ARACHIDONIC ACID AND FEVER
Arachidonic acid (AA or ARA) is an extremely important fatty acid involved in cell regulation. It is a polyunsaturated fatty acid (20:4n6) covalently bound in esterified form in membrane phospholipids of most body cells. Following irritation or injury, arachidonic acid is released and oxygenated by enzyme systems leading to the formation of an important group of inflammatory mediators, to the prostaglandins products (PGE₂) by the cyclooxygenase enzyme.
In 1983 already it was claimed that PGE₂ derived from arachidonic acid plays a clear role in the regulation of cellular and humoral responses (JS Godwin et al., J Clin Immunol. 1983 3, 295-315). PGE₂ regulates macrophage derived TNF-α. (S Kunkel et al., J Biol Chem. 1988, 11, 5380-84). These studies confirmed that this prostaglandin can regulate macrophage activity. PUFAs promote the phagocytosis of bacteria (S Adolph et al. Curr Microbiol 2012 65, 649-55). PGE₂ have potent inflammatory properties and they are readily detectable in acute inflammatory exudates. Temperature is regulated in response to the hormone PGE₂. A modest fever may develop. Long regarded as a harmful by-product of infection, fever may instead be an ancient ally against disease. Redness, swelling and pain are normal primary effects of arachidonic acid. It ensures that our body responds properly to a physical insult or pathogen, and it also helps ensure that the inflammatory response is turned off when it’s no longer needed. It may momentarily exacerbate symptoms of joint pain (B Samuelsson, Z Rheumat, 1991 50-1, 3-6). It’s especially necessary during periods of bodily growth or repair, and is thus a natural and important component of breast milk.
In most mammals, linoleic acid is converted to arachidonic acid. Some mammals lack the ability to—or have a very limited capacity to—convert linoleic acid into arachidonic acid, making it an essential part of their diets. Since little or no arachidonic acid is found in common plants, such animals are obligate carnivores; the cat is a common example.
The antimalarial properties of polyunsaturated fatty acids and arachidonic acid are well known. We have described them in two blogs on www.malariaworld.org :”Cod liver oil: a stronger prophylactic against malaria than vaccines” and “The strong prophylactic and antimalarial properties of polyunsaturated fatty acids”.
A possible link with malaria is that the addition of ARA to several Plasmodium falciparum strains grown in vitro led to a significant increase in prostaglandins, molecules which are detrimental for the parasite. In the absence of ARA the production of prostaglandins was insignificant (K Kubata et al., JEMM, 1998, 188, 1197-1202).
Already in 2000 it had been demonstrated in a study on Gabonese children with and without malaria that prostaglandins are important pro-inflammatory mediators of the host-immune response to infection. (JB Weinberg et al., Blood. 2000, 96). The authors postulate that PGE₂ levels in healthy malaria-exposed children protects against malaria, while decreases in PGE₂ during acute malaria increase susceptibility to severe disease. This has been confirmed in Tanzanian children (GJ Perkins et al., DJ Perkins et al., JID, 2005, 191, 1548-57). The authors suggest that high levels of PGE₂ in children with asymptomatic parasitemia may contribute to the maintenance of malaria tolerance, which is the ability to tolerate circulating parasites without fever. In children with cerebral malaria their production is impaired and this often leads to adverse outcomes.
The effect on bilharzia of arachidonic acid, ARA, has been extensively studied at the University of Cairo (R El Ridi et al., Antimicrob Agents and Chemother. 2010, 54, 3383-3389) (R Barakat et al., Am J Trop Med Hyg 2015, 92, 797-804). They have demonstrated that 5 nM ARA leads to irreversible killing of ex vivo 1-, 3-, 4-, 5- and 6- weeks old Schistosoma manzoni within 3 to 4 hours. This efficiency could be duplicated in vivo in mice indicating that using ARA in pure form or included in an infant formula consistently led to a 40 to 80% decrease in total worm burden. Royal DSM has introduced an international patent claiming prevention and treatment of schistosomiasis with arachidonic acid combined with praziquantel (WO/2015/123480).
BIOLOGICAL SOURCES OF ARACHIDONIC ACID
Arachidonic acid is present in red meat, eggs, algae, fish oil. 0.1 in fatty meat, 0.7 in fish oil, 0.3 % in eggs, 0.4 % of the total fat of breast milk, traces in cow milk.
Higher plants and vegetables do not produce or contain arachidonic acid. It is only found and extracted from mosses and algae. For this reason several laboratories have tried to genetically modify plants for the production of arachidonic acid. Patent US7943816 for example introduces foreign genes into soy beans to this effect.
A phytochemical analysis of five Artemisia species in Turkey shows that saturated fatty acids in these plants represent on the average 40 % of the total and the unsaturated fatty acids 60 %, including those with antimalarial activities like linoleic acid, arachidonic acid and linolenic acid (M Kursat et al., Notulae Scientia Biologicae, 2015, 7, 495-499). The real surprise is that based on the total fatty acid content Artemisia armeniaca contains 6.47% arachidonic acid, A incana 7.79%, A tournefortiana 2.61%, A hausknechtii 7.44% A scoparia 3.17%.
This is ten times higher than in meat, eggs or fish oil. And it is possibly related to the prophylactic and therapeutic properties of all Artemisia plants. It could explain the extraordinary results obtained in randomized, double blind clinical trials in DRCongo on 1000 patients infected by malaria and another cohort of 1000 patients suffering from bilharzia. See blog “Breaking news from clinical trials with Artemisia plants” on www.malariaworld.org.
A fascinating new field of research!