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Could pre-infection exercise training improve the efficacy of specific antiparasitic chemotherapy for Chagas disease?

Published online by Cambridge University Press:  28 August 2019

Elda Gonçalves Santos ,
Reggiani V. Gonçalves Open the ORCID record for Reggiani V. Gonçalves [Opens in a new window] ,
Thaiany G. Souza-Silva ,
Izabel R. S. C. Maldonado ,
Eliziária C. Santos ,
André Talvani ,
Antônio J. Natali  and
Rômulo D. Novaes Open the ORCID record for Rômulo D. Novaes [Opens in a new window]
Elda Gonçalves Santos
Affiliation:
Department of Structural Biology, Institute of Biomedical Sciences, Universidade Federal de Alfenas, Alfenas, MG, 37130-001, Brazil
Reggiani V. Gonçalves
Affiliation:
Department of Animal Biology, Universidade Federal de Viçosa, Viçosa, MG, 36570-000, Brazil
Thaiany G. Souza-Silva
Affiliation:
Department of Structural Biology, Institute of Biomedical Sciences, Universidade Federal de Alfenas, Alfenas, MG, 37130-001, Brazil
Izabel R. S. C. Maldonado
Affiliation:
Department of General Biology, Universidade Federal de Viçosa, Viçosa, MG, 36570-000, Brazil
Eliziária C. Santos
Affiliation:
School of Medicine, Universidade Federal dos Vales do Jequitinhonha e Mucuri, Diamantina, MG, 39100-000, Brazil
André Talvani
Affiliation:
Department of Biological Science and NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, MG, 35400-000, Brazil
Antônio J. Natali
Affiliation:
Department of Physical Education, Universidade Federal de Viçosa, Viçosa, MG, 36570-000, Brazil.
Rômulo D. Novaes*
Affiliation:
Department of Animal Biology, Universidade Federal de Viçosa, Viçosa, MG, 36570-000, Brazil
*
Author for correspondence: Rômulo Dias Novaes, E-mail: romuonovaes@yahoo.com.br, romulo.novaes@unifal-mg.edu.br
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Abstract

Considering a potential exercise-drug interaction, we investigated whether exercise training could improve the efficacy of specific antiparasitic chemotherapy in a rodent model of Chagas disease. Wistar rats were randomized into five groups: sedentary and uninfected (CT); sedentary and infected (SI); sedentary, infected and treated (SIT); trained and infected (TI); trained, infected and treated (TIT). After 9-weeks running training, the animals were infected with T. cruzi and followed up for 4 weeks, receiving 100 mg kg−1 day−1 benznidazole. No evidence of myocarditis was observed in CT animals. TI animals exhibited reduced parasitemia, myocarditis, and reactive tissue damage compared to SI animals, in addition to increased IFN-γ, IL-4, IL-10, heart non-protein antioxidant (NPA) levels and glutathione-s transferase activity (P < 0.05). The CT, SIT and TIT groups presented similar reductions in parasitemia, cytokines (IFN-γ, TNF-α, IL-4, IL-10, IL-17 and MCP-1), inflammatory infiltrate, oxidative heart damage and antioxidant enzymes activity compared to SI and TI animals, as well as reduced heart microstructural remodeling (P < 0.05). By modulating heart inflammation and redox metabolism, exercise training exerts a protective effect against T. cruzi infection in rats. However, the antiparasitic and cardioprotective effects of benznidazole chemotherapy are more pronounced, determining similar endpoints in sedentary and trained T. cruzi-infected rats.

