Abstract
Amoebiasis is a human parasitic disease caused by Entamoeba histolytica. The parasite can invade the large intestine and other organs such as liver; resistance to the host tissue oxygen is a condition for parasite invasion and survival. Thioredoxin reductase of E. histolytica (EhTrxR) is a critical enzyme mainly involved in maintaining reduced the redox system and detoxifying the intracellular oxygen; therefore, it is necessary for E. histolytica survival under both aerobic in vitro and in vivo conditions. In the present work, it is reported that rabeprazole (Rb), a drug widely used to treat heartburn, was able to inhibit the EhTrxR recombinant enzyme. Moreover, Rb affected amoebic proliferation and several functions required for parasite virulence such as cytotoxicity, oxygen reduction to hydrogen peroxide, erythrophagocytosis, proteolysis, and oxygen and complement resistances. In addition, amoebic pre-incubation with sublethal Rb concentration (600 μM) promoted amoebic death during early liver infection in hamsters. Despite the high Rb concentration used to inhibit amoebic virulence, the wide E. histolytica pathogenic-related functions affected by Rb strongly suggest that its molecular structure can be used as scaffold to design new antiamoebic compounds with lower IC50 values.
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Acknowledgments
This work is part of the doctoral dissertation of Y. M-P. We acknowledge Anayantzin P. Heredia-Antúnez, MSc for the professional animal care.
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This research was supported by DGAPA grant IN-214617 and CONACyT-Mexico grant 247430.
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All experiments involving animals were performed in strict accordance with the Mexican Law for the Production, Care and Use of Laboratory Animals (NOM-062-ZOO-1999). All animal procedures were carried out under the protocol number 026–CIC-2019, approved by the Institutional Animal Care and Use Committees of the Facultad de Medicina, Universidad Nacional Autónoma de México. All efforts were made to minimize animal suffering.
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In memoriam of Alfonso Olivos-García. May 26th, 2020.
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Supplementary Figure 1.
Histological images of amoebae preincubated with rabeprazole at different concentrations. Amoebae were incubated with 0, 200, 400 and 600 μM of Rb for 6 h at 37°C. After they were washed and 1x106 parasites were injected into the portal vein of hamster liver. After 7 days, the animals were sacrificed and the livers were processed for histological studies. In the figure, some parasites are indicated with arrows. A, Amoeba control (without Rb). B and C, show the histological sections with amoebae pretreated with 200 and 400 μM of Rb respectively. The presence of amoebae, tissue damage and polymorphonuclear infiltrate is observed. D, at 600 μM Rb, there is only residual tissue damage without the presence of amoebae in the liver tissue. (PNG 2063 kb)
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Martínez-Pérez, Y., Nequiz-Avendaño, M., García-Torres, I. et al. Rabeprazole inhibits several functions of Entamoeba histolytica related with its virulence. Parasitol Res 119, 3491–3502 (2020). https://doi.org/10.1007/s00436-020-06868-0
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DOI: https://doi.org/10.1007/s00436-020-06868-0