allopurinol and Malaria

The killing of blood-stage malaria parasites in vivo has been attributed to reactive intermediates of oxygen (ROI) and of nitrogen (RNI). However, in the case of the latter, this contention is challenged by recent observations that parasitemia was not exacerbated in nitric oxide synthase (NOS) knockout (KO) (NOS2-/- or NOS3-/-) mice or in mice treated with NOS inhibitors. We now report that the time course shows that Plasmodium chabaudi parasitemia in NADPH oxidase KO (p47phox-/-) mice also was not exacerbated, suggesting a minimal role for ROI-mediated killing of blood-stage parasites. It is possible that the production of protective antibodies during malaria may mask the function of ROI and/or RNI. However, parasitemia in B-cell-deficient JH-/- x NOS2-/- or JH-/- x p47phox-/- mice was not exacerbated. In contrast, the magnitude of peak parasitemia was significantly enhanced in p47phox-/- mice treated with the xanthine oxidase inhibitor allopurinol, but the duration of patent parasitemia was not prolonged. Whereas the time course of parasitemia in NOS2-/- x p47phox-/- mice was nearly identical to that seen in normal control mice, allopurinol treatment of these double-KO mice also enhanced the magnitude of peak parasitemia. Thus, ROI generated via the xanthine oxidase pathway contribute to the control of ascending P. chabaudi parasitemia during acute malaria but alone are insufficient to suppress parasitemia to subpatent levels. Together, these results indicate that ROI or RNI can contribute to, but are not essential for, the suppression of parasitemia during blood-stage malaria.

Topics: Allopurinol; Animals; Enzyme Inhibitors; Guanidines; Malaria; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase; Parasitemia; Plasmodium chabaudi; Reactive Oxygen Species

Plasmodium yoelii nigeriensis (P. y. nigeriensis) produces lethal malaria infection in Swiss albino mice. Reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide along with endogenously produced tumor necrosis factor (TNF) have been implicated in the pathogenesis of malaria.. Study the effect of TNF on hepatic oxidative stress and antioxidant defense indices in normal and P. y. nigeriensis infected mice.. Mice were divided into four groups. Normal group, TNF treated group, P. y. nigeriensis infected group, and P. y. nigeriensis infected mice treated with TNF group (250 microg/kg body weight, i.p.).. TNF treatment of normal mice caused a highly significant decrease in hepatic superoxide dismutase (SOD) while changes in other oxidative stress and antioxidant defense indices were nonsignificant. On the other hand, TNF treatment of P. y. nigeriensis infected mice caused a highly significant increase in hepatic xanthine oxidase, lipid peroxidation and a significant decrease in hepatic SOD with respect to infected mice.. These results suggest that exogenous TNF acts synergistically with P. y. nigeriensis infection to generate oxidative stress in the host and also causes an impairment of antioxidant defense enzyme such as superoxide dismutase.

Topics: Analysis of Variance; Animals; Antioxidants; Glutathione; Glutathione Reductase; Humans; Lipid Peroxidation; Liver; Malaria; Mice; Oxidative Stress; Plasmodium yoelii; Recombinant Proteins; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Xanthine Oxidase

Reactive Oxygen species play an important role in pathology during malaria infection. The status of hepatic oxidative stress and antioxidant defence indices was studied during Plasmodium yoelii nigeriensis (P. y. nigeriensis) infection in mice and arteether treatment of P. y. nigeriensis infected mice. P. y. nigeriensis infection caused a significant increase in hepatic xanthine oxidase, rate of lipid peroxidation, reduced glutathione (GSH) and glutathione reductase with progressive rise in parasitemia. This was accompanied by a significant decrease in hepatic superoxide dismutase (SOD) and catalase with increase in parasitemia. Arteether treatment (10 mg/kg body weight of mice) of infected mice from day 2 of post infection resulted in complete clearance of parasitemia on day 4 of post infection which was accompanied by restoration of all the oxidative stress and antioxidant defence indices to normal levels.

Topics: Animals; Antimalarials; Antioxidants; Artemisinins; Liver; Malaria; Mice; Oxidative Stress; Plasmodium yoelii; Sesquiterpenes; Xanthine Oxidase

Pathophysiological significance of hypoxia in malarial infection was investigated in mice infected with Plasmodium berghei NK65. Intraperitoneal inoculation of mice with 1 X 10(7) parasitized red blood cells resulted in death of the hosts 6-7 days later. Anaemia of infected animals developed on day 4 after inoculation and oxygen affinity of whole blood, measured as P50 act pH, increased simultaneously. This change may be a physiological adaptive response to a reduction in oxygen delivery to the tissues to day 5. However, the blood oxygen supply on day 6 appeared to be deteriorating and this is thought to be an important factor contributing to the death of the host. The value of adenylate energy charge in red cells during malarial infection, however, was comparatively well-maintained. Allopurinol stimulated the multiplication of malaria parasites and seems to have induced collapse in host-parasite balance more rapidly. Decrease in blood pH and in blood oxygen transport may be important factors for the pathogenesis of the allopurinol-treated hosts.

Topics: Adenine Nucleotides; Allopurinol; Animals; Erythrocytes; Hematocrit; Hemoglobins; Hydrogen-Ion Concentration; Malaria; Male; Mice; Oxygen; Plasmodium berghei

Topics: Animals; Diet; Iron; Lipid Peroxides; Liver; Malaria; Mice; Plasmodium berghei; Xanthine Oxidase; Zinc; Zinc Oxide

Topics: Adenine; Allopurinol; Animals; Carcinoma, Ehrlich Tumor; Liver; Malaria; Mice; Plasmodium berghei; Staphylococcal Infections; Superoxide Dismutase; Time Factors; Xanthine Oxidase

Topics: Animals; Carcinoma, Ehrlich Tumor; Liver; Macrophages; Malaria; Mice; Neutrophils; Plasmodium berghei; Staphylococcal Infections; Superoxide Dismutase; Time Factors; Xanthine Oxidase

Topics: Animals; Liver; Malaria; Male; Mice; Plasmodium berghei; Xanthine Oxidase

Injection of 1.2 U xanthine oxidase in Plasmodium vinckei-infected mice showing high parasitemias prolonged the duration of the asexual cycle by about 10% and slightly decreased the multiplication factor of the parasites. This appears to be of theoretical interest only since the rapid and fatal course of the infection remained essentially unaltered.

Topics: Animals; Female; Malaria; Mice; Plasmodium; Purines; Reproduction, Asexual; Xanthine Oxidase

Topics: Allopurinol; Animals; Cell Division; Female; Hypoxanthines; Malaria; Mice; Mice, Inbred Strains; Plasmodium; Plasmodium berghei; Rats