Keywords

Cardiovascular pathologycomplementary therapyexperimental chemotherapyoxidative stressTrypanosoma cruzi
Type
Research Article
Information
Parasitology , Volume 146 , Issue 13 , November 2019 , pp. 1655 - 1664
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Copyright
Copyright © Cambridge University Press 2019 

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References

Adamopoulos, S, Parissis, J, Karatzas, D, Kroupis, C, Georgiadis, M, Karavolias, G, Paraskevaidis, J, Koniavitou, K, Coats, AJ and Kremastinos, DT (2002) Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fas ligand system in patients with chronic heart failure. Journal of the American College of Cardiology 39, 653–663.Google Scholar
Aebi, H (1984) Catalase in vitro. Methods in Enzymology 105, 121–126.Google Scholar
Antinori, S, Galimberti, L, Bianco, R, Grande, R, Galli, M and Corbellino, M (2017) Chagas disease in Europe: a review for the internist in the globalized world. European Journal of Internal Medicine 43, 6–15.Google Scholar
Bern, C (2015) Chagas’ disease. The New England Journal of Medicine 373, 456–466.Google Scholar
Bocchi, EA (2010) Exercise training in Chagas' cardiomyopathy: trials are welcome for this neglected heart disease. European Journal of Heart Failure 12, 782–784.Google Scholar
Bradford, MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry 72, 248–254.Google Scholar
Brener, Z (1962) Therapeutic activity and criterion of cure on mice experimentally infected with Trypanosoma cruzi. Revista do Instituto de Medicina Tropical 4, 389–396.Google Scholar
Brooks, GA, Donovan, CM and White, TP (1984) Estimation of anaerobic energy production and efficiency in rats during exercise. Journal of Applied Physiology 56, 520–525.Google Scholar
Caldas, IS, Menezes, APJ, Diniz, LF, Nascimento, ÁFDSD, Novaes, RD, Caldas, S and Bahia, MT (2019) Parasitaemia and parasitic load are limited targets of the aetiological treatment to control the progression of cardiac fibrosis and chronic cardiomyopathy in Trypanosoma cruzi-infected dogs. Acta Tropica 189, 30–38.Google Scholar
Camara, EJN, Mendonça, VRR, Souza, LCL, Carvalho, JS, Lessa, RA, Gatto, R, Barreto, LO, Chiacchio, G, Amarante, E, Cunha, M, Alves-Silva, LS, Guimarães, BAC and Barral-Netto, M (2019) Elevated IL-17 levels and echocardiographic signs of preserved myocardial function in benznidazole-treated individuals with chronic Chagas’ disease. International Journal of Infectious Disease 79, 123–130.Google Scholar
Campos-Estrada, C, Liempi, A, González-Herrera, F, Lapier, M, Kemmerling, U, Pesce, B, Ferreira, J, López-Muñoz, R and Maya, JD (2015) Simvastatin and benznidazole-mediated prevention of Trypanosoma cruzi-induced endothelial activation: role of 15-epi-lipoxin A4 in the action of simvastatin. PLoS Neglected Tropical Diseases 9, e0003770.Google Scholar
Cruz-Orive, LM and Weibel, ER (1990) Recent stereological methods for cell biology: a brief survey. American Journal of Physiology 25, 8148–8156.Google Scholar
De Andrade, MF, De Almeida, VD, De Souza, LMS, Paiva, DCC, Andrade, CM and De Medeiros Fernandes, TAA (2018) Involvement of neutrophils in Chagas disease pathology. Parasite Immunology 40:e12593.Google Scholar
Diniz, LF, Mazzeti, AL, Caldas, IS, Ribeiro, I and Bahia, MT (2018) Outcome of E1224-benznidazole combination treatment for infection with a multidrug-resistant Trypanosoma cruzi strain in mice. Antimicrobial Agents and Chemotherapy 62, e00401-18.Google Scholar
Echeverria, LE and Morillo, CA (2019) American trypanosomiasis (Chagas disease). Infectious Disease Clinics of North America 33, 119–134.Google Scholar
