Eicosanoids Lecture Notes

Eicosanoids

Introduction

  • Eicosanoids are members of a family of polyunsaturated fatty acids.

  • They are derived from the fatty acid precursor arachidonic acid.

  • Eicosanoids include:

    • Prostaglandins (PGs): PGD2, PGF2α, PGE2, PGI2

    • Thromboxanes (TXs): TXA2

    • Leukotrienes (LTs): LTB4, LTC4, LTD4, LTE4

Reading Assignments

  • Required Reading: Golan Chapter 42

  • Recommended Reading: Goodman and Gilman Chapter 33

Learning Objectives

  • Recognize the important substrates, products, and enzymes for the following pathways:

    • COX pathway: Synthesis of Prostaglandins (PGs), Thromboxane (TXA)

    • LOX pathway: Synthesis of Leukotrienes (LT)

    • Explain the structure activity relationships of various PGs, noting:

    • All are derived from 20-carbon polyunsaturated arachidonic acid.

    • Structural differences: oxane ring vs cyclopentane ring.

  • Understand the physiological effects of various types of PGs and LTs, including their tissue-specific actions (e.g., effects on kidneys, smooth muscles, platelets, macrophages, and brain).

  • Pharmacological modulation of these effects:

    • PG receptor agonists and antagonists.

    • LT receptor modulators.

Eicosanoids Functionality

  • Autacoid Function:

    • Autacoids: self-effecting substances that also have receptors on the same cells releasing them (e.g., TXA2 on platelets).

    • Paracrine Function: involve neighboring cell effects, like neurotransmitters, where PG, TX, or LT can affect adjacent cells; e.g., PG release from hypothalamus to pituitary gland.

  • Eicosanoids have a short half-life in serum, indicating localized action.

Characteristics of Eicosanoids

  • Eicosanoids are lipid-derived, not stored, and produced on demand.

  • They are typically bound to lipid (membrane) or protein (serum) structures.

  • Highly active in very low concentrations, displaying localized synthesis.

  • They exhibit short-lived biological activity with local actions.

Eicosanoid Synthesis

  • The synthesis of eicosanoids begins with the release of arachidonic acid (AA) from membrane phospholipids.

    • Release Mechanism:

    • AA substrate released by acyl hydrolases, particularly phospholipase A2 (PLA2).

    • Activation of cytosolic PLA2 (cPLA2) involves Ca²⁺ mediated translocation to the membrane.

    • Membrane phospholipids (e.g., phosphatidyl choline, phosphatidyl ethanolamine) are cleaved to release AA, which is necessary for the synthesis of specific PGs, TXs, and LTs.

Eicosanoid Signaling

  • Membrane Phospholipids to Arachidonic Acid: AA is the central substrate in the production of various eicosanoids.

  • Receptors:

    • All eicosanoid receptors are GPCRs (G protein-coupled receptors), demonstrating different responses depending on the cell type and local environment.

    • Each eicosanoid's action is influenced by its receptor activation, affecting ion concentrations and intracellular signaling:

    • Contractile effects lead to increased intracellular Calcium (Ca2+Ca^{2+}).

    • Relaxing effects lead to increased cAMP production.

COX Pathway Eicosanoids

Cyclopentane Ring:

Required for the function of prostaglandins OH needed as well

  • Key Enzymes:

    • COX-1 and COX-2 synthesize eicosanoids, where COX-1 is present in all tissues performing housekeeping functions (e.g., gastric protection), and COX-2 is induced under inflammation and stress.

  • COX Products:

    • Substitutions on the cyclopentane ring characterize individual PGs; TXA2 characterized by six-membered oxane ring.

  • Physiological Effects:

    • PGI2: Vasodilation and inhibition of platelet aggregation.

    • PGE2: Induces contraction, regulates temperature (fever), and mucosal protection.

    • PGD2: Induces sleep and bronchoconstriction.

