Eicosanoids

What are Eicosanoids?

Oxidation products of 20 carbon fatty acids

What is the main Eicosanoid?

Arachidonic acid

What are Eicosanoids the precursors for?

Prostanoids, Leukotrienes

What are the classical prostanoids?

Prostaglandin, prostacyclins, thromboxanes

What are the non classical eicosanoids?

Lipoxins, Resolvins, Isoprostanes, Endocannabinoids

Prostaglandin biosynthesis?

Start with membrane phospholipids → phospholipase A → AA → cyclooxygenase → PGH2 unstable intermediate → Tissue specific prostanoids

Prostaglandin biosynthesis elevation?

Synthesis low at basal conditions, increase in rate and profile due to COX2

PGE2 G couple receptors

EP1 EP2 EP3 EP4

PGI2 G couple receptors

IP

Thromboxane (Tx) G couple receptors?

TP

PGD2 G couple receptors?

DP1 DP2

Functions of PGs

Initiation of labour PGE2

Inhibit Gastric Acid secretion PGE2

Inhibition of Platelet aggregation PGI2

Pro Platelet aggregation THA2

Pro inflammatory action of PGs?

EP2 potential pro inflammatory receptor, increases smooth muscle vasodilation and increases blood flow

Anti inflammatory action of PGs

EP2 potential anti inflammatory receptor decreases Leukocyte function

What do PGs do in fever?

Resets the hypothalamus, fever protective, dangerous if prolonged regulated by PGE2 and EP3 receptor

What does COX 1 do?

Homeostatic function, products important for normal function of many parts of the body

What does COX2 do?

It is induced in inflammation

What part of the COX enzyme is a target for aspirin?

Acylation Serine 529, so Arachidonic acid cant access the active site, irreversibly inhibited via a covalent bond

What do NSAIDs do?

Inhibit COX enzymes

What is ibuprofen?

A competitive inhibitor of Arachidonic acid, can be over come by high concentrations of AA

Side effects of NSAIDs?

Due to inhibition of COX1 as not selective, Increased gastric acid, increased bleeding, decreases anti-thrombotic effects, decreases mucus production

What does COX selectivity rely on?

Ability to fit into active site

What was the Von Fey pain receptor test?

Knocked of EP1 receptor in mice and decreased pain perception

What does EP3 do?

Activates leukocytes and mast cells as decreases cAMP so increased leukocyte function and oedema

Adverse effects of COX2 selectivity?

Increased Cardiovascular problems

Adverse effects of COX1 selectivity?

Increased GI problems

NSAIDs Anti thrombotic?

Stops production of TXA2 and PGI2 as blood vessel endothelial cox resynthesized rapidly level maintained, useful in myocardial infractions, may help prevent colon cancer and alzehimer’s disease

Bronchoconstriction Leukotrienes?

LTC4 and LTD4 constrict more than 1000x more than histamine

Oedema Leukotrienes?

LTC4 and LTD4 stimulate increased vascular permeability (neutrophil independent)

LTB4 increases vascular permeability (neutrophil dependent)

Chemotaxis Leukotrienes?

LTB4 and BLT1 receptor

Future targets for anti-inflammatory drugs?

•PGE2 main mediator of inflammation

•Prostaglandin E synthase inhibitors – mPGES-1

•Increase degradation of PGE2 

•Antagonists of EP receptor

What do Glucorticoids do?

Stop production of Leukotrienes and PGS

Direct through interfering with transcription of enzyme,

Can increase transcription of other inflammatory agents

Indirect via lipoxin interferes with PLA