Felizardo, AA, Caldas, IS, Mendonca, AAS, Reggiani, VG, Tana, FL, Almeida, LA and Novaes, RD (2018) Impact of Trypanosoma cruzi infection on nitric oxide synthase and arginase expression and activity in young and elderly mice. Free Radical Biology and Medicine 129, 227–236.Google Scholar
Freitas, HFG, Chizzola, PR, ÂT, Paes, Lima, ACP and Mansur, AJ (2005) Risk stratification in a Brazilian hospital-based cohort of 1220 outpatients with heart failure: role of Chagas’ heart disease. International Journal of Cardiology 102, 239–247.Google Scholar
Gallo, L Jr., Neto, JA, Manço, JC, Rassi, A and Amorim, DS (1975) Abnormal heart rate responses during exercise in patients with Chagas' disease. Cardiology 60, 147–162.Google Scholar
Gleeson, M (2007) Immune function in sport and exercise. Journal of Applied Physiology 103, 693–699.Google Scholar
Gupta, S, Bhatia, V, Wen, JJ, Wu, Y, Huang, MH and Garg, NJ (2009 a) Trypanosoma cruzi infection disturbs mitochondrial membrane potential and ROS production rate in cardiomyocytes. Free Radicals Biology and Medicine 47, 1414–1421.Google Scholar
Gupta, S, Wen, J-J and Garg, NJ (2009 b) Oxidative stress in Chagas disease. Interdisciplinary Perspectives on Infectious Diseases 2009, 190354.Google Scholar
Gutteridge, JMC and Halliwel, B (1990) The measurement and mechanism of lipid peroxidation in physiological systems. Trends in Biochemistry 15, 129–135.Google Scholar
Habig, WH, Pabst, MJ and Jakoby, WB (1974) Glutathione S-transferases. The first enzymatic step in mercapturic acid formation Journal of Biological Chemistry 249, 7130–7139.Google Scholar
Hall, BS and Wilkinson, SR (2012) Activation of benznidazole by trypanosomal type I nitroreductases results in glyoxal formation. Antimicrobial Agents and Chemotherapy 56, 115–123.Google Scholar
Lenz, TL, Lenz, NJ and Faulkner, MA (2004) Potential interactions between exercise and drug therapy. Sports Medicine 34, 293–306.Google Scholar
Levine, RL, Garland, D, Oliver, CN, Amici, A, Climent, I, Lenz, AG, Ahn, BW, Shaltiel, S and Stadtman, ER (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymology 186, 464–478.Google Scholar
Lima, MM, Rocha, MO, Nunes, MC, Sousa, L, Costa, HS, Alencar, MC, Britto, RR and Ribeiro, AL (2010) A randomized trial of the effects of exercise training in Chagas cardiomyopathy. European Journal of Heart Failure 12, 866–873.Google Scholar
Lima, MM, Nunes, MC, Nascimento, B, Costa, HS, Sousa, LA, Teixeira, AL, Rocha, MO and Ribeiro, AL (2013) Improvement of the functional capacity is associated with BDNF and autonomic modulation in Chagas disease. International Journal of Cardiology 167, 2363–2366.Google Scholar
Lowenthal, DT and Kendrick, ZV (1985) Drug-exercise interactions. Annual Review of Pharmacology and Toxicology 25, 275–305.Google Scholar
Lucchetti, BFC, Zanluqui, NG, de Ataides Raquel, H, Lovo-Martins, MI, Tatakihara, VLH, de Oliveira Belém, M, Michelini, LC, de Almeida Araújo, EJ, Pinge-Filho, P and Martins-Pinge, MC (2017) Moderate treadmill exercise training improves cardiovascular and nitrergic response and resistance to Trypanosoma cruzi infection in mice. Frontiers in Physiology 8, 315.Google Scholar
Machado, FS, Jelicks, LA, Kirchhoff, LV, Shirani, J, Nagajyothi, F, Mukherjee, S, Nelson, R, Coyle, CM, Spray, DC, de Carvalho, AC, Guan, F, Prado, CM, Lisanti, MP, Weiss, LM, Montgomery, SP and Tanowitz, HB (2012) Chagas heart disease: report on recent developments. Cardiology Reviews 20, 53–65.Google Scholar
