Ellagic acid microspheres restrict the growth of Babesia and Theileria in vitro and Babesia microti in vivo

Abstract Background There are no effective vaccines against Babesia and Theileria parasites; therefore, therapy depends heavily on antiprotozoal drugs. Treatment options for piroplasmosis are limited; thus, the need for new antiprotozoal agents is becoming increasingly urgent. Ellagic acid (EA) is a...

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Main Authors: Amani Magdy Beshbishy, Gaber El-Saber Batiha, Naoaki Yokoyama, Ikuo Igarashi
Format: Article
Language:English
Published: BMC 2019-05-01
Series:Parasites & Vectors
Subjects:
Online Access:http://link.springer.com/article/10.1186/s13071-019-3520-x
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author Amani Magdy Beshbishy
Gaber El-Saber Batiha
Naoaki Yokoyama
Ikuo Igarashi
author_facet Amani Magdy Beshbishy
Gaber El-Saber Batiha
Naoaki Yokoyama
Ikuo Igarashi
author_sort Amani Magdy Beshbishy
collection DOAJ
description Abstract Background There are no effective vaccines against Babesia and Theileria parasites; therefore, therapy depends heavily on antiprotozoal drugs. Treatment options for piroplasmosis are limited; thus, the need for new antiprotozoal agents is becoming increasingly urgent. Ellagic acid (EA) is a polyphenol found in various plant products and has antioxidant, antibacterial and effective antimalarial activity in vitro and in vivo without toxicity. The present study documents the efficacy of EA and EA-loaded nanoparticles (EA-NPs) on the growth of Babesia and Theileria. Methods In this study, the inhibitory effect of EA, β-cyclodextrin ellagic acid (β-CD EA) and antisolvent precipitation with a syringe pump prepared ellagic acid (APSP EA) was evaluated on four Babesia species and Theileria equi in vitro, and on the multiplication of B. microti in mice. The cytotoxicity assay was tested on Madin-Darby bovine kidney (MDBK), mouse embryonic fibroblast (NIH/3T3) and human foreskin fibroblast (HFF) cell lines. Results The half-maximal inhibitory concentration (IC50) values of EA and β-CD EA on B. bovis, B. bigemina, B. divergens, B. caballi and T. equi were 9.58 ± 1.47, 7.87 ± 5.8, 5.41 ± 2.8, 3.29 ± 0.42 and 7.46 ± 0.6 µM and 8.8 ± 0.53, 18.9 ± 0.025, 11 ± 0.37, 4.4 ± 0.6 and 9.1 ± 1.72 µM, respectively. The IC50 values of APSP EA on B. bovis, B. bigemina, B. divergens, B. caballi and T. equi were 4.2 ± 0.42, 9.6 ± 0.6, 2.6 ± 1.47, 0.92 ± 5.8 and 7.3 ± 0.54 µM, respectively. A toxicity assay showed that EA, β-CD EA and APSP EA affected the viability of cells with a half-maximal effective concentration (EC50) higher than 800 µM. In the experiments on mice, APSP EA at a concentration of 70 mg/kg reduced the peak parasitemia of B. microti by 68.1%. Furthermore, the APSP EA-atovaquone (AQ) combination showed a higher chemotherapeutic effect than that of APSP EA monotherapy. Conclusions To our knowledge, this is the first study to demonstrate the in vitro and in vivo antibabesial action of EA-NPs and thus supports the use of nanoparticles as an alternative antiparasitic agent.
