title: Dual antiplasmodial activity of vitamin D3 and its analog, 22-oxacalcitriol, by direct and indirect mechanisms.
abstract: Recent evidence suggests that 1α,25-dihydroxyvitamin D3 (calcitriol, VD3), the active form of vitamin D (VD), can inhibit the proliferation of microorganisms. In the present study, we conducted in vitro experiments and utilized in vivo murine models to investigate the antimalarial activity of VD3 and its analog, 22-oxacalcitriol (22-OCT), which was designed to cause less hypercalcemia than VD3. VD3 and 22-OCT treatments effectively resolved a Plasmodium chabaudi (Pc) infection in wild-type mice. Reduced parasitemia was observed during the acute phase of infection in the presence of VD3 and 22-OCT, followed by a delayed peak during the chronic stage of infection. Some anti-Pc activity was observed in VD receptor knockout (KO) mice. VD3 and 22-OCT also completely inhibited the proliferation of P. falciparum (Pf) in human red blood cells in vitro. Plasma levels of interferon (IFN)-γ in VD3-treated B10 and B6 mice were lower than those in vehicle-treated animals, and VD3 resolved a Pc infection in IFN-γ-KO mice, which greatly improved survival. These data suggest that the protective effects of VD3 are elicited through an IFN-γ-independent mechanism. Effective antiplasmodial doses of VD3 and 22-OCT resulted in a loss of body weight in mice. This loss in body weight occurred concomitantly with the development of hypercalcemia. Zoledronic acid partially attenuated VD3-induced hypercalcemia and abrogated the antiparasitic effects of VD3. This study highlights a potential therapeutic role for VD3 in the treatment of malarial infections and shows that hypercalcemia is excellent indicator of the antiplasmodial activity of VD3.
authors.affiliation: Section of Environmental Parasitology, Tokyo Medical and Dental University, Japan; Department of Immunology, National Institute of Infectious Diseases, Japan. Electronic address: kyama-q3.3@mopera.net.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Tropical Medicine and Malaria Research Institute, National Center for Global Health and Medicine, Japan.
authors.forename: Moritoshi
authors.initials: M
authors.lastname: Iwagami
authors.affiliation: Section of Environmental Parasitology, Tokyo Medical and Dental University, Japan.
authors.forename: Takenori
authors.initials: T
authors.lastname: Seki
authors.affiliation: Department of Tropical Medicine and Malaria Research Institute, National Center for Global Health and Medicine, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kano
authors.affiliation: Section of Environmental Parasitology, Tokyo Medical and Dental University, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Ota
authors.affiliation: Department of Immunology, National Institute of Infectious Diseases, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Ato
mesh_terms: D000208:Acute Disease / Q000628:therapy; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002762:Cholecalciferol / Q000008:administration & dosage / Q000494:pharmacology*; D002908:Chronic Disease / Q000188:drug therapy; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D006934:Hypercalcemia / Q000097:blood / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007371:Interferon-gamma / Q000097:blood / Q000172:deficiency; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018512:Parasitemia / Q000188:drug therapy / Q000276:immunology / Q000469:parasitology; D016788:Plasmodium chabaudi / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D018167:Receptors, Calcitriol / Q000172:deficiency; D000077211:Zoledronic Acid
chemical_list: D000962:Antimalarials; D004164:Diphosphonates; D007093:Imidazoles; D018167:Receptors, Calcitriol; D002762:Cholecalciferol; D000077211:Zoledronic Acid; D007371:Interferon-gamma; D002117:Calcitriol; C051883:maxacalcitol
keywords: Antiplasmodial activity; Direct and indirect mechanism; Hypercalcemia; Rodent malaria; Vitamin D3