Aspirin in Combination with Benznidazole During the Acute Phase of Chagas Disease Prevents Cardiovascular Dysfunction and Decrease Typical Cardiac Lesions in Mice Chronically Infected with Trypanosoma cruzi

Abstract

Chagas disease, caused by protozoan Trypanosoma cruzi, is one of the main causes of death due to cardiomyopathy and consequent heart failure in Latin American countries. The goal of treatment is to eliminate the parasite and decrease the probability of cardiomyopathy and interrupt the cycle of disease transmission. Benznidazole (BZ) and nifurtimox (NFX) are recognized by the World Health Organization as effective drugs for treatment of disease, but both are very toxic with limited efficacy, especially in the chronic phase. Studies have shown that low doses of aspirin (ASA) were protective in experimental T. cruzi Infection. We evaluated the efficacy of BZ in combination with ASA in low doses using a chronic infection model with T. cruzi Y strain. Our results show that ASA treatment prevented the typical cardiovascular dysfunction (hypertension and tachycardia) and cardiac lesions on chronic phase of disease. Moreover, mice treated with BZ+ASA had a smaller cardiac fibrotic area than those of BZ‐treated mice. These results were associated with an increase of eosinophils and reticulocytes and high levels of nitric oxide in plasma and cardiac tissue of animals treated with ASA compared to the controls. The protective effects of ASA or BZ+ASA on chronically infected mice disappeared when we used Boc‐2 (LXA4 receptor antagonist), indicating that the protector effect of ASA was mediated by aspirin‐triggered lipoxin. These results emphasize the importance of exploring new drug combinations in treatments that can be used in the acute phase of Chagas disease that are beneficial to chronic patients.Support or Funding InformationThe present study was supported by grants from Fundação Araucária ‐ chamada de projeto 09/2016 Programa Institucional de Pesquisa Básica e Aplicada ‐ Conv. 001/2017 ‐ protocolo 47.396 ‐ SIT. 31675, Conselho Nacional Desenvolvimento Científico e Tecnológico (CNPq), CAPES. PPF, MCMP, MILM, WAVJ, LMYL, SFYO are research fellows of CNPq. BFCL and ERT are research fellows of CAPES. RPS was supported by Ministério da Ciência e Tecnologia, Ensino Superior e Técnico Profissional de Mocambique.Graphical abstractFigure 1