title: 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 Ca(2+) 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.
authors.affiliation: Unit for Drug Discovery, Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Flávia Silva
authors.initials: FS
authors.lastname: Damasceno
authors.affiliation: Unit for Drug Discovery, Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: María Julia
authors.initials: MJ
authors.lastname: Barisón
authors.affiliation: Unit for Drug Discovery, Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Elisabeth Mieko Furusho
authors.initials: EM
authors.lastname: Pral
authors.affiliation: Unit for Drug Discovery, Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Lisvane Silva
authors.initials: LS
authors.lastname: Paes
authors.affiliation: Unit for Drug Discovery, Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Ariel Mariano
authors.initials: AM
authors.lastname: Silber
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002468:Cell Physiological Phenomena / Q000187:drug effects*; D003412:Cricetulus; D008018:Life Cycle Stages / Q000187:drug effects; D008559:Memantine / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D014349:Trypanosoma cruzi / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D000255:Adenosine Triphosphate; D002118:Calcium; D008559:Memantine