We evaluated the influence of metabolic syndrome (MS) on acute Trypanosoma cruzi infection. Obese Swiss mice, 70 days of age, were subjected to intraperitoneal infection with 5 × 102 trypomastigotes of the Y strain. Cardiovascular, oxidative, inflammatory, and metabolic parameters were evaluated in infected and non-infected mice. We observed higher parasitaemia in the infected obese group (IOG) than in the infected control group (ICG) 13 and 15 days post-infection. All IOG animals died by 19 days post-infection (dpi), whereas 87.5% of the ICG survived to 30 days. Increased plasma nitrite levels in adipose tissue and the aorta were observed in the IOG. Higher INF-γ and MCP-1 concentrations and lower IL-10 concentrations were observed in the IOG compared to those in the ICG. Decreased insulin sensitivity was observed in obese animals, which was accentuated after infection. Higher parasitic loads were found in adipose and hepatic tissue, and increases in oxidative stress in cardiac, hepatic, and adipose tissues were characteristics of the IOG group. Thus, MS exacerbates experimental Chagas disease, resulting in greater damage and decreased survival in infected animals, and might be a warning sign that MS can influence other pathologies.
Chagas disease, caused by the protozoan Trypanosoma cruzi, is one of the main causes of death due to cardiomyopathy and heart failure in Latin American countries. The treatment of Chagas disease is directed at eliminating the parasite, decreasing the probability of cardiomyopathy and disrupting the disease transmission cycle. Benznidazole (BZ) and nifurtimox (Nfx) are recognized as effective drugs for the treatment of Chagas disease by the World Health Organization, but both have high toxicity and limited efficacy, especially in the chronic disease phase. At low doses, aspirin (ASA) has been reported to protect against T. cruzi infection. We evaluated the effectiveness of BZ in combination with ASA at low doses during the acute disease phase and evaluated cardiovascular aspects and cardiac lesions in the chronic phase. ASA treatment prevented the cardiovascular dysfunction (hypertension and tachycardia) and typical cardiac lesions. Moreover, BZ+ASA-treated mice had a smaller cardiac fibrotic area than BZ-treated mice. These results were associated with an increase in numbers of eosinophils and reticulocytes and levels of nitric oxide in the plasma and cardiac tissue of ASA-treated mice relative to respective controls. These effects of ASA and BZ+ASA in chronically infected mice were inhibited by pretreatment with the lipoxin A4 (LXA4) receptor antagonist Boc-2, indicating that the protective effects of ASA are mediated by ASA-triggered lipoxin. These results emphasize the importance of exploring new drug combinations for treatments of the acute phase of Chagas disease that are beneficial for patients with chronic disease.
Chagas disease, caused by Trypanosoma cruzi infection, is endemic to much of Latin America, but also present in the United States (U.S.) The goal of treatment is to eliminate the parasite and decrease the probability of cardiomyopathy and interrupt the cycle of disease transmission. Currently, only benznidazole (BZN) and nifurtimox are recognized by the World Health Organization as effective drugs for treatment of Chagas disease, but both present low cure rates in the chronic phase and often have serious side effects. T. cruzi infection produces an intense inflammatory response in several tissues which is critical for controlling parasites proliferation and evolution of Chagas disease. Compounds liberating nitric oxide (NO donors) have been used as therapeutic agents against T. cruzi. Here we test HNO donor, Angeli's salt (AS) in the outcome of T. cruzi infection. C57BL/6 mice were infected with T. cruzi (Y strain, 5 × 103 trypomastigotes) intraperitoneally (ip). After 15 minutes of infection and the subsequent 12 days, the animals were treated with different concentrations of AS ip. The control group received 100 uL of PBS by the same route. Treatment with AS showed decreased parasitemia and in the number of nests in the cardiac tissue, decreased oxidative stress in erythrocytes and improved leukopenia and thrombocytopenia resulting in reduced disease severity. The in vitro treatment was able to reduce the parasite internalization rate and release of infective trypomastigotes by these cells. Our results suggest for the first time the therapeutic potential of AS in a mouse model of Chagas disease.Support or Funding InformationCAPES, Fundação Araucária, CNPQ, UniZambeze and MCTESTP Mozambique.