Fish oil against malaria
Arginine nitric oxide
In 1957 the University of London found that dietary cod liver oil suppressed the multiplication of Plasmodium berghei in mice D.G. Godfrey, Antiparasitic action of dietary cod liver oil upon Plasmodium berghei and its reversal by vitamin “E” Experimental Parasitology Volume 6, Issue 6, November 1957, Pages 555-56 of Babesia rodhaini D.G Godfrey The influence of dietary cod liver oil and vitamin E upon Babesia rodhaini in mice Experimental Parasitology Volume 6, Issue 6, November 1957, Pages 555-565 and on Trypanosoma congolense, T. cruzi, T. vivax and T. brucei. G. Godfrey. Influence of dietary cod liver oil upon Trypanosoma congolense, T. cruzi, T. vivax and T. brucei. Experimental Parasitology, 1958, 3, 255-268. A study in Africa showed that the combination of artesunate and cod liver oil is more effective against Plasmodium berghei than artesunate alone O Awodele, MO Araoye, DF Anisu. The suggestive potentiating of cod liver oil on the efficacy of artesunate. MIM16697872, MIM conv ference Nairobi 2009. Why was this research lead never taken up by Bigpharma-WHO? An attitude similar to the 20 year long contempt for the Chinese herb Artemisia annua. Probably because you cannot make money with an herb or a fish oil accessible to everybody ! Research on dietary fish oil and diseases was only resumed in the nineties. A Chinese paper confirmed that fish liver oil protected mice from Plasmodium Zhuang Guozheng, Medicinal J of National Defending Forces in Southwest China 1998-06, 221-227 in Chinese. A Dutch team studied the effects of artemisinin and a fish oil, separately or in combination, against Klebsiella pneumoniae and Plasmodium berghei Blok WL, Vogels MT, Curfs JH, Eling WM, Buurman WA, van der Meer JW. Dietary fish-oil supplementation in experimental gram-negative infection and in cerebral malaria in mice. J Infect Dis. 1992 May;165(5):898-903. After a low inoculum of K. pneumoniae, 90% of fish-oil-fed mice survived and 0% in normal chow fed mice. Cerebral malaria developed in 23% of the fish-oil-fed mice and 75% in the control. One important element in the work of Godfrey needs to be mentionned: large doses of vitamin E completely reversed the suppressive action due to cod liver oil. The author advances the following hypothesis : the unsaturated fatty acids of the cod liver oil are oxidised by the host to peroxides. These create a pro-oxidant state inimical to the parasites. Vitamin E (tocopherol) prevents the peroxidation by virtue of its strong strong anti-oxidant properties. A USDA team extensively studied this effect of vitamin E on malarial parasites. Vitamin E deficiency enhanced the antimalarial action of artemisinin against Plasmodium yoelii, both in terms of decreased parasitemia and improved survival. A vitamin E-deficient diet containing 5% cod-liver oil had such strong antimalarial activity in itself that no additional therapeutic effect of artemisinin could be demonstrated. The same effect was noticed for the fish-body oil from the Atlantic menhaden fish or for anchovy and salmon oil. O.A. Levander Vitamin E and selenium: contrasting and interacting nutritional determinants of host resistance to parasitic and viral infections. Proceedings of the Nutrition Society 1995, ISSN : 0029-6651 O. A. Levander, Rosa Fontela, Virginia C. Morris and Arba L. Ager, Jr. Protection against Murine Cerebral Malaria by Dietary-Induced Oxidative Stress The Journal of Parasitology . Vol. 81, No. 1 (Feb., 1995), pp. 99-103 The University of Lagos found that the effect of artesunate was significantly reduced when co-administered with vitamin E, but that animals receiving the combination of both artesunate and cod liver oil demonstrated a better clearance with 98.9 suppression on day 7 O. Awodele, P. M. Emeka, A. Akintonwa, O. O. Aina. Antagonistic Effect of Vitamin E on the Efficacy of Artesunate against Plasmodium berghei Infection in Mice African Journal of Biomedical Research.Vol 10, No 1 (2007) If vitamin E is really enhancing