Cerabral malaria, interleukin 10, nitric oxide

Artemisia cerebral malaria

Several papers published twenty, even thirty years ago should have attracted more attention. In 1992 it was found that interleukin IL-10, in a dose-dependent manner, inhibits the microbicidal activity of macrophages against intracellular Toxoplasma gondii as well as the extracellular killing of schistosomula of Schistosoma mansoni. This suppression correlates with the inhibition by IL-10 of the production of toxic nitrogen oxide metabolites, an effector mechanism previously implicated in the killing by macrophages of both parasite targets. Gazzinelli RT1, Oswald IP, James SL, Sher A. IL-10 inhibits parasite killing and nitrogen oxide production by IFN-gamma-activated macrophages. J Immunol. 1992 Mar 15;148(6):1792-6. While investigating the in vitro susceptibility of the human malaria parasite Plasmodium falciparum to killing by nitric oxide and related molecules, it was found that a saturated solution of nitric oxide did not inhibit parasite growth, but two oxidation products of nitric oxide (nitrite and nitrate ions) were toxic to the parasite in millimolar concentrations. K A Rockett, M M Awburn, W B Cowden, and I A Clark. Killing of Plasmodium falciparum in vitro by nitric oxide derivatives. Infect Immun. 1991 Sep; 59(9): 3280–3283. Nussler AK, Eling W, Kremsher PG. Patients with Plasmodium falciparum malaria and Plasmodium vivax malaria show increased nitrite and nitrate plasma levels. J Infect Dis. 1994 Nitrioxide production can be higher in symptom-free parasitised individuals, who are termed malaria-tolerant. Dr IA Clark, FM Al-Yaman, , WB Cowden, , KA Rockett, Does malarial tolerance, through nitric oxide, explain the low incidence of autoimmune disease in tropical Africa? The Lancet , Volume 348, No. 9040, p1492–1494, 30 November 1996 In Tanzania high NO levels and NOS2 in asymptomatic infection suggest that increased NO synthesis might protect against clinical disease. NO appears to have a protective rather than pathological role in African children with malaria. Anstey NM, Weinberg JB, Hassanali MY, Mwaikambo ED, Manyenga D, Misukonis MA, Arnelle DR, Hollis D, McDonald MI, Granger DL. Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. J Exp Med. 1996 Aug 1;184(2):557-67. NO levels were determined in asymptomatic adults from Papua, Indonesia. Adults with Plasmodium falciparum parasitemia had markedly increased basal systemic NO production relative to aparasitemic Papuan controls, who in turn produced more NO than healthy controls from a region without malaria in Australia. Craig S. Boutlis, Emiliana Tjitra, Helena Maniboey, Mary A. Misukonis, Jocelyn R. Saunders, Sri Suprianto, J. Brice Weinberg, and Nicholas M. Anstey. Nitric Oxide Production and Mononuclear Cell Nitric Oxide Synthase Activity in Malaria-Tolerant Papuan Adults. Infect Immun. 2003 Jul; 71(7): 3682–3689. doi: 10.1128/IAI.71.7.3682-3689.2003 The suppression of NO synthesis in cerebral malaria appears to enhance pathogenesis and increased NO synthesis protects against clinical disease. The work was based on in vivo results obtained in Tanzanian children. Anstey, N. M., J. B. Weinberg, Z. Wang, E. D. Mwaikambo, P. E. Duffy, and D. L. Granger. 1999. Effects of age and parasitemia on nitric oxide production/leukocyte nitric oxide synthase type 2 expression in asymptomatic, malaria-exposed children. Am. J. Trop. Med. Hyg. 61:253-258. These seminal findings probably were ignored because in these years the phobia and paranoia against nitrates and nitrites was still virulent: particularly the claim that N-nitrosamines derived from nitrites caused cancer, but so far no causative link could be found. Over recent years the pharmaceutical stance on nitrite has undergone a surprising metamorphosis, from vilified substance to a live-saving drug that liberates a protective agent. Recent rediscoveries have rendered nitrite a fundamental role in biology. All life requires nitrogen compounds. Nitrite is also a biomarker for disease, an endogenous signaling molecule. Nathan S. Bryan. Nitrite in nitric oxide biology: Cause or consequence? A systems-based review. Free Radical Biology & Medicine 2006, 41, 691-701. Due to the growing interest in nitric-based therapies, it is critical to understand the metabolism of nitric oxide derivatives. There are many unanswered questions. Nitrite and nitrate are formed de novo in the human intestine; exogenous nitrate from water or diet is not the only source. There are two main exogenous sources (inhalation of nitrogen oxides is negligible and the phobia of traffic generated NOx probably ridiculous) Dietary sources of nitrates are a source of nitrite in the human body. Plasma nitrite increases after ingestion of large amounts of nitrates, mainly from vegetables. The supply by drinking-water is negligible. Nitrate is rapidly absorbed in the small intestine and and readily