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spelling doaj.art-08b3fa7c5d4d4deeb9bf700419ad60a02022-12-22T00:55:45ZengBMCParasites & Vectors1756-33052019-05-0112111310.1186/s13071-019-3520-xEllagic acid microspheres restrict the growth of Babesia and Theileria in vitro and Babesia microti in vivoAmani Magdy Beshbishy0Gaber El-Saber Batiha1Naoaki Yokoyama2Ikuo Igarashi3National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary MedicineNational Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary MedicineNational Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary MedicineNational Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary MedicineAbstract Background There are no effective vaccines against Babesia and Theileria parasites; therefore, therapy depends heavily on antiprotozoal drugs. Treatment options for piroplasmosis are limited; thus, the need for new antiprotozoal agents is becoming increasingly urgent. Ellagic acid (EA) is a polyphenol found in various plant products and has antioxidant, antibacterial and effective antimalarial activity in vitro and in vivo without toxicity. The present study documents the efficacy of EA and EA-loaded nanoparticles (EA-NPs) on the growth of Babesia and Theileria. Methods In this study, the inhibitory effect of EA, β-cyclodextrin ellagic acid (β-CD EA) and antisolvent precipitation with a syringe pump prepared ellagic acid (APSP EA) was evaluated on four Babesia species and Theileria equi in vitro, and on the multiplication of B. microti in mice. The cytotoxicity assay was tested on Madin-Darby bovine kidney (MDBK), mouse embryonic fibroblast (NIH/3T3) and human foreskin fibroblast (HFF) cell lines. Results The half-maximal inhibitory concentration (IC50) values of EA and β-CD EA on B. bovis, B. bigemina, B. divergens, B. caballi and T. equi were 9.58 ± 1.47, 7.87 ± 5.8, 5.41 ± 2.8, 3.29 ± 0.42 and 7.46 ± 0.6 µM and 8.8 ± 0.53, 18.9 ± 0.025, 11 ± 0.37, 4.4 ± 0.6 and 9.1 ± 1.72 µM, respectively. The IC50 values of APSP EA on B. bovis, B. bigemina, B. divergens, B. caballi and T. equi were 4.2 ± 0.42, 9.6 ± 0.6, 2.6 ± 1.47, 0.92 ± 5.8 and 7.3 ± 0.54 µM, respectively. A toxicity assay showed that EA, β-CD EA and APSP EA affected the viability of cells with a half-maximal effective concentration (EC50) higher than 800 µM. In the experiments on mice, APSP EA at a concentration of 70 mg/kg reduced the peak parasitemia of B. microti by 68.1%. Furthermore, the APSP EA-atovaquone (AQ) combination showed a higher chemotherapeutic effect than that of APSP EA monotherapy. Conclusions To our knowledge, this is the first study to demonstrate the in vitro and in vivo antibabesial action of EA-NPs and thus supports the use of nanoparticles as an alternative antiparasitic agent.http://link.springer.com/article/10.1186/s13071-019-3520-xEllagic acidβ-cyclodextrin ellagic acidAPSP EANanoparticlesBabesiaTheileria
spellingShingle Amani Magdy Beshbishy
Gaber El-Saber Batiha
Naoaki Yokoyama
Ikuo Igarashi
Ellagic acid microspheres restrict the growth of Babesia and Theileria in vitro and Babesia microti in vivo
Parasites & Vectors
Ellagic acid
β-cyclodextrin ellagic acid
APSP EA
Nanoparticles
Babesia
Theileria
title Ellagic acid microspheres restrict the growth of Babesia and Theileria in vitro and Babesia microti in vivo
title_full Ellagic acid microspheres restrict the growth of Babesia and Theileria in vitro and Babesia microti in vivo
title_fullStr Ellagic acid microspheres restrict the growth of Babesia and Theileria in vitro and Babesia microti in vivo
title_full_unstemmed Ellagic acid microspheres restrict the growth of Babesia and Theileria in vitro and Babesia microti in vivo
title_short Ellagic acid microspheres restrict the growth of Babesia and Theileria in vitro and Babesia microti in vivo
title_sort ellagic acid microspheres restrict the growth of babesia and theileria in vitro and babesia microti in vivo
topic Ellagic acid
β-cyclodextrin ellagic acid
APSP EA
Nanoparticles
Babesia
Theileria
url http://link.springer.com/article/10.1186/s13071-019-3520-x
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