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Pathways of arachidonic acid oxidation. Metabolism of arachidonic acid

Arachidonic acid (AA) is an omega-6 fatty acid, being the essential fatty acid when considering the ratio of omega-3 to omega-6 fatty acids (relative to fatty acids fish oil). It is pro-inflammatory and immunosupportive.

Pharmacological group: omega-6 fatty acids
Pharmacological action: synthesis of prostaglandins; increasing blood flow to muscles, increasing local sensitivity to IGF-L and , supporting satellite cell activation, cell proliferation and differentiation and increasing overall levels of protein synthesis and promoting muscle growth.

General information

Arachidonic acid (5-cis,8-cis,11-cis,14-cis-eicosantetraenoic acid) is an omega-6 fatty acid that serves as a major building block for the synthesis of prostaglandins (eg, PGE2 and PGF2a). These prostaglandins are integral to protein metabolism and muscle construction, and perform important functions such as increasing blood flow to muscles, increasing local sensitivity to IGF-L and , supporting satellite cell activation, cell proliferation and differentiation, and increasing overall levels of protein synthesis and maintenance. muscle growth. Arachidonic acid serves as the primary thermostat for prostaglandin turnover in skeletal muscle tissue and is also responsible for initiating many of the immediate biochemical changes that occur during resistance exercise that ultimately lead to muscle hypertrophy. Thus, arachidonic acid is a highly anabolic substance.
Among the wide variety of supplements for athletes and bodybuilders, arachidonic acid, along with protein, is an essential substance for muscle growth.

Not to be confused with: linoleic acid (parent omega-6 fatty acid).

Worth noting:

It is possible that arachidonic acid may worsen joint inflammation and pain.

Represents:

Muscle-forming substance.

Not compatible with:

Fish oil supplements (interfering with the ratio of omega-3 to omega-6 in favor of omega-6).

Arachidonic acid: instructions for use

There is not enough information at this time to recommend any ideal dosage of arachidonic acid, but a dosage of about 2000 mg taken 45 minutes before exercise is commonly used occasionally. It is unclear if this dosage is optimal, or for how long it is active. It is also worth noting that for individuals with chronic inflammatory diseases, such as rheumatoid arthritis or inflammatory bowel disease, the ideal dosage of arachidonic acid may need to be adjusted downward. In conditions of inflammatory diseases, the use of arachidonic acid may be contraindicated.

Sources and structure

Sources

Arachidonic acid (AA) is the most biologically relevant omega-6 fatty acid, and in the lipid membrane of the cell is the fatty acid that competes with two fish oil fatty acids (EPA and DGU) in determining the ratio of omega-3 to omega-6 fatty acids . Current evidence suggests that consuming 50-250 mg of arachidonic acid per day with some other sources adds up to a total of 500 mg per day; arachidic acid intake is usually less than that of vegetarians. Food sources of arachidonic acid include:

Arachidonic acid is found in the visible fat of meat products at the same level as meat; Despite the above indicators, it is unknown what happens to arachidonic acid during the cooking process. Some studies note an increase in fatty acids per weight during cooking, while others do not note any significant differences (relative to other fatty acids). Arachidonic acid is found naturally in foods, mainly in animal products. If arachidonic acid is not available in the diet, linoleic acid (the parent omega-6 fatty acid found in animal products) can be used to produce arachidonic acid in the body. Body AA concentrations follow a nonlinear dose-response relationship with dietary intake of linoleic acid (the parent omega-6 fatty acid), where human diets consisting of less than 2% linoleic acid contribute to increases in plasma arachidonic acid levels when supplemented with linoleic acid. acids; with a share of 6% (classical Western diet), this was not detected. On the other hand, dietary intake of arachidonic acid increases plasma arachidonic acid in a dose-dependent manner. Linoleic acid (the parent omega-6 fatty acid) obtained from food may increase plasma levels of arachidonic acid, demonstrating how omega-6 fatty acids mediate their effects. Apparently, at this stage there is a so-called limit, and the use of arachidonic acid allows you to bypass it, increasing plasma concentrations of arachidonic acid in a dose-dependent manner. Reducing the proportion of arachidonic acid in the diet slightly (244% instead of 217%) increases the amount of EPA contained in the membranes of red blood cells (when consuming fish oil) without affecting DHA.

Biosynthesis

Arachidonic acid is the reason that linoleic acid (a dietary source of omega-6 fatty acids) has the status of an essential fatty acid, since the latter is required in the diet to be converted into the previously mentioned one. In addition, arachidonic acid can be produced as a catabolite of anandamide (one of the main endogenous cannabinoids acting on the cannabinoid system, also known as arachidonoylethanolamide) through the enzyme FAAH, and may also have some properties similar to anandamide, such as effects on TRPV4 receptors. The endocannabinoid 2-arachidonoylglycerol can also be hydrolyzed to arachidonic acid by monoacylglycerol lipase or similar esterases. Arachidonic acid is also produced in the body when cannabinoids are broken down.

Regulation

Older rats and humans have lower levels of arachidonic acid in the body and neurons (in plasma membranes), which is associated with lower activity of the biosynthetic enzymes that convert linoleic acid to arachidonic acid. Arachidonic acid appears to be reduced in older subjects compared to younger subjects due to lower conversion of dietary linoleic acid to arachidonic acid.

Eicosanoids

Biological activation of eicosanoids

Eicosainodes are fatty acid metabolites that are derived from either arachidonic acid or eicosapentaenoic acid and docosahexaenoic acid (EPA and DHA, two fish oil fatty acids, belong to the omega-3 fatty acid class). DHA, EPA and AA are typically found in the middle of the triglyceride backbone (at the sn-2 binding position) and are thus present in free form in the membrane while the phospholipase A2 enzyme is activated; when this enzyme is activated (seizures, ischemia, NMDA receptor stimulation, as well as various inflammatory cytokines such as IL-1beta, TNF-alpha, PMA and stress cells), and due to the non-discriminatory nature of the phospholipase A2 enzyme (releasing DHA/ EPA and AA with such efficiency), the number of eicosainoids produced depends on the ratio of omega-3 to omega-6 fatty acids in the cell membrane. Eicosanoids are action molecules derived from long chain fatty acids, and the eicosanoids from arachidonic acid are released from the same enzyme as fish oil fatty acids. This step determines which eicosanoids will be used in cellular action, being the mechanism underlying the importance of the dietary ratio of omega-3 to omega-6 fatty acids (since the eicosanoids released in the cell reflect the ratio in the membrane). Like fish oil fatty acids, arachidonic acid can follow one of three pathways for release from the membrane, namely:

COX-dependent pathway for producing PGH2 (the parent of prostaglandins, and all prostaglandins are derivatives of this pathway); prostaglandins are signaling molecules with a pentacyclic structure (pentagonal) in the fatty acid side chain;

LOX-dependent pathway, which produces lipoxins and leukotrienes;

The P450 pathway, which is a downstream entity of either the epoxygenase enzyme (to produce epoxyeicosatrienoic acids or EET) or the hydroxylase enzyme (to produce hydroxyeicosatrienoic acids or HETE).

Arachidonic acid can take one of three routes once it is released; The COX-dependent pathway (for prostaglandins), the LOX-dependent pathway (for lipoxins and leukotrienes), or one of the two P450 pathways to form EET or HETE. All of these classes of signaling molecules are known as omega-6 eicosanoids.