parasitaemia, caution is recommended in the use of Moringa oleifera. This plant is claimed to contain 113 mg of vitamin E per 100 g, 10 times more than the recommended daily intake. Fish oil and seafood are very rich in arginine: 1g/100g. Much more than vegetables. Arginine is the amino acid which generates NO via the NOS enzymes. Nitric oxide is a strong pro-oxidant which kills the parasites. Palm oil, corn oil also inhibit parasitemia but the effect is negligible compared to fish oil. The arginine contained in fish oil leads to CD4 T-cell proliferation Kai Kang MM 1 , Xiao-liang Shu PhD, Jing-xia Zhong MM, Ting-ting Yu MM, Tao Lei PhD Effect of L-arginine on immune function: a meta-analysis. Asia Pac J Clin Nutr. 2014;23(3):351-359. doi: 10.6133/apjcn.2014.23.3.09 The arginine nitric-oxide hypothesis and the unsaturated fatty acid hypothesis Fish oils are rich in polyunsaturated fatty acids (PUFA), often of the so called omega-type. Some of them like docosahexaenoic acid (DHA), eicosapentaeonic acid (EPA), arachidonic acid cause marked in vitro growth inhibition of Plasmodium falciparum. Parasite killing is significantly increased when oxidised forms of polyunsaturated fatty acids are used. Saturated fatty acids are less effective because they are more resistant to oxidative attack. It is even likely that oxidation of polyunsaturated fatty acids is a defense mechanism of the host. Similar effects were seen in vivo on mice infected with Plasmodium berghei and treated during 4 days with these acids, The effect is thus not only prophylactic but also suppressive. But antioxidants like vitamin E, catalase, superoxide dismutase or commercial antioxidant food additives markedly reduce the antimalarial activity of fatty acids. L M Kumaratilake, A Ferrante, T Jaeger, and C M Rzepczyk. Effects of cytokines, complement, and antibody on the neutrophil respiratory burst and phagocytic response to Plasmodium falciparum merozoites. Infect Immun. 1992 Sep; 60(9): 3731–3738. L M Kumaratilake, A Ferrante, B S Robinson, T Jaeger, and A Poulos. Enhancement of neutrophil-mediated killing of Plasmodium falciparum asexual blood forms by fatty acids: importance of fatty acid structure. Infect Immun. 1997 Oct; 65(10): 4152–4157 Arginine regulates macrophage functions. N Wanasen, L Soong. L-arginine metabolism and its impact on host immunity against Leishmania infection. Immunol Res 2008. 41, 15-25 Aneta Janecki, Beitrag zur Kenntnis der Inhaltsstoffe und der Wirkung des Pelargonium Extraktes. Dissertation Dr rer nat. Freie Universität Berlin. 2012 NO generated by arginine acts as an extremely strong ligand and its binding to the iron of heme groups has been shown to exert a large repulsive force. Otentially disrupting the linkages within the crystal lattice of hemozoin, Melissa D Carter, Hemozoin : a pardigm for biomineralization in disease. Thesis, Vanderbilt University, Nashville, Tennessee. But artemisinin and derivatives may have an antagonistic role in NO generation. E Aldieri, D Atragene, C Costamagna. Artemisinin inhibits inducible nitroc oxide synthase and nuclear factor NF-kB aactivation. FEBS letters, 2003, 552, 141-144 Neutrophils are the first line of defense against infection and their involvement in the control of blood parasites of malaria is known. In a subsequent study the same authors showed that the antiparasitic activity of neutrophils can be greatly increased by treatment with fatty acids with 20 to 24 carbon atoms and at least 3 double bonds. Fatty acids with 18 or 28 carbon atoms were less efficient in neutrophil-mediated killing of Plasmodium falciparum parasites Plants of the Artemisia family also contain unsaturated fatty acids ranging from 0,3 to 1.7 %. The acids with 18 carbon atoms are more abundant than those with 20 carbons. The predominant acid in all species were linoleic and linolenic acid. Carvalho IS, Teixeira MC, Brodelius M (2011a). Fatty acids profile ofselected Artemisia spp. plants: Health promotion. LWT - FoodScience and Technology 44:293-298 Carvalho IS, Cavaco T, Brodelius M (2011b). Phenolic compositionand antioxidant capacity of six Artemisia species. Industrial Crops and Products 3:382-388. Linoleic acid plays a complex and ambigous role in malaria. The antimalarial activity of unsaturated fatty acids and particularly linoleic acid has been well documented. Their action is very rapid, in less than 30 minutes. Krugliak M, Deharo E, Shalmiev G, Sauvain M, Moretti C, Ginsburg H.. Antimalarial effects of C18 fatty acids on Plasmodium falciparum in culture and on Plasmodium vinckei petteri and Plasmodium yoelii nigeriensis in vivo. Exp Parasitol. 