    • TXA2: Involved in platelet aggregation and vasoconstriction.

LOX Pathway Eicosanoids

  • Leukotriene Synthesis:

    • Begins with arachidonic acid through the lipoxygenase (LOX) pathway, specifically using 5-lipoxygenase (5-LOX) along with activating proteins such as FLAP.

    • Key products include:

    • LTB4: Functions as a neutrophil chemoattractant.

    • LTC4, LTD4, LTE4: Potent bronchoconstrictors associated with anaphylaxis and inflammatory responses.

  • Physiological Roles: Important in asthma and other inflammatory conditions, causing bronchoconstriction and involvement in immune responses.

Pharmacological Modulation of Eicosanoids

  • Prostanoid Agonists:

    • Dinoprostone: A synthetic PGE preparation used to stimulate uterine contractions and soften the cervix.

    • Misoprostol: Synthetic PGE for abortion and gastric protection in NSAID users.

    • Carboprost tromethamine: Synthetic PGF for abortion.

    • Alprostadil: Used for impotence and also causes smooth muscle relaxation in the eye.

    • Latanoprost: PGF2 analog used to treat glaucoma by reducing intraocular pressure.

  • Prostanoid Antagonists and NSAIDs:

    • NSAIDs inhibit COX enzymes, affecting eicosanoid synthesis leading to reduced inflammation and pain relief.

    • Corticosteroids suppress the synthesis of both PGs and LTs via inhibition of the initial pathways.

Conclusions

  • Understanding the role of eicosanoids in physiology and pharmacology is crucial for the development of therapies targeting inflammation, pain relief, and various diseases.