Prostaglandins

After being released from the cell membrane by phospholipase A2, arachidonic acid is converted to prostaglandin H2 (PGH2) by endoperoxide H synthases 1 and 2 (alternative names for the cyclooxygenase enzymes COX1 and COX2); This process involves the use of oxygen molecules to convert arachidonic acid into the unstable peroxide intermediate PGG2, which is then passively converted to PGH2; PGH2 serves as an intermediate parent for all AA-derived prostaglandins (a subset of eicosanoids). This first step in eicosanoid synthesis is one of the reasons for the anti-inflammatory and antiplatelet effects of COX inhibitors (eg, aspirin), which prevents AA eicosanoids from reducing PGH2 production. With respect to the enzymes that mediate this conversion, COX2 is an inducible form that can be activated in response to inflammatory stresses within 2-6 hours in a variety of cells, although it may be expressed under basal conditions in some cells (brain, testis, kidney cells , known as dense spots), while COX1 is only generally expressed in all cells; this is due to variation in COX2, which is an inducible variant, and COX1 is a constitutive variant. Arachidonic acid (AA) is released from the cell membrane by phospholipase A2, then converted to PGH2 (prostaglindin) by one of two COX enzymes. Inhibition of this step inhibits the production of all AA-derived eicosanoids, and PGH2 is then synthesized to other eicosanoids. PGH2 can be converted to prostaglandin D2 by the enzyme prostaglandin D synthase (in the presence of sulhydryl compounds), and PDG2 is known to act through the DP2 receptor (originally studied on T cells and known as CRTh2, related to GRP44, binding to Gi proteins or G12). In this sense and due to signaling through its receptor, PGD2 is biologically active. PGD2 can be converted to PGF2alpha, which binds to its receptor (PGF2alpha receptor) in the same way as the DP2 receptor, although 3.5 times weaker than PGF2. The PGF2alpha isomer known as 9alpha, 11beta-PGF2 can also be derived from PGD2, being equivalent to the DP2 receptor. PGH2 can be converted to prostaglandin D2, which is one of several metabolic "branches" of prostaglandins. Once converted to PGD2, further metabolism of 9alpha, 11beta-PGF2 and PGF2alpha occurs, which can produce the effects of all three molecules. PGH2 (the parent prostaglandin) can thus be converted into prostaglandin E2 (PGE2) by the enzyme PGE synthase (of which the membrane binds mPGES-1 and mPGES-2 and cytosolic cPGES), with further metabolism of PGE2 leading to the formation of PGF2. Interestingly, selective inhibition of the inducible enzyme (mPGES-1) appears to attenuate PGE2 production without affecting the reduction in concentrations of other PGH2 prostaglandins, which in a non-discriminatory manner inhibits COX enzymes, which in turn inhibit all prostaglandins; inhibition of PGE2 production causes slight recompensation and an increase in PGI2 levels (due to COX2). PGE2 is generally implicated in the nature of pain as it is expressed through sensory neurons, inflammation, and potential loss of muscle mass. There are four receptors for prostaglandin E2, called EP1-4, each of which is a G protein receptor. EP1 is coupled to the Gq/11 protein, and its activation can increase phospholipase C activity (producing IP3 and diacylglycerol by activating protein kinase C). EP2 and EP4 receptors in combination with Gs protein can activate adenyl cyclase (creatine cAMP and protein kinase A activation). EP3 receptors appear to be slightly more complex (splicing time alpha, beta and gamma variants; EP3alpha, EP3beta and EP3gamma), all combined with Gi, which inhibits adenyl cyclase activity (and thus opposes EP2 and EP4) , with the exception of EP3gamma, which binds to the Gi and Gs proteins (inhibition and activation of adenyl cyclase). A group of enzymes known as PGE synthase, but specifically mPGES-1, converts the parent prostaglandin into PGE2, which plays a role in promoting inflammation and pain perception. PGE2 activates prostaglandin E receptors (EP1-4). PGH2 (parent prostaglandin) can be subject to the enzyme prostacyclin synthase and can be converted to a metabolite known as prostacyclin or PGI2, which is then converted to 6-keto-PGF1alpha (then converted to a urinary metabolite known as 2,3-dinor-6-keto Prostaglandin F1alpha). PGI2 is known to activate the prostanoid I (PI) receptor, which is expressed in the endothelium, kidney, platelets and brain. Prostacyclin production impairs the pro-platelet function of thromboxanes (see next section). PGH2 can be converted into PGI2, which is also called prostacyclin, and this prostaglandin then acts through the PI receptor. There is some association with the prostaglandin class, which is still based on the parent prostaglandin, with PGH2 acting as the subject of an enzyme known as thromboxane synthase, which is converted to thromboxane A2. Thromboxane A2 (TxA2) acts through T-prostanoid (TP) receptors, which are G protein-coupled receptors with two splice variants (TPalpha and TPbeta) coupled to Gq, G12/13. Thromboxane A2 is best known for its production in activated platelets during periods when platelets are stimulated and arachidonic acid is released, and its inhibition by COX inhibitors (namely aspirin) underlies the antiplatelet effects of COX inhibition. Thromboxane A2 is a metabolite of the parent prostaglandin (PGH2) that acts on T-prostanoid receptors, best known to form platelets, to enhance blood clotting (inhibition of thromboxane A2 underlies the antiplatelet benefits of aspirin).

Epoxy/Hydroxyeicosatrienoic acids

Epoxyeicosatrienoic acids (EET) are eicosanoid metabolites that are produced when arachidonic acid is a subject of the P450 pathway and then immediately subject to the epoxygenase enzyme; Hydroxyeicosatrienoic acids (HETE) are also metabolites of the P450 pathway, but are subject to the hydroxylase enzyme instead of the epoxygenase enzyme. HETE includes mainly 19-HETE and 20-HETE. EET includes 5,6-EET (which is converted to 5,6-DHET by the soluble enzyme epoxide hydroxylase), 8,9-EET (also converted, but to 8,9-DHET), 11,12-EET (to 11 ,12-DHET) and 14,15-EET (14,15-DHET). The P450 pathway mediates the synthesis of EET and HETE.

Leukotrienes

LOX pathway (to confirm, prostaglandins are due to the COX pathway, and EET and HETE are due to the P450 pathway) the main metabolites of eicosanoids are leukotrienes. Arachidonic acid is directly converted by LOX enzymes to a new metabolite, 5-hydroperoxyeicosatrienoic acid (5-HPETE), which is then converted to leukotriene A4. Leukotriene A4 can take one of two routes: either conversion to leukotriene B4 (LTB4) by the addition of a water group, or conversion to leukotriene C4 by glutanione S-transferase. If it is converted to a C4 metabolite, it can then convert to leukotriene D4 and then to leukotriene E4. Leukotrienes can form near nuclei. The LOX pathway typically mediates the synthesis of leukotrienes.

Pharmacology

Blood serum

Supplementation of 240–720 mg arachidonic acid in older adults for 4 weeks may increase plasma membrane arachidonic acid concentrations (within 2 weeks with no subsequent effect at 4 weeks), but there was no significant effect on urinary metabolites in serum PGE2 and lipoxin A4. . Arachidic acid intake does not necessarily increase plasma levels of eicosanoid metabolites, despite increasing arachidonic acid concentrations.

