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Arachidonic acid
Identifiers
CAS number 506-32-1 Yes check.svgY
SMILES
Properties
Molecular formula C20H32O2
Molar mass 304.5 g/mol
Melting point

-49.5 °C

Boiling point

°C (dec.)

 Yes check.svgY (what is this?)  (verify)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Arachidonic acid (AA, sometimes ARA) is an omega-6 fatty acid 20:4(ω-6). It is the counterpart to the saturated arachidic acid found in peanut oil, (L. arachis – peanut.)[1]

Contents

Chemistry

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In chemical structure, arachidonic acid is a carboxylic acid with a 20-carbon chain and four cis double bonds; the first double bond is located at the sixth carbon from the omega end.

Some chemistry sources define 'arachidonic acid' to designate any of the eicosatetraenoic acids. However, almost all writings in biology, medicine and nutrition limit the term to all-cis 5,8,11,14-eicosatetraenoic acid.

Biology

Arachidonic acid is a polyunsaturated fatty acid that is present in the phospholipids (especially phosphatidylethanolamine, phosphatidylcholine and phosphatidylinositides) of membranes of the body's cells, and is abundant in the brain and muscles.

In addition to being involved in cellular signaling as a lipid second messenger involved in the regulation of signaling enzymes, such as PLC-ɣ, PLC-δ and PKC-α, -β and -ɣ isoforms, arachidonic acid is a key inflammatory intermediate. [2] (Note separate synthetic pathways, as described in section below)

Essential fatty acid

Arachidonic acid in the human body usually comes from dietary animal sources—meat, eggs, dairy—or is synthesized from linoleic acid.

Arachidonic acid is one of the essential fatty acids required by most mammals. 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 diet. Since little or no arachidonic acid is found in common plants, such animals are obligate carnivores; the cat is a common example.[3][4] A commercial source of arachidonic acid has been derived, however, from the fungus Mortierella alpina [5]

Synthesis and cascade

Eicosanoid synthesis.

Arachidonic acid is freed from a phospholipid molecule by the enzyme phospholipase A2 (PLA2), which cleaves off the fatty acid, but can also be generated from DAG by Diacylglycerol lipase. [2]

Arachidonic acid generated for signaling purposes appears to be derived by the action of a phosphatidylcholine-specific cytosolic phospholipase A2 (cPLA2, 85 kDa), whereas inflammatory arachidonic acid is generated by the action of a low-molecular-weight secretory PLA2 (sPLA2, 14-18 kDa). [2]

Arachidonic acid is a precursor in the production of eicosanoids:

The production of these derivatives and their action in the body are collectively known as the arachidonic acid cascade; see essential fatty acid interactions for more details.

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PLA2 activation

PLA2, in turn, is activated by ligand binding to receptors, including:

Furthermore, any agent increasing intracellular calcium may cause activation of some forms of PLA2.[8]

PLC activation

Alternatively, arachidonic acid may be cleaved from phospholipid by phospholipase C (PLC), yielding diacylglycerol (DAG), which subsequently is cleaved by DAG lipase to yield arachidonic acid. [7]

Receptors that activate this pathway include:

PLC may also be activated by MAP kinase. Activators of this pathway include PDGF and FGF.[8]

Arachidonic acid in the body

Muscle growth

Arachidonic acid is necessary for the repair and growth of skeletal muscle tissue. One of the lead researchers of the Baylor study on arachidonic acid, Mike Roberts MS, CSCS, has authored an article published under the title Arachidonic Acid, The New Mass Builder explaining the role of this nutrient in muscle anabolism, and its potential for the enhancement of muscle size and strength.[9]

Roberts claims that for optimal muscle growth a training stimulus must elicit localized inflammation and soreness. He also shows that arachidonic acid (AA, 20:4n-6) is an essential Omega-6 (1-6) polyunsaturated fatty acid that is abundant in skeletal muscle membrane phospholipids (figure 2). It is also the body's principle building block for the production of prostaglandins, which are known to have various physiological roles including a close involvement in inflammation. Also, the prostaglandin isomer PGF2a has a potent ability to stimulate muscle growth. As such, Roberts says that arachidonic acid is a regulator of localized muscle inflammation, and he claims that it may be a central nutrient controlling the intensity of the anabolic/tissue-rebuilding response to weight training.

