2.11 - Eicosanoids

Eicosanoids are derived from

membrane lipids

The precursor fatty acids for eicosanoids contain how many carbons

20

Most abundant eicosanoid precurser in humans

Arachadonic Acid (AA)

How is Arachadonic Acid stored?

as part of cell membrane phospholipids

How is Arachadonic Acid released

released from phospholipids by hydrolysis mediated phospholipases (notably PLA2)

What initiates the release of arachadonic acid from phospholipids mediated by Phospholipases

initiated by Ca2+ dependent translocation of PLA2 from cyrosol membrane

Metabolites of Arachadonic Acid include:

Prostandlandins (PG)

Leukotrienes (LT)

Thromboxanes (TXA)

all are autocoids

How are eicosanoids stored

Eicosanoids are NOT stored. They are produced as needed when physical, chemical and/or hormonalstimuli activate phospholipases

Biosynthesis of eicosanoids is limited by availability of

Arachadonic Acid

How are Leukotrienes (LTA,B,C,D, or E) synthesized from AA

Lipoxygenases (LOX): Convert AA to leukotrienes (LTA, B, C, D or E)

LT: potent inflammatory + bronchoconstrictors: asthma, anaphylaxis

How are prostaglandins synthesized from AA?

Cyclooxygenases (COX): Convert AA to prostaglandins (PGD, E, F, G, H or I)

Diverse functions: fever, sleep, pain; ↑inflammation

How are Thromboxanes synthesized from AA

Thromboxane synthase: PGH2 converted to thromboxanes (TxA)

TxA: smooth muscle cell mitogen and potent platelet aggregator

rostaglandin synthesis is accomplished in a _________________ by a complex of microsomal enzymes.

stepwise oxidation

What serves are a major intermediate for the stepwise oxidation for prostaglandin synthesis?

PGH2

Prostaglandins with subscript 2 are derived from___ and are major series in mammals

AA

Which enxyme involved in Prostaglandin synthesis is "Expressed constitutively in most cells; main source of PG"

Cyclooxygenase 1 (COX-1)

Which enzyme involved in prostaglandin synthesis is "ctivated by cytokines, stress; produces PG in cancer, inflammation"

Cyclooxygenase 2 (COX-2)

How do COX inhibitors (NSAIDs) affect prostaglandin production

decrease PG production (aspirin, ibuprofin, naproxen)

How do COX-2 Inhibitors (Celecoxib) work and what is the result?

Selective inhibition of COX-2

reduce induced inflammation and pain

How do PLA2 inhibitors (annexins, glucocorticoids) work?

decrease AA release therby decreasing synthesis of all eicosanoids

Prostaglandin release from the synthesizing cell is accomplished by the

prostaglandin transporter (PGT)

PGs are highly lipophilic, and may cross cells through __________ (but this is insufficient by itself)

Passive diffusion

Prostaglandin release mediated by

ATP-dependent multidrug resistance protein 4 (MRP4) specific transporter

Metabolism of Eicosinoids Steps:

Most (95%) of eicosanoids are rapidly catabolized

1) Rapid initial step by PG-specific enzyme (PGE 2:prostaglandin dehydrogenase)

PGs lose most of their biological activity after action

2)Second step in which metabolites are oxidized throughmultiple enzyme

What effect would a cox-2 inhibitor have onfever? What is the mechanism?

It would decrease fever by decreasing prostaglandin production, thereby lowering PGE2 release

Release of eicosanoids activate ______________ locally near the producing cell

membrane receptors

-Receptors widely distributed throughout brain and body

-PG effects vary greatly due to diverse family of distinct receptors

Eicosanoid membrane receptors are all:

All metabotropic receptors: members of 7TM GPCR superfamily

Receptors (mostly) share high homology; ancient origin

Diversity suggests biological importance

DP 1 and 2

Binds PGD2 .

DP1: Gs-linked; DP 2: Gi-linked!

