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Study of interference of drugs that act via receptors and/or transport of GABA and glutamate in the life cycle of Trypanosoma cruzi.

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Author(s):
Flávia Silva Damasceno
Total Authors: 1
Document type: Master's Dissertation
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas
Defense date:
Examining board members:
Ariel Mariano Silber; Guillermo Roberto Labadie; Anita Hilda Straus Takahashi
Advisor: Ariel Mariano Silber
Abstract

Chagas disease, also known as American trypanosomiasis is caused by the flagellate protozoan Trypanosoma cruzi and affects approximately 10 million people in endemic areas of Mexico, Central America and South America, with about 25 million people living in areas at risk of infection. The currently available chemotherapy is limited to two compounds, which are: Nifurtimox and Benznidazole. Both drugs reduce symptoms of the disease and mortality of infected people when used in the acute phase, but its efficacy in chronic phase (phase in which the majority of cases are diagnosed) is still controversial. Moreover these drugs have several side effects. T. cruzi is able to utilize carbohydrate and amino acids as carbon and energy source. Our group has studied the involvement of glutamate in parasite resistance to thermal, oxidative and metabolic stress, as well as the importance of the amino acid GABA metabolism in T. cruzi. The aim of this study was to evaluate the interference of drugs, that act in GABA and glutamate transporters or receptors, in the life cycle of T. cruzi. The drugs selected were: vigabatrin, pregabalin, MK-801, memantine and MTEP. The results showed that only memantine has a better trypanocidal effect. Memantine inhibited the proliferation of epimastigotes, interfered in metacyclogenesis, and affected the energy metabolism of the parasite with decreased levels of ATP, and trigger mechanisms that lead to apoptosis of epimastigotes. Moreover interferes with intracellular cycle of the parasite, specifically in amastigote stage. Interesting that stages of the parasite that require more energy are more affected: replicative stages (epimastigote and amastigote) as well as the processes of differentiation and cell invasion. IC50 value is more than that described to epimastigotes treateds with Benznidazole, but Memantine could be used as leader compound for the design of drugs with optimized trypanocidal activity. (AU)

FAPESP's process: 11/05037-4 - Study of interference of drugs that act via receptors and / or transport of GABA and glutamate in the life cycle of Trypanosoma cruzi.
Grantee:Flávia Silva Damasceno
Support type: Scholarships in Brazil - Master