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

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.

Could pre-infection exercise training improve the efficacy of specific antiparasitic chemotherapy for Chagas disease?

“…This method is based on the inhibition of endogenous antioxidant enzymes and blocking Cu 2+ oxidation by small non-protein antioxidant molecules, which were detected in a spectrophotometer at 570 nm. The antioxidant capacity was estimated from a standard curve, using trolox as the antioxidant reference (Novaes et al ., 2018).…”

E-NTPDases: Possible Roles on Host-Parasite Interactions and Therapeutic Opportunities

“…Thus, the apparent disagreement between the works of Santos et al. (2009) and Novaes et al. (2018) seems due to the absence of specificity of Suramin, acting on both P2 receptors and T. cruzi E-NTPDase.…”

“…This unexpected result could be explained by the fact that Santos et al. (2009) used Suramin only in the parasites, before infection, while Novaes et al. (2018) used Suramin in the host cells.…”

“…Studies have shown that suramin is a potent inhibitor of T. cruzi E-NTPDase, and in vivo experiments suggest that this drug can negatively affect the purinergic signaling of host cells infected with T. cruzi ( Bisaggio et al., 2003 ; Santos et al., 2009 ). Novaes et al. (2018) studied the effect of suramin in the chemotherapy of murine model of Chagas disease.…”

“…T. cruzi -infected mice submitted to Suramin-based chemotherapy showed increased reactive tissue damage, inflammation, and parasitism. In addition, Suramin-based treatment aggravated myocarditis cases and increased the mortality rates ( Novaes et al., 2018 ). This unexpected result could be explained by the fact that Santos et al.…”