Machado, FS, Tanowitz, HB and Ribeiro, AL (2013) Pathogenesis of Chagas cardiomyopathy: role of inflammation and oxidative stress. Journal of the American Heart Association 2, e000539.Google Scholar
Malm, C (2004) Exercise immunology: the current state of man and mouse. Sports Medicine 34, 555–566.Google Scholar
Manarin, R, Pascutti, MF, Ruffino, JP, De Las Heras, B, Boscá, L, Bottasso, O, Revelli, S and Serra, E (2010) Benznidazole blocks NF-κB activation but not AP-1 through inhibition of IKK. Molecular Immunology 47, 2485–2491.Google Scholar
Manque, PA, Probst, CM, Pereira, MC, Rampazzo, RC, Ozaki, LS, Pavoni, DP, Silva Neto, DT, Carvalho, MR, Xu, P, Serrano, MG, Alves, JM, Meirelles Mde, N, Goldenberg, S, Krieger, MA and Buck, GA (2011). Trypanosoma cruzi infection induces a global host cell response in cardiomyocytes. Infection and Immunity 79, 1855–1862.Google Scholar
Mendonça, AAS, Coelho, CM, Veloso, MP, Caldas, IS, Gonçalves, RV, Teixeira, AL, de Miranda, AS and Novaes, RD (2018) Relevance of trypanothione reductase inhibitors on Trypanosoma cruzi infection: a systematic review, meta-analysis, and in silico integrated approach. Oxidative Medicine and Cellular Longevity. 2018, 8676578.Google Scholar
Nogueira, SS, Felizardo, AA, Caldas, IS, Gonçalves, RV and Novaes, RD (2018) Challenges of immunosuppressive and antitrypanosomal drug therapy after heart transplantation in patients with chronic Chagas disease: a systematic review of clinical recommendations. Transplantations Review 32, 157–167.Google Scholar
Novaes, RD, Penitente, AR, Gonçalves, RV, Talvani, A, Neves, CA, Maldonado, IR and Natali, AJ (2011) Effects of Trypanosoma cruzi infection on myocardial morphology, single cardiomyocyte contractile function and exercise tolerance in rats. International Journal of Experimental Pathology 92, 299–307.Google Scholar
Novaes, RD, Penitente, AR, Gonçalves, RV, Talvani, A, Peluzio, MCG, Neves, CA, Natali, AJ and Maldonado, IRSC (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, 270–279.Google Scholar
Novaes, RD, Sartini, MV, Rodrigues, JP, Gonçalves, RV, Santos, EC, Souza, RL and Caldas, IS (2016 a) Curcumin enhances the anti-Trypanosoma cruzi activity of benznidazole-based chemotherapy in acute experimental Chagas disease. Antimicrobial Agents and Chemotherapy 60, 3355–3364.Google Scholar
Novaes, RD, Goncalves, RV, Penitente, AR, Bozi, LHM, Neves, CA, Maldonado, IRSC, Natali, AJ and Talvani, A (2016 b) Modulation of inflammatory and oxidative status by exercise attenuates cardiac morphofunctional remodeling in experimental Chagas cardiomyopathy. Life Science 150, 210–219.Google Scholar
Novaes, RD, Gonçalves, RV, Penitente, AR, Cupertino, MC, Maldonado, IRSC, Talvani, A and Natali, AJ (2017) Parasite control and skeletal myositis in Trypanosoma cruzi-infected and exercised rats. Acta Tropica, 170, 8–15.Google Scholar
Novaes, RD, Santos, EC, Cupertino, MC, Bastos, DSS, Mendonça, AAS, Marques-da-Silva, EA, Cardoso, SA, Fietto, JLR and Oliveira, LL (2018) Purinergic antagonist suramin aggravates myocarditis and increases mortality by enhancing parasitism, inflammation, and reactive tissue damage in Trypanosoma cruzi-infected mice. Oxidative Medicine and Cellular Longevity 2018, 7385639.Google Scholar
Paiva, CN, Figueiredo, RT, Kroll-Palhares, K, Silva, AA, Silvério, JC, Gibaldi, D, Pyrrho Ados, S, Benjamim, CF, Lannes-Vieira, J and Bozza, MT (2009) CCL2/MCP-1 controls parasite burden, cell infiltration, and mononuclear activation during acute Trypanosoma cruzi infection. Journal of Leukocyte Biology 86, 1239–1246.Google Scholar
Pérez-Molina, JA and Molina, I (2018) Chagas disease. Lancet 6, 82–94.Google Scholar
Quindry, JC and Franklin, BA (2018) Cardioprotective exercise and pharmacologic interventions as complementary antidotes to cardiovascular disease. Exercise and Sport Sciences Reviews 46, 5–17.Google Scholar
Ranjbar, K, Nazem, F, Nazari, A, Gholami, M, Nezami, AR, Ardakanizade, M, Sohrabi, M, Ahmadvand, H, Mottaghi, M and Azizi, Y (2015) Synergistic effects of nitric oxide and exercise on revascularisation in the infarcted ventricle in a murine model of myocardial infarction. EXCLI Journal 14, 1104–1115.Google Scholar
Rassi, A Jr., Rassi, A and Marin-Neto, JA (2010) Chagas disease. Lancet 375, 1388–1402.Google Scholar
Rassi, A Jr., Marin-Neto, JA and Rassi, A (2017) Chronic Chagas cardiomyopathy: a review of the main pathogenic mechanisms and the efficacy of aetiological treatment following the BENznidazole evaluation for interrupting trypanosomiasis (BENEFIT) Trial. Memorias do Instituto Oswaldo Cruz 112, 224–235.Google Scholar
Santos, EC, Novaes, RD, Cupertino, MC, Bastos, DS, Klein, RC, Silva, EA, Fietto, JL, Talvani, A, Bahia, MT and Oliveira, LL (2015) Concomitant benznidazole and suramin chemotherapy in mice infected with a virulent strain of Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 59, 5999–6006.Google Scholar
Sarban, S, Kocyigit, A, Yazar, M and Isikan, UE (2005) Plasma total antioxidant capacity, lipid peroxidation, and erythrocyte antioxidant enzyme activities in patients with rheumatoid arthritis and osteoarthritis. Clinical Biochemistry 38, 981–986.Google Scholar
Savino, W, Villa-Verde, DM, Mendes-da-Cruz, DA, Silva-Monteiro, E, Perez, AR, Aoki Mdel, P, Bottasso, O, Guiñazú, N, Silva-Barbosa, SD and Gea, S (2007) Cytokines and cell adhesion receptors in the regulation of immunity to Trypanosoma cruzi. Cytokine Growth Factor Reviews 18, 107–124.Google Scholar
Schebeleski-Soares, C, Occhi-Soares, RC, Franzói-de-Moraes, SM, De Oliveira Dalálio, MM, Almeida, FN, De Ornelas Toledo, MJ and De Araújo, SM (2009) Preinfection aerobic treadmill training improves resistance against Trypanosoma cruzi infection in mice. Applied Physiology Nutrition and Metabolism, 34, 659–665.Google Scholar
Soares, MB, De Lima, RS, Rocha, LL, Vasconcelos, JF, Rogatto, SR, Dos Santos, RR, Iacobas, S, Goldenberg, RC, Iacobas, DA, Tanowitz, HB, De Carvalho, AC and Spray, DC (2010) Gene expression changes associated with myocarditis and fibrosis in hearts of mice with chronic chagasic cardiomyopathy. Journal of Infection disease 202, 416–426.Google Scholar
Teixeira, MM, Gazzinelli, RT and Silva, JS (2002) Chemokines, inflammation and Trypanosoma cruzi infection. Trends in Parasitology 18, 262–265.Google Scholar
Teixeira, AR, Hecht, MM, Guimaro, MC, Sousa, AO and Nitz, N (2011) Pathogenesis of chagas' disease: parasite persistence and autoimmunity. Clinical Microbiology Reviews 24, 592–630.Google Scholar
Urbina, JA (2010) Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches. Acta Tropica, 115, 55–68.Google Scholar
WHO (2019). Chagas Disease American Trypanosomiasis, Fact sheet No. 340. Geneva: World Health Organization.Google Scholar
Wilkinson, SR and Kelly, JM (2009) Trypanocidal drugs: mechanisms, resistance and new targets. Expert Reviews in Molecular Medicine 11, e31.Google Scholar
Yoshizawa, M, Maeda, S, Miyaki, A, Misono, M, Choi, Y, Shimojo, N, Ajisaka, R and Tanaka, H (2009) Additive beneficial effects of lactotripeptides and aerobic exercise on arterial compliance in postmenopausal women. American Journal of Physiology-Heart and Circulatory Physiology 297, H1899–H1903.Google Scholar