Skip to main content
SpringerLink
Log in

Trypanosoma cruzi infection and benznidazole therapy independently stimulate oxidative status and structural pathological remodeling of the liver tissue in mice

  • Original Paper
  • Published:
Parasitology Research Aims and scope Submit manuscript

Abstract

This study used a murine model of Chagas disease to investigate the isolated and combined impact of Trypanosoma cruzi infection and benznidazole (BZ) therapy on liver structure and function. Male C57BL/6 mice were challenged with T. cruzi and BZ for 15 days. Serum levels of cytokines and hepatic enzymes, liver oxidative stress, morphology, collagen, and glycogen content were monitored. Separately, T. cruzi infection and BZ treatment resulted in a pro-oxidant status and hepatic reactive damage. Concurrently, both T. cruzi infection and BZ treatment induced upregulation of antioxidant enzymes and pathological reorganization of the liver parenchyma and stroma. T. cruzi infection increased serum levels of Th1 cytokines, which were reduced by BZ in both infected and non-infected animals. BZ also induced functional organ damage, increasing serum levels of liver enzymes. When combined, T. cruzi infection and BZ therapy elicited intense hepatic reactive damage that was not compensated by antioxidant enzymatic reaction, subsequently culminating in more severe morphofunctional hepatic injury. Taken together, these findings indicate that during specific treatment of Chagas disease, hepatic pathology may be a result of an interaction between BZ metabolism and specific mechanisms activated during the natural course of T. cruzi infection, rather than an isolated toxic effect of BZ on liver structure and function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  PubMed  Google Scholar 

  • Amacher DE (1998) Serum transaminase elevations as indicators of hepatic injury following the administration of drugs. Regul Toxicol Pharmacol 27:119–130

    Article  CAS  PubMed  Google Scholar 

  • Bahia MT, de Andrade IM, Martins TA, do Nascimento ÁF, Diniz LF, Caldas IS, Talvani A, Trunz BB, Torreele E, Ribeiro I (2012) Fexinidazole: a potential new drug candidate for Chagas disease. PLoS Negl Trop Dis 6, e1870

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bergeron M, Olivier M (2006) Trypanosoma cruzi-mediated IFN-γ-inducible nitric oxide output in macrophages is regulated by iNOS mRNA stability. J Immunol 177:6271–6280

    Article  CAS  PubMed  Google Scholar 

  • Bissel DM, Gores GJ, Laskin DL, Hoofnagle JH (2001) Drug-induced liver injury: mechanisms and test systems. Hepatology 33:1009–1013

    Article  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. Anal Biochem 7:248–254

    Article  Google Scholar 

  • Brener Z (1962) Therapeutic activity and criterion of cure on mice experimentally infected with Trypanosoma cruzi. Rev Inst Med Trop Sao Paulo 4:389–396

    CAS  PubMed  Google Scholar 

  • Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310

    Article  CAS  PubMed  Google Scholar 

  • Caldas IS, Talvani A, Caldas S, Carneiro CM, De Lana M, Da Matta Guedes PM, Bahia MT (2008) Benznidazole therapy during acute phase of Chagas disease reduces parasite load but does not prevent chronic cardiac lesions. Parasitol Res 103:413–421

    Article  PubMed  Google Scholar 

  • Cançado JR (2002) Long term evaluation of etiological treatment of chagas disease with benznidazole. Rev Inst Med Trop Sao Paulo 44:29–37

    Article  PubMed  Google Scholar 

  • Castro JA, De Mecca MM, Bartel LC (2006) Toxic side effects of drugs used to treat Chagas’ disease (American trypanosomiasis). Hum Exp Toxicol 25:471–479

    Article  CAS  PubMed  Google Scholar 

  • Cupertino MC, Costa KLC, Santos DCM, Novaes RD, Condessa SS, Neves AC, Oliveira JA, Matta SLP (2013) Long-lasting morphofunctional remodelling of liver parenchyma and stroma after a single exposure to low and moderate doses of cadmium in rats. Int J Exp Pathol 94:343–351

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Davies C, Dey N, Negrette OS, Parada LA, Basombrio MA, Garg NJ (2014) Hepatotoxicity in mice of a novel anti-parasite drug candidate hydroxymethylnitrofurazone: a comparison with benznidazole. PLoS Negl Trop Dis 8, e3231

