonyl content in oxidatively modified proteins. Methods in Enzymology 186(1983), 464–78.
Maçao, L. B., Wilhelm Filho, D., Pedrosa, R. C., Pereira, A., Backes, P., Torres, M. A. and Fröde, T. S. (2007). Antioxidant therapy attenuates oxidative stress in chronic cardiopathy associated with Chagas’ disease. International Journal of Cardiology 123(1), 43–9.
Machado, F. S., Tanowitz, H. B. and Ribeiro, A. L. (2013). Pathogenesis of chagas cardiomyopathy: role of inflammation and oxidative stress. Journal of the American Heart Association 2, e000539.
Mandarim-de-Lacerda, C. A. (2003). Stereological tools in biomedical research. Anais da Academia Brasileira de Ciencias 75(4), 469–86.
Marim, R. G., Gusmão, A. S., Castanho, R. E., Deminice, R., Therezo, A. L., Jordão Júnior, A. A. and Martins, L. P. (2012). Effects of vitamin C supplementation on acute phase Chagas disease in experimentally infected mice with Trypanosoma cruzi QM1 strain. Revista do Instituto de Medicina Tropical de São Paulo 54(6), 319–23.
Marin-Neto, J. A., Cunha-Neto, E., Maciel, B. C. and Simões, M. V. (2007). Pathogenesis of chronic Chagas heart disease. Circulation 115(9), 1109–23.
Molina-Berríos, A., Campos-Estrada, C., Henriquez, N., Faúndez, M., Torres, G., Castillo, C., Escanilla, S., Kemmerling, U., Morello, A., López-Muñoz, R. A. and Maya, J. D. (2013). Protective role of acetylsalicylic acid in experimental Trypanosoma cruzi infection: evidence of a 15-epi-lipoxin A4-mediated effect. PLoS Neglected Tropical Diseases 7(4), e2173.
NIH, National Institutes of Health. (2016). Vitamin E, Fact Sheet for Health Professionals. Updated: November 2016.
Novaes, R. D., Penitente, A. R., Gonçalves, R. V., Talvani, A., Neves, C. A., Maldonado, I. R. and Natali, A. J. (2011). Effects of Trypanosoma cruzi infection on myocardial morphology, single cardiomyocyte contractile function and exercise tolerance in rats. International Journal of Experimental Pathology 92(5), 299307.
Novaes, R. D., Penitente, A. R., Gonçalves, R. V., Talvani, A., Peluzio, M. C., Neves, C. A., Natali, A. J. and Maldonado, I. R. (2013). Trypanosoma cruzi infection induces morphological reorganization of the myocardium parenchyma and stroma, and modifies the mechanical properties of atrial and ventricular cardiomyocytes in rats. Cardiovascular Pathology 22(4), 270279.
Novaes, R. D., Sartini, M. V., Rodrigues, J. P., Gonçalves, R. V., Santos, E. C., Souza, R. L. and Caldas, I. S. (2016 a). Curcumin enhances the anti-Trypanosoma cruzi activity of benznidazole-based chemotherapy in acute experimental Chagas disease. Antimicrobial agents and chemotherapy 60(6), 3355–64.
Novaes, R. D., Gonçalves, R. V., Penitente, A. R., Bozi, L. H., Neves, C. A., Maldonado, I. R., Natali, A. J., Talvani, A. (2016 b). Modulation of inflammatory and oxidative status by exercise attenuates cardiac morphofunctional remodeling in experimental Chagas cardiomyopathy. Life Sciences 152, 210–9.
Ricciotti, E. and FitzGerald, G. A. (2011). Prostaglandins and inflammation. Arteriosclerosis, thrombosis, and vascular biology 31(5), 9861000.
Rossi, S. P., Windschüttl, S., Matzkin, M. E., Rey-Ares, V., Terradas, C., Ponzio, R., Puigdomenech, E., Levalle, O., Calandra, R. S., Mayerhofer, A. and Frungieri, M. B. (2016). Reactive oxygen species (ROS) production triggered by prostaglandin D2 (PGD2) regulates lactate dehydrogenase (LDH) expression/activity in TM4 Sertoli cells. Molecular and Cellular Endocrinology 434, 154–65.
Santos, E. C., Novaes, R. D., Bastos, D. S., Oliveira, J. M., Penitente, A. R., Gonçalves, W. G., Cardoso, S. A., Talvani, A. and Oliveira, L. L. (2015). Modulation of oxidative and inflammatory cardiac response by nonselective 1- and 2-cyclooxygenase inhibitor and benznidazole in mice. Journal of Pharmacy and Pharmacology 67(11), 1556–66.
Sarban, S., Kocyigit, A., Yazar, M. and Isikan, U. E. (2005). Plasma total antioxidant capacity, lipid peroxidation, and erythrocyte antioxidant enzyme activities in patients with rheumatoid arthritis and osteoarthritis. Clinical biochemistry 38(11), 981–6.
Somaio Neto, F., Ikejiri, A. T., Bertoletto, P. R., Chaves, J. C., Teruya, R., Fagundes, D. J. and Taha, M. O. (2014). Gene expression related to oxidative stress in the heart of mice after intestinal ischemia. Arquivos Brasileiros de Cardiologia 102(2), 165–73.
Tsatsanis, C., Androulidaki, A., Venihaki, M. and Margioris, A. N. (2006). Signalling networks regulating cyclooxygenase-2. International Journal of Biochemistry and Cell Biology, 38(10), 1654–61.
Tsikas, D. (2007). Analysis of nitrite and nitrate in biological fluids by assays based on the Griess reaction: appraisal of the Griess reaction in the L-arginine/nitric oxide area of research. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 851(1–2), 5170.
Wen, J.-J., Gupta, S., Guan, Z., Dhiman, M., Condon, D., Lui, C. and Garg, N. J. (2010). Phenyl-alpha-tert-butyl-nitrone and benzonidazole treatment controlled the mitochondrial oxidative stress and evolution of cardiomyopathy in chronic chagasic rats. Journal of the American College of Cardiology, 55(22), 2499–508.
Wen, J.-J., Bhatia, V., Popov, V. L. and Garg, N. J. (2006). Phenyl-α-tert-butyl nitrone reverses mitochondrial decay in acute Chagas’ disease. The American Journal of Pathology, 169(6), 1953–64.
WHO, World Health Organization. (2016). Chagas disease (American trypanosomiasis). Updated March 2016.
Wolfram, R., Oguogho, A., Palumbo, B. and Sinzinger, H. (2005). Enhanced oxidative stress in coronary heart disease and chronic heart failure as indicated by an increased 8-epi-PGF(2alpha). European Journal of Heart Failure, 7(2), 167–72.
Yin, M. J., Yamamoto, Y. and Gaynor, R. B. (1998). The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature, 396(6706), 7780.



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed