Eicosanoids are signalling molecules derived from polyunsaturated fatty acids like arachidonic acid. They include prostaglandins, thromboxanes, leukotrienes, and lipoxins. Eicosanoids function as local hormones and have diverse physiological effects, such as modulating inflammation and immune responses. They are synthesized from cell membranes when needed and act locally before being rapidly degraded.

1. EICOSANOIDS
Dr. Asiimwe Anthony MPS
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2. What are eicosanoids?
• Eicosanoids are signalling molecules derived from polyunsaturated 20-
carbon fatty acids:
• Δ8,11,14 eicosatrienoic acid
• arachidonic acid (Δ5,8,11,14-eicosatetraenoic acid
• Δ5,8,11,14,17-eicosapentaenoic acid
• Arachidonic acid is the most important because it is the most abundant.
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3. Families of eicosanoids
• The eicosanoids consist of the
1. Prostaglandins (PG),
2. Prostacyclins (PGI2)
3. Thromboxanes (TX),
4. Leukotrienes (LT)
5. Lipoxins (LX) – non-classic eicosanoids
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4. EICOSANOIDS
Eicosanoids are considered "local hormones."
 They function in diverse physiological systems and pathological processes
 Are not stored in cells; they are synthesized when needed
 They have specific effects on target cells close to their site of formation.
 They are rapidly degraded, so they are not transported to distal sites within
the body
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5. Eicosanoids (cont’d)
• PGs and TXs are collectively known as prostanoids
Origin:
• First in prostate gland (prostaglandins)
• Thromboxanes from platelets (thrombocytes)
• Leukotrienes from leukocytes, hence the derivation of their names
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6. Lipoxins
• Are specialized pro resolving mediator eicosanoids (anti-
inflammatory eicosanoids)
• Synthesized through lipoxygenase interactions
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7. Eicosanoids (cont’d)
• All mammalian cells except erythrocytes synthesize eicosanoids
• They cause profound physiological effects at very dilute
concentrations
• All eicosanoids function locally at the site of synthesis
• Their actions are mediated through receptor-mediated G-protein
linked signaling pathways.
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8. Biological effects of eicosanoids
• Induce or inhibit inflammatory responses (predominantly those of the joints,
skin and eyes)
• Determine the intensity and duration of pain and fever
• Reproductive function (including the induction of labor and regulation of
abortion).
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9. Biologica responses
•Inhibit gastric acid secretion
•Important in regulating blood pressure through
vasodilation or constriction
•Inhibit or activate platelet aggregation and
thrombosis.
•Regulation of cell growth
•Modulate the regional flow of blood to tissues
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10. Roles …
They have roles in:
• Immune system modulation
• Regulation of sleep/wake cycle.
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11. Nomenclature
• Majority of biologically active prostaglandins and thromboxanes are series 2
molecules
• due to the presence of two double bonds.
• Predominant leukotrienes are series 4 molecules (have four double bonds).
• Prostaglandins (PG), followed with an additional capital letter and a numeric
subscript
• Numeric subscript = no. of double bonds outside the ring
• 7 kinds of substituents on the ring are found in natural PGs: A, B, D, E, F, G,
and I.
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12. Structure of PG s vs arachidonate
PRECURSOR MOLECULE
Arachidonic acid
COOH
EXAMPLE OF PG
COOH
O
HO
OH
PGE2
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13. Prostaglandin-structure
• Contains a 5-carbon ring
• Has a OH group at C15 projecting
below the plane of the ring
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14. Synthesis of Eicosanoids
• Is from cell membrane and nuclear membrane lipids
• Occurs when a cell is activated by mechanical trauma, ischemia,
other physical perturbations, attack by pathogens; or stimuli made by
nearby cells, tissues, or pathogens such as chemotactic
factors, cytokines, growth factors, and even certain eicosanoids.
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15. Synthesis (cont’d)
• The immediate dietary precursor of arachidonate is linoleic acid.
• Synthesis of arachidonate from linoleate requires a desaturase
enzyme
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16. Biosynthesis of eicosanoids
• There are 2 pathways:
1. PG and TBX are synthesized by the cyclic pathway
2. Leukotrienes by the linear pathway.
• Synthesis begins with activation of PLA2
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Various stimuli: Activation of
Hormones, autacoids, etc. Membrane-bound
Receptors
Ca+2
PLA2
Activity

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Synthesis of clinically relevant PGs and TXs
Arachidonate release
and eicosanoid
synthesis
are important
mediators of tissue
injury and
inflammation
Bradykinin works on
blood vessels
through
the release of
prostacyclin