Brain

Arachidonic acid is one of the most abundant fatty acids in the brain, and is present in similar quantities to DHA (docosahexaenoic acid). The two account for approximately 20% of its fatty acid content[10]. Like DHA, neurological health is reliant upon sufficient levels of arachidonic acid. Among other things, arachidonic acid helps to maintain hippocampal cell membrane fluidity[11]. It also helps protect the brain from oxidative stress by activating perioxisomal proliferator-activated receptor-y[12]. ARA also activates syntaxin-3 (STX-3), a protein involved in the growth and repair of neurons[13].

Arachidonic acid is also involved in early neurological development. In one study funded by the U.S. National Institute of Child Health and Human Development, infants (18 months) given supplemental arachidonic acid for 17 weeks demonstrated significant improvements in intelligence, as measured by the Mental Development Index (MDI)[14]. This effect is further enhanced by the simultaneous supplementation of ARA with DHA.

In adults, the disturbed metabolism of ARA may be associated with neurological disorders such as Alzheimer’s Disease and Bipolar Disorder[15]. This may involve the increased consumption of ARA at the cellular level, and significant alterations in its conversion to other bioactive molecules (overexpression or disturbances in the ARA enzyme cascade). The increased consumption of dietary arachidonic acid is not believed to cause these neurological disorders. In the Journal of Lipid Research, an American Society for Biochemical and Molecular Biology journal, a study dated 2005-05-25 used the Flinders Sensitive Line rats to investigate the link between omega-3 fatty acids and depression. An examination of the brains of depressed rats compared them with brains from normal rats. Surprisingly, they found that the main difference between the two types of rats was in omega-6 fatty acid levels and not omega-3 fatty acid levels. Specifically, they discovered that brains with depression had higher concentrations of arachidonic acid, a long-chain unsaturated metabolite of omega-6 fatty acid. The findings suggest that it is not a lack of omega-3 fatty acids but a higher increase of arachidonic that is implicated in depression.

Bodybuilding supplement

Arachidonic acid is marketed as an anabolic bodybuilding supplement in a variety of products. The first clinical study concerning the use of arachidonic acid as a sport supplement was conducted at Baylor University and published in the Journal of the International Society of Sports Nutrition.[16]

The performance data results from the paper include the following statistically significant improvement, and statistically strong trends:

A significant group × time interaction for relative Wingate peak power was observed among groups (P = 0.02) with gains in peak power being significantly greater in the AA group (0.3 ± 1.2 W·kg-1) vs. PLA (0.2 ± 0.7 W·kg-1, Figure 1). Using repeated measures ANOVA with delta scores, AA experienced significantly greater increases in comparison to the PLA group at day 50 (P < 0.05). Statistical trends were seen in Wingate total work (AA: 1,292 ± 1,206 vs. PLA: 510 ± 1,249 J, P = 0.09, ηp 2 = 0.052), favoring the AA group.

WIth regard to inflammation, the paper reported a statistiically significant reduction in resting IL-6 levels (a central regulator of inflammation):

IL-6 levels experienced a significant group × time interaction (P = 0.04) among groups with subsequent post-hoc analyses revealing that IL-6 was significantly lower at day 25 of the study. One way ANOVA of IL-6 delta values at day 25 revealed significantly greater increases in PLA when compared to AA group (AA: 0.8 ± 13.5 pg·ml-1 vs. PLA: 52.5 ± 1.6 pg·ml-1, P = 0.01; Figure 2)

Arachidonic acid was shown to improve peak muscle power, reduce resting IL-6 levels, and produce statistically strong trends of improvements in muscle endurance, average power, and bench press 1-rep maximum lift. This study provides preliminary evidence supporting the use of arachidonic acid in sports nutrition. Further research is needed.