    Article  PubMed Central  PubMed  Google Scholar 

  • Diniz LF, Urbina JA, de Andrade IM, Mazzeti AL, Martins TA, Caldas IS, Talvani A, Ribeiro I, Bahia MT (2013) Benznidazole and posaconazole in experimental Chagas disease: positive interaction in concomitant and sequential treatments. PLoS Negl Trop Dis 7, e2367

    Article  PubMed Central  Google Scholar 

  • Esperandim VR, da Silva Ferreira D, Sousa Rezende KC, Cunha WR, Saraiva J, Bastos JK, Andrade E, Silva ML, de Albuquerque S (2013) In vivo infection by Trypanosoma cruzi: a morphometric study of tissue changes in mice. Parasitol Res 112:431–436

    Article  PubMed  Google Scholar 

  • Gonçalves RV, Novaes RD, Leite JPV, Vilela EF, Cupertino MC, Nunes LG, Matta SLP (2012) Hepatoprotective effect of Bathysa cuspidata in a murine model of severe toxic liver injury. Int J Exp Pathol 93:370–376

    Article  PubMed Central  PubMed  Google Scholar 

  • Guedes PM, Silva GK, Gutierrez FR, Silva JS (2011) Current status of Chagas disease chemotherapy. Expert Rev Anti Infect Ther 9:609–620

    Article  PubMed  Google Scholar 

  • Gupta S, Wen JJ, Garg NJ (2009) Oxidative stress in Chagas disease. Interdisc Perspect Infect Dis 190354:1–8

    Google Scholar 

  • Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases: the first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130–7139

    CAS  PubMed  Google Scholar 

  • Harris ED (1992) Regulation of antioxidant enzymes. FASEB J 6:2675–2683

    CAS  PubMed  Google Scholar 

  • Hassid WZ, Abraham S (1957) Chemical procedures for analisys of polyssacarides. Methods Enzymol 3:34–50

    Article  Google Scholar 

  • Kappus HA (1987) A survey of chemicals inducing lipid peroxidation in biological systems. Chem Phys Lipids 45:105–111

    Article  CAS  PubMed  Google Scholar 

  • Lee WM (2003) Drug-induced hepatotoxicity. N Engl J Med 349:474–481

    Article  CAS  PubMed  Google Scholar 

  • Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S, Stadtman ER (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186:464–478

    Article  CAS  PubMed  Google Scholar 

  • López-De León A, Rojkind M (1985) A simple micromethod for collagen and total protein determination in formalin-fixed paraffin-embedded sections. Histochem Cytochem 33:737–743

    Article  Google Scholar 

  • Maya JD, Cassels BK, Iturriaga-Vásquez P, Ferreira J, Faúndez M, Galanti N, Ferreira A, Morello A (2007) Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host. Comp Biochem Physiol A Mol Integr Physiol 146:601–620

    Article  PubMed  Google Scholar 

  • Maya JD, Orellana M, Ferreira J, Kemmerling U, López-Muñoz R, Morello A (2010) Chagas disease: present status of pathogenic mechanisms and chemotherapy. Biol Res 43:323–331

    Article  PubMed  Google Scholar 

  • Mecca MM, Bartel LC, Castro CR, Castro JÁ (2008) Benznidazole biotransformation in rat heart microsomal fraction without observable ultrastructural alterations: comparison to Nifurtimox-induced cardiac effects. Mem Inst Oswaldo Cruz 103:549–553

    Article  PubMed  Google Scholar 

  • Nagajyothi F, Zhao D, Weiss LM, Tanowitz HB (2012) Curcumin treatment provides protection against Trypanosoma cruzi infection. Parasitol Res 110:2491–2499

    Article  PubMed Central  PubMed  Google Scholar 

  • Novaes RD, Gonçalves RV, Marques DC, Cupertino MC, Peluzio MC, Leite JP, Maldonado IR (2012) Effect of bark extract of Bathysa cuspidata on hepatic oxidative damage and blood glucose kinetics in rats exposed to paraquat. Toxicol Pathol 40:62–70

    Article  PubMed  Google Scholar 

  • Novaes RD, Penitente AR, Gonçalves RV, Talvani A, Peluzio MC, Neves CA, Natali AJ, Maldonado IR (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. Cardiovasc Pathol 22:270–279