18. Synthesis (cont’d)
• Stimuli (e.g. epinephrine, thrombin and bradykinin etc) activate PLA2
• PLA2 hydrolyzes arachidonate from membrane phospholipids
• Prostaglandin PGI2 (prostacyclin) and PGE2 are synthesized from PGH2
• PGD2 synthase forms PGD2 from PGH2.
• Prostaglandin F synthase (PGFS) converts PGH2 to PGF2α or PGD2 to
9α,11β-PGF2α,β.
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19. Thromboxanes
 Are active metabolites of PGG2 and PGH2 that have a cyclopentane ring
replaced by a 6-membered oxygen containing (oxane) ring
 Have a thrombus-forming potential
 Are produced in plateletes
 Cause contraction of arteries and trigger platelet aggregation
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20. Thromboxane A2
•The two major TXs
are TXA2 and TXB2.
• Thromboxane is
• a vasoconstrictor
• a potent
hypertensive agent
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21. Prostanoids in physiological processes
• TXA2 facilitates platelet aggregation
• PGD2 (the principal COX product of the mast cells and the nervous system)
• it inhibits platelet aggregation)
• PGE2 and PGI2 are vasodilators in endothelial cells
• PGE2 in gastric mucosa suppresses gastric acid secretion
• Reduces the risk of gastric damage-gastric and duodenal ulcer
• PGE2 and PGF2α in the endomentrium induce uterine contraction
• Can be used for induction of abortion
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22. Cyclooxygenase
• There are two forms of cyclooxygenase:
1. COX -1 – (“good COX”)
• It is constitutively expressed in gastric mucosa, kidney, platelets, and vascular
endothelial cells.
2. COX -2 – inducible (“bad” COX):
• expressed in macrophages and monocytes in response to injury, inflammation and growth
factors.
• primary triggers are: platelet-activating factor (PAF) & IL-1
• others are growth factors, other cytokines, & endotoxins
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23. Cyclooxygenase...
• NB: Both COX-1 and COX-2 catalyze the 2-step conversion of arachidonic
acid to PGG2 and then to PGH2.
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Steroids inhibit

25. Cyclooxygenases …
• COX-2 expression is increased in some cancer cells.
• Angiogenesis (blood vessel development), which is essential to tumor
growth, requires COX-2.
• Over-expression of COX-2 leads to increased expression of vascular endothelial
growth factor.
• Regular use of NSAIDs has been shown to decrease the risk of developing colorectal
cancer.
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26. Inhibition of COX
• Non-steroidal anti-inflammatory drugs (NSAIDs) e.g aspirin, ibuprofen,
diclofenac, indomethacin, naproxen, and phenylbutazone all inhibit both
COX-1 and COX-2.
• Aspirin relieves pain (analgesia),
• has an anti-inflammatory
• is a heart protective drug but its actions are not solely due to its ability to inhibit COX
activity
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27. NSAID
• They inhibit formation of prostaglandins involved in fever, pain, &
inflammation.
• They inhibit blood clotting by blocking thromboxane formation in
blood platelets.
• Many people take a daily aspirin for its anti-clotting effect.
• Ibuprofen and related compounds block the hydrophobic channel by
which arachidonate enters the cyclooxygenase active site.
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28. COX-2 selective inhibitors
• Why?
• Because inhibition of COX-1 activity in the gut is associated with NSAID-induced
ulcerations
• Examples of drugs which selectively inhibit COX-2: Celebrex® (celecoxib) and
Prexige® (lumiracoxib)
NB: These drugs do not induce the synthesis of anti-inflammatory lipids
(lipoxins).
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29. Glucocorticoids
• Corticosteroids are anti-inflammatory because they prevent inducible
PLA2 expression, reducing arachidonate release.
• Glucocorticoids and IL-4 block COX-2 expression
• Oral or inhaled glucocorticoids are used to suppress various allergic,
inflammatory, and autoimmune disorders.
• Inhaled glucocorticoids are the second-line treatment for asthma.
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30. Biosynthesis of leukotrienes
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31. Synthesis of leukotrienes
• Numerous stimuli lead to activation of PLA2
• Arachidonate is hydrolyzed from membrane phospholipids.
• Enzyme 5-lipoxygenase (5-LOX) with the protein, 5-LOX activating
protein (FLAP), catalyzes the conversion of arachidonic acid, to 5-
hydroperoxyeicosatetraenoic acid (5-HPETE)
• The pathway is active in leukocytes, mast cells, neutrophils, eosinophils,
monocytes
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32. LTs
• Production of LTs usually accompanies production of histamine
• LTC4, LTD4 and LTE4 are components of slow-reacting substance of
anaphylaxis (SRSA).
• LTs, particularly LTD4 trigger contractions in the smooth muscles lining the
trachea
• Are produced in blood vessel walls as part of the pathology of
atherosclerosis
• Overproduction of LTs is a major cause of inflammation in asthma and
allergic rhinitis
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33. LTs
• Cysteinyl-LT act on target cells to:
• contract bronchial and vascular smooth muscle
• increase permeability of small blood vessels
• enhance secretion of mucus in the airway and gut
• recruit leukocytes to sites of inflammation.
• Anti-asthma medications include:
• Inhibitors of 5-Lipoxygenase, e.g., Zyflo (zileuton)
• Drugs that block leukotriene-receptor interactions. E.g. Singulair (montelukast) &
Accolate (zafirlukast)
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34. Lipoxins
• Are anti-inflammatory eicosanoids.
• Their appearance in inflammation signals the resolution of inflammation.
• Biosynthesis is by 3 pathways:
1. “Classic” pathway: Involves 5-LOX activity in leukocytes followed by 12-LOX
action in platelets.
2. The action of 15-LOX in epithelial cell (such as in the airway) followed by 5-LOX
action in leukocytes
3. Aspirin triggered lipoxins, formed through the action of aspirin on COX-2
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35. Lipoxins (cont’d)
• Are synthesized through lipooxygenase interactions of
• 15-LOX , followed by 5-LOX in leukocytes or
• Through the actions of 5-LOX in leukocytes followed by 12-LOX action in platelets.
• Aspirin-triggered lipoxins are generated by interactions between 5-LO
and aspirin-acetylated cyclooxygenase-2
• Lipoxins inhibit the inflammatory function of leukotrienes & PGs
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