Arachidonic acid (ARA) is a 20-carbon chain fatty acid with four methylene-

interrupted cis double bonds, the first with respect to the methyl end (omega, ω or
n) is located between carbon 6 and 7. Hence, ARA belongs to the omega-6 (n-6)
polyunsaturated fatty acids (PUFA), is designated as 20:4ω-6, with a biochemical
nomenclature of all-cis-5,8,11,14-eicosatetraenoic acid, and usually assumes a
hairpin configuration
Arachidonic Acid and Its Metabolites
Arachidonic acid and its metabolites (prostaglandins and leukotrienes) are now
considered intracellular messengers.31 Arachidonic acid is a component of membrane
phospholipids
released either in a one-step process, after phospholipase A2
(PLA2) action, or a two-step process, after phospholipase C
and DAG lipase actions. Arachidonic acid is then metabolized
by cyclooxygenase (COX) and 5-lipoxygenase, resulting in the
synthesis of prostaglandins and leukotrienes, respectively. These
intracellular messengers play an important role in the regulation of signal
transduction implicated in pain and inflammatory responses. Corticosteroids inhibit
PLA2 activity, whereas
nonsteroidal antiinflammatory drugs inhibit COX activity.

Prostaglandins and related compounds (collectively referred to as prostanoids or

eicosanoids) such as prostacyclin (PGI2), leukotrienes (LTs) and thromboxanes (TXs)
are produced by many different cells in the body. Although their primary
physiological actions are generally related to inflammation and hemostasis, by
nature they all are vasoactive and can modulate cardiovascular function,
particularly vascular tone. Their effects are very localized because they are
paracrine hormones; that is, they are released by one cell and act on nearby cells.

Prostanoids
formation and actions of prostaglandins, prostacyclin, thromboxanes and
leukotrienesProstanoids are fatty acid compounds derived from membrane
phospholipids. When these phospholipids are acted upon by phospholipase A2,
arachidonic acid is formed. Two important pathways for arachidonic acid metabolism
are the cyclooxygenase (COX) and 5-lipoxygenase (5-LO) pathways. The COX pathway
forms intermediate compounds called cyclo-endoperoxides (PGG2 and PGH2). Enzymes,
many of which are tissue specific, then convert the cyclo-endoperoxides into the
final biologically active prostanoid.
There are different forms of the COX enzyme, two of which are COX-1 and COX-2.
Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen
and acetaminophen (Tylenol®) are non-selective inhibitors of the COX enzymes. Newer
NSAIDs are relatively selective for COX-2, and generally have fewer
gastrointestinal-related side effects. COX-1 is constitutive and therefore produces
prostanoids under basal conditions. In contrast, COX-2 is inducible and is
upregulated during inflammation.

Smooth muscle cells in blood vessels produce prostaglandins (PGs). PGE2 generally
acts as a vasodilator by stimulating the Gs-protein pathway, whereas PGF2α commonly
produces vasoconstriction by stimulating the Gq-protein pathway.

Vascular endothelium produces PGI2 as its primary derivative of arachidonic acid.

This prostanoid is a potent vasodilator and inhibitor of platelet adhesion to the
endothelium, and acts through the Gs-protein pathway. Therefore, it is anti-
thrombotic. These actions are similar to those of endothelium-derived nitric oxide.
Endothelial dysfunction or damage, which occurs in atherosclerosis, for example,
can cause vasospasm and thrombosis.

Platelets produce TXA2, which is a potent vasoconstrictor acting through the Gq-
protein pathway. Its production is enhanced during inflammation and tissue injury,
and following platelet activation. It is important in producing arterial
vasoconstriction when a vessel is cut and bleeding (hemostatic function).

Leukocytes produce leukotrienes such as LTC4 in response to inflammation and tissue

injury. Like TXA2, it is a potent vasoconstrictor and acts through the Gq-protein
pathway. Leukotrienes (and prostaglandins) can also make the vascular endothelium
more "leaky" thereby promoting edema formation during inflammation.

t is time to shift the arachidonic acid (ARA) paradigm from a harm-generating

molecule to its status of polyunsaturated fatty acid essential for normal health.
ARA is an integral constituent of biological cell membrane, conferring it with
fluidity and flexibility, so necessary for the function of all cells, especially in
nervous system, skeletal muscle, and immune system. Arachidonic acid is obtained
from food or by desaturation and chain elongation of the plant-rich essential fatty
acid, linoleic acid. Free ARA modulates the function of ion channels, several
receptors and enzymes, via activation as well as inhibition. That explains its
fundamental role in the proper function of the brain and muscles and its protective
potential against Schistosoma mansoni and S. haematobium infection and tumor
initiation, development, and metastasis. Arachidonic acid in cell membranes
undergoes reacylation/deacylation cycles, which keep the concentration of free ARA
in cells at a very low level and limit ARA availability to oxidation. Metabolites
derived from ARA oxidation do not initiate but contribute to inflammation and most
importantly lead to the generation of mediators responsible for resolving
inflammation and wound healing. Endocannabinoids are oxidation-independent ARA
derivatives, critically important for brain reward signaling, motivational
processes, emotion, stress responses, pain, and energy balance. Free ARA and
metabolites promote and modulate type 2 immune responses, which are critically
important in resistance to parasites and allergens insult, directly via action on
eosinophils, basophils, and mast cells and indirectly by binding to specific
receptors on innate lymphoid cells. In conclusion, the present review advocates the
innumerable ARA roles and considerable importance for normal health.