1995 Aug;81(1):97-105 In vivo trials on Plasmodium berghei in mice by oral administration test of a mixture of linoleic and linolenic acids in a suppressive assay showed that after a 4 day treatment parasitemia was reduced to 0.5% and the growth inhibition of the parasite was 96% versus 69% for the chloroquine control. Particularly highly unsaturated fatty acids like arachidonic acid are toxic for Plasmodium. Palmitic and stearic acids are lesss toxic. Since exogenous unsaturated fatty acids are toxic to malaria parasites, how do these protect themselves from this expanded pool of fatty acids, The situation is complex because Plasmodium has its own biosynthetic machinery for the production of fatty acids in the apicoplast and these lipids are used for the biocrystallization of heme into hemozoin. When the parasite is invading a host it needs protecting itself from the immune system of the host by creating a so-called parasitophorous vacuole. One possibility is sequestration of these endogenous lipids in the acidic food vacuole. The unsaturated lipid would precipitate with hemozoin. The insoluble precipitate renders the unsaturated lipid nontoxic, while hemozoin polymerization proceeds. Strengthening of the immune system: The effect of dietary fish oils appears to be long lasting ; and not instantaneous or reduced to a few hours or days like common antimalarial drugs (chloroquine, artemisinine, lumefantrine…). For mice fed a fish-oil-diet poor in vitamin E the survival rate improved to at least 70%. Protection against malaria did not seem to be related to the fish oil dose used. Increasing the fish oil dose above 2% in the chow did not seem to increase protection. However a shorter prefeeding interval of two weeks was generally less effective than four weeks of prefeeding. Furthermore all the mice surviving the primary infection survived the rechallenge infection with low parasitaemias and the resistance against reinfection was enhanced for some time after discontinuing fish oil intake Fevang P, Sääv H, Høstmark AT. Dietary fish oils and long-term malaria protection in mice. Lipids. 1995 May;30(5):437-41. Dietary consumption of fish oil and/or polyunsaturated fatty acids may lead to an effect which is similar to acquired immunity in high endemic areas. The results suggest that an acquired immune response involving T and B cells may be an important component in both cases. IL-1α and TNFα are significantly enhanced in fish oil-fed mice compared with controls. Blok WL, Vogels MT, Curfs JH, Eling WM, Buurman WA, van der Meer JW.Dietary fish-oil supplementation in experimental gram-negative infection and in cerebral malaria in mice. J Infect Dis. 1992 May;165(5):898-903 Concerning vitamin D in fish oil, although many anecdotical reports suggest that it may play a role in modulating immune functions, no strong evidence exists in the scientific literature. The antirachitic claim used 50 years for the oral gavage of children with fish oil was probably a blunt sales tool to sell a surplus of fish oil. Action against other parasites Fish oil is effective against helminthic diseases like trichinellosis. A reduction of 30,6 % of adult worms in Wistar rats was noticed in a fish oil group as compared to the standard diet group Gómez García V , Sanz Sampelayo MR , Fernández Navarro JR , Carmona López FD , Gil Extremera F , Rodríguez Osorio M. Polyunsaturated fatty acids and parasitism: effect