Drugs glucose modulators Echinococcus granulosus: implications for anticestodial therapy.

LOOS JULIA A; CUMINO ANDREA C

Buenos Aires

Congreso; I Congreso Internacional de Zoonosis y Enfermedades Emergentes y VII Congreso Argentino de Zoonosis; 2011

Asociación Argentina de Zoonosis

Echinococcosis is a near-cosmopolitan zoonosis caused by helminthic parasites belonging to the genus Echinococcus sp. Glucose and other simple carbohydrates are the main energy source in both larval and adult of the cestode, while glycogen serves as the most important energy reserve in these parasites. The glycogen concentration and metabolism in helminthes are known to be affected by a number of anthelmintic agents (benzimidazole derivates, praziquantel, and genistein). Here, we investigated the effects of possible glucose modulators, metformin and glibenclamide, in the viability of protoscoleces and metacestode of Echinocuccus granulosus, causative agent of the cystic hydatid disease. Metformin (biguanide) inhibit gluconeogenesis and mitochondrial respiratory chain complex I, and activates the AMP-activated kinase (AMPK) in insulin-sensitive tissues. On the other hand, glibenclamide is an ABC-transporter blocker which inhibits anion transporters such as P-glycoprotein and modulated the function of glucose transporters. Both drugs reduced the vitality of protoscoleces in a dose-dependent manner and induce the deleterious effect on laminated layer of intact cysts. Scanning electron and confocal microscopy were determined. Hence, we observed on treated protoscoleces with glibenclamide an increase in intracellular Ca2+ concentration determined by labelling with Fluo-3 AM and imaged by a confocal laser microscope and on treated protoscoleces with metformin decrease in the expression of gene encoding key enzymes in the type 2 fermentation (CO2-fixation and malate dismutation steps). As metformin sensitivity is the major criterion used to detect AMP kinase, we identified and analyzed in silico critical residues of putative homologs in Echinococcus genome. BLAST searches revealed witch these genes predict ORFs have 42% and 75% of identity compared with ortholog gene in human and S. mansoni, respectively. Conclusiones Parasites, like other organisms have to have a supply of energy for the synthesis of macromolecules, growth and reproduction. Inhibition of energy metabolism is likely to be rapidly fatal so it is a potential target for chemotherapy. These preliminary results will let us continue subsequent studies that may improve the outline for further identification of downstream target proteins, a promising target for chemotherapy of cystic echinococcosis.