Neurology

Autism

Autism spectrum disorders are neurological conditions typically associated with impairments in social functioning and communication. Arachidonic acid, as well as DHA from fish oil and AA, have been studied to be critical for neuronal development in newborns; Disturbances in the metabolism of polyunsaturated fatty acids are known to be associated with autistic disorders (somewhat unreliable data). Supplementation of 240 mg AA and 240 mg DHA (together with 0.96 mg antioxidant astaxanthin) for 16 weeks in 13 patients with autism (half the dose for ages 6 to 10 years) showed no reduction in SRS rating scale scores. and ABC for autism, although there was some improvement on the Social Isolation (ABC) and Connection (SHD) subscales, the percentage of patients experiencing a 50% reduction in symptoms was not significantly different than placebo. There is very limited evidence to suggest that arachidonic acid with DHA fish oil reduces autism symptoms, although there is some effectiveness in improving social symptoms, so more research is needed.

Memory and learning

Activation of phospholipase A2 has been noted to promote axonal growth while simultaneously damaging neurons and elongating them. These effects of eicosanoids (derived from arachidonic acid and fish oil, predominantly DHA), and arachidonic acid in general, are noted to promote axonal growth through the 5-LOX pathway with maximum effectiveness at 100 µM, although at high concentrations (10 mm) this pathway is neurotoxic due to excess oxidation (prevented by vitamin E). Neurite outgrowth may be associated with effects on calcium channels. In the body, arachidonic acid plays a role in promoting neural development and lengthening, although unnaturally high concentrations of arachidonic acid appear to be cytotoxic. As noted in rats, the activity of the enzymes that convert linoleic acid to arachidonic acid decreases with age; Dietary ingestion of arachidonic acid in aged rats promotes cognitive development, and this effect was replicated in relatively healthy aged men with 240 mg of AA (due to 600 mg of triglycerides) as assessed by P300 amplitude and latency. By reducing arachidonic acid production during aging, arachidonic acid supplementation may have a role in enhancing cognitive performance in older adults (it is not yet clear if the effect extends to younger subjects; this seems unlikely).

Nerve

Activation of phospholipase A2 has been reported to be involved in immune cell communication and neuronal demyelination, possibly a COX-dependent mechanism, such as celecoxib (a COX2 inhibitor); this helps improve neural healing parameters. This process involves eicosanoids of omega-3 and omega-6 origin.

Cardiovascular diseases

blood flow

Arachidonic acid (4.28% of rat diet) appears to reverse the aging-associated increase in vasoconstriction induced by phenylephrine in rats through endothelial-dependent mechanisms; there is a slight increase in the acetylcholine-induced vasorelaxant effect; no beneficial effect was observed in young rats. When testing older adults (65 years on average), taking 240 mg of arachidonic acid with 240 mg of DHA (one of the fatty acids in fish oil) for three months resulted in improved coronary blood flow during periods of hyperemia, but not at rest. Arachidonic acid supplementation in old age may have a cardioprotective effect by promoting blood flow, although evidence in humans is very sparse.

Skeletal muscle and performance

Mechanisms

Arachidonic acid is thought to be an important element in relation to skeletal muscle metabolism, as phospholipids in the sarcoplasmic membrane are thought to be reflected in the diet; exercise itself appears to promote changes in muscle phospholipid content (independent of muscle fiber composition, associated with a lower ratio of omega 6 to omega 3 fatty acids); eicosanoids from arachidonic acid interact with muscle protein synthesis through receptors. Arachidonic acid affects muscle protein synthesis through a COX-2 dependent pathway (suggesting the involvement of prostaglandins), which is associated with an increase in prostaglandin E2 (PGE2) and PGF(2alpha), although incubation with isolated PGE2 and PGF(2alpha) does not fully reproduce the hypertrophic effects arachidonic acid. PGE2 and PGF(2alpha) are also induced by exercise (particularly when stretching muscle cells in vitro), and this is also observed in serum and intramuscularly (fourfold - from 0.95+/-0.26 ng per ml to 3.97+/-0.75 ng per ml) in exercising subjects, in whom normalization occurs one hour after completion of exercise. The ability of the stretch reflex to increase concentrations of PGE2 and PGF(2alpha) may simply be due to stretch increasing COX-2 activity. It is worth noting that consuming 1500 mg of arachidonic acid (compared to a control diet containing 200 mg) for 49 days was found to increase PGE2 secretion from stimulated immune system cells (by 50-100%) in relatively healthy young adults, but the relevance of this fact in relation to skeletal muscle is not known. This study also notes that without stimulation, there was no difference between groups. However, there was a trend towards increased serum PGE2 concentrations, at least in trained men, when consuming 1000 mg arachidonic acid for 50 days. Arachidonic acid, through eicosainodes known as PGF(2alpha) and PGE2, stimulates the synthesis of muscle proteins. They are produced from arachidonic acid, but do not usually form their corresponding muscle-binding eicosanoids unless the cells are stimulated by a stressor (for example, the stretch reflex on a muscle cell), which then induces their production. The PGF(2alpha) receptor (FP receptor) appears to be activated by COX1 inhibitors (acetaminophen used in this study), enhancing the effects of PGF(2alpha) which appears to underlie the improvements in muscle protein synthesis observed in older people when using anti-inflammatory drugs. Arachidonic acid supplementation does not appear to affect the number of FP receptors in young adults; While exercise alone may increase EP3 receptors, but not COX1 inhibitors and arachidonic acid, it appears to continue to influence the processes. However, use of COX2 inhibitors (in young adults) has been shown to reverse exercise-induced increases in PGF(2alpha) (ibuprofen and acetaminophen) as well as PGE2, which are thought to occur due to the conversion of PGH2 to these metabolites, depending on from COX2 activity. By producing these eicosanoids, which are dependent on COX2 enzymes, inhibition of this enzyme is thought to reduce the anabolic effects of exercise when taken before exercise. Arachidonic acid (like EPA from fish oil) has not been noted to attenuate glucose uptake in isolated muscle cells, and 10 µM fatty acids may attenuate saturated fat-induced insulin resistance; this phenomenon is observed when using saturated fats with 18 carbon chains or more, which does not seem to apply to polyunsaturated fatty acids of equal chain length; This is associated with an increase in intracellular ceramides, which contributes to the deterioration of the effects of Akt, reducing GLUT4-mediated glucose uptake from insulin. Arachidonic acid and omega-3 polyunsaturated acids are associated with improved insulin sensitivity in muscle cells, which may be secondary to a reduction in saturated fat levels in the lipid membrane, reducing intracellular ceramide concentrations. It is possible that this is not related to eicosainodes or the ratio of omega-3 to omega-6 fatty acids.

Exercise is known to release vasoactive metabolites that cause relaxation of blood vessels, from which, along with some general vasodilatory agents (nitric oxide, adenosine, hydrogen ions), prostanoids are also released. Serum arachidonic acid levels are acutely suppressed by exercise (normalizing within minutes); There are increases in several arachidonic acid eicosanoids, including 11,12-DHET, 14,15-DHET, 8,9-DHET, and 14,15-EET, cycling at 80% of VO2 max in the acute setting; Higher urinary concentrations of 2,3-dinor-6-keto-prostaglandin F1alpha (indicative of higher concentrations of PGI2 and 6-keto-PGF1alpha) were observed after at least 4 weeks of training in previously untrained youth.

Interventions

In a sample of 31 trained men subject to a weightlifting program and a specialized diet (500 kcal excess at 2 g protein per kg body weight) supplemented with either 1 g arachidonic acid or placebo, after 50 days a small increase in peak power was found (by 7.1%) and average power (3.6%) during Wingate testing; there is no positive effect on muscle mass or weight lifting (bench press or leg press).

