Trypanosoma cruzi: Biological characterization of a isolate from an endemic area and its susceptibility to conventional drugs

Grosso, Noelia L.; Búa, Jacqueline; Perrone, Alina E.; González, Mariela Natacha; Bustos, Patricia Laura; Postan, Miriam; Fichera, Laura E.

doi:10.1016/j.exppara.2010.05.010

Cited by 20 publications

(24 citation statements)

References 35 publications

(39 reference statements)

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“…A study of a TcI strain from Nicaragua showed the benefits of early BZ treatment, which led to significant reductions in parasitemia, mortality, and the number of parasites in the skeletal muscle during CP, but no significant differences were observed in the frequencies of lesions in the heart and smooth muscles of these mice. 38 The pathological changes observed with TcII confirm the results of previous studies that used TcII strains of different origins 8,[39][40][41] and from chronic patients in Paraná (Meza SKL and others, unpublished data). 34 The TcII parasites invade heart cell cultures in lower numbers than TcI parasites; however, intracellular multiplication of TcII parasites was more efficient than that of TcI parasites, strongly suggesting that intracellular development is important to determine parasite tissue tropism.…”

Section: Discussionsupporting

confidence: 79%

Impact of Benznidazole on Infection Course in Mice Experimentally Infected with Trypanosoma cruzi I, II, and IV

Gruendling

Massago

Teston

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. American trypanosomiasis is an emerging zoonosis in the Brazilian Amazon. Studies on benznidazole (BZ) chemotherapy with Trypanosoma cruzi from this region have great relevance, given the different discrete typing units (DTUs) that infect humans in the Amazon and other regions of Brazil. We performed a parasitological, histopathological, and molecular analysis of mice inoculated with strains of T. cruzi I, II, and IV that were BZ-treated during the acute phase of infection. Groups of Swiss mice were inoculated; 13 received oral BZ, whereas the other 13 comprised the untreated controls. Unlike parasitemia, the infectivity and mortality did not vary among the DTUs. Trypanosoma cruzi DNA was detected in all tissues analyzed and the proportion of organs parasitized varied with the parasite DTU. The BZ treatment reduced the most parasitological parameters, tissue parasitism and the inflammatory processes at all infection stages and for all DTUs. However, the number of significant reductions varied according to the DTU and infection phase.

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Section: Discussionsupporting

confidence: 79%

Impact of Benznidazole on Infection Course in Mice Experimentally Infected with Trypanosoma cruzi I, II, and IV

Gruendling

Massago

Teston

et al. 2015

The American Society of Tropical Medicine and Hygiene

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“…8 As shown in Figure 2, treatments with BNZ-nps 25, 50 μg/mL and R-BNZ 50 μg/mL exhibited no significant differences in the percentage of amastigote growth inhibition on Vero and cardiac myocyte cells. It is worth mentioning that with half the dose of BNZ-nps, the same inhibitory effect on the growth of amastigotes is achieved.…”

Section: Resultsmentioning

confidence: 97%

“…19 Previously, it was observed that TcN epimastigotes DTU I were more resistant to BNZ than CL Brener epimastigotes DTU VI. 8 In this regard, although there are limits to determine the efficacy of BNZ, its affinity for cardiac tissue and resistance to BNZ makes it interesting to study these BNZ-nps in the isolated TcN.…”

Section: Resultsmentioning

confidence: 99%

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Promising Efficacy of Benznidazole Nanoparticles in Acute Trypanosoma cruzi Murine Model: In-Vitro and In-Vivo Studies

Scalise

Arrúa

Rial

et al. 2016

The American Society of Tropical Medicine and Hygiene

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Abstract. The aim of this study was to evaluate the effectiveness of benznidazole nanoparticles (BNZ-nps) on trypomastigote forms and on intracellular infection in mammalian cells and primary cardiac myocyte cells. Its effectiveness was also evaluated on acute Trypanosoma cruzi Nicaragua mice infection. Trypomastigotes from culture were treated with different concentrations of BNZ-nps to determine the drug concentration that lyses 50% of trypomastigotes (LC 50 ). Infected mammalian cells were incubated with different concentrations of BNZ-nps to determine the percentage of amastigote inhibition. C 3 H/HeN mice with lethal acute infection were treated with 10, 25, and 50 mg/kg/day of BNZnps for 30 and 15 days to control the survival rate of animals. BNZ-nps having a mean particle size of 63.3 nm, a size distribution of 3.35, and a zeta potential of −18.30 were successfully prepared using poloxamer 188 as a stabilizer. BNZ-nps 25 and 50 μg/mL showed no significant differences in the percentage of inhibition of infected mammalian cells. Infected mice treated with BNZ-nps (50, 25, and 10 mg/kg/day) for 30 days and with BNZ-nps (50 and 25 mg/kg/day) for 15 days presented a 100% survival, whereas the animals treated with 10 mg/kg/day for 15 days of BNZ-nps showed a 70% survival rate. The results obtained demonstrate, for the first time, that benznidazole nanoparticles are a useful and attractive approach to treat Chagas disease in infected mice.

