In vivo curative and protective potential of orally administered 5-aminolevulinic acid plus ferrous ion against malaria.
5-Aminolevulinic acid (ALA) is a naturally occurring amino acid present in diverse organisms and a precursor of heme biosynthesis. ALA is commercially available as a component of cosmetics, dietary supplements, and pharmaceuticals for cancer diagnosis and therapy. Recent reports demonstrated that the combination of ALA and ferrous ion (Fe(2+)) inhibits the in vitro growth of the human malaria parasite Plasmodium falciparum. To further explore the potential application of ALA and ferrous ion as a combined antimalarial drug for treatment of human malaria, we conducted an in vivo efficacy evaluation. Female C57BL/6J mice were infected with the lethal strain of rodent malaria parasite Plasmodium yoelii 17XL and orally administered ALA plus sodium ferrous citrate (ALA/SFC) as a once-daily treatment. Parasitemia was monitored in the infected mice, and elimination of the parasites was confirmed using diagnostic PCR. Treatment of P. yoelii 17XL-infected mice with ALA/SFC provided curative efficacy in 60% of the mice treated with ALA/SFC at 600/300 mg/kg of body weight; no mice survived when treated with vehicle alone. Interestingly, the cured mice were protected from homologous rechallenge, even when reinfection was attempted more than 230 days after the initial recovery, indicating long-lasting resistance to reinfection with the same parasite. Moreover, parasite-specific antibodies against reported vaccine candidate antigens were found and persisted in the sera of the cured mice. These findings provide clear evidence that ALA/SFC is effective in an experimental animal model of malaria and may facilitate the development of a new class of antimalarial drug.
Department of Biomedical Chemistry, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
Shigeo
S
Suzuki
Department of Biomedical Chemistry, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
Kenji
K
Hikosaka
Department of Biomedical Chemistry, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan Department of Applied Biology, Graduate School of Science and Technology, Kyoto Institute of Technology, Kyoto, Japan Department of Biochemistry, Ahmadu Bello University, Zaria, Nigeria.
Emmanuel O
EO
Balogun
Department of Biomedical Chemistry, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
Keisuke
K
Komatsuya
Department of Infectious Diseases, Kyorin University School of Medicine, Tokyo, Japan.
Mamoru
M
Niikura
Department of Infectious Diseases, Kyorin University School of Medicine, Tokyo, Japan.
Fumie
F
Kobayashi
SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
Kiwamu
K
Takahashi
SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
Tohru
T
Tanaka
SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
Motowo
M
Nakajima
Department of Biomedical Chemistry, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan kitak@m.u-tokyo.ac.jp.
Kiyoshi
K
Kita
D000622:Aminolevulinic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects / Q000472:pathogenicity; D016133:Polymerase Chain Reaction
D000622:Aminolevulinic Acid