Metformin improves the therapeutic efficacy of low-dose albendazole against experimental alveolar echinococcosis

Abstract

Alveolar echinococcosis (AE) is a severe disease caused by Echinococcus multilocularis. Its chemotherapeutic treatment is based on benzimidazoles, which are rarely curative and cause several adverse effects. Therefore, it is necessary to develop alternative and safer chemotherapeutic strategies against AE. It has previously been shown that metformin (Met) exhibits considerable in vivo activity on an early-infection model of AE when administered at 50 mg kg−1 day−1 for 8 weeks. Here, the challenge is heightened by a 2-fold increase in parasite inoculum or by starting the treatment 6 weeks post-infection. In both cases, only the combination of Met (100 mg kg−1 day−1) together with a sub-optimal dose of albendazole (ABZ) (5 mg kg−1 day−1) led to a significant reduction in parasite weight compared to the untreated group. Coincidentally, drug combination showed the highest level of damage in E. multilocularis metacestodes. Likewise, Met alone or combined with ABZ led to a decrease in parasite glucose availability, which was evidenced as a lower intracystic glucose concentration. Therefore, the results demonstrate that combination therapy with Met and ABZ offers an alternative to improve the efficacy and reduce the toxicity of the high-dose ABZ monotherapy currently employed.

Resveratrol against Echinococcus sp.: Discrepancies between In Vitro and In Vivo Responses

“…An advantage of using Met as an anti-echinococcal drug is that it reaches effective concentrations in the cyst [12]. Thus, regardless of the pharmacological effect of Rsv, its combination with Met did not prevent Met from achieving the control of parasite development, this being due to its high stability and bioavailability, as well as the ability to penetrate the cysts, conducive to achieving an effective concentration of Met in the parasite [12][13][14]. In addition, a SEM study revealed that, although germinal layers of metacestodes obtained from Rsv-treated mice exhibited some kind of damage, they showed evident parasitic development with the presence of protoscoleces.…”

“…Previously, we have demonstrated that metformin (Met), an anti-diabetic drug with high safety for normoglycemic individuals, restricts the development of metacestodes in murine models of cystic and alveolar echinococcosis [12][13][14]. The drug acts by inhibiting mitochondrial complex I of E. granulosus and E. multilocularis, leading to the activation of AMPK, suppression of TORC1 and induction of autophagy [15][16][17].…”

“…The drug acts by inhibiting mitochondrial complex I of E. granulosus and E. multilocularis, leading to the activation of AMPK, suppression of TORC1 and induction of autophagy [15][16][17]. In addition, a combination of Met with low doses of ABZ improves the antiparasitic therapy efficiency in late stages of metacestode development [12,14]. Met treatment also increased levels of parasite-released lactate, suggesting that the parasite switched to fermentation for energy generation when complex I (of both the electron transport chain and the malate dismutation) was blocked [14,15].…”

“…In addition, a combination of Met with low doses of ABZ improves the antiparasitic therapy efficiency in late stages of metacestode development [12,14]. Met treatment also increased levels of parasite-released lactate, suggesting that the parasite switched to fermentation for energy generation when complex I (of both the electron transport chain and the malate dismutation) was blocked [14,15]. Targeting the Warburg effect may thus be a good strategy to hinder these parasites or even improve Met anti-echinococcal activity.…”

Characterization of protein cargo of Echinococcus granulosus extracellular vesicles in drug response and its influence on immune response

“…We determined that the sEVs of this cestode induced the production of pro-inflammatory cytokines from BMDC, which promoted a Th1 profile in T cells, mainly with those vesicles derived from metformin treatment. These results contribute to our understanding of the high pharmacological efficacy of these drugs in in vivo echinococcosis experimental models, where the sEVs can participate in the potentiation of the host immune response for parasite growth control [ 31 , 91 ]. In this study, we provide the first evidence of the common, enriched, and unique protein cargo of sEVs obtained under albendazole and metformin treatment.…”