Bone metabolism and skeleton

Mechanisms

Prostaglandin F2 alpha (PGF2alpha) is capable of positive effects on bone growth due to its action as a mitogen on osteoclasts.

Inflammation and immunology

Arthritis

In patients with rheumatoid arthritis, reducing arachidonic acid from dietary sources (from 171 mg to 49 mg; the increase in eicosapentaenoic acid is minor) and linoleic acid (from 12.7 g to 7.9 g) can reduce pain symptoms associated with rheumatoid arthritis (by 15%), improving the effectiveness of fish oil consumption from 17% to 31-37%. Limiting dietary intake of arachidonic acid is thought to promote symptoms of rheumatoid arthritis by increasing the effectiveness of fish oil supplementation.

Interactions with hormones

Testosterone

Cortisol

In trained men, 1000 mg of arachidonic acid for 50 days did not result in significant changes in cortisol concentrations compared to placebo.

Interactions with the lungs

Asthma

Prostaglandin D2 (PGD2) is a potent substance on the bronchi, somewhat more powerful than the similar prostaglandin PGF2alpha (3.5 times) and much more powerful than histamine itself (10.2 times). Action through the DP-1 and DP-2 receptors is thought to mediate the pro-asthmatic effects of these prostaglandins, as these receptors, and their downregulation, are known to be associated with a reduction in airway inflammation. The eicosanoids arachidonic acid appear to be pro-asthmatic.

Interactions with aesthetic parameters

Hair

Prostaglandin D2 (from arachidonic acid) and the enzyme that produces it (prostaglandin D2 synthase) are 10.8 times higher in the scalp of men with androgenetic alopecia compared to the scalp where hair is present; The substance appears to promote hair growth suppression by acting on the DP2 receptor (also known as GRP44 or CRTh2), with PGD2 receptor 1 not associated with hair growth suppression, and prostaglandin 15-ΔPGJ2 having suppressive effects. Excess enzyme is capable of mimicking androgenetic alopecia, suggesting that the enzyme is a therapeutic target, and this enzyme is known to respond strongly to androgen exposure. Prostaglandin D2 and its metabolites (produced from prostaglandin H2 by the enzyme prostaglandin D2 synthase) are increased in areas of androgenetic alopecia compared to hairy areas; the enzyme itself increases the activity of androgens. Exposure through the DP2 receptor (named after prostaglandin D2) appears to inhibit hair growth. Exposure to prostaglandin F2alpha (PFG2alpha; binds to the PGF2alpha receptor at 50-100 nM) appears to mediate hair growth. There appears to be a greater presence of prostaglandin E2 (PGE2) in hairy areas of the scalp in balding men compared to balding areas (2.06-fold). An increase in PGE2 appears to be one of the possible mechanisms of minoxidil in promoting hair growth. Other prostaglandins are derived from arachidonic acid.

Safety and toxicology

Pregnancy

Arachidonic acid appears to increase in the mammary gland following oral intake (either from foods or supplements in a dose-dependent manner), although consumption of DHA (from fish oil) alone may reduce the concentration of arachidonic acid in breast milk. The increase was noted to be 14-23% after 2-12 weeks (consuming 220 mg arachidonic acid), while consuming 300 mg arachidonic acid for a week was found to be ineffective without significantly increasing concentrations. This apparent delay in effect is due to fatty acids being obtained from the mother's so-called reserves rather than from her immediate diet. Concentrations of arachidonic acid in breast milk are correlated with diet, with some studies reporting low concentrations with reduced dietary intake of arachidonic acid overall; increased concentrations in breast milk are observed with increased intake of arachidonic acid. Arachidonic acid is known to accumulate in mothers' breast milk, and its concentrations in breast milk correlate with dietary intake.

Arachidonic acid belongs to the class of omega-6 unsaturated fatty acids. Interestingly, there is disagreement as to whether arachidonic acid should be considered essential, since it is produced in small quantities in the human body.

Formally, to classify a fatty acid as essential, the body must obtain it from external environment, being unable to synthesize it. However, since our body cannot fully meet its requirement for arachidonic acid through endogenous synthesis, most medical and nutritional supplement sites classify arachidonic acid as an essential rather than non-essential fatty acid.

In this regard, in this material we will also call arachidonic acid essential. The article will list the sources of arachidonic acid, its functions, as well as controversial issues regarding of this component nutrition.

Possible side effects of arachidonic acid

Insomnia
Fatigue
Cerebrovascular accident
Heart diseases
Hair fragility
Peeling skin
Increased cholesterol levels
Stimulation of labor

Areas of application of arachidonic acid

Alzheimer's disease
Arterial hypertension
Increased mental abilities
Blood clotting
Inflammation
Memory
Muscle strength
Peptic ulcer
Induction of labor

Where to get arachidonic acid?

Arachidonic acid is found in fatty foods and is a component of fat in lean dishes. You can get arachidonic acid from red meat, pork, poultry, eggs, and many other foods. Since arachidonic acid makes up a certain proportion of fat in everyday foods, it is important to adjust your diet, since excess fat can negatively affect your health.

Since arachidonic acid is a polyunsaturated fat, many people mistakenly consider it a “healthy fat.” The truth is that this fatty acid comes from animal fats, and like all fats, if consumed in excess, it does more harm to the body than good.

Arachidonic acid preparations

Another source of arachidonic acid is dietary supplements. You can take arachidonic acid in tablet, capsule, or powder form. The most common is the powder form, as it is best absorbed by the body. Note that the additive tastes bitter, and many people dilute the powder in citrus juice in order to somehow hide this bitterness.

You will also find that arachidonic acid is sold both in pure form and in complex preparations. The price of these products varies widely, from $10 to $100, depending on how much you buy and what is included in the complex besides arachidonic acid.

Biological role of arachidonic acid

Many functions of arachidonic acid have already been proven, and some are still under study. Since arachidonic acid is an essential fatty acid, several independent clinical studies are currently being conducted to study the role and effectiveness of this acid in various fields of medicine.

One such area is the effect of arachidonic acid on the progression of Alzheimer's disease when used in the early stages of the disease. Preliminary data indicate that arachidonic acid may be prescribed both to prevent Alzheimer's disease and to slow the rate of progression of the disease when treating patients with already diagnosed pathology.

Arachidonic acid is involved in the synthesis of prostaglandins, which support muscle function. It is prostaglandins that ensure proper contraction and relaxation of muscle fibers during exercise. This function is important for everyone, but it is especially important for athletes and bodybuilders.

Prostaglandins help regulate the lumen of the vascular bed and promote the formation of new blood vessels, control blood pressure and model inflammation in the muscles. One form of prostaglandins increases blood clotting, while another form, on the contrary, prevents increased thrombus formation where it does not belong. This form of prostaglandin, known as PGE2, is also used to induce labor in pregnant women.

Arachidonic acid prevents excessive synthesis hydrochloric acid in the digestive tract, in addition, it increases the production of protective mucus, which helps prevent the development of peptic ulcers and other stomach problems, including gastric bleeding.

In addition, arachidonic acid promotes the growth and regeneration of skeletal muscles and muscle fibers. Its role is especially great in the development of the musculoskeletal system in children; without arachidonic acid adequate physical development child is virtually impossible.

