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Nitrite therapy for cerebral malaria

November 12, 2015 - 08:34 -- Pierre Lutgen

A paper published twenty years ago should have attracted more attention (NM Anstey et al., J Exp Med 1996, 184, 557-567) : 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. Already five years earlier the killing of Plasmodium falciparum in vitro by nitric oxide derivatives (NO, nitrite, nitrate) had been demonstrated (KA Rockett et al., Infection and Immunity, 1991, 59, 3280-3283). Surprisingly a saturated solution of nitric oxide did not inhibit parasite growth, but nitrite and nitrate ions were toxic to the parasite in millimolar concentrations.

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 (Deutsche Forschungsgemeinschaft, April 15th 2014)

Over recent years the pharmaceutical stance on nitrite has undergone a surprising metamorphosis, from vilified substance to a live-saving drug that liberates the protective agent NO. 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 (NS Bryan., et al 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. (see also on www.malariaworld .org « Arginine, a deadly weapon » Jul 5, 2015 and « Ammonia, arginine and cerebral malaria » Oct 31, 2015) But it can be influenced by other elements. Iron supplementation for example decreases NO generation. Iron chelators present in many medicinal herbs may reverse this effect (G Weiis et al., J Infect Dis. 1997, 175, 226-30).

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 (P Sobolewski et al., Trends Parasitol, 2005, 21, 414-22). This suggestion is based on the findings described in the first paragraph of the present memo (NM Anstey op.cit.) These authors found that the suppression of NO synthesis increased with disease severity leading finally to cerebral malaria in these Tanzanian children. A protective effect of NO in human pathology had already been suggested 20 years ago (P Ringwald et al., J Infect Dis 1994, 169, 1417-18). 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 (I Gramaglia et al., Nature Medicine, 2006, 12, 1417-22) A more recent trial in murine cerebral malaria 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 (P Cabrales et al., J Infect Diseases, 2011, 203, 1454-63).

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 the 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.