DP2 receptor linked to airway inflam.; also called CRTH2

EP 1,2,3 and, 4

Binds PGE2. Linked to big variety of G proteins;

FP

Binds PGF2α. Excitatory: Gq-linked

IP

Binds PGI 2. Excitatory: Gs-linked

May now have a second receptor (IP2); also binds PGI

TP alpha and beta

Binds TxA2. Gq,s,i,12/13,+16 linked (!) Mediates clotting.

ctivates RhoGEF pathway; promotes growth and repair

BLT1:

Binds LTB 4. Inhibitory: Gi-linked

BLT 2

Binds LTB 4. Excitatory: Gq-linked

CysLT1

Binds LTD4 Excitatory: Gq-linke

CycLT2

Binds LTC4/LTD4 Excitatory: Gq-linked

Three phylogenic clusters among PGs are all___ linked

Gs

DP2 genetically distinct; more closely related to ______receptor family.

fMLP

CNS effects of PG receptors are primarily mediated by:

PGD2,PGE2,PGI2

DP receptor: primarly ligand, key function, CNS function

primary ligand: PGD2

Key function: allergic athsma

CNS: PGD2 increases sleep (receptor uncertain)

DP2/CHRT2 receptor: primary ligand and key finction

Primary ligand: PGD2

Key function: airway inflammation

EP1 receptor: key ligand, key function, and CNS function:

Primary ligand: PGE2

Key function: vasoconstriction, GIT smooth muscle contraction

CNS: sensitize noiciceptoer threshold, increased hyperalgesia and pain

EP2 Receptor: primary ligand and key function

Primary ligand: PGE2

Key function: bronchodilation, vasodilation, GIT smooth muscle relaxation

EP3 I-VI,e,f receptor: primary ligand, key functions, and CNS functions

Key ligand: PGE2

Key function: cardiovascular protection, GIT smooth muscle contraction, pltalet aggregation, decreased gastric acid, increased autonomic neurotransmitters

CNS: increased fever and body temp

EP4 Receptor: Primary ligand and key functions

Primary Ligand: PGE2

Key function: immune responses in skin, activates T-cells

CNS: sensitixe noiciceptor threshold, increased hyperalgeisia and pain

FP A+B Recetor: primary ligand and key functions

Primary ligand: PGF 2 alpha

Key function: bronchoconstriction, uterine contraction

IP receptor: primary ligand, key function, CNS functions

Primary Ligand: PGI2

Key functions: vasodilation, inhibit platlet aggregation, bronchodilation

CNS: sensitize noiciceptor threshold, increased hyperalgesia and pain

Prostaglandins (esp. PGE2 and PGI 2) generally promote

acute inflammation (although exceptions exist).

PGE2 a major promotor of:

fever. Hypothalamus releases PGE 2 acts on neuronal EP 3 to ↑body temp

PGD2 promotes:

sleep. Increases adenosine in basal forebrain that, in turn, promotes sleep

PGE2 and PGI 2 increase excitability in spinal and brain pain path pathways resulting in:

Amplifies perception of pain; also ↑hyperalgesia and ↑allodynia

_____ are potently pro-inflammatory and bronchoconstrictors: asthma, anaphylaxis

Leukotrienes

____ have diverse physiological functions, but also promote fever, sleep, inflammation and pain- PGD2, PGE2 and PGI 2 of importance in CNS, pain and inflammation

Prostaglandins

_____ are smooth muscle cell mitogens and potent platelet aggregator, and promote repair

Thromboxanes

Aspirin

WHO essential medicine

nonselective NSAID; permanently inhibits COX-1 and COX-2. Anti-inflammatory; weak analgesic

Increases clotting time (blocks TxA synthesis indirectly)

Salicylic acid (methylsalicylate):

Non selective NSAID; absorbed through skin. Inhibits COX-1 and COX-2.

Suppresses expression of COX-1 and COX-2. Anti-inflammatory; weak analgesic.

WHO essential medicine

Ibuprofin, Naproxen:

-WHO essential medicine

reversible NSAID. Anti-inflammatory, weak analgesic, antipyretic.

Acetominophen

WHO essential medicine

Reversible "NSAID." Modest analgesic, antipyretic. No efficacy against inflammation.

Celecoxib

NSAID; selective COX-2 inhibitor. Analgesic; significant anti-inflammatory; used totreat rheumatoid arthritis. #20 on the list of Top 100 drugs.