Arachidonic acid and inflammation

This fatty acid is pro-inflammatory, meaning that it promotes inflammation in tissues and muscles. But this is not always a bad thing, except in cases where you suffer from inflammatory diseases. And the severity of the inflammatory response can be reduced by taking aspirin, other supplements or foods that have an anti-inflammatory effect.

In the case of arachidonic acid, we are dealing with inflammation, which bodybuilders and weightlifters should take on board. There is an assumption that the stimulating effect of arachidonic acid during training sessions is due to the fact that the muscles receive an additional inflammatory signal, which increases the effectiveness of training.

However, this assumption has not been confirmed by clinical studies. In contrast, some trials found no additional inflammation after training sessions. However, data from a study at Baylor University showed that taking 1,200 mg of arachidonic acid daily did lead to increases in peak muscle strength and muscle endurance (30 people took the drug for 50 days).

Note that this study was not long enough to reliably prove the effectiveness of arachidonic acid, and the results of this work are considered preliminary. Baylor University is not currently evaluating long-term results, as their original goal was to prove that arachidonic acid supplementation did NOT provide any benefit to weightlifters.

Arachidonic acid and increased mental performance

Research conducted by the American National Institute of Child Health and Human Development examined the effects of arachidonic acid on brain development in children aged 18 months and older. This 17-week study showed no significant increase in IQ in this group of children. The goal of further research is to explore the presence of other positive effects.

But studies conducted in the past have already confirmed the beneficial effects of arachidonic acid on memory abilities in adults. It was these works that initiated research on the effect of arachidonic acid on the development of mental abilities in children.

Resume. Arachidonic acid:

Enhances blood clotting during injuries
Improves memory in adults
Promotes proper muscle function
Has been actively studied in the recent past
Promotes the physical and mental development of the child
New areas of its application are currently being explored.
Essential fatty acid
Used to stimulate labor
Can help weightlifters achieve new goals
May have beneficial effects on Alzheimer's disease

Side effects and problems associated with arachidonic acid

As already mentioned, the source of arachidonic acid is fats. It has already been proven that high doses of arachidonic acid can lead to pathology of the cardiovascular system, myocardial infarction and cerebrovascular accident. Moreover, in too high a concentration, arachidonic acid becomes toxic and can cause death. For this reason, you should not take arachidonic acid without medical supervision.

An overdose of arachidonic acid may be manifested by the following subjective symptoms and clinical signs: fatigue, insomnia, brittle hair, peeling skin, skin rashes, constipation, heart attacks and increased cholesterol levels.

Since arachidonic acid can stimulate labor, it should never be taken by pregnant women or women who are trying to conceive. In these cases, taking the drug may lead to miscarriage. In addition, arachidonic acid is contraindicated in the following diseases:

Oncological pathology
Asthma
Increased cholesterol levels
Diseases of the cardiovascular system
Prostate enlargement
Inflammatory diseases
Irritable bowel syndrome

In any case, you should not start taking arachidonic acid without your doctor's knowledge and permission. This is especially true if you have a medical condition or are taking medications.

There is a widespread misconception that we are safe when we take natural medications. Don’t forget, poison ivy is also natural, but we won’t, we eat it only because it grows in nature.

(English abbr. ARA) - polyunsaturated fatty acid omega-6 20:4 (ω-6), plays an important role in the human body. Arachidonic acid is an essential fatty acid, meaning the body can synthesize it autonomously. Arachidonic acid is subject to oxidation by atmospheric oxygen, and therefore requires special storage conditions.
In the body, arachidonic acid is part of phospholipids (especially phosphatidylethanolamine, phosphatidylcholine), they are the backbone of cell membranes. Maximum amounts are found in the brain and muscles. Arachidonic acid is involved in cell signaling as an inflammatory mediator.

Arachidonic acid in foods
Arachidonic acid is present in greatest quantities in the brain, as well as in liver, meat and milk fat.

Arachidonic acid in bodybuilding
Arachidonic acid is needed for the restoration and growth of skeletal muscles. More recently, Mike Roberts of Baylor University conducted a study and published an article in the International Society of Sports Nutrition entitled "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."
Mike Roberts states that the main cause of muscle growth is local inflammation of muscle tissue, which originates as a result of microtrauma acquired as a result of physical exercise. This theory is supported today by many scientists. Roberts presented in his study that arachidonic acid is stored in large quantities in muscle tissue and is a source for the synthesis of prostaglandins, which cause local inflammation. In addition, the prostaglandin isomer PGF2a has the ability to stimulate muscle growth. Arachidonic acid is a regulator of local muscle inflammation and may be a major factor in the regulation of muscle anabolic processes in response to strength training.

Arachidonic acid cycle:
1. As a result of physical exercise, phospholipase A2 (or cPLA2 - intramuscular enzyme) is activated.
2. cPLA2 provokes the release of arachidonic acid into the cytoplasm of the muscle cell
3. Another intracellular enzyme, cyclooxygenase, catalyzes arachidonic acid to create prostaglandins (PGE2, PGF2a), which leave the cell and initiate a series physiological reactions(vasodilation, increased blood circulation, inflammation, etc.)
4. Prostaglandins (especially the PGF2a isomer) bind to prostaglandin receptors on skeletal muscle cells and initiate a cascade reaction that generates muscle growth.
Arachidonic acid and PGF2a enhance ribosome function in muscle cells by activating enzymes of the phosphoinositol 3-kinase complex. In the ribosomes of cells, new proteins are synthesized, which are supplied to the construction of new muscle cells.

PGF2a has been found to have a similar effect to insulin-like growth factor (IGF-1), which has a pronounced anabolic effect.
Another significant confirmation that arachidonic acid is effective for muscle growth was the study of Dr. Dr. Todd Trappe from Ball State University. He found levels of protein synthesis in athletes who were receiving drugs that inhibit prostaglandin synthesis (NSAIDs). As a result, in the group that did not receive the drug, protein synthesis increased by 76%, while in the group that took NSAIDs, protein synthesis remained at the original level.

Reasonable effects of arachidonic acid:
Forced recovery
Increase in strength indicators
Increased stamina
Muscle growth

Recommendations for use
To increase strength and gain muscle mass, arachidonic acid should be taken at a dose of 500 mg-1000 mg per day. When purchasing sports nutrition, pay attention to the doses; quite often they are not sufficient to obtain the appropriate effect.

Side effects and harm
Arachidonic acid is a natural product and is included in common products. Studies have shown that arachidonic acid is not harmful to health and has a low number of side effects. Due to its pro-inflammatory effect, arachidonic acid can cause side effects such as increased muscle pain after training, joint pain, and headache, but this is very rare.

You can buy it in the online sports nutrition store Fitness Live

Arachidonic acid(English) arachidonic acid) is the predominant polyunsaturated fatty acid in the human body. Common abbreviations and designations in different systems: ARK (eng. AA or ARA), 20:4ω6, 20:4n-6, 20:4Δ5,8,11,14.

Arachidonic acid is sometimes called “essential”, in other cases “semi-essential” for human physiology. Arachidonic acid is synthesized in the human body from the uniquely “essential” fatty acid - linoleic acid with the help of desaturase enzymes Δ5 and Δ6. However, some mammals cannot synthesize arachidonic acid and it is “essential” for them.

Essential compounds are compounds that are not synthesized in the human body and, therefore, must be present in food products consumed by humans.

