Arachidonic Acid: Synthesis, Function in the Body, Supplementation and Administration

It is structurally related to the saturated arachidic acid found in Cupuaçu butter (L. arachis – peanut).

Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20: 4 (ω-6).

Chemistry

In the chemical structure, arachidonic acid is a carboxylic acid with a chain of 20 carbons and four cis double bonds; the first double bond is found in the sixth carbon from the omega end.

Some chemical sources define ‘arachidonic acid’ to designate any of the eicosatetraenoic acids. However, almost all those written 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 present in phospholipids (especially phosphatidylethanolamine, phosphatidylcholine and phosphatidylinositides) of the membranes of body cells, and is abundant in the brain, muscles and liver.

Skeletal muscle is a particularly active site for the retention of arachidonic acid, which represents approximately 10-20% of the fatty acid content of phospholipids on average.

In addition to being involved in cell signaling as a second lipid messenger involved in the regulation of signaling enzymes, such as PLC-γ isoforms, PLC-δ and PKC-α, -β and -γ, arachidonic acid is an inflammation intermediate key and can also act as a vasodilator.

Conditionally essential fatty acid

Essential fatty acids are fatty acids that humans and other animals must ingest because the body needs them for good health but can not synthesize them. Those that are not essential are non-essential fatty acids.

Arachidonic acid is not one of the essential fatty acids. However, it becomes essential if there is a deficiency in linoleic acid or if there is an inability to convert linoleic acid into arachidonic acid.

Some mammals lack the capacity, or have a very limited ability to convert linoleic acid into arachidonic acid, making it an essential part of their diets.

Since there is little or no arachidonic acid in common plants, such animals are obligate carnivores; The cat is a common example that has an inability to desaturate essential fatty acids.

However, a commercial source of arachidonic acid has been obtained from the fungus Mortierella alpina.

The synthesis and cascade in humans

Arachidonic acid is released from a molecule of phospholipids by the enzyme phospholipase A2 (PLA2), which cleaves the fatty acid, but can also be generated from DAG by the diacylglycerol lipase.

Generated for signaling purposes seems to derive from the action of the cytosolic phospholipase group A2 IVA (cPLA2, 85 kDa), whereas the inflammatory arachidonic acid is generated by the action of a low molecular weight secretory PLA2 (sPLA2, 14-18 kDa) .

Arachidonic acid is the precursor that is metabolized by various enzymes to a wide range of biologically and clinically important eicosanoids and metabolites of these eicosanoids:

Cyclooxygenase-1 and -2 enzymes (ie prostaglandin G / H synthase 1 and 2 {PTGS1 and PTGS2) metabolize arachidonic acid to Prostaglandin G2 and prostaglandin H2, which in turn can be converted into various prostaglandins, to prostacyclin , to thromboxanes.

The 5-lipoxygenase enzyme metabolizes arachidonic acid in 5-hydroperoxycosatetraeneic acid (5-HPETE), which in turn is metabolized to several leukotrienes (i.e. leucotriene B4, leucotriene C4, leucotriene D4 and leucotriene E4, as well as acid 5 -hydroxyacetethraine (5-HETE).

The 15-lipoxygenase-1 enzymes (ALOX15 and 15-lipoxygenase-2 (ALOX15B) metabolize arachidonic acid to 15-hydroperoxicosatetraemoic acid (15-HPETE) which can then be further metabolized to 15-hydroxycosatetraenoic acid.

The enzyme 12-lipoxygenase (ALOX12) metabolizes arachidonic acid to 12-hydroperoxieicosatetraenoic acid (12-HPETE0) which can then be metabolized to 12-hydroxyceicosatetraenoic acid (12-HETE) and to hepoxilins.

Arachidonic acid is also used in the biosynthesis of anandamide.

Part of the arachidonic acid is converted to hydroxy-acetic acid (HETE) and epoxy-acetic acid (TSE) acids by the epoxygenase.

The production of these derivatives and their action in the body are collectively known as the “arachidonic acid cascade”.

Activation of PLA2

Due to the importance of PLA2 in inflammatory responses, regulation of the enzyme is essential. PLA2 is regulated by phosphorylation and calcium concentrations. PLA2 is phosphorylated by a MAPK in Serine-505.

When phosphorylation is combined with an influx of calcium ions, PLA2 is stimulated and can be translocated to the membrane to begin catalysis.

PLA2, in turn, is activated by binding the ligand to the receptors, which include:

  • 5-HT2 receptors.
  • MGLUR1.
  • Receptor de bFGF.
  • Receptor de IFN-α.
  • IFN-γ receptor.

In addition, any agent that increases intracellular calcium can cause the activation of some forms of PLA2.

PLC activation

Alternatively, arachidonic acid can be cleaved from phospholipids after phospholipase C (PLC) cleaves the inositol triphosphate group, producing diacylglycerol (DAG), which is subsequently cleaved by diacylglycerol lipase to produce arachidonic acid.

