Abstract
Suramin (Sur) acts as an ecto-NTPDase inhibitor in Trypanosoma cruzi and a P2-purinoceptor antagonist in mammalian cells. Although the potent antitrypanosomal effect of Sur has been shown in vitro, limited evidence in vivo suggests that this drug can be dangerous to T. cruzi-infected hosts. Therefore, we investigated the dose-dependent effect of Sur-based chemotherapy in a murine model of Chagas disease. Seventy uninfected and T. cruzi-infected male C57BL/6 mice were randomized into five groups: SAL = uninfected; INF = infected; SR5, SR10, and SR20 = infected treated with 5, 10, or 20 mg/kg Sur. In addition to its effect on blood and heart parasitism, the impact of Sur-based chemotherapy on leucocytes myocardial infiltration, cytokine levels, antioxidant defenses, reactive tissue damage, and mortality was analyzed. Our results indicated that animals treated with 10 and 20 mg/kg Sur were disproportionally susceptible to T. cruzi, exhibiting increased parasitemia and cardiac parasitism (amastigote nests and parasite load (T. cruzi DNA)), intense protein, lipid and DNA oxidation, marked myocarditis, and mortality. Animals treated with Sur also exhibited reduced levels of nonprotein antioxidants. However, the upregulation of catalase, superoxide dismutase, and glutathione-S-transferase was insufficient to counteract reactive tissue damage and pathological myocardial remodeling. It is still poorly understood whether Sur exerts a negative impact on the purinergic signaling of T. cruzi-infected host cells. However, our findings clearly demonstrated that through enhanced parasitism, inflammation, and reactive tissue damage, Sur-based chemotherapy contributes to aggravating myocarditis and increasing mortality rates in T. cruzi-infected mice, contradicting the supposed relevance attributed to this drug for the treatment of Chagas disease.
Highlights
American trypanosomiasis or Chagas disease (ChD) is a neglected tropical illness caused by the protozoan parasite T. cruzi, which is the main infectious agent responsible for nonischemic cardiomyopathy worldwide [1, 2]
When investigating Sur as a potential chemotherapy candidate for T. cruzi in a preliminary study, we identified that mice infected by ecto-NTPDaseinhibited trypomastigotes developed lower parasitemia and higher host survival than animals infected with control parasites [10]
The antioxidant capacity was estimated from a standard curve, using trolox as the antioxidant reference. Infected animals and those in the SR5 group presented similar mean parasitemia, peak parasitemia, and mortality rates (p > 0 05). These parameters were increased in SR10 and SR20 animals compared to the INF group (p < 0 05)
Summary
American trypanosomiasis or Chagas disease (ChD) is a neglected tropical illness caused by the protozoan parasite T. cruzi, which is the main infectious agent responsible for nonischemic cardiomyopathy worldwide [1, 2]. 7 million people are infected in Latin America and the Caribbean, and at least 300,000 new cases are diagnosed each year [2, 3] This disease has high morbidity and is responsible for 14,000 deaths/year from heart failure in South America [3]. Our research group confirmed that Sur acts as a potent inhibitor of T. cruzi ecto-nucleoside triphosphate diphosphohydrolase (ecto-NTPDase), a member of the CD39 family described in trypanosomatids [10]. This enzyme is essential for the metabolism and survival of T. cruzi, acting as an important factor of parasite virulence [10, 11]. In addition to parasitism of the blood and heart, the participation of inflammatory mediators, antioxidant defenses, and reactive tissue damage in the pathogenesis of acute Chagas cardiomyopathy was analyzed
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