Memantine, an Antagonist of the NMDA Glutamate Receptor, Affects Cell Proliferation, Differentiation and the Intracellular Cycle and Induces Apoptosis in Trypanosoma cruzi

Abstract

Chagas' disease is caused by the protozoan parasite Trypanosoma cruzi and affects approximately 10 million people in endemic areas of Mexico and Central and South America. Currently available chemotherapies are limited to two compounds: Nifurtimox and Benznidazole. Both drugs reduce the symptoms of the disease and mortality among infected individuals when used during the acute phase, but their efficacy during the chronic phase (during which the majority of cases are diagnosed) remains controversial. Moreover, these drugs have several side effects. The aim of this study was to evaluate the effect of Memantine, an antagonist of the glutamate receptor in the CNS of mammals, on the life cycle of T. cruzi. Memantine exhibited a trypanocidal effect, inhibiting the proliferation of epimastigotes (IC50 172.6 µM). Furthermore, this compound interfered with metacyclogenesis (approximately 30% reduction) and affected the energy metabolism of the parasite. In addition, Memantine triggered mechanisms that led to the apoptosis-like cell death of epimastigotes, with extracellular exposure of phosphatidylserine, increased production of reactive oxygen species, decreased ATP levels, increased intracellular Ca2+ and morphological changes. Moreover, Memantine interfered with the intracellular cycle of the parasite, specifically the amastigote stage (IC50 31 µM). Interestingly, the stages of the parasite life cycle that require more energy (epimastigote and amastigote) were more affected as were the processes of differentiation and cell invasion.

The Uptake of GABA in Trypanosoma cruzi

“…) following a modified protocol as described (Damasceno et al. ). Parasite viability was determined by microscopic observation of cell motility and MTT assay as described (Damasceno et al.…”

“…Parasite viability was determined by microscopic observation of cell motility and MTT assay as described (Damasceno et al. ).…”

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

“…Briefly, 50 l of phosphate-buffered saline (PBS) was added to 100 l of cellular ATP-releasing reagent, and the mixture was added to a 50-l suspension of 5.0 ϫ 10 6 parasites, either treated or untreated (controls). Light emission levels were measured on a Spectra Max I3 fluorometer at 570 nm (23).…”

“…The infection index (percentage of infected cells ϫ the number of parasites per cell) was calculated. To measure the effect of MB17 on the infection of CHO-K 1 cells, trypomastigotes were collected from the extracellular medium on the fifth day and counted in a Neubauer chamber (23). All experiments were performed in technical and biological triplicates.…”

Crystallization and X Ray Diffraction Data Analyses of the Enzyme Urocanate Hydratase fromTrypanosoma cruzi

“…17 In this regard, some of the main amino acid-metabolism therapeutic targets considered up to now are arginine kinase, 18 proline racemase, 19 as well as the proline uptake system 5 and glutamate uptake/receptor system. 20 More recently, other possibilities that have been considered in the search for therapeutic targets are enzymes of amino acid metabolism pathways, which contribute as energy sources to T. cruzi. 7,9 Among amino acids, L-histidine degradation leads to glutamate and other final products.…”