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The effect of memantine, an antagonist of the NMDA glutamate receptor, in in vitro and in vivo infections by Trypanosoma cruzi.

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.

SUBMITTER: Santos Souza HF

PROVIDER: S-EPMC6752752 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The effect of memantine, an antagonist of the NMDA glutamate receptor, in in vitro and in vivo infections by Trypanosoma cruzi.

Santos Souza Higo Fernando HF Rocha Sandra Carla SC Damasceno Flávia Silva FS Rapado Ludmila Nakamura LN Pral Elisabeth Mieko Furusho EMF Marinho Claudio Romero Farias CRF Silber Ariel Mariano AM

PLoS neglected tropical diseases 20190919 9

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 limi ...[more]

PMID: 31536489

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Project description:Arylimidamides (AIAs) have been shown to have considerable biological activity against intracellular pathogens, includingTrypanosoma cruzi, which causes Chagas disease. In the present study, the activities of 12 novel bis-AIAs and 2 mono-AIAs against different strains ofT. cruziin vitroandin vivowere analyzed. The most active wasm-terphenyl bis-AIA (35DAP073), which had a 50% effective concentration (EC50) of 0.5 ?M for trypomastigotes (Y strain), which made it 26-fold more effective than benznidazole (Bz; 13 ?M). It was also active against the Colombiana strain (EC50= 3.8 ?M). Analysis of the activity against intracellular forms of the Tulahuen strain showed that this bis-AIA (EC50= 0.04 ?M) was about 100-fold more active than Bz (2 ?M). The trypanocidal effect was dissociated from the ability to trigger intracellular lipid bodies within host cells, detected by oil red labeling. Both an active compound (35DAP073) and an inactive compound (26SMB060) displayed similar activation profiles. Due to their high selectivity indexes, two AIAs (35DAP073 and 35DAP081) were moved toin vivostudies, but because of the results of acute toxicity assays, 35DAP081 was excluded from the subsequent tests. The findings obtained with 35DAP073 treatment of infections caused by the Y strain revealed that 2 days of therapy induced a dose-dependent action, leading to 96 to 46% reductions in the level of parasitemia. However, the administration of 10 daily doses in animals infected with the Colombiana strain resulted in toxicity, preventing longer periods of treatment. The activity of the combination of 0.5 mg/kg of body weight/day 35DAP073 with 100 mg/kg/day Bz for 10 consecutive days was then assayed. Treatment with the combination resulted in the suppression of parasitemia, the elimination of neurological toxic effects, and survival of 100% of the animals. Quantitative PCR showed a considerable reduction in the parasite load (60%) compared to that achieved with Bz or the amidine alone. Our results support further investigations of this class with the aim of developing novel alternatives for the treatment of Chagas disease.

Dataset Information

The effect of memantine, an antagonist of the NMDA glutamate receptor, in in vitro and in vivo infections by Trypanosoma cruzi.

Publications

The effect of memantine, an antagonist of the NMDA glutamate receptor, in in vitro and in vivo infections by Trypanosoma cruzi.

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