Arachidonic acid - chemical substance

Arachidonic acid is a monobasic carboxylic acid with four isolated double bonds, is tetraenoic acid, systematic name is cis-5,8,11,14-eicosatetraenoic acid, chemical formula compounds CH 3 -(CH 2) 4 -CH=CH-CH 2 -CH=CH-CH 2 -CH=CH-CH 2 -CH=CH-(CH 2) 3 -COOH. Arachidonic acid is a colorless oily liquid. The empirical formula of arachidonic acid is C 20 H 32 O 2.

Arachidonic acid belongs to the omega-6 (ω-6) family of unsaturated fatty acids, having a carbon-carbon double bond at the omega-6 position, between the sixth and seventh carbon atoms, counting from the methyl end of the fatty acid chain.

Arachidonic acid in human physiology

Arachidonic acid is part of the phospholipids of the cell membranes of platelets and endothelial cells. Free arachidonic acid is rapidly metabolized into prostaglandins and thromboxanes. The metabolism of arachidonic acid occurs in two main ways - cyclooxygenase and lipoxygenase. The cyclooxygenase pathway of arachidonic acid metabolism leads to the formation of prostaglandins and thromboxane A2, while the lipoxygenase pathway leads to the formation of leukotrienes.

Prostaglandins and thromboxanes are formed from arachidonic acid under the influence of phospholipase A2 and with the participation of cyclooxygenase (COX) in endothelial cells, platelets and polymorphonuclear granulocytes. The formation of leukotrienes with the participation of lipoxygenase occurs in eosinophils, polymorphonuclear granulocytes and mast cells (Rakhimova O.Yu. et al.).

The role of arachidonic acid in the formation of the fetal cerebral cortex

Arachidonic acid along with docosahexaenoic acid (long-chain fatty acids) are key building blocks of cell membranes in the brain and retina. Arachidonic and docosahexaenoic acids account for a total of 20% of the total fatty acid content in brain phospholipids. These polyunsaturated fatty acids affect signal transmission between nerve cells through synapses.

The child’s body should receive not only essential fatty acids, but also their derivatives, especially arachidonic and docosahexaenoic acids. In the last trimester of pregnancy, increased uptake and transfer of arachidonic and docosahexaenoic acids occurs through the placenta to the fetus. Premature babies, whose development is interrupted prematurely, therefore receive insufficient long-chain polyunsaturated fatty acids during the prenatal period. Although infants' enzyme systems are capable of metabolizing essential fatty acids into long-chain fatty acids, the capacity of these systems may not be sufficient to meet the needs of infants in the first year of life, especially premature infants. The increased need for arachidonic and docosahexaenoic acids in children of the first year of life is due to the rapid growth of the brain, the weight of which increases 3 times in the first year of life.

Mother's breast milk, along with essential fatty acids - linoleic and linolenic, also contains arachidonic and docosahexaenoic acid in amounts of 0.3–0.6% and 0.1–1.4%, respectively. At the same time, formulas for artificial feeding of both healthy full-term and premature infants traditionally contain only essential fatty acids and very small amounts of long-chain fatty acids. Autopsy data from children who died from accidental death syndrome indicate that the brain, red blood cells and phospholipids in the blood plasma of breastfed children contain more arachidonic acid and docosahexaenoic acid than in babies receiving artificial nutrition. Therefore, it can be argued that arachidonic and docosahexaenoic acids may be conditionally essential for children in the first year of life and especially for premature infants who are bottle-fed (Kon I.Ya. et al.).

Arachidonic acid in foods

Arachidonic acid is found in the following foods (percentage in fat, by weight, including triglycerides):

cod fat (muscle) - 1-4%
whale oil - 0.6-5%
salmon oil - 0.5-1%
pork fat - 0.5%
beef fat - 0.5%
lamb fat - 0.5%
chicken eggs - 0.5%
seal oil - 0.4-12%
herring fat - 0.3-1%
milk fat - 0.1-1.7%
Ghee cow butter - 0.09%

Vegetable oils contain virtually no arachidonic acid.

Arachidonic acid in human milk

The content of arachidonic acid in human milk in the early stages of lactation, in% of the total fatty acids by weight (Fateeva E.M., Mamonova L.G.):

in colostrum - 0.3-0.4%
in transition milk - 0.3-0.8%
in mature milk - 0.1-0.2%

General information

Arachidonic acid is usually included in the so-called "

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MINISTRY OF EDUCATION OF THE REPUBLIC OF BELARUS BELARUSIAN STATE UNIVERSITY FACULTY OF CHEMISTRY

Coursework

REGULATION OF ARACHIDONIC ACID METABOLISM BY DRUGS IN INFLAMMATION

Completed

Yablonsky M.S.

Supervisor:

Semenkova G. L.

INTRODUCTION

1. METABOLISM OF ARACHIDONIC ACID

2. REGULATION OF ARACHIDONIC ACID METABOLISM BY DRUGS

2.1 Ways to regulate the inflammatory response

2.2 Inhibition of cyclooxygenase as a method of regulating the inflammatory process. Nonsteroidal anti-inflammatory drugs

2.3 Medicines that primarily affect the lipoxygenase pathway of arachidonic acid metabolism

2.4 Glucocorticosteroids

REFERENCES

INTRODUCTION

Inflammation is the body’s response to damage or infection, aimed at destroying the infectious agent and restoring damaged tissue. Acute inflammation develops directly following the action of a damaging factor and is associated with the release in tissues of so-called inflammatory mediators - “local” hormones or autacoids (substances that affect the cells of a tissue or organ at the site of their formation, without entering the systemic bloodstream). There are 3 main groups of autacoids: biological amines (histamine, serotonin), kinins (bradykinin) and eicosanoids (prostaglandins, leukotrienes and others). Eicosanoids include biologically active substances, oxidized derivatives of polyunsaturated fatty acids containing 20 carbon atoms. These are highly active regulators of cellular functions, quickly disintegrating hormones of “local action”. They are involved in many processes: they affect blood pressure, the condition of the bronchi, intestines, and uterus, regulate the secretion of water and sodium by the kidneys, and influence the formation of blood clots. Different types of eicosanoids are involved in the development of the inflammatory process that occurs after tissue damage or infection. Signs of inflammation such as pain, swelling, fever are largely due to the action of eicosanoids - prostaglandins and leukotrienes.

The main substrate for the synthesis (precursor) of eicosanoids in humans is arachidonic acid (eicosatetraenoic acid - an omega-6-unsaturated fatty acid containing 20 carbon atoms), since its content in the human body is much higher than other polyenoic acids-precursors of eicosanoids. Therefore, the regulation of arachidonic acid metabolism during inflammation is an important issue in pharmaceutical chemistry.

1 . METABOLISM OF ARACHIDONIC ACID

Arachidonic acid can enter the human body with food or be formed from linoleic acid, also supplied with food (Fig. 1).

Rice. 1. Scheme of the formation of arachidonic acid from linoleic acid.

Arachidonic acid is part of membrane glycerophospholipids. Under the action of membrane-associated phospholipase A2, eicosatetraenoic acid is cleaved from glycerophospholipid and used for the synthesis of eicosanoids.

Thus, phospholipase A2 cleaves off one acyl group, which hydrolyzes the B bond (Fig. 2), which leads to the release of arachidonic acid (R" is the radical corresponding to arachidonic acid).

Rice. 2. Phosphotidylcholine molecule.

Activation of membrane-associated phospholipases occurs under the influence of many factors: hormones, histamine, cytokines, mechanical stress.

