title: Probucol dramatically enhances dihydroartemisinin effect in murine malaria.
abstract: Artemisinin-based combination therapy (ACT) has been adopted as national policy for the first-line treatment in large number of malaria-endemic regions. However, artemisinin-resistant parasites have emerged and are spreading, with slow-cleaning parasites being reported in patients treated with ACT. It means that more parasites are exposed to the partner drug alone and the risk of developing resistant parasites against the partner drug is increasing. Therefore, the development of a new method to enhance the effect of artemisinin is required. In this study, the potential effect of probucol as a combination drug of dihydroartemisinin (DHA), an artemisinin derivative, was examined.
  
  
  
  C57BL/6 J mice infected with Plasmodium yoelii XL-17 were treated with probucol and/or DHA. The mice were fed with a probucol mixed diet from 2 weeks before infection and through infection period. DHA was injected to mice three to 5 days post infection once a day. In addition, 0.5 % (w/w) probucol was mixed with vitamin E supplemented diet (800 mg/kg) and fed to mice infected with P. yoelii XL-17 to examine the mechanisms of probucol on murine malaria. Furthermore, 8-OHdG, a biomarker of oxidized DNA, was detected in infected red blood cells (iRBC) taken from infected mice by immunofluorescent staining.
  
  
  
  With dose-dependent manner, both probucol and DHA decreased parasitaemia and increased survival rate of mice infected with P. yoelii XL-17. A significantly larger amount of 8-OHdG was detected in iRBC taking from probucol-treated mice than control mice. In addition, a large amount of vitamin E supplementation eliminated the effect of probucol against P. yoelii XL-17 infection and lowered the effect of probucol on host plasma vitamin E concentration. The effective doses for probucol and DHA were 0.5 % and 30 mg/kg, respectively, in each single treatment. While the combination treatment of 0.25 % probucol and 7.5 mg/kg DHA was effective in all mice from P. yoelii XL-17 infection.
  
  
  
  This study demonstrated that probucol has some impact on malaria by oxidative stress through the induction of host plasma vitamin E deficiency. Moreover, the effective dose of DHA on malaria was decreased by prophylactic treatment of probucol. This finding indicates that probucol might be a candidate for a prophylactic treatment drug to enhance the effect of DHA.
authors.affiliation: Research Unit for Functional Genomics, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro City, Hokkaido, Japan.|The United Graduate School of Veterinary Sciences, Gifu University, Gifu City, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Kume
authors.affiliation: Research Unit for Functional Genomics, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro City, Hokkaido, Japan.|Microbiology and Immunology Department, Pasteur Institute in Ho Chi Minh City, Ministry of Health, Ho Chi Minh City, Vietnam.
authors.forename: Dang Trinh Minh
authors.initials: DT
authors.lastname: Anh
authors.affiliation: Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ikeda City, Osaka, Japan.
authors.forename: Mototada
authors.initials: M
authors.lastname: Shichiri
authors.affiliation: Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ikeda City, Osaka, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ishida
authors.affiliation: Research Unit for Functional Genomics, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro City, Hokkaido, Japan. hisuzuki@obihiro.ac.jp.|The United Graduate School of Veterinary Sciences, Gifu University, Gifu City, Japan. hisuzuki@obihiro.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000494:pharmacology*; D037621:Artemisinins / Q000008:administration & dosage* / Q000494:pharmacology*; D018890:Chemoprevention / Q000379:methods; D004195:Disease Models, Animal; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D008810:Mice, Inbred C57BL; D010967:Plasmodium yoelii / Q000187:drug effects; D011341:Probucol / Q000008:administration & dosage* / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C039060:artenimol; D011341:Probucol
keywords: C57BL/6 J mice; Dihydroartemisinin; Malaria; Oxidative stress; Plasmodium yoelii XL-17; Probucol; Vitamin E