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British Journal of Experimental Pathology logoLink to British Journal of Experimental Pathology
. 1989 Jun;70(3):293–303.

Antioxidants can prevent cerebral malaria in Plasmodium berghei-infected mice.

C M Thumwood 1, N H Hunt 1, W B Cowden 1, I A Clark 1
PMCID: PMC2040571  PMID: 2669924

Abstract

A/J and CBA/H mice infected with Plasmodium berghei ANKA, a murine model of cerebral malaria, were used to see whether antioxidants influenced the outcome of this disease. Untreated, infected mice died 7 to 9 days after infection, often with cerebral symptoms. Haemorrhages, mononuclear infiltration and oedema were present in the central nervous system (CNS). Feeding a diet containing 0.75% (w/w) butylated hydroxyanisole (BHA) greatly altered the course of this disease. Death was delayed by up to 2 weeks and mice appeared healthy at parasitaemias that would have caused cerebral symptoms and death had they been on a conventional diet. BHA-fed mice showed few or no cerebral symptoms at a time at which control mice were clearly affected, and greatly reduced haemorrhages, mononuclear infiltration and oedema when the CNS was examined. Similar, but more consistent, protective effects were seen after administration of BHA by repeated injections or in osmotic pumps. The combination of superoxide dismutase and catalase, coupled to polyethylene glycol, when administered intravenously also protected mice against death from cerebral complications. Permeability of the blood-brain barrier was monitored by the use of 125I-labelled bovine serum albumin, 51Cr-labelled erythrocytes and the dye Evans blue, all of which are normally excluded from the CNS. Infected mice on control diet showed an increase in Evans blue staining and 125I and 51Cr retention in the CNS tissue itself. Feeding the diet containing BHA reduced these indices of increased blood-brain barrier permeability. In view of the potent radical scavenging activity of BHA in many other systems it is likely, but unproven, that this is its main role here. The protective effect of superoxide dismutase and catalase lends support to the idea that reactive oxygen species are involved in the pathology of experimental cerebral malaria.

