Preventive and clinical efficacies of metformin against experimental cyst echinococcosis

JULIA A. LOOS; ANDREA C. CUMINO

Manchester

Conferencia; 2nd International Conference on Parasitology; 2016

OMICS International

Metformin (Met) is an antihyperglycemic and a potential anticancer agent which may exert its anti-proliferative effects, bothindirectly through the systemic reduction of insulin levels and directly, via the induction of energetic stress, involving theinhibition of ATP production, the activation of AMP activated protein kinase (AMPK) and the inhibition of the target of rapamycincomplex (TORC1). The drug shows good oral bioavailability (50-60%), is stable and not metabolized and its pharmacokinetics isregulated by transporters of the major facilitator superfamily (MFS). The aim of this study was to test the in vitro effect of Met alone orin combination with low concentrations of albendazole (ABZ) on Echinococcus granulosus larval stage and to report on their effectsin vivo employing murine cyst echinococcosis infection model. Viable protoscoleces (PTS, N=3000) and metacestodes (MTC, N=20)were cultured in vitro in 199 medium and mortality was calculated daily. To determine the in vivo clinical and chemoprophylacticefficacies, mice were inoculated intraperitoneally with viable PTS and then treated once daily by intragastric administration for 60days with the Met (50 mg kg-1 day-1) and ABZ (5 mg kg-1 day-1), separately and in combination (both Met at 50 mg kg-1 day-1 andABZ at 50 mg kg-1 day-1). Next, the hydatid cysts collected from the peritoneal cavity of the animals were weighed and analyzed byscanning and transmission electron microscopy, determining also the Met intracyst concentration. Administration of Met to culturedPTS and MTC showed significant dose and time dependent killing effects and the combination of Met and ABZ-SO, (the main activemetabolite of ABZ), had an synergistic effect from day 12 or 4 in PTS and MTC, respectively. RT-PCR analysis indicated expressionof the five genes encoding for Echinococcus organic cation transporters in PTS and MTC. In Met treated MTC an overexpression ofall studied genes was observed, except for Eg-slcD; while that in PTS no changes in the transcriptional expression level of these geneswas detected, except for Eg-slcE. In the clinical efficacy study, the weight of hydatid cysts was significantly decreased upon treatmentwith each drug (P