Eicosanoid Notes

What are Eicosanoids?

• Phospholipid-derived mediators, synthesized on demand, not stored.
• Act as 'local hormones' with rapid breakdown and local effects.
• Involved in platelet aggregation, smooth muscle contraction, gastric mucosa protection, and inflammation.
• Can be used as drugs or act as drug targets.

Discovery of Eicosanoids

• Prostaglandins were first found in seminal fluid and named for the prostate gland.
• Eicosanoids include prostaglandins, thromboxanes, leukotrienes, lipoxins, and resolvins.
• Primary source: polyunsaturated fatty acids (PUFAs) in the diet.

Sources of Fatty Acids

• Fish: Eicosapentaenoic acid (w-3) → 3 series eicosanoids, e.g., PGE3, TXA3.
• Vegetables: Eicosatrienoic acid (w-6) → 1 series eicosanoids, e.g., PGE1, TXA1.
• Meat: Eicosatetraenoic acid (w-6) → 2 series eicosanoids, e.g., PGE2, TXA2.

Prostanoid Structure & Nomenclature

• Letter (E, F, I) denotes the head-group.
• Numerical subscript denotes number of double bonds.
• Example: Prostaglandin E2 (PGE2).

Synthesis of Eicosanoids

• Derived from 5,8,11,14-eicosatetraenoic acid (arachidonic acid, AA).
• Initial step: liberation of AA from phospholipid by phospholipase A2 (PLA2).

Activation of Phospholipase A2

• AA liberated from phospholipids by PLA2.
• PLA2 activated by phosphorylation, triggered by thrombin, chemokines, bradykinin, and antibody-antigen interaction.

Pathways of Eicosanoid Synthesis

• Prostanoids and Leukotrienes are synthesized through different pathways from AA.

Synthesis of Prostanoids

• AA liberated from membrane by PLA2.
• Synthesis of unstable endoperoxides (PGG2 & PGH2) by cyclo-oxygenase (COX) enzymes.
• Specific isomerases/synthases produce PGE2, PGD2, and PGF2a.
• PGI2 by prostacyclin synthase (vascular endothelium).
• TXA2 by thromboxane synthase (platelets).

Cyclo-oxygenase Enzymes

• COX enzymes (COX1 and COX2) are targeted by NSAIDs and coxibs.
• COX1: constitutive, ubiquitous, homeostatic regulation.
• COX2: inducible, localized, inflammation.

Cell-Specific Prostanoid Synthesis

• Platelets: thromboxane synthase → TXA2.
• Vascular endothelium: prostacyclin synthase → PGI2.
• Macrophages, neutrophils, mast cells: broad spectrum.
• Diet rich in w-3 fatty acids: high PGE3, reduced PGE2 and TXA2.

Degradation of Prostanoids

• Rapidly degraded via multi-step process.
• Actively transported into cells, inactivated by 15-hydroxyprostaglandin dehydrogenase.
• Short half-life in blood (less than 1 minute).

Prostanoid Receptors

• Five main classes of prostanoid receptors: IP, FP, TP, DP, EP; all GPCRs.
• Single receptors for PGI, PGF, and TXA; subtypes for PGD2 and PGE2.

Physiological Effects of Prostanoids

• Uterine smooth muscle: contraction by PGF2a, PGE2; relaxation by PGD2.
• Bronchial smooth muscle: constriction by PGD2, PGF2a, PGE2; relaxation by PGE2.
• Vascular smooth muscle: vasoconstriction by TXA2; vasodilation by PGD2, PGI2, PGE2.
• Platelet aggregation: TXA2 promotes, PGD2 and PGI2 inhibit.
• GI secretions: PGE2 inhibits gastric acid, increases gastric mucus and GI fluids.

Role of Prostanoids in Inflammation

• Acute inflammation: PGE2 and PGI2 (tissues & blood vessels), PGD2 (mast cells).
• Chronic inflammation: PGE2 & TXA2 (macrophages and monocytes).
• Vasodilation, sensitize nerve endings, potentiate oedema, pyrogenic effects.

Therapeutic Uses of Prostanoids

• Epoprostenol (PGI2): pulmonary arterial hypertension, inhibit platelet aggregation.
• Misoprostol (PGE2): prevent gastric ulcers.
• Misoprostol (PGE2), carboprost (PGF2a): gynaecological uses.
• Latanoprost (PGF2a): glaucoma.

Pulmonary Arterial Hypertension (PAH)

• Narrowing of pulmonary arteries.
• Imbalance in prostanoid pathway; reduced vasodilation, increased vasoconstriction.
• Prostacyclin (PGI2) analogues, prostacyclin receptor agonists, thromboxane synthase inhibitors are used in treatment.

Therapeutic Targeting of Prostanoid Synthesis

• Glucocorticoids, NSAIDs, and COX2 inhibitors target prostanoid synthesis.

Glucocorticoids

• Increase annexin-1, reduce COX1 & COX2 expression.
• Suppress PLA2, reduce eicosanoid synthesis, cytokine production, T cell activation, and neutrophil chemotaxis.
• Used for inflammatory disorders.
• Adverse effects: fat redistribution, poor wound healing, osteoporosis.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Inhibit COX enzymes (mostly non-selective).
• Reduce prostanoid synthesis.
• Used for rheumatoid/osteoarthritis, headache, musculoskeletal pain, post-operative pain.
• Beneficial effects via COX2 inhibition, adverse effects via COX1 inhibition.

COX2 Inhibitors

• Selective for COX2 inhibition.
• Fewer GI effects, but cardiovascular concerns.

Synthesis of Leukotrienes

• Synthesized from AA via lipoxygenase pathway (5-lipoxygenase).
• Formation of 5-HPETE, LTA4, LTB4, and cysteinyl-leukotrienes (LTC4, LTD4, LTE4, LTF4).

Leukotriene Actions

• Act via BLT1/BLT2 (LTB4) and CysLT1/CysLT2 (LTC4, LTD4, LTE4) receptors.
• LTB4 is a potent chemotactic agent.
• Cysteinyl-LTs constrict bronchial smooth muscle, increase mucus secretion and are vasodilators.

Leukotrienes as Drug Targets

• CysLT receptor antagonists (zafirlukast, montelukast) and 5-lipoxygenase inhibitor (zileuton) for asthma treatment.

Other Eicosanoids

• Lipoxins A & B, resolvins, and platelet-activating factor (PAF).
• Lipoxins & resolvins reduce inflammation.
• PAF is anti-inflammatory.

Summary

• Eicosanoids are phospholipid-derived molecules (prostanoids & leukotrienes) from arachidonic acid.
• Prostanoids (prostaglandins & thromboxane) are products of the cyclo-oxygenase pathway.
• Leukotrienes are produced by lipoxygenase activity.
• Physiological effects on bronchial, vascular, and GI smooth muscle; major role in inflammation.
• Prostanoids have therapeutic uses, glucocorticoids reduce expression of all eicosanoids, NSAIDs and coxibs reduce synthesis of prostanoids via inhibition of COX1/COX2.