Recipients that activate this path include:

  • Receptor A1.
  • Receptor D2.
  • Adrenergic receptor α-2.
  • Receptor 5-HT1.

Phospholipase C can also be activated by MAP kinase. Activators of this pathway include PDGF and FGF.

In the body

Muscle development:

Arachidonic acid promotes repair and growth of skeletal muscle tissue by conversion to prostaglandin PGF2alpha during and after physical exercise.

PGF2alpha promotes the synthesis of muscle proteins by signaling through the Akt / mTOR pathway, similar to leucine, β-hydroxy-β-methylbutyric acid and phosphatidic acid.

Due to the association with the maintenance of muscle tissue, arachidonic acid supplements are being used by some bodybuilders to improve the effects of training.

A study in the “Journal of the International Society of Sports Nutrition” published in November 2007 found that after 25 days there was evidence of reduced inflammation in people who were taking arachidonic acid supplements but did not increase muscle strength or growth.

Brain:

Arachidonic acid is one of the most abundant fatty acids in the brain, and is present in amounts similar to docosahexaenoic acid (DHA). Both represent approximately 20% of their fatty acid content.

Like docosahexaenoic acid, neurological health depends on sufficient levels of arachidonic acid. Among other things, arachidonic acid helps maintain fluidity of the hippocampal cell membrane.

It also helps protect the brain from oxidative stress by activating the gamma receptor activated by the peroxisome proliferator.

Arachidonic acid also activates syntaxin-3 (STX-3), a protein involved in the growth and repair of neurons.

He is also involved in early neurological development.

In a study funded by the US National Institute of Child Health and Human Development. In the US, infants (18 months) who received supplemental arachidonic acid for 17 weeks showed significant improvements in intelligence, as measured by the Mental Development Index.

This effect is reinforced by the simultaneous administration of arachidonic acid with docosahexaenoic acid.

In adults, the altered metabolism of arachidonic acid may contribute to neuropsychiatric disorders, such as Alzheimer’s disease and bipolar disorder.

There is evidence of significant alterations in the conversion of arachidonic acid to other bioactive molecules (overexpression or alterations in the cascade of the arachidonic acid enzyme) under these conditions.

Alzheimer disease:

Studies on arachidonic acid and the pathogenesis of Alzheimer’s disease are mixed, with a study of arachidonic acid and its metabolites suggesting that they are associated with the onset of Alzheimer’s disease.

While another study suggests that arachidonic acid supplementation during the early stages of this disease may be effective in reducing symptoms and slowing the progression of the disease.

Additional studies on the administration of arachidonic acid supplements for patients with Alzheimer’s are needed.

Another study indicates that air pollution is the source of inflammation and the metabolites of arachidonic acid promote inflammation to signal the immune system to cell damage.

Bodybuilding supplement:

Arachidonic acid is marketed as an anabolic bodybuilding supplement in a variety of products. It has been shown that arachidonic acid supplementation (1,500mg / day for 8 weeks) increases lean body mass, strength and anaerobic power in experienced men trained in resistance.

This was demonstrated in a placebo-controlled study at the University of Tampa. Thirty men (20.4 ± 2.1 years old) took arachidonic acid or a placebo for 8 weeks and participated in a controlled resistance training program.

After 8 weeks, lean body mass (LBM for its acronym in English) had increased significantly, and to a greater extent, in the group of arachidonic acid (1.62kg) versus placebo (0.09kg) (p <0, 05).

The change in muscle thickness was also greater in the arachidonic acid group (0.47 cm) than in the placebo group (0.25 cm) (p <0.05).

The anaerobic power of Wingate increased to a greater extent also in the arachidonic acid group (723.01 to 800.66 W) versus placebo (738.75 to 766.51 W).

Finally, the change in total strength was significantly greater in the arachidonic acid group (109.92 pounds) compared to placebo (75.78 pounds).

These results suggest that supplementation with arachidonic acid can positively increase adaptations in skeletal muscle strength and hypertrophy in men trained in resistance.

A previous clinical study that examined the effects of 1,000mg / day of arachidonic acid for 50 days found supplements to improve anaerobic capacity and exercise performance in men.

During this study, a significant effect of group-time interaction was observed in the relative maximum power of Wingate (AA: 1.2 ± 0.5, P: -0.2 ± 0.2 W • kg-1, p = 0.015).

Statistical trends were also observed in 1RM bench press (AA: 11.0 ± 6.2, P: 8.0 ± 8.0 kg, p = 0.20), average Wingate power (AA: 37.9 ± 10.0, P: 17.0 ± 24.0 W, p = 0.16), and the total work of Wingate (AA: 1292 ± 1206; P: 510 ± 1249 J, p = 0.087).

Supplementation with arachidonic acid during resistance training promoted significant increases in relative maximum potency with other performance-related variables that approach significance.

These findings support the use of arachidonic acid as an ergogenic.

