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

Author(s)

Damasceno, Flavia Silva ^[1] ; Barison, Maria Julia ^[1] ; Furusho Pral, Elisabeth Mieko ^[1] ; Paes, Lisvane Silva ^[1] ; Silber, Ariel Mariano ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, Unit Drug Discovery, BR-05508 Sao Paulo - Brazil

• Document type: Journal article
• Source: PLoS Neglected Tropical Diseases; v. 8, n. 2 FEB 2014.
• Web of Science Citations: 8

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 mu M). 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 mu M). 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. Author SummaryTrypanosoma cruzi is a parasite transmitted to mammal hosts by insect vectors known as kissing bugs. This species can result pathogenic for humans, causing Chagas' disease in the Americas. Its treatment relies on two drugs discovered more than 40 years ago. Besides their toxicity, a main drawback of these drugs is the fact that they are highly efficient only during the acute phase of the infection. But due to the lack of specific symptoms, the acute phase of the infection is largely not diagnosed. In fact, most of patients are diagnosed in the chronic phase, where the treatments are not satisfactory. In view of that, it is urgent to look for new drugs with low toxicity and able to kill the parasite in chronic patients. On the basis of previous finding, we looked for drugs against glutamate recognizing surface molecules, keeping special attention on those that are already in use in humans for other purposes (this strategy is called drug repositioning, and allow to save time and money in clinical trials: several parameters such as toxicity, pharmacokinetics, side effects in humans are already known). Here we report that Memantine, a NMDA glutamate receptors antagonist already in use to treat Alzheimer's disease, presents interesting perspectives as a trypanocidal drug. (AU)