distributed troughout the body. Commensal bacteria that reside within the human body can reduce nitrate to nitrite. The amino acid arginine from medicinal plants, nuts, fish oil converted by enzymes of the NOS family is the other main source of NO and nitrites, and probably the major one. NO can be influenced by other elements. Iron supplementation for example decreases NO generation. Iron chelators present in many medicinal herbs may reverse this effect. Weiss G, Thuma PE, Mabeza G, Werner ER, Herold M, Gordeuk VR. Modulatory potential of iron chelation therapy on nitric oxide formation in cerebral malaria. J Infect Dis. 1997 Jan;175(1):226-30. The flavonoid luteolin also induces nitric oxide Hongwei Si, R Wyeth, D Liu. The flavonoid luteolin induces nitric oxide production and arterial relaxation. Eur J Nutr 2014 53(1) 269-275. For Artemisia nilargirica de production of NO has been demonstrated. Sumanta Kumar Naik, Soumitra Mohanty, Avinash Padhi, Rashmirekha Pati, and Avinash Sonawane. Evaluation of antibacterial and cytotoxic activity of Artemisia nilagirica and Murraya koenigii leaf extracts against mycobacteria and macrophages. BMC Complement Altern Med. 2014; 14: 87 In vivo NO is rapidly converted into the stable metabolites nitrite and nitrate, but homeostasis implies that the opposite reaction also is possible maintaining an equilibrium which is only disturbed by diseases. The steady-state concentrations of nitrite in the body is tightly regulated. Nitrite is a reservoir of NO and acts as signal in pathophysiology. During diseases characterized by oxydative stress like malaria NOS is partially uncoupled and can no longer maintain NO production and nitrite reduction acts as a backup system to the NOS system. The fact that both systems still exist to-day highlights the importance of nitrite in all cellular processes. Nitrite which was a vilified molecule may emerge as an essential nutrient. Some authors even suggest that the stringent regulations and restrictions on nitrite/nitrate in drinking water and in foods contribute to contemporary diseases (NS Bryan op.cit.) It is thus not surprising that restoring NO biovailability in severe malaria might represent an effective anti-disease therapy. Others confirmed that nitrate plus nitrite concentrations were decreased in children with cerebral malaria. Hypoarginemia is often a cause of this low nitric oxide availability in cerebral malaria Gramaglia I, Sobolewski P, Meays D, Contreras R, Nolan JP, Frangos JA, Intaglietta M, van der Heyde HC. Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria. Nat Med. 2006 Dec; 12(12):1417-22. There is an opposite theory stating that, despite the contribution of NO in the destruction of Plasmodium falciparum, too much NO causes immuno-suppression and leads to the developement of cerebral malaria. A recent trial in murine cerebral malaria however showed that the supply of exogenous NO caused a reduction of cerebral malaria from 79% to 29%, and a proportionate increase in survival in P berghei infected mice. The treatment was associated with improved brain microvascular hemodynamics, particularly with decreased vasoconstriction and improved blood flow, decreased brain vascular inflammation, and decreased incidence of hemorrhages. Cabrales P, Zanini GM, Meays D, Frangos JA, Carvalho LJ. Nitric oxide protection against murine cerebral malaria is associated with improved cerebral microcirculatory physiology. J Infect Dis. 2011 May 15;203(10):1454-63. doi: 10.1093/infdis/jir058. Inhibition of NOS enzymes favors the development of severe forms of malaria. S Percario, DR Moreira,. Oxidative stress in malaria. Int J Mol.sci. 2012, 13, 16346-72. Endothelial dysfunction in malaria is nearly universal in severe disease due to reduced levels of NO. NO prevents platelet aggregation and inhibits adhesion of lymphocytes and monocytes to the endothelium. In an in vivo study in Indonesia it was shown that intravenous arginine increases exhaled NO and raises peripheral arterial tonometry. Tsin W. Yeo, Daniel A. Lampah, Retno Gitawati, Emiliana Tjitra, Enny Kenangalem, Yvette R. McNeil, Christabelle J. Darcy, Donald L. Granger, J. Brice Weinberg, Bert K. Lopansri, Ric N. Price, Stephen B. Duffull, David S. Celermajer, Nicholas M. Anstey. Impaired nitric oxide bioavailability and l-arginine–reversible endothelial dysfunction in adults with falciparum malaria. JEM, 2007, 204-11, 2693-2704 Artemisia annua is a medicinal plant very rich in nitrates (3% d.w.) and arginine (1% d.w). This probably contributes to the strong prophylactic and curative properties of the plant against malaria. Cerebral malaria is a leading cause of the death toll of 1 million children each year, the cause of irreversible neurological defects and incommensurable human suffering. Unfortunately, clinical trials with Artemisia annua are forbidden by WHO.

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