MCM-SV-Eicosanoids and Lipid Mediators-1 -1

How many carbon compounds are eicosanoids? What is it derived from? Where do they act out their effects? What are the four classes? How are they different then hormones? What are their secondary messengers?

20, arachidoinic acid; on same cell or close by; protraglandins, leukotreins, thromboxanes, lipoxins;

not transported in blood; cAMP or Ca

Describe the chemical strucutre of Arachidonic Acid. How is AA freed from the cell membrane? How is AA synthesized?

20 carbon omega 6 poly unsaturated acid (PUFA), phospholipase A 2 (PLA2), synthesized from linoleic acid

What is the difference between linolenic Acid and linoleic acid?

linolenic = omega 3; linoleic = omega 6

what is the difference between Omega 6 and omega 3 fatty acids? What is their correlation with mortality from CVD?

omega 3 FA is less inflamatory then Omega 6. Because of this, the recommended ration of omega 6/ omega 3 is 1:1 to 4:1; LOWER RATIONS = LOWER MORTALITY FROM CARDIOVASCULAR DISEASE

what can deficiency of omega 3 cause? Why?

decrease in learning and memory, increased aggression and depression, alters auditory/olfactory senses to stimuli

why? several theories

1. omega 3 contribute to fluidity of cell membrane which affects protein membranes

2. omega 3 is a precurosr to resolvin which inhibits against oxidative-stress induced apoptosis and proinflammatory cells

3. omega 3 is crucial for neruon development and helps protect against apoptosis

Describe the pathway in which arachidonic acid is generated

stress factors (cytokines or atp from dead cells) activates GCPR

—> phospholipase C cleapves IP3—> DAG and Ca created

DAG with help of other lipases (diacylglycerol and monoacylclycerol lipase) creates AA

CA activates PKC—>MAPK—>PLA2—>phosphoatidylcholine—>AA

what three things stimulates PLA2? What inhibits PLA2? What can dysregulation of PLA2 cause?

stimluates: interleuken 1, angiotensen 2, thrombins

Inhibites: glucocorticoid (dexamethasone)

Dysregulation: alzheimers disease, multiple myeosis, epilepsy, ischemia

how is eicosanoids created? what is the difference between cox 1 and cox 2?

Created in one of two pathways

1. AA—>COX1,2—>PGH2, with help of PG synthases creates—>prostaglandins, thromboxanes , prostacyclins

2. AA —> LOX (lox 5,12,15); AKA lipoxygenases —> lipoxins (LX), leukotrienes (LT)

Cox-1 is constitutive, Cox-2 is inducible

Give examples in which PGE2 can have different effects depending on which receptor it binds on

PGE2 binds to neurons which illicit pain caused by inflamation

PGE2 binds (autocrine) to macrophages cells which leads to down regulation of TNF and upregulation of IL10 = less inflamation response

what are the three different precursor for prostraglandis?

AA

eicosatrienoic acid

eicopentaenoic acid

describe the synthesis of prostacycline and thromboxanes from AA. How do cell types affect this?

AA —> COX1,2 —> PGG2, with help of perixomes —> PGH2

Then, in endolethial cells: Prostacyclins (PGI2)

in platelets; thromboxanes (TXA2)

list the pathway, secondary messenger and physiological effects of:

PGD2

PGE2

PGF2a

PGI2

TxA2

Describe the effect of aspirin on Cox 1/ cox 2. Side effects?

irreversibly inhibits COX1; this reduces platelet aggregation (TXA2)

acetylates COX2; this causes production of 15R-HETE. 15R-HETE is converted into LIPOXINS by 5-lox in leukocytes; IF DHA or EPA comes into contact with COX2, converts into resolvins

Side effects: stomach iritation

what are resolvins made from? what does it do?

they are made from acetylated COX2 (via aspirin). They play an important role in the resolution stage in inflammation

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describe the effects of the four classic analgesics (pain reliever) on Cox1/2

Aspirin: cox1/2 irreversible inhibitor

tyenol: cox2 inhibitor in CNS

ibuproferin/naproxen = nonspecific cox1/2 inhibitor

compare and contrast ibuproferin/naproxen and celebrexx/vioxx

ibuproferin/naproxen = nonspecific Cox1/2 inhibitor, can lead to stomach ulcers due to lower pH

celebrexx/vioxx = specific cox 2 inhibitor, Targets inflammatory response; no side effects of advil bc does not touch Cox 1

list out the functions of these protaglandins/thronboxanes

PGI2, PGE2, PGD2,

PGF2a

TXA2

What is PGE2/PGF2 used for clinically? what is the name of the clinical drug that mimics this synthetically?

used to induce child birth or abortion; relaxing smooth muscles of passage ways. DINOPROSTONE

what is PGE1 used for clinically? what is the name of the clinical drug that mimics this synthetically?

Erectile dysfunction (aloprostadil), peptic ulcers, prevent closure of patent ductus arteriosus in newborns with particular cyanotic heart disease

what is PGI2 used for clinically? what is the name of the clinical drug that mimics this synthetically?

pulmonary hypertension (epoprostenol)

what is PGF2a used for clinically? what is the name of the clinical drug that mimics this synthetically?

induce labor through uterine muscle contraction (dinoprost) and in treatment of glaucoma (latanoprost)