Purinergic Antagonist Suramin Aggravates Myocarditis and Increases Mortality by Enhancing Parasitism, Inflammation, and Reactive Tissue Damage in<i>Trypanosoma cruzi</i>‐Infected Mice

Abstract

Suramin (Sur) acts as an <i>ecto</i>-NTPDase inhibitor in <i>Trypanosoma cruzi</i> and a P2-purinoceptor antagonist in mammalian cells. Although the potent antitrypanosomal effect of Sur has been shown <i>in vitro</i>, limited evidence <i>in vivo</i> suggests that this drug can be dangerous to <i>T. cruzi</i>-infected hosts. Therefore, we investigated the dose-dependent effect of Sur-based chemotherapy in a murine model of Chagas disease. Seventy uninfected and <i>T. cruzi</i>-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 <i>T. cruzi</i>, exhibiting increased parasitemia and cardiac parasitism (amastigote nests and parasite load (<i>T. cruzi</i> 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 <i>T. cruzi</i>-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 <i>T. cruzi</i>-infected mice, contradicting the supposed relevance attributed to this drug for the treatment of Chagas disease.