Curcumin Enhances the Anti-Trypanosoma cruzi Activity of Benznidazole-Based Chemotherapy in Acute Experimental Chagas Disease

Abstract

Although curcumin can increase the effectiveness of drugs against malaria, combination therapies using the molecule have never been investigated in Chagas disease (ChD). Therefore, we evaluated the efficacy of curcumin as a complementary strategy to benznidazole (Bz)-based chemotherapy in mice acutely infected with Trypanosoma cruzi. Eighty-four 12-week-old Swiss mice were equally randomized into seven groups: uninfected (NI), T. cruzi infected and untreated (INF), infected and treated with 100 mg/kg of body weight Bz (B100), 50 mg/kg Bz (B50), 100 mg/kg curcumin (C100), 100 mg/kg Bz plus 100 mg/kg curcumin (B100 plus C100), and 50 mg/kg Bz plus 100 mg/kg curcumin (B50 plus C100). After microscopic identification of blood trypomastigotes (4 days after inoculation), both drugs were administered by gavage once a day for 20 days. Curcumin showed limited antiparasitic, anti-inflammatory, and antioxidant effects when administered alone. When curcumin and Bz were combined, there was a drastic reduction in parasitemia, parasite load, mortality, anti-T. cruzi IgG reactivity, circulating levels of cytokines (gamma interferon [IFN-␥], interleukin 4 [IL-4], and MIP1-␣), myocardial inflammation, and morphological and oxidative cardiac injury; these results exceeded the isolated effects of Bz. The combination of Bz and curcumin was also effective at mitigating liver toxicity triggered by Bz, increasing the parasitological cure rate, and preventing infection recrudescence in noncured animals, even when the animals were treated with 50% of the recommended therapeutic dose of Bz. By limiting the toxic effects of Bz and enhancing its antiparasitic efficiency, the combination of the drug with curcumin may be a relevant therapeutic strategy that is possibly better tolerated in ChD treatment than Bz-based monotherapy.

Cytotoxicity, antiprotozoal, and anti‐inflammatory activities of eight curry powders and comparison of their UPLC‐ESI‐QTOF‐MS chemical profiles

“…These diarylheptanoids seemed to contribute slightly to the trypanocidal activity piperine present in cur 8 and this might suggest why cur 8 was more active than cur 2 . Such enhancement by curcumin of the benznidazole antitrypanosomal activity has been reported previously . Moreover, the curcuminoid complex, including curcumin, demethoxycurcumin and bisdemethoxycurcumin, proved to be individually active on T. cruzi and might justify why cur 6 (Table S6 and Figs S22 and S23 in File S1) was more potent than the other active spices.…”

“…Such enhancement by curcumin of the benznidazole antitrypanosomal activity has been reported previously. 34 Moreover, the curcuminoid complex, including curcumin, demethoxycurcumin and bisdemethoxycurcumin, proved to be individually active on T. cruzi 35 and might justify why cur 6 (Table S6 and Figs S22 and S23 in File S1) was more potent than the other active spices. Cur 6 was exclusively rich in curcuminoids and aromatic sesquiterpenes.…”

Potential Role of Antioxidants as Adjunctive Therapy in Chagas Disease

“…The number of parasites used for challenge infection was variable, ranging from 1 × 10 1 to 1 × 10 5 blood trypomastigotes, that was mostly related to virulence of the parasite isolates but unrelated to the development of the acute or chronic phase. The antioxidant compounds used in these studies included phenyl-α-tert-butyl nitrone (PBN) [50,51], carvedilol, vitamin E (vitE) and/or vitamin C (vitC) [52,53], melatonin [54], curcumin [55], resveratrol, and astaxanthin [56]. Vitamin C was the most commonly used antioxidant, evalu-ated in five of the published studies.…”

“…Curcumin has been studied in CD as well as in other parasitic diseases, focused mainly on its immunomodulatory and antiparasitic action because of its diphasic effect as a scavenger of ROS in low doses (1-15 μM) and as an inductor of ROS in high doses (20-50 μM) [83]. Novaes et al [55] reported positive effects of treatment with curcumin alone as well as in combination with benznidazole in controlling oxidative stress. Mice infected with T. cruzi Y strain and treated with curcumin for 20 days showed reduced MDA and PCN levels in cardiac and liver tissues compared to that noted in infected/untreated controls.…”

“…Mice infected with T. cruzi Y strain and treated with curcumin for 20 days showed reduced MDA and PCN levels in cardiac and liver tissues compared to that noted in infected/untreated controls. When used in combination with benznidazole, curcumin offered a greater reduction in MDA and PCN levels in cardiac tissue [55]. Contrarily, Nagajyothi et al [84] showed in mice infected with the Brazil strain of T. cruzi that curcumin treatment for 35 days during the acute phase resulted in a decline in the expression levels of antioxidants including SOD, CAT, and peroxidases, though curcumin was beneficial in controlling the parasite burden.…”