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The drugs nifurtimox (NFX) and benznidazole (BZN) have been used for the treatment of Chagas disease since the 1970s. Alternative strategies are being designed to identify candidates among drugs already available on the market that could be used in combination to improve the efficacy of Chagas disease treatment. This work evaluates the effect of the association benznidazole (BZN) with aspirin (ASA) for the treatment of experimental Chagas disease in the chronic stage. This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Brazilian National Council of Animal Experimentation (http://www.cobea.org.br/). The protocol was approved by the Committee on the Ethics of Animal Experiments at Londrina State University (CEEA, process number 4628.2016.40). To date, experiments were performed using 40 mice with 8 to 12 weeks old. Infected BALB/c mice with 5×103 by an intra‐peritoneal route were treated by gavage with ASA 25 mg/kg/day and BZN 25 mg/kg/day, each separately or together diluted in the drinking water. The drinking water was administered by gavage as a control for the potential impact of the stress associated with the daily handling associated with gavaging mice. The gavaging was initiated two days post‐infection (dpi) and parasitemia was performed using the Brener method on alternate days for 30 days from the third dpi. Efficacy of the treatment was evaluated through cardiovascular parameters, nitric oxide (NO) quantification in the plasma, cardiac tissue and spleen at 180 dpi. The treatments with BZN (25 mg/kg/day) alone or in association with ASA (25 mg/kg/day) significantly (P < 0.05) reduced mortality and decreased parasitemia. However, the mice treated with BZN and ASA combination maintained the levels of mean arterial pressure (MAP), systolic blood pressure (SBP) and heart rate (HR) closer to the levels observed in control animals. While those of BZN group, had these parameters statistically increased. BZN combined with ASA showed an increase in NO production than mice treated only with BZN. Interesting, the treated with BZN and the ASA combination prevented heart enlargement characteristically observed in infected animals. The therapeutic results from the combination of BZN with ASA presented lesser side effects than the treatment with BZN.Support or Funding InformationThis work was supported by Programa Institucional de Pesquisa Básica e Aplicada, da Fundação Araucária de Apoio ao Desenvolvimento Científico e Tecnológico do Estado do Paraná,, Convênio 09/2016). BFCL, HTS and MILM received scholarships from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). PPF, MCMP and SFYO received research fellowship from CNPq. RSP received scholarships from UniZambeze and MCTESTP Mozambique.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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 Information The 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 abstract
Chagas disease (CD), caused by Trypanosoma cruzi, is a neglected tropical disease prevalent in Latin America. The treatment of infected patients is aimed at eliminating the parasite, reducing the risk of cardiomyopathy, and interrupting the disease transmission cycle. At present, the World Health Organization only recognizes benznidazole (BZ) and nifurtimox as effective drugs for treating CD. However, both present low cure rates in the chronic phase and often have serious side effects. T. cruzi infection produces an intense inflammatory response in several tissues, critical for controlling parasite proliferation and CD evolution. Compounds that liberate nitric oxide (NO) (NO donors) have been used as therapeutic agents against T. cruzi. However, to date, there is no evidence about the related nitrogen oxide, nitroxyl (HNO) on the outcome of T. cruzi infection. In this study, we investigated the effect of the HNO donor Angeli's salt (AS) on C57BL/6 mice infected with T. cruzi (Y strain, 5 × 103 trypomastigotes, i.p.). The use of AS showed positive results, such as a decrease in the number of parasites present in the bloodstream and in nests within the heart, as well as improved the protective antioxidant capacity of erythrocytes in infected animals, leading to an overall decrease in the severity of the disease. Furthermore, in vitro experiments showed that AS treatment reduced parasite uptake and the release of trypomastigotes by macrophages. Taken together, these findings from both the mouse model and in vitro testing suggest that AS could be a promising therapy for CD.
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