Deferoxamine inhibition of malaria is independent of host iron status.

Abstract

The mechanism whereby deferoxamine (DF) inhibits the growth of malaria parasites was studied in rats infected with Plasmodium berghei. Peak parasitemia was 32.6% (day 14) in untreated controls and 0.15% (day 7) in rats receiving 0.33 mg/g in 8 hourly DF injections, subcutaneously. DF inhibition of parasite growth was achieved without any reduction in transferrin saturation or hemoglobin synthesis and with only a partial (56%) depletion of hepatic iron stores. Dietary iron depletion resulted in anemia (hematocrit 25 vs. 46%), microcytosis (MCV 54 vs. 60 fl), and reduced transferrin saturation (17 vs. 96%) without any effect on infection (peak parasitemia 30 vs. 36%). Similarly, parenteral iron loading with ferric citrate over 10 d (75 mg iron/kg) failed to aggravate infection. In a search for evidence of direct interaction between DF and parasitized erythrocytes, gel filtration and ultrafiltration was performed on hemolysates obtained from in vivo 59Fe-labeled parasitized erythrocytes. This showed that 1.1-1.9% of the intracellular radioiron was located in a chelatable, labile iron pool. Incubation of intact cells with 0-500 microM DF resulted in a proportional increase in intracellular iron chelation, and the chelation of all available labile intracellular iron was completed within 6 h. These observations indicate that the severity of P. berghei infection in rats and its in vivo suppression by DF are independent of host iron status and suggest that DF inhibition of malaria involves intracellular chelation of a labile iron pool in parasitized erythrocytes.

Changes in Iron and Ferritin in Anemic Calves Infected with Theileria sergenh.

“…In contrast, little increase in these parameters has been found in human [16] and rat [7] malaria. Hepatic non-heme iron was found in the present study to be markedly elevated in Theileria-infected calves, whereas there is no significant increase in hepatic non-heme iron in malaria-infected rats with anemia [7].…”

Chloroquine inhibits the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. A potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens.

“…The source ofthis iron for the malaria parasite is unclear. Some evidence suggests that it derives from host iron transferrin (28)(29)(30) and other evidence suggests that it derives from host erythrocyte hemoglobin (31,32). Whatever the source of iron, its intracellular mobilization is likely dependent upon acidic conditions.…”

The antimalarial action of desferal involves a direct access route to erythrocytic (Plasmodium falciparum) parasites.

“…The information available indicates that DFO acts without affecting serum (4,10) or normal red cell iron pools (3,10), that it gains a restricted access to infected cells ( 11 ), and that its antimalarial action is manifested only in the advanced stages of parasite development and only after prolonged exposure of cells to drug (3,12). All this evidence implies that DFO gains a slow and limited access to the mature stages of erythrocytic parasites where it exerts cytotoxic action on still unidentified parasite targets.…”

“…Recently it was shown that DFO congeners display effective antimalarial activity both in vitro (2)(3)(4)(5) and in vivo (4,(6)(7)(8)(9), but as with many other drugs, their mode of action has remained elusive (1). The information available indicates that DFO acts without affecting serum (4,10) or normal red cell iron pools (3,10), that it gains a restricted access to infected cells ( 11 ), and that its antimalarial action is manifested only in the advanced stages of parasite development and only after prolonged exposure of cells to drug (3,12).…”

“…Ingress ofDFO and ofMA-DFO into normal and infected cells (10% hematocrit, > 80% parasitemia) was measured either with free drug (MA-DFO) or after complexation of DFO or MA-DFO (at 40 ,M) with 4 ,uM unlabeled iron(III)CI3 and 59Fe citrate (5 x 105 cpm/ ml) in RPMI. After various times of incubation at 37°C (0-24 h), cells were thoroughly washed with isotonic NaCl containing 10 mM EDTA, pH 7.4, and lysed with distilled water.…”