Eicosanoids ## Introduction - Eicosanoids are members of a family of polyunsaturated fatty acids. - They are derived from the fatty acid precursor arachidonic acid. - Eicosanoids include:- Prostaglandins (PGs): PGD2, PGF2α, PGE2, PGI2 - Thromboxanes (TXs): TXA2 - Leukotrienes (LTs): LTB4, LTC4, LTD4, LTE4 ## Reading Assignments - Required Reading: Golan Chapter 42 - Recommended Reading: Goodman and Gilman Chapter 33 ## Learning Objectives - Recognize the important substrates, products, and enzymes for the following pathways:- COX pathway: Synthesis of Prostaglandins (PGs), Thromboxane (TXA) - LOX pathway: Synthesis of Leukotrienes (LT) - Explain the structure activity relationships of various PGs, noting: - All are derived from 20-carbon polyunsaturated arachidonic acid. - Structural differences: oxane ring vs cyclopentane ring. - Understand the physiological effects of various types of PGs and LTs, including their tissue-specific actions (e.g., effects on kidneys, smooth muscles, platelets, macrophages, and brain). - Pharmacological modulation of these effects:- PG receptor agonists and antagonists. - LT receptor modulators. ## Eicosanoids Functionality - Autacoid Function: - Autacoids: self-effecting substances that also have receptors on the same cells releasing them (e.g., TXA2 on platelets). - Paracrine Function: involve neighboring cell effects, like neurotransmitters, where PG, TX, or LT can affect adjacent cells; e.g., PG release from hypothalamus to pituitary gland. - Eicosanoids have a short half-life in serum, indicating localized action. ## Characteristics of Eicosanoids - Eicosanoids are lipid-derived, not stored, and produced on demand. - They are typically bound to lipid (membrane) or protein (serum) structures. - Highly active in very low concentrations, displaying localized synthesis. - They exhibit short-lived biological activity with local actions. ## Eicosanoid Synthesis - The synthesis of eicosanoids begins with the release of arachidonic acid (AA) from membrane phospholipids.- Release Mechanism: - AA substrate released by acyl hydrolases, particularly phospholipase A2 (PLA2). - Activation of cytosolic PLA2 (cPLA2) involves Ca²⁺ mediated translocation to the membrane. - Membrane phospholipids (e.g., phosphatidyl choline, phosphatidyl ethanolamine) are cleaved to release AA, which is necessary for the synthesis of specific PGs, TXs, and LTs. ## Eicosanoid Signaling - Membrane Phospholipids to Arachidonic Acid: AA is the central substrate in the production of various eicosanoids. - Receptors:- All eicosanoid receptors are GPCRs (G protein-coupled receptors), demonstrating different responses depending on the cell type and local environment. - Each eicosanoid's action is influenced by its receptor activation, affecting ion concentrations and intracellular signaling: - Contractile effects lead to increased intracellular Calcium (Ca2+Ca^{2+}). - Relaxing effects lead to increased cAMP production. ## COX Pathway Eicosanoids - Cyclopentane Ring: Required for the function of prostaglandins. - Key Enzymes: - COX-1 and COX-2 synthesize eicosanoids, where COX-1 is present in all tissues performing housekeeping functions (e.g., gastric protection), and COX-2 is induced under inflammation and stress. - COX Products: - Substitutions on the cyclopentane ring characterize individual PGs; TXA2 characterized by six-membered oxane ring. - Physiological Effects:- PGI2: Vasodilation and inhibition of platelet aggregation. - PGE2: Induces contraction, regulates temperature (fever), and mucosal protection. - PGD2: Induces sleep and bronchoconstriction. - TXA2: Involved in platelet aggregation and vasoconstriction. ## LOX Pathway Eicosanoids - Leukotriene Synthesis:- Begins with arachidonic acid through the lipoxygenase (LOX) pathway, specifically using 5-lipoxygenase (5-LOX) along with activating proteins such as FLAP. - Key products include: - LTB4: Functions as a neutrophil chemoattractant. - LTC4, LTD4, LTE4: Potent bronchoconstrictors associated with anaphylaxis and inflammatory responses. - Physiological Roles: Important in asthma and other inflammatory conditions, causing bronchoconstriction and involvement in immune responses. ## Pharmacological Modulation of Eicosanoids - Prostanoid Agonists: - Dinoprostone: A synthetic PGE2 analog, primarily acting on EP2 and EP4 receptors. Used for cervical ripening and labor induction. Can cause uterine hyperstimulation. - Misoprostol: A synthetic PGE1 analog, primarily acting on EP3 receptors. Used for medically induced abortion (often with mifepristone) and prevention of NSAID-induced gastric ulcers through increased mucus/bicarbonate and decreased acid secretion. - Carboprost tromethamine: A synthetic 15-methyl PGF2α analog. A potent uterotonic agent acting on FP receptors. Used for induction of abortion and treatment of postpartum hemorrhage unresponsive to oxytocin. Side effects include nausea, vomiting, diarrhea, and fever. - Alprostadil: Synthetic PGE1, acting on EP2 and EP4 receptors. Used for erectile dysfunction, and to maintain patency of the ductus arteriosus in neonates with certain congenital heart defects. - Latanoprost: A PGF2α analog (prodrug) that acts on FP receptors to increase uveoscleral outflow, reducing intraocular pressure in open-angle glaucoma and ocular hypertension. - Prostanoid Antagonists and NSAIDs: - NSAIDs (Non-Steroidal Anti-Inflammatory Drugs): Inhibit COX enzymes. Non-selective NSAIDs block both COX-1 (involved in gastric protection and platelet function) and COX-2 (primarily involved in inflammation). COX-2 selective inhibitors target inflammation with potentially fewer gastrointestinal side effects but may carry cardiovascular risks. - Corticosteroids: Suppress the synthesis of both PGs and LTs by inhibiting phospholipase A2 (PLA2) activity, thereby preventing the release of arachidonic acid from membrane phospholipids, which is the precursor for both COX and LOX pathways. ## Conclusions - Understanding the role of eicosanoids in physiology and pharmacology is crucial for the development of therapies targeting inflammation, pain relief, and various diseases.