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“…To evaluate the significance of TcAKR activity in Bz metabolism, we studied TcAKR expression and its related enzymatic activities in two T. cruzi strains with differential susceptibilities to Bz: CL Brener and Nicaragua (24). CL Brener was more susceptible to Bz than Nicaragua, presenting IC 50 s of 10 and 20.5 M, respectively ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism

Garavaglia

Laverrière

Cannata

et al. 2016

Antimicrob Agents Chemother

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b Benznidazole (Bz), the drug used for treatment of Chagas' disease (caused by the protozoan Trypanosoma cruzi), is activated by a parasitic NADH-dependent type I nitroreductase (NTR I). However, several studies have shown that other enzymes are involved. The aim of this study was to evaluate whether the aldo-keto reductase from T. cruzi (TcAKR), a NADPH-dependent oxido-reductase previously described by our group, uses Bz as the substrate. We demonstrated that both recombinant and native TcAKR enzymes reduce Bz by using NADPH, but not NADH, as a cofactor. TcAKR-overexpressing epimastigotes showed higher NADPH-dependent Bz reductase activity and a 50% inhibitory concentration (IC 50 ) value for Bz 1.8-fold higher than that of the controls, suggesting that TcAKR is involved in Bz detoxification instead of activation. To understand the role of TcAKR in Bz metabolism, we studied TcAKR expression and NADPH/NADH-dependent Bz reductase activities in two T. cruzi strains with differential susceptibility to Bz: CL Brener and Nicaragua. Taking into account the results obtained with TcAKR-overexpressing epimastigotes, we expected the more resistant strain, Nicaragua, to have higher TcAKR levels than CL Brener. However, the results were the opposite. CL Brener showed 2-fold higher TcAKR expression and 5.7-fold higher NADPH-Bz reduction than the Nicaragua strain. In addition, NADH-dependent Bz reductase activity, characteristic of NTR I, was also higher in CL Brener than in Nicaragua. We conclude that although TcAKR uses Bz as the substrate, TcAKR activity is not a determinant of Bz resistance in wild-type strains and may be overcome by other enzymes involved in Bz activation, such as NADPH-and NADH-dependent reductases.C hagas' disease, caused by the protozoan Trypanosoma cruzi, affects 11 million people in Latin America (1). The parasite is usually transmitted to humans and other mammals by triatomine bugs. However, transmission can also be oral (through contaminated food), congenital, or transfusional or by organ transplantation, even in countries where the disease is not endemic (2). The course of infection includes an acute phase followed by an indeterminate phase without symptoms, which lasts throughout life in most infected people. Approximately 30% of patients can develop a chronic phase characterized by cardiac and/or digestive pathologies that can lead to death (3).Benznidazole (Bz) and, to a lesser extent, nifurtimox (Nx) are the drugs currently used for treatment of T. cruzi infection (4). Although the mechanism of action of these nitroheterocyclic compounds is not clearly understood, it is known that, to exert their trypanocidal effects, they need to be activated through the reduction of their nitro group (5). Several studies have proposed that an NADH-dependent trypanosomal type I nitroreductase (NTR I) is a key enzyme which catalyzes Bz and Nx activation in vivo (6,7,8,9). However, evidence indicates that although Bz is reduced to its anion radical, redox cycling may not be relevant for its mode of action, as ...

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Trypanosoma cruzi: Biological characterization of a isolate from an endemic area and its susceptibility to conventional drugs

Cited by 20 publications

References 35 publications

Impact of Benznidazole on Infection Course in Mice Experimentally Infected with Trypanosoma cruzi I, II, and IV

Impact of Benznidazole on Infection Course in Mice Experimentally Infected with Trypanosoma cruzi I, II, and IV

Promising Efficacy of Benznidazole Nanoparticles in Acute Trypanosoma cruzi Murine Model: In-Vitro and In-Vivo Studies

Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism

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