Cerebral malaria, ammonia and arginine

Plasmodium falciparum generates substantial amounts of ammonia as a metabolic by-product, but lacks detoxification mechanisms (S Kimoloi et al., Hypothesis and Theory, 2015, 9,article 234). It imports large amounts of glutamine from the host serum. Deamidation and deamination reactions generate two molecules of ammonia per glutamine molecule, particularly in the early trophozoite stages (T Zeuthen et al., Mol Microbiol 2006, 61, 1598-608). In severe malaria a large number of parasites in the brain can directly generate substantial amounts of ammonia, which may in turn overwhelm brain ammonia metabolism. Elevated levels of ammonia alter brain functions, initiating a cascade of toxic effects that ultimately lead to various clinical manifestations including brain edema, seizures, coma. Elevated brain ammonia can cause long term neurocognitive sequelae, observed among cerbral malaria survivors.

Arginine compounds are highly effective in preventing an increase in blood ammonia (L Zieve et al., Metab Brain Dis 1986, 1, 25-35). This effect is known for more than 50 years (J Fabey et al., Am J Med. 1957, 23, 860-69).  Arginine also reduces exercise induced increase in ammonia (A Schaefer et al., Int J Sports Med 2002, 23, 403-407). Arginine deficiency may lead to hyperammonemia as demonstrated for young ferrets after feeding an arginine-free diet (P Thomas et al., The Journal of Nutrition, 27 Nov 1987).

Ammonia, like carbon dioxide, fatty acids etc (Bart Knols, The Lancet, 1996, 348 , p. 1322) in the human sweat is also an attractant for Anopheles gambiae and Aedes aegytii. Human sweat contains kairomones. A Dutch research group found that ammonia is an important kairomone for Anopheles gambiae (MAH Braks et al., Physiol Entomol 2001, 26, 142-148 ; RC Smallegange et al., J Med Entom 2010, 47, 338-44). Especially in stinky feet. The higher attractivity of malaria infected persons for female A gambiae may be related to their ammonia concentration in the blood. The mosquito „knows“ that in this blood he will find large amounts of gametocytes.

Artemisia annua is very rich in arginine (see « Arginine, a deadly weapon against gametocytes » on www.malariaworld.org, July 5 2015). It could be a life saving weapon against cerebral malaria.

Pierre Lutgen

30 octobre 2015

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