FORM & FUNCTION (Eicosanoid) Flashcards by Danielle Groenendijk

Eicosanoid:

-modified 20 carbon polyunsaturated fatty acids
-3 major classes
-synthesized from dietary fats (Omega-3 and Omega-6)
-mediate several processes

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3 major classes:

-prostaglandins (PGs)
-thromboxanes (Txs)
-Leukotrienes (LTs)

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Eicosanoids mediate

several processes:-inflammatory response
-production of pain and fever
-regulation of blood pressure
-induction of blood clot
-induction of labor
-etc.

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Eicosanoids AND. hormones:

-induce profound physiological effects at extremely low concentrations
-bind to GPCR to initiate a signal transduction cascade (cAMP)

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Eicosanoids different from hormones:

-are not transported in the blood to their site of action
-produced by all mammalian organ cells except RBC
-very unstable and rapidly degraded
-promotes local and cell specific actions

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Palmitic acid:

-generated from lipid biosynthesis
-further modified to form other lipids

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Animals can’t make omega-3 and omega-6:

-missing desaturases that form the double bonds past the 9th carbon

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Double bonds in omega-3 and omega-6:

-double bond is 3 C away from the terminal group: omega-6
-double bond is 6C away from the terminal group: omega-3

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Dietary supplement:

-plant oil (flaxseed) or fish oil
-fish omega-3 comes from their dietary consumption of microalgae

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How are omega-3 and omega-6 stored?

-as a phospholipids
*important for cell membranes

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Omega-3 family breakdown:

Alpha-linolenic acid
Eicosapentaenoic acid (EPA)
Docosahexaenoic acid (DHA)

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Omega-6 family breakdown:

Linoleic acid
Arachidonic acid (AA)

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Delta-6 desaturase:

-enzyme that converts:
>alpha-linolenic acid to EPA
>linoleic acid to AA

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AA, EPA, DHA:

-precursors to:
>prostaglandins
>thromboxanes
>leukotrienes

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Omega-3 and omega-6 generally produce eicosanoids:

-omega-6: associated with pro-inflammatory
-omega-3: with anti-inflammatory response

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Healthy diet:

-low omega-6/omega-3 ratio is recommended

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Cats and omega-3/6 processing:

-lack delta-6 desaturase activity
-must obtain EPA, DHA, or AA from other animal organs or via transport

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Eicosanoid synthesis:

-omega-3/6 are stored in the cell membrane
-phospholipase A2 cleaves AA, EPA, DHA to get them in active form
-2 pathways

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Phospholipase A2 activated by:

-greater [Ca2+]
-physical trauma
-immunoglobulins
-microbial products

Phospholipase A2 inhibited by:

-anti-inflammatory signals (glucocorticoids)

2 pathways: eicosanoid synthesis:

Cyclooxygenase (COX-1 and COX-2)
Lipooxygenase
*compete for the same substrates
*oxidation reaction

Cyclooxygenase (COX-1 and COX-2):

-prostanoids
>prostaglandins
>thromboxane

Lipooxygenase:

-leukotrienes

Prostanoids:

-COX-1 is constitutively expressed
-COX-2 is inducible by inflammation stimuli
-different prostaglandins are produced by specific cell types to regulate local responses

Different prostaglandins local responses:

-control muscle function (vessel constriction and dilation) -regulate CNS activity (pain reception) -mediate cytokine production for inflammation response

NSAIDS:

-nonsteroidal anti-inflammatory drug *inhibit COX-1 and COX-2 >side effects

NSAIDS used to:

-reduce pain -decrease fever -decrease inflammation -commonly used to treat prescribed (arthritis)

COX-1:

-constitutive enzyme that generates the signal ligand for homeostatic intracellular signaling

COX-2:

-inducible enzyme with increased activity accompanying acute and chronic inflammatory conditions

NSAIDS block PGE2 production:

-PGE2 normally inhibits gastric secretion -inhibition consequences: >increase HCl secretion (can’t control how much HCl is in mucous) >decrease mucous secretion (barrier) in the stomach >GI bleeding

NSAIDS: PGI2

-vasodilators that increase renal perfusion -inhibition consequence: >reduced afferent blood flow that can lead to acute kidney injuries

COX-2 specific inhibitor:

-developed to treat acute and chronic inflammations -reduce side effects of GI bleeding and kidney necrosis *not used in humans -effective in reducing prostaglandins, but increase the ration of thromboxane that regulates clotting

COX-2 specific inhibitor examples:

-Firocoxib (Equioxx) -Previcox (used to treat canine arthritis and tumors)

Don’t use COX-2 specific inhibitors in humans:

-can lead to 40% increase in risk for cardiovascular complications

Thromboxanes:

-synthesized primarily in platelets (thrombocytes) -activated by damage to the arterial wall

Activated Thromboxanes:

-induce platelet aggregation and vascular muscle contraction

Normal conditions thromboxanes:

-PGI2 and nitric oxide cause vasodilation to inhibit thromboxanes

Increased Thromboxanes from COX-2 inhibtion:

-constricted vessel -platelet aggregation *increase risk of heart attacks

Leukotrienes:

-synthesized by the enzyme lipoxygenase (LO) -primarily act as inflammatory mediators -various biologic responses >bind to receptors on individual cells

Lipoxygenase (LO):

-synthesizes leukotrienes -primarily found in leukocytes

Leukotrienes biologic responses:

-pro-inflammatory action -bronchoconstriction (10-100x more potent than histamine) -mucus secretion -edema in airways

Leukotrienes and asthma:

-elevated leukotrienes levels (chronic inflammation, allergies) lead to asthma in humans and similar in cats

Asthma:

-characterized by increased mucous production and bronchoconstriction -laboured breathing and wheezing

Asthma treatment:

-with bronchodilator (beta-agonist) or corticosteroid (reduce inflammation)

Leukotriene receptor agonist:

-blocks leukotriene binding in target cells (montelukast & zafirlukast) -promising anti-inflammatory agents *need further validation in vet med