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Selected References

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  1. Adam C., Géniteau M., Gougerot-Pocidalo M., Verroust P., Lebras J., Gibert C., Morel-Maroger L. Cryoglobulins, circulating immune complexes, and complement activation in cerebral malaria. Infect Immun. 1981 Feb;31(2):530–535. doi: 10.1128/iai.31.2.530-535.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Badwey J. A., Karnovsky M. L. Active oxygen species and the functions of phagocytic leukocytes. Annu Rev Biochem. 1980;49:695–726. doi: 10.1146/annurev.bi.49.070180.003403. [DOI] [PubMed] [Google Scholar]
  3. Chaudhri G., Clark I. A., Hunt N. H., Cowden W. B., Ceredig R. Effect of antioxidants on primary alloantigen-induced T cell activation and proliferation. J Immunol. 1986 Oct 15;137(8):2646–2652. [PubMed] [Google Scholar]
  4. Chaudhri G., Hunt N. H., Clark I. A., Ceredig R. Antioxidants inhibit proliferation and cell surface expression of receptors for interleukin-2 and transferrin in T lymphocytes stimulated with phorbol myristate acetate and ionomycin. Cell Immunol. 1988 Aug;115(1):204–213. doi: 10.1016/0008-8749(88)90174-8. [DOI] [PubMed] [Google Scholar]
  5. Clark I. A., Cowden W. B., Butcher G. A., Hunt N. H. Possible roles of tumor necrosis factor in the pathology of malaria. Am J Pathol. 1987 Oct;129(1):192–199. [PMC free article] [PubMed] [Google Scholar]
  6. Clark I. A. Does endotoxin cause both the disease and parasite death in acute malaria and babesiosis? Lancet. 1978 Jul 8;2(8080):75–77. doi: 10.1016/s0140-6736(78)91386-7. [DOI] [PubMed] [Google Scholar]
  7. Clark I. A., Hunt N. H., Cowden W. B. Oxygen-derived free radicals in the pathogenesis of parasitic disease. Adv Parasitol. 1986;25:1–44. doi: 10.1016/s0065-308x(08)60341-3. [DOI] [PubMed] [Google Scholar]
  8. Clark I. A., Hunt N. H. Evidence for reactive oxygen intermediates causing hemolysis and parasite death in malaria. Infect Immun. 1983 Jan;39(1):1–6. doi: 10.1128/iai.39.1.1-6.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cowden W. B., Lewis-Hughes P. H., Clark I. A. Protection against alloxan-induced diabetes in mice by the free radical scavenger butylated hydroxyanisole. Biochem Pharmacol. 1985 Oct 1;34(19):3601–3603. doi: 10.1016/0006-2952(85)90741-5. [DOI] [PubMed] [Google Scholar]
  10. Daroff R. B., Deller J. J., Jr, Kastl A. J., Jr, Blocker W., Jr Cerebral malaria. JAMA. 1967 Nov 20;202(8):679–682. [PubMed] [Google Scholar]
  11. Freeman B. A., Young S. L., Crapo J. D. Liposome-mediated augmentation of superoxide dismutase in endothelial cells prevents oxygen injury. J Biol Chem. 1983 Oct 25;258(20):12534–12542. [PubMed] [Google Scholar]
  12. Gamble J. R., Harlan J. M., Klebanoff S. J., Vadas M. A. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8667–8671. doi: 10.1073/pnas.82.24.8667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Grau G. E., Fajardo L. F., Piguet P. F., Allet B., Lambert P. H., Vassalli P. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science. 1987 Sep 4;237(4819):1210–1212. doi: 10.1126/science.3306918. [DOI] [PubMed] [Google Scholar]
  14. Grau G. E., Piguet P. F., Engers H. D., Louis J. A., Vassalli P., Lambert P. H. L3T4+ T lymphocytes play a major role in the pathogenesis of murine cerebral malaria. J Immunol. 1986 Oct 1;137(7):2348–2354. [PubMed] [Google Scholar]
  15. Hoffman M., Weinberg J. B. Tumor necrosis factor-alpha induces increased hydrogen peroxide production and Fc receptor expression, but not increased Ia antigen expression by peritoneal macrophages. J Leukoc Biol. 1987 Dec;42(6):704–707. doi: 10.1002/jlb.42.6.704. [DOI] [PubMed] [Google Scholar]
  16. Janota I., Doshi B. Cerebral malaria in the United Kingdom. J Clin Pathol. 1979 Aug;32(8):769–772. doi: 10.1136/jcp.32.8.769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Le J., Vilcek J. Tumor necrosis factor and interleukin 1: cytokines with multiple overlapping biological activities. Lab Invest. 1987 Mar;56(3):234–248. [PubMed] [Google Scholar]
  18. Leech J. H., Barnwell J. W., Aikawa M., Miller L. H., Howard R. J. Plasmodium falciparum malaria: association of knobs on the surface of infected erythrocytes with a histidine-rich protein and the erythrocyte skeleton. J Cell Biol. 1984 Apr;98(4):1256–1264. doi: 10.1083/jcb.98.4.1256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. MacPherson G. G., Warrell M. J., White N. J., Looareesuwan S., Warrell D. A. Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol. 1985 Jun;119(3):385–401. [PMC free article] [PubMed] [Google Scholar]
  20. Mackey L. J., Hochmann A., June C. H., Contreras C. E., Lambert P. H. Immunopathological aspects of Plasmodium berghei infection in five strains of mice. II. Immunopathology of cerebral and other tissue lesions during the infection. Clin Exp Immunol. 1980 Dec;42(3):412–420. [PMC free article] [PubMed] [Google Scholar]
  21. Nathan C. F., Murray H. W., Cohn Z. A. The macrophage as an effector cell. N Engl J Med. 1980 Sep 11;303(11):622–626. doi: 10.1056/NEJM198009113031106. [DOI] [PubMed] [Google Scholar]
  22. Nathan C. F., Murray H. W., Wiebe M. E., Rubin B. Y. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med. 1983 Sep 1;158(3):670–689. doi: 10.1084/jem.158.3.670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rest J. R. Cerebral malaria in inbred mice. I. A new model and its pathology. Trans R Soc Trop Med Hyg. 1982;76(3):410–415. doi: 10.1016/0035-9203(82)90203-6. [DOI] [PubMed] [Google Scholar]
  24. Sacks T., Moldow C. F., Craddock P. R., Bowers T. K., Jacob H. S. Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes. An in vitro model of immune vascular damage. J Clin Invest. 1978 May;61(5):1161–1167. doi: 10.1172/JCI109031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sato N., Goto T., Haranaka K., Satomi N., Nariuchi H., Mano-Hirano Y., Sawasaki Y. Actions of tumor necrosis factor on cultured vascular endothelial cells: morphologic modulation, growth inhibition, and cytotoxicity. J Natl Cancer Inst. 1986 Jun;76(6):1113–1121. [PubMed] [Google Scholar]
  26. Stolpen A. H., Guinan E. C., Fiers W., Pober J. S. Recombinant tumor necrosis factor and immune interferon act singly and in combination to reorganize human vascular endothelial cell monolayers. Am J Pathol. 1986 Apr;123(1):16–24. [PMC free article] [PubMed] [Google Scholar]
  27. Thomas J. D. Clinical and histopathological correlation of cerebral malaria. Trop Geogr Med. 1971 Sep;23(3):232–238. [PubMed] [Google Scholar]
  28. Thumwood C. M., Hunt N. H., Clark I. A., Cowden W. B. Breakdown of the blood-brain barrier in murine cerebral malaria. Parasitology. 1988 Jun;96(Pt 3):579–589. doi: 10.1017/s0031182000080203. [DOI] [PubMed] [Google Scholar]
  29. Tracey K. J., Beutler B., Lowry S. F., Merryweather J., Wolpe S., Milsark I. W., Hariri R. J., Fahey T. J., 3rd, Zentella A., Albert J. D. Shock and tissue injury induced by recombinant human cachectin. Science. 1986 Oct 24;234(4775):470–474. doi: 10.1126/science.3764421. [DOI] [PubMed] [Google Scholar]
  30. Udeinya I. J., Schmidt J. A., Aikawa M., Miller L. H., Green I. Falciparum malaria-infected erythrocytes specifically bind to cultured human endothelial cells. Science. 1981 Jul 31;213(4507):555–557. doi: 10.1126/science.7017935. [DOI] [PubMed] [Google Scholar]
  31. White N. J., Warrell D. A., Looareesuwan S., Chanthavanich P., Phillips R. E., Pongpaew P. Pathophysiological and prognostic significance of cerebrospinal-fluid lactate in cerebral malaria. Lancet. 1985 Apr 6;1(8432):776–778. doi: 10.1016/s0140-6736(85)91445-x. [DOI] [PubMed] [Google Scholar]
  32. Wright D. H., Masembe R. M., Bazira E. R. The effect of antithymocyte serum on golden hamsters and rats infected with Plasmodium berghei. Br J Exp Pathol. 1971 Oct;52(5):465–477. [PMC free article] [PubMed] [Google Scholar]
  33. Wright D. H. The effect of neonatal thymectomy on the survival of golden hamsters infected with Plasmodium berghei. Br J Exp Pathol. 1968 Aug;49(4):379–384. [PMC free article] [PubMed] [Google Scholar]

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