Arachidonic acid and inflammation in the diet:

The increase in the consumption of arachidonic acid will not cause inflammation during normal metabolic conditions unless the lipid peroxidation products are mixed.

Arachidonic acid is metabolized to proinflammatory and anti-inflammatory eicosanoids during and after the inflammatory response, respectively.

Arachidonic acid is also metabolized to inflammatory and anti-inflammatory eicosanoids during and after physical activity to promote growth.

However, chronic inflammation due to exogenous toxins and excessive exercise should not be confused with the acute inflammation of exercise and sufficient rest that requires the inflammatory response to promote repair and growth of microtears in tissues.

However, the evidence is mixed. Some studies that provide between 840mg and 2,000mg per day to healthy individuals for up to 50 days have not shown an increase in inflammation or related metabolic activities.

However, others show that increased levels of arachidonic acid are actually associated with reduced proinflammatory IL-6 and IL-1 levels and an increase in beta anti-inflammatory tumor necrosis factor. This can result in a reduction of systemic inflammation .

Arachidonic acid still plays a central role in inflammation related to injuries and 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 consumption of arachidonic acid exacerbates symptoms, presumably because it is more easily becoming inflammatory compounds.

Similarly, high intake of arachidonic acid is not recommended for people with a history of inflammatory disease or who have health problems.

It should be noted that although the administration of arachidonic acid supplements does not seem to have proinflammatory effects in healthy individuals, it may counteract the anti-inflammatory effects of omega-3 fatty acid supplements.

The discovery of COX enzymes and the role of eicosanoids derived from arachidonic acid in pain and inflammation led to the understanding that aspirin works by blocking COX enzymes.

Medications that are COX inhibitors, called nonsteroidal anti-inflammatory drugs or NSAIDs such as ibuprofen, celebrex, celecoxib, also block COX enzymes and relieve pain, inflammation, and prevent heart attacks by blocking the actions of molecules derived from the body. arachidonic acid.

However, non-steroidal anti-inflammatory drugs can cause ulcers because they also block the formation of eicosanoids that help repair damage to the stomach and intestinal lining.

Effects of arachidonic acid supplementation on health

The administration of arachidonic acid supplements in daily doses of 1,000mg – 1,500mg for 50 days has been well tolerated during several clinical studies, with no significant side effects reported.

All common health markers, which include kidney and liver function, serum lipids, immunity and platelet aggregation, appear to be unaffected by this level and duration of use.

In addition, higher concentrations of arachidonic acid in muscle tissue can be correlated with better insulin sensitivity. The supplementation with arachidonic acid in the diets of healthy adults seems to offer no toxicity or significant risk of safety.

Although studies analyzing the administration of arachidonic acid supplements in sedentary subjects failed to find changes in resting inflammatory markers at doses of up to 1,500 mg per day, subjects trained in strength may respond differently.

A study at Baylor University reported a significant reduction in resting inflammation (through the IL-6 marker) in young men supplementing 1,000mg / day of arachidonic acid for 50 days in combination with resistance training.

This suggests that, the administration of arachidonic acid supplements during resistance training can actually improve the regulation of systemic inflammation.

A meta-analysis from the University of Cambridge looking for associations between the risk of heart disease and individual fatty acids reported a significantly lower risk of heart disease with higher levels of EPA and docosahexaenoic acid (Omega-3 fats), as well as acid Omega-6 arachidonic.

Scientific advice from the American Heart Association has also favorably evaluated the health impact of omega-6 fats in the diet, including arachidonic acid.

The group does not recommend limiting this essential fatty acid. In fact, the document recommends that people follow a diet consisting of at least 5-10% calories from omega-6 fats, including arachidonic acid.

It suggests that arachidonic acid in the diet is not a risk factor for heart disease, and may play a role in maintaining optimal metabolism and reducing the risk of heart disease.

Therefore, it is recommended to maintain sufficient levels of intake of omega-3 and omega-6 fatty acids for optimal health.

Arachidonic acid is not carcinogenic, and studies show that the level of the diet is not associated (positively or negatively) with the risk of cancer.

However, arachidonic acid remains an integral part of the inflammatory process and cell growth, which is altered in many types of diseases, including cancer.

Therefore, the safety of the administration of arachidonic acid supplements in patients suffering from cancer, inflammation or other disease states is not known, and supplementation is not recommended.

Administration of arachidonic acid

Currently there is not enough evidence to recommend an ideal dose of arachidonic acid supplements, but anecdotally it is used in doses of around 2,000mg taken 45 minutes before a workout. It is not clear if this is an optimal dose or if the time is necessary.

It should also be noted that for people with chronic inflammatory disorders, such as rheumatoid arthritis or inflammatory bowel diseases, that the ideal dose of arachidonic acid may actually be a dietary restriction thereof.

In cases of inflammatory diseases, the administration of arachidonic acid supplements is probably contraindicated.