| Autor: |
Loos JA; IIPROSAM, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mar del Plata, Argentina., Negro PS; Parasitología y Enfermedades Parasitarias, Facultad de Ciencias Veterinarias, Universidad Nacional de Rosario, Casilda, Santa Fe, Argentina., Ortega HH; Centro de Medicina Comparada, ICiVet-Litoral, Universidad Nacional del Litoral-CONICET, Esperanza, Santa Fe, Argentina., Salinas FJ; Centro de Medicina Comparada, ICiVet-Litoral, Universidad Nacional del Litoral-CONICET, Esperanza, Santa Fe, Argentina., Arán M; Fundación Instituto Leloir e Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA)-CONICET, Buenos Aires, Argentina., Pellizza L; Fundación Instituto Leloir e Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA)-CONICET, Buenos Aires, Argentina., Salerno GL; Fundación Para Investigaciones Biológicas Aplicadas (FIBA), Mar del Plata, Argentina., Cumino AC; IIPROSAM, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mar del Plata, Argentina.; Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina. |
| Abstrakt: |
Metformin, a safe biguanide derivative with antiproliferative properties, has shown antiparasitic efficacy against the Echinococcus larval stage. Hence, we assessed the efficacy of a dose of 250 mg kg -1 day -1 in experimental models of advanced CE, at 6 and 12 months post-infection with oral and intraperitoneal administration, respectively. At this high dose, metformin reached intracystic concentrations between 0.7 and 1.7 mM and triggered Eg-TOR inhibition through AMPK activation by AMP-independent and -dependent mechanisms, which are dependent on drug dose. Cystic metformin uptake was controlled by increased expression of organic cation transporters in the presence of the drug. In both experimental models, metformin reduced the weight of parasite cysts, altered the ultrastructural integrity of their germinal layers, and reduced the intracystic availability of glucose, limiting the cellular carbon and energy charge and the proliferative capacity of metacestodes. This glucose depletion in the parasite was associated with a slight increase in cystic uptake of 2-deoxiglucose and the transcriptional induction of GLUT genes in metacestodes. In this context, drastic glycogen consumption led to increased lactate production and altered intermediary metabolism in treated metacestodes. Specifically, the fraction of reducing soluble sugars decreased twofold, and the levels of non-reducing soluble sugars, such as sucrose and trehalose, were modified in both cystic fluid and germinal cells. Taken together, our findings highlight the relevance of metformin as a promising candidate for CE treatment and warrant further research to improve the therapeutic conditions of this chronic zoonosis in humans. |