    Article  CAS  PubMed  Google Scholar 

  • Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S (2008) The current state of serum biomarkers of hepatotoxicity. Toxicology 245:194–205

    Article  CAS  PubMed  Google Scholar 

  • Pedrosa RC, De Bem AF, Locatelli C, Pedrosa RC, Geremias R, Wilhelm Filho D (2001) Time-dependent oxidative stress caused by benznidazole. Redox Rep 6:265–270

    Article  CAS  PubMed  Google Scholar 

  • Pérez-Fuentes R, Guégan J-F, Barnabé C, López-Colombo A, Salgado-Rosas H, Torres-Rasgado E, Briones B, Romero-Díaz M, Ramos-Jiménez J, Sánchez-Guillén Mdel C (2003) Severity of chronic Chagas disease is associated with cytokine/antioxidant imbalance in chronically individuals. Int J Parasitol 33:293–299

    Article  PubMed  Google Scholar 

  • Pupulin ART, Paludetto A, da Silva SV, Bracht AMK (2005) Benznidazol effects in perfunded rat liver. RBAC 37:153–156

    Google Scholar 

  • Rendon D (2014) Alterations of mitochondria in liver but not in heart homogenates after treatment of rats with benznidazole. Hum Exp Toxicol 33:1066–1070

    Article  CAS  PubMed  Google Scholar 

  • Rodrigues Coura J, De Castro SL (2002) A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz 97:3–24

    Article  Google Scholar 

  • Sagara Y, Dargusch R, Chambers D, Davis J, Schubert D, Maher P (1998) Cellular mechanisms of resistance to chronic oxidative stress. Free Radic Biol Med 24:1375–1389

    Article  CAS  PubMed  Google Scholar 

  • Sarban S, Kocyigit A, Yazar M, Isikan UE (2005) Plasma total antioxidant capacity, lipid peroxidation, and erythrocyte antioxidant enzyme activities in patients with rheumatoid arthritis and osteoarthritis. Clin Biochem 38:981–986

    Article  CAS  PubMed  Google Scholar 

  • 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. J Chromatogr B Analyt Technol Biomed Life Sci 15:51–70

    Article  Google Scholar 

  • Urbina JA (2010) Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches. Acta Trop 115:55–68

    Article  PubMed  Google Scholar 

  • Wen JJ, Nagajyothi F, Machado FS, Weiss LM, Scherer PE, Tanowitz HB, Garg NJ (2014) Markers of oxidative stress in adipose tissue during Trypanosoma cruzi infection. Parasitol Res 113:3159–3165

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge the “Fundação de Amparo a Pesquisa do Estado de Minas Gerais - FAPEMIG” and “Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq”. André Talvani is CNPq fellow.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed.

Author information

Authors and Affiliations

  1. Department of Structural Biology, Federal University of Alfenas, Alfenas, 37130-000, Minas Gerais, Brazil

    Rômulo Dias Novaes

  2. Department of Biological Sciences and NUPEB, Federal University of Ouro Preto, Ouro Preto, 35400-000, Minas Gerais, Brazil

    Rômulo Dias Novaes & André Talvani

  3. Department of General Biology, Federal University of Viçosa, Viçosa, 36570-000, Minas Gerais, Brazil

    Eliziária C. Santos, Marli C. Cupertino, Daniel S. S. Bastos, Jerusa M. Oliveira, Thaís V. Carvalho, Mariana M. Neves & Leandro L. Oliveira

  4. Laboratório de Imunobiologia da Inflamação DECBI/NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, 35400-000, MG, Brazil

    Rômulo Dias Novaes & André Talvani

Authors
  1. Rômulo Dias Novaes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eliziária C. Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marli C. Cupertino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel S. S. Bastos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jerusa M. Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thaís V. Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mariana M. Neves
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leandro L. Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. André Talvani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rômulo Dias Novaes.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Novaes, R.D., Santos, E.C., Cupertino, M.C. et al. Trypanosoma cruzi infection and benznidazole therapy independently stimulate oxidative status and structural pathological remodeling of the liver tissue in mice. Parasitol Res 114, 2873–2881 (2015). https://doi.org/10.1007/s00436-015-4488-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00436-015-4488-x

Keywords

Search

Navigation