Abstract
Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease that affects 5–6 million people in endemic areas of the Americas. Presently, chemotherapy relies on two compounds that were proposed as trypanocidal drugs four decades ago: nifurtimox and benznidazole. Both drugs are able to eliminate parasitemia and to avoid seroconversion in infected people when used in the acute phase; however, their use in the chronic phase (the time when the majority of cases are diagnosed) is limited due to their serious side effects. Memantine is a glutamate receptor antagonist in the central nervous system of mammals that has been used for the treatment of Alzheimer’s disease. Our group previously reported memantine as a trypanocidal drug that is able to induce apoptosis-like death in T. cruzi. In the present work, we further investigated the effects of memantine on the infection of RAW 264.7 macrophages and in vivo (in BALB/c mice). Here, we showed that memantine is able to diminish NO and Ca2+ entry in both LPS-activated and non-activated cells. These results, together with the fact that memantine was also able to reduce the infection of macrophages, led us to propose that this drug is able to activate a pro-oxidant non-NO-dependent cell defense mechanism. Finally, infected mice that were treated with memantine had diminished parasitemia, cardiac parasitic load, and inflammatory infiltrates. In addition, the treated mice had an increased survival rate. Taken together, these results indicate memantine to be a candidate drug for the treatment of Chagas disease.
Highlights
Chagas disease is caused by the protozoan Trypanosoma cruzi and affects 5–6 million people in the Americas [1]
We show that memantine affects the infection of macrophages by T. cruzi, diminishing the number of infected cells
The cells were treated with different concentrations of memantine (10–800 μM) for 24, 48 and 72 h; we observed that the macrophages tolerated memantine at concentrations up to 100 μM, showing an inhibitory concentration of 50% of cells (IC50) of 580 ± 22 μM, 279 ± 2 μM and 257 ± 4.7 μM, respectively (Fig 1A–1F)
Summary
Chagas disease is caused by the protozoan Trypanosoma cruzi and affects 5–6 million people in the Americas [1]. Mammals (including humans) become infected when an infected triatomine insect defecates on the skin and expels metacyclic trypomastigotes with the feces, one of the nonproliferative, infective forms of the parasite. These forms are able to internalize into mammalian hosts through the mucosa and small wounds caused by scratching. After a variable number of cellular divisions, amastigotes undergo a complex differentiation process, yielding a new generation of infective, nonproliferative forms called trypomastigotes These trypomastigotes burst from the infected cells into the extracellular environment and are able to infect the neighboring cells or to reach the bloodstream, allowing them to extend the infection to other tissues. The bloodstream trypomastigotes can be taken by the blood to a new, noninfected triatomine insect during its blood-meal, can infect the insect, and can convert this newly infected insect into a new transmitter of the infection [2]
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