title: Probucol-Induced α-Tocopherol Deficiency Protects Mice against Malaria Infection.
abstract: The emergence of malaria pathogens having resistance against antimalarials implies the necessity for the development of new drugs. Recently, we have demonstrated a resistance against malaria infection of α-tocopherol transfer protein knockout mice showing undetectable plasma levels of α-tocopherol, a lipid-soluble antioxidant. However, dietary restriction induced α-tocopherol deficiency is difficult to be applied as a clinical antimalarial therapy. Here, we report on a new strategy to potentially treat malaria by using probucol, a drug that can reduce the plasma α-tocopherol concentration. Probucol pre-treatment for 2 weeks and treatment throughout the infection rescued from death of mice infected with Plasmodium yoelii XL-17 or P. berghei ANKA. In addition, survival was extended when the treatment started immediately after parasite inoculation. The ratio of lipid peroxidation products to parent lipids increased in plasma after 2 weeks treatment of probucol. This indicates that the protective effect of probucol might be mediated by the oxidative stressful environment induced by α-tocopherol deficiency. Probucol in combination with dihydroartemisin suppressed the proliferation of P. yoelii XL-17. These results indicated that probucol might be a candidate for a drug against malaria infection by inducing α-tocopherol deficiency without dietary α-tocopherol restriction.
authors: Research Unit for Functional Genomics, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, Japan.
authors: Maria Shirely
authors: MS
authors: Herbas
authors: Health Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Osaka, Japan.
authors: Mototada
authors: M
authors: Shichiri
authors: Health Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Osaka, Japan.
authors: Noriko
authors: N
authors: Ishida
authors: Research Unit for Functional Genomics, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, Japan; Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.
authors: Aiko
authors: A
authors: Kume
authors: Health Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Osaka, Japan.
authors: Yoshihisa
authors: Y
authors: Hagihara
authors: Health Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Osaka, Japan.
authors: Yasukazu
authors: Y
authors: Yoshida
authors: Research Unit for Functional Genomics, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, Japan; Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.
authors: Hiroshi
authors: H
authors: Suzuki
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects; D008288:Malaria / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D018512:Parasitemia / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010962:Plasmodium berghei / Q000187:drug effects / Q000502:physiology; D010967:Plasmodium yoelii / Q000187:drug effects / Q000502:physiology; D011341:Probucol / Q000494:pharmacology*; D016019:Survival Analysis; D024502:alpha-Tocopherol / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D000975:Antioxidants; D037621:Artemisinins; C039060:artenimol; D024502:alpha-Tocopherol; D011341:Probucol