After arachidonic acid is separated from the phospholipid, it enters the cytosol and is converted into different eicosanoids in different cell types. There are 3 main pathways for the conversion of arachidonic acid in cells: cyclooxygenase, leading to the synthesis of prostaglandins, prostacyclins and thromboxanes, lipoxygenase, ending in the formation of leukotrienes, lipoxins, and cytochrome (monooxygenase), leading to the formation of eicosatretraenoic acids.

Cyclooxygenases catalyze the conversion of arachidonic acid to prostaglandin H2 (PG H2, the precursor of the remaining prostaglandins, prostacyclin and thromboxane A2). The enzyme contains two active centers: a cyclooxygenase site, which converts arachidonic acid into prostaglandin G2 (the reaction is essentially the cyclization of linear arachidonic acid with the addition of oxygen molecules) and heme, which has peroxidase activity, converts prostaglandin G2 into prostaglandin H2.

Prostaglandins are designated by symbols such as PG A, where PG stands for the word prostaglandin and the letter A stands for a substituent on the five-membered ring in the eicosanoid molecule.

PG I - prostacyclins. They have 2 rings in their structure: one five-membered, like other prostaglandins, and the other with the participation of an oxygen atom. They are also divided depending on the number of double bonds in the radicals (PG I2, PG I3).

Each of these groups of prostaglandins consists of 3 types of molecules, differing in the number of double bonds in the side chains. The number of double bonds is indicated by a lower digital index, for example, PG E2.

There are 3 types of cyclooxygenases in the body: cyclooxygenase-1 (COX-1, COX-1), cyclooxygenase-2 (COX-2, COX-2) and cyclooxygenase-3 (COX-3, COX-3).

Rice. 3. Prostaglandin synthase as a combination of cyclooxygenases and peroxidase

The first two types of cyclooxygenases catalyze the incorporation of 4 oxygen atoms into arachidonic acid and the formation of a five-membered ring. This results in the formation of an unstable hydroperoxide derivative called PG G2. The hydroperoxide at the 15th carbon atom is quickly reduced to a hydroxyl group by peroxidase to form PG H2. Before the formation of PG H2, the synthesis route different types prostaglandins are the same. Further transformations of PG H2 are specific for each cell type.

Rice. 4. Cyclooxygenase pathway for the conversion of arachidonic acid.

The synthesis of leukotrienes follows a path different from the synthesis of prostaglandins and begins with the formation of hydroxyperoxides - hydroperoxide deicosatetraenoates (HPETE). These substances are either reduced to form hydroxyeicosatetroenoates (HETE) or converted to leukotrienes or lipoxins (Fig. 4).

Rice. 5. Lipoxygenase pathway for the conversion of arachidonic acid.

The synthesis of lipoxins begins with the action of 15-lipoxygenase on arachidonic acid, then a series of reactions occurs leading to the formation of lipoxin A4. In the P450 monooxygenase pathway, arachidonic acid is oxidized to 19-hydroxy or 20-hydroxy-eicosatetraenoic acids (19-HETE and 20-HETE), as well as epoxyeicosatetraenoic acid (OETE).

Rice. 7 General scheme of arachidonic acid metabolism (simplified).

2. REGULATION OF ARACHIDONIC ACID METABOLISM BY DRUGS

2.1 Ways to regulate the inflammatory response

Prostaglandins are the main mediators of inflammation. They cause the following biological effects: sensitize nociceptors to pain mediators (histamine, bradykine) and lower the threshold of pain sensitivity, increase the sensitivity of the vascular wall to other inflammatory mediators (histamine, serotonin), causing local vasodilation (redness), increased vascular permeability (edema) , increase the sensitivity of the hypothalamic thermoregulation centers to the action of secondary pyrogens formed under the influence of microorganisms (bacteria, viruses, fungi, protozoa) and their toxins.

Leukotrienes are involved in the pathogenesis of bronchial asthma. Together with histamine, leukotrienes are mediators of the early phase of an immediate allergic reaction. As a result of the action of histamine, immediate and short-term bronchospasm occurs, while leukotrienes cause delayed and longer bronchospasm.

Based on the process of eicosanoid formation presented above, the following approaches to regulating the inflammatory response can be proposed: suppression of phospholipase A2 activity, suppression of COX activity, blockade of prostaglandin receptors, suppression of LOX activity, blockade of leukotriene receptors

2.2 Inhibition of cyclooxygenase as a method of regulationinflammatory process. Nonsteroidal anti-inflammatory drugs

COX-1 is constitutive, that is, it works almost constantly and performs physiologically important functions. Inhibition of COX-1 by non-selective NSAIDs causes many side effects: bronchospasm, ulcerogenesis (since prostaglandins play a protective role in the gastric mucosa), ear pain, water retention in the body, hepato- and nephrotoxicity, etc.

COX-2 is inducible, that is, it begins to function in certain situations, for example, during inflammation its expression increases sharply. Like other enzymes from the COX group, COX-3 is also involved in the synthesis of prostaglandins and plays a role in the development of pain and fever, but unlike COX-1 and COX-2, COX-3 does not participate in the development of inflammation.

The concept of the mechanism of anti-inflammatory, analgesic and antipyretic effects of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of the synthesis of inflammatory prostaglandins by inhibiting COX.

An example of a non-selective cyclooxygenase inhibitor is acetylsalicylic acid. Unlike other non-selective NSAIDs, aspirin irreversibly inhibits cyclooxygenase by acetylation of serine in the active site (Fig. 7).

Rice. 7. The mechanism of inhibition of COX by acetylsalicylic acid.

It has been established that in small doses (up to 375 mg/day) aspirin blocks predominantly COX-1, while in higher doses it blocks COX-1 and COX-2. inhibition of anti-inflammatory drug metabolism

There are also alternative (COX-independent) mechanisms of anti-inflammatory action. Aspirin suppresses the activation of NF-B, a gene transcription factor that is necessary for the synthesis of a number of inflammatory cytokines and cell adhesion molecules. In the absence of the synthesis of these cytokines, the activity of the chronic inflammatory process is suppressed. The anti-inflammatory and analgesic effects of the drugs are associated with the blockade of prostaglandin synthesis, and the mechanism of the antipyretic effect is associated with the effect of NSAIDs on the thermoregulation center of the hypothalamus. The hypothalamus has a special group of neurons - the temperature-setting center. During inflammation and infection, cells of the immune system, macrophages, produce pyrogens, which sharply increase the setting signal, and the neurons of the thermosetting center perceive normal blood temperature as “reduced.” In the thermal setting center, intensive synthesis of PgE2 begins and the activity of the heat production center increases. Taking NSAIDs disrupts the synthesis of prostaglandins, and the activation of the heat production center stops, and the work of the heat transfer center increases. As a result, excess heat is removed from the body through radiation (skin blood vessels dilate) and evaporation (sweat glands turn on). The antiaggregation effect is due to the fact that ASA irreversibly blocks COX in platelets and endothelium and disrupts the synthesis of thromboxane A2 and prostacyclin in them, respectively.

The “Aspirin triad” or Fernon-Vidal syndrome can be observed with complete intolerance to aspirin in combination with bronchial asthma. It is believed that this phenomenon is associated with a violation of the metabolism of arachidonic acid along the COX-dependent pathway and a compensatory increase in the LOX-dependent pathway, during which leukotrienes are formed that can cause bronchospasm. Selective leukotriene receptor inhibitors are used to help patients develop this complication.