of a diet supplemented with fish oil on the course of rat trichinellosis.Veterinary Parasitology [2003, 117(1-2):85-97] For schistosomiasis trials were made with castor oil, praziquantel and fish oil. The oils, particularly castor oil, given by oral gavage for 7 days had the unexpected result to reduce cercarial penetration by 93% Salafsky B , Fusco AC , Li LH , Mueller J , Ellenberger B. Schistosoma mansoni: experimental chemoprophylaxis in mice using oral anti-penetration agents. Experimental Parasitology [1989, 69(3):263-271] This observation suggests that dietary supplementation of lipids may lead to prophylaxis by an antipenetration activity. McDonald MI, Graham I, Harvey KJ, Sinclair A. Antibacterial activity of hydrolysed linseed oil and linolenic acid against methicillin-resistant staphylococcus aureus. Lancet. 1981 Nov 7;2(8254):1056. Several recent studies are devoted to the impact of polyunsaturated acids on tuberculosis N.M. Carballeira. New Advances in Fatty Acids as Antimalarial, Antimycobacterial and Antifungal Agents. Prog Lipid Res. 2008 Jan; 47(1): 50–61. doi: 10.1016/j.plipres.2007.10.002 Nitric oxide has a well known anti-leishmanial effect. But artemisinin contributes very little to NO production. S. Nemati, H. Nahrevanian, A. Haniloo, M. Farahmand. Investigation on nitric oxide and C-reactive protein involvement in anti-leishmanial effects of artemisinin and glucantim on cutaneous leishmaniasis. Adv Stud Biol, 5 (1) (2013), pp. 27–36 Arginine seems to play a key role against this disease not only by NO production but also by CD4 proliferation Munder M, Choi BS, Rogers M, Kropf P. L-arginine deprivation impairs Leishmania major-specific T-cell responses. Eur J Immunol. 2009 Aug;39(8):2161-72. doi: 10.1002/eji.200839041. Arginine generates NO which serves several important functions, including the maintenance of normal erythrocyte deformability, thereby ensuring efficient passage of the red blood cell through narrow microcapillaries. Following invasion by the malaria parasite Plasmodium falciparum the arginine pool in the host erythrocyte compartment is sequestered and metabolized by the parasite into ornithine and citrulline which do not generate NO. The uptake and metabolism of arginine by the parasite may contribute to the decreased deformability of infected erythrocytes. Cobbold SA, Llinás M, Kirk K. Sequestration and metabolism of host cell arginine by the intraerythrocytic malaria parasite Plasmodium falciparum. Cell Microbiol. 2016 Jun;18(6):820-30. doi: 10.1111/cmi.12552. Alkaitis MS, Wang H, Ikeda A, Rowley CA, MacCormick IJ, Chertow JH, Billker, Suffredini AF, Roberts DJ, Taylor TE,, Seydel KB, Ackerman HC. Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria. J Infect Dis. 2016 Dec 15;214(12):1840-1849. Ammonium generated by the Plasmodium infection enhances the severity of cerebral malaria. Arginine mitigates this effect Sammy Kimoloi, Khalid Rashid. Potential role of Plasmodium falciparum-derived ammonia in the pathogenesis of cerebral malaria: Frontiers in Neuroscience. DOI: 10.3389/fnins.2015.00234 MW Goodman, L Zieve, FB Cerra. Mechanism of arginine protection against ammonia intoxicationin the rat. Am J Physiol. 1984, 247, G290-5 Naomi K, L-arginine and ammonia toxicity. Nutrition Reviews 1959, 187-188 Arginine and nitric oxide may be protective against P. falciparum infection by inhibiting cytoadherence, and underscore the therapeutic potential of NO in the treatment of severe falciparum malaria. Serirom S, Raharjo WH, Chotivanich K, Anti-adhesive effect of nitric oxide on Plasmodium falciparum cytoadherence under flow. Am J Pathol. 2003 May;162(5):1651-60. Research on fish oils against malaria has again disappeared from our screens over the last 5 years. Maybe it is time to resume it. Appropriate testing of fish oils in humans should be encouraged by WHO, like it is done for the chemical vaccines of the pharmaceutical industry. It would also be important to study the effect on malaria of staple food rich in arginine, like peanuts.