Dietary arachidonic acid and inflammation

Under normal metabolic conditions, the increased consumption of arachidonic acid is unlikely to increase inflammation[citation needed]. ARA is metabolized to both pro-inflammatory and anti-inflammatory molecules[17]. Studies giving between 840 mg and 2,000 mg per day to healthy individuals for up to 50 days have shown no increases in inflammation or related metabolic activities[18][17][19][20]. Increased arachidonic acid levels are actually associated with reduced pro-inflammatory IL-6 and IL-1 levels, and increased anti-inflammatory tumor-necrosis factor-beta[21]. This may reduce inflammation under certain conditions.

Arachidonic acid does still play a central role in inflammation related to many diseased states. How it is metabolized in the body dictates its inflammatory or anti-inflammatory activity. Individuals suffering from joint pains or active inflammatory disease may find that increased arachidonic acid consumption exacerbates symptoms, probably because it is being more readily converted to inflammatory compounds. Likewise, high arachidonic acid consumption is not advised for individuals with a history of inflammatory disease, or that are in compromised health. It is also of note that while ARA supplementation does not appear to have pro-inflammatory effects in healthy individuals, it may counter the anti-inflammatory effects of omega-3 EFA supplementation[22].

Health effects of arachidonic acid supplementation

Arachidonic acid supplementation in daily dosages of 1,000-1,500 mg for 50 days has been well tolerated during several clinical studies, with no significant side effects reported. All common markers of health including kidney and liver function[19], serum lipids[23], immunity[24], and platelet aggregation[18] appear to be unaffected with this level and duration of use. Furthermore, higher concentrations of ARA in muscle tissue may be correlated with improved insulin sensitivity[25]. Arachidonic acid supplementation by healthy adults appears to offer no toxicity or significant safety risk. The safety of arachidonic acid supplementation in patients suffering from inflammatory or other diseased states is unknown, and is not recommended.