Other non-steroidal anti-inflammatory (non-selective) drugs act by a competitive mechanism, binding to the active site of the enzyme, and also reduce the synthesis of prostaglandins. Among them, the most famous representatives are Diflunisal, Diclofenac, Indomethacin, Ibuprofen, Naproxen, Phenylbutazone.

Inhibition of COX-2 is considered to be one of the main mechanisms of anti-inflammatory activity of NSAIDs, since by selectively inhibiting this cyclooxygenase, many of the side effects observed with inhibition of cyclooxygenase 1 can be minimized. The ratio of the activity of NSAIDs in terms of blocking COX-1/COX-2 allows us to judge their potential toxicity. The lower this value, the more selective the drug is for COX-2 and the less toxic. The main representatives of selective COX-2 inhibitors include celecoxib, Pirroxicam (from the group of oxicams), Nimesulide.

Various literature describes cases of negative effects of celecoxib on the human body (taking celecoxib in women leads to the development of reversible infertility, long-term use of celecoxib can lead to renal failure). For celecoxib, as well as for nimesulide, the ability to induce the development of thrombosis has been proven.

2.3 Drugs that primarily affect the lipoxygenase pathway of arachidonic acid metabolism

Drugs that primarily affect the lipoxygenase pathway include 5-lipoxygenase inhibitors: (zileuton) and leukotriene cysLT1 receptor antagonists (zafirlukast, montelukast, verlukast, pranlukast, cinalukast, iralukast, pobilukast).

Zileuton reversibly binds to the active site of 5-LOG and blocks the synthesis of all leukotrienes. Zafirlukast, like other leukotriene cysLT1 receptor antagonists, binds to the cysteinyl cysLT1 type of leukotriene receptors and blocks them. At the same time, leukotrienes C4, D4 and E4 are not able to activate these receptors and cause corresponding effects on the side of bronchial smooth muscles. These drugs are used for bronchial asthma.

2.4 Glucocorticosteroids

Steroid drugs have a much stronger anti-inflammatory effect than non-steroidal drugs. The mechanism of their action is that after passing through the cell membrane, glucocorticoids in the cytoplasm bind to a specific steroid receptor. As a result of RNA translation, various regulatory proteins are synthesized on ribosomes. One of the most important is lipocortin, which inhibits the enzyme phospholipase-A2 and suppresses the synthesis of prostaglandins and leukotrienes (as they prevent the release of the substrate for the synthesis of eicosanoids - arachidonic acid), which play a key role in the development of the inflammatory reaction.

The use of steroidal anti-inflammatory drugs is especially important for patients suffering from bronchial asthma. The development of symptoms of this disease (bronchospasm and exudation of mucus into the bronchial lumen) is caused, in particular, by the excessive production of leukotrienes by mast cells, leukocytes and bronchial epithelial cells. Taking aspirin in patients with a high-activity lipoxygenase isoform can cause an attack of bronchial asthma. The reason for “aspirin-induced” bronchial asthma is that aspirin and other non-steroidal anti-inflammatory drugs inhibit only the cyclooxygenase pathway of arachidonic acid conversion and, thus, increase the availability of the substrate for the action of lipoxygenase and, accordingly, the synthesis of leukotrienes. Steroid drugs inhibit the use of arachidonic acid in both the lipoxygenase and cyclooxygenase pathways, so they cannot cause bronchospasm.

It should be noted that glucocorticosteroids have a number of side effects: osteoporosis, increased blood clotting, acne, obesity, slower tissue regeneration processes, sodium and water retention, mental disorders, etc.

To the most famous representatives glucocorticoids include prednisolone, flumethasone. Prednisolone is a synthetic glucocorticoid drug medium strength, the pharmacological action of which is determined, among other things, by the inhibition of phospholipase A2. This drug has anti-inflammatory, anti-allergic, anti-shock, immunosuppressive effects, but has a number of side effects characteristic of this type of drug.

CONCLUSIONS

In this course work The ways of transformation of arachidonic acid in the human body, some options for disrupting the metabolism of arachidonic acid in order to weaken inflammatory processes were considered, and the corresponding drugs were briefly presented. Groups of drugs (in particular NSAIDs) with a mechanism of action related to the effect on the metabolism of arachidonic acid are widely used in clinical practice.

REFERENCES

1. Nasonov E.L./Specific inhibitors of cyclooxygenase (COX)-2, solved and unresolved problems // Klin. pharm. ter. - 2000. - vol. 9, no. 1. - pp. 57-64.

2. Fundamentals of biochemistry: in 3 volumes, T. 2 / A. White, F. Hendler, E. Smith, R. Hill, I. Lehman. - Mir, 1981. - P. 766.

3. Biochemistry: Textbook for Universities / Ed. E. S. Severina. -- GEOTAR-Media, 2003. -- P. 371,372,417,418.

4. Rang, H. P. Pharmacology. -- 5th. -- Edinburgh: Churchill Livingstone, 2003. -- P. 232-235.

5. Integrated Pharmacology. 2nd ed. / C. Page, M. Curtis, M Sutter et al. - Mosby International Ltd., 2002. - 670 p.

6. Lawrence D. R., Benitt P. N. Clinical pharmacology: in 2 volumes / trans. from English M.: Medicine, 1991.

7. Pharmacotherapy. Clinical pharmacology. Per with him. / Ed. G. Fühlgraffa, D. Palma. - Mn.: Belarus, 1996. - 689 p.

8. Zhang Y, Mills GL, Nair MG/ “Cyclooxygenase inhibitory and antioxidant compounds from the mycelia of the edible mushroom Grifola frondosa.” J. Agric. Food Chem. 50 (26): 7581-5.

9. Kukes V.G. Clinical pharmacology: Textbook. - M.: GEOTAR MEDICINE, 1999. - 513 p.

10. Zubay G. Biochemistry. - Wm. C. Brown Publishers, 1993. - 1024 p.

11. Yabluchansky N.I., Lysenko N.V./ Non-steroidal anti-inflammatory drugs// 2003

12. Leukotriene antagonists and/or inhaled corticosteroids for asthma // Klin. pharm. ter. - 2002. - vol. 11, no. 5. - pp. 4-12.

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Pathways of arachidonic acid oxidation. Metabolism of arachidonic acid

General information

Arachidonic acid: instructions for use

Sources and structure

Sources

Biosynthesis

Regulation

Eicosanoids

Biological activation of eicosanoids

Prostaglandins

Epoxy/Hydroxyeicosatrienoic acids

Leukotrienes

Pharmacology

Blood serum

Neurology

Autism

Memory and learning

Nerve

Cardiovascular diseases

blood flow

Skeletal muscle and performance

Mechanisms

Interventions

Bone metabolism and skeleton

Mechanisms

Inflammation and immunology

Arthritis

Interactions with hormones

Testosterone

Cortisol

Interactions with the lungs

Asthma

Interactions with aesthetic parameters

Hair

Safety and toxicology

Pregnancy

Possible side effects of arachidonic acid

Areas of application of arachidonic acid

Where to get arachidonic acid?

Arachidonic acid preparations

Biological role of arachidonic acid

Arachidonic acid and inflammation

Arachidonic acid and increased mental performance

Resume. Arachidonic acid:

Side effects and problems associated with arachidonic acid

Arachidonic acid - chemical substance

Arachidonic acid in human physiology

The role of arachidonic acid in the formation of the fetal cerebral cortex

Arachidonic acid in foods

Arachidonic acid in human milk

General information

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