See also

References

  1. ^ "Dorland's Medical Dictionary – 'A'". http://www.mercksource.com/pp/us/cns/cns_hl_dorlands.jspzQzpgzEzzSzppdocszSzuszSzcommonzSzdorlandszSzdorlandzSzdmd_a_56zPzhtm. Retrieved 2007-01-12. 
  2. ^ a b c Baynes, John W.; Marek H. Dominiczak (2005). Medical Biochemistry 2nd. Edition. Elsevier Mosby. p. 555. ISBN 0723433410. 
  3. ^ MacDonald M, Rogers Q, Morris J (1984). "Nutrition of the domestic cat, a mammalian carnivore". Annu Rev Nutr 4: 521–62. doi:10.1146/annurev.nu.04.070184.002513. PMID 6380542. http://nutr.annualreviews.org/doi/abs/10.1146/annurev.nu.04.070184.002513. Retrieved 2007-02-09. 
  4. ^ Rivers J, Sinclair A, Crawford M (1975). "Inability of the cat to desaturate essential fatty acids". Nature 258 (5531): 171–3. doi:10.1038/258171a0. PMID 1186900. http://www.nature.com/nature/journal/v258/n5531/abs/258171a0.html. 
  5. ^ http://www.martek.com/About/History.aspx
  6. ^ Page 108 in: Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. pp. 1300. ISBN 1-4160-2328-3. 
  7. ^ a b c d e f Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. pp. 1300. ISBN 1-4160-2328-3.  Page 103
  8. ^ a b c d e f Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. pp. 1300. ISBN 1-4160-2328-3.  Page 104
  9. ^ http://www.bodybuilding.com/fun/llewellyn2.htm
  10. ^ Crawford, M.A. and Sinclair, A.J. (1972) Nutritional influences in the evolution of the mammalian brain. In Lipids, malnutrition and the developing brain: 267 292. Elliot, K. and Knight, J. (Eds.). A Ciba Foundation Symposium (19 21 October, 1971). Amsterdam, Elsevier.
  11. ^ Fukaya, T.; Gondaira, T.; Kashiyae, Y.; Kotani, S.; Ishikura, Y.; Fujikawa, S.; Kiso, Y.; Sakakibara, M. (2007). "Arachidonic acid preserves hippocampal neuron membrane fluidity in senescent rats". Neurobiology of aging 28 (8): 1179–1186. doi:10.1016/j.neurobiolaging.2006.05.023. PMID 16790296.  edit
  12. ^ Wang, Z.; Liang, C.; Li, G.; Yu, C.; Yin, M. (2006). "Neuroprotective effects of arachidonic acid against oxidative stress on rat hippocampal slices". Chemico-biological interactions 163 (3): 207–217. doi:10.1016/j.cbi.2006.08.005. PMID 16982041.  edit
  13. ^ Darios, F.; Davletov, B. (2006). "Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3". Nature 440 (7085): 813–817. doi:10.1038/nature04598. PMID 16598260.  edit
  14. ^ Developmental Medicine and Child Neurology, March 2000
  15. ^ Rapoport, SI (2008). "Arachidonic acid and the brain". The Journal of nutrition 138 (12): 2515–20. PMID 19022981.  edit
  16. ^ Effects of arachidonic acid supplementation on training adaptations in resistance-trained males [1]
  17. ^ a b Harris, W.; Mozaffarian, D.; Rimm, E.; Kris-Etherton, P.; Rudel, L.; Appel, L.; Engler, M.; Engler, M. et al. (2009). "Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention". Circulation 119 (6): 902–907. doi:10.1161/CIRCULATIONAHA.108.191627. PMID 19171857.  edit
  18. ^ a b Nelson, GJ; Schmidt, PC; Bartolini, G; Kelley, DS; Kyle, D (1997). "The effect of dietary arachidonic acid on platelet function, platelet fatty acid composition, and blood coagulation in humans". Lipids 32 (4): 421–5. PMID 9113631.  edit
  19. ^ a b Changes in whole blood and clinical safety markers over 50 days of concomitant arachidonic acid supplementation and resistance training. Wilborn, C, M Roberts, C Kerksick, M Iosia, L Taylor, B Campbell, T Harvey, R Wilson, M. Greenwood, D Willoughby and R Kreider. Proceedings of the International Society of Sports Nutrition (ISSN) Conference June 15-17, 2006.
  20. ^ Pantaleo, P.; Marra, F.; Vizzutti, F.; Spadoni, S.; Ciabattoni, G.; Galli, C.; La Villa, G.; Gentilini, P. et al. (2004). "Effects of dietary supplementation with arachidonic acid on platelet and renal function in patients with cirrhosis". Clinical science (London, England : 1979) 106 (1): 27–34. doi:10.1042/CS20030182. PMID 12877651.  edit
  21. ^ Ferrucci, L.; Cherubini, A.; Bandinelli, S.; Bartali, B.; Corsi, A.; Lauretani, F.; Martin, A.; Andres-Lacueva, C. et al. (2006). "Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers". The Journal of clinical endocrinology and metabolism 91 (2): 439–446. doi:10.1210/jc.2005-1303. PMID 16234304.  edit
  22. ^ Li, B; Birdwell, C; Whelan, J (1994). "Antithetic relationship of dietary arachidonic acid and eicosapentaenoic acid on eicosanoid production in vivo". Journal of lipid research 35 (10): 1869–77. PMID 7852864.  edit
  23. ^ Nelson, GJ; Schmidt, PC; Bartolini, G; Kelley, DS; Phinney, SD; Kyle, D; Silbermann, S; Schaefer, EJ (1997). "The effect of dietary arachidonic acid on plasma lipoprotein distributions, apoproteins, blood lipid levels, and tissue fatty acid composition in humans". Lipids 32 (4): 427–33. PMID 9113632.  edit
  24. ^ Kelley, DS; Taylor, PC; Nelson, GJ; MacKey, BE (1998). "Arachidonic acid supplementation enhances synthesis of eicosanoids without suppressing immune functions in young healthy men". Lipids 33 (2): 125–30. doi:10.1007/s11745-998-0187-9. PMID 9507233.  edit
  25. ^ Borkman, M; Storlien, LH; Pan, DA; Jenkins, AB; Chisholm, DJ; Campbell, LV (1993). "The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids". The New England journal of medicine 328 (4): 238–44. PMID 8418404.  edit

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