| Arachidonic acid is a second messenger regulating phospholipases and protein kinases
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| Figure 38.12 Fatty acid side chains in phosphatidylinositol 4,5-bisphosphate (PIP2) phosphatidylcholine, and phosphatidylethanolamine. |
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| ANTI-INFLAMMATORY DRUGS TARGET PROSTAGLANDIN SYNTHESIS |
Non-steroid anti-inflammatory drugs (NSAIDs) such as aspirin and ibruprofen decrease inflammation, pain, and fever through inhibition of the synthesis of prostaglandins, by blocking the first stage whereby arachidonic acid is converted to the common prostaglandin precursor, PGG2 by a cyclo-oxygenase enzyme. There are two forms of the enzyme. Cyclo-oxygenase 1 (Cox-1) is mainly constitutive and found in platelets, stomach, and kidney. Cyclo-oxygenase 2 (Cox-2) is mainly inducible and responsible for synthesis of inflammatory prostaglandins. Aspirin (acetylsalicylate) covalently modifies and irreversibly inactivates both forms of the enzyme by acetylation. Because abrogation of cyclo-oxygenase activity will also block production of the potent vasoconstrictor and aggregator of blood platelets, thromboxane A2 (TXA2, also derived from the common precursor, PGG2), aspirin can also be used as a prophylactic agent, to prevent the excessive blood clotting that can lead to heart attacks and stroke. The Antiplatelet Trialists Collaboration meta-analysis of aspirin in secondary prevention showed that the reduction in risk of recurrent stroke was about 15%. The combination of aspirin with dipyridamole, which reduces platelet aggregation by increasing cAMP concentrations may further reduce risk. Other effective antiplatelet drugs are the thienopyridines, ticlopicline and clopidogrel which block ADP-induced platelet aggregation. Selective inhibitors of Cox-2 such as celecoxib are also effective treatments for inflammatory conditions such as rheumatoid arthritis and their effectiveness and tolerability are being compared with conventional NSAIDs. Corticosteroid hormones, such as cortisone, are also anti-inflammatory drugs that target prostaglandin synthesis; in this case, however, such reagents do not affect cyclo-oxygenase but, rather, appear to inhibit activation of the PLA2 activity that generates the key intermediate, arachidonic acid. Such drugs are therefore useful for treating inflammatory responses involving leukocyte recruitment or asthma, as targeting arachidonic acid production will, in addition to blocking synthesis of prostaglandin, also abrogate the production of leukotriene. |
| Comment. Prostaglandins orchestrate a myriad of physiologic responses: they stimulate inflammation, regulate blood flow to organs such as the kidney, control ion transport across membranes, modulate synaptic transmission, and induce sleep. Prostaglandins are generally derived from the key inflammatory mediator, arachidonic acid, which in turn can be produced by PLA2-mediated hydrolysis of various phospholipids such as phosphatidylcholine. |
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| Arachidonic acid is a C20 polyunsaturated fatty acid containing four double bonds (see Fig. 38.12). In addition to being implicated as a lipid second messenger involved in
the regulation of signaling enzymes, such as PLC-γ, PLC-δ and PKC-α,-β and -γ isoforms, arachidonic acid is a key inflammatory intermediate. However, the arachidonic acid involved in these disparate functions appears to be generated by two distinct PLA2 routes. Arachidonic acid generated for signaling purposes appears to be derived by the action of a phosphatidylcholine-specific cytosolic phospholipase A2 (cPLA2), which has a molecular mass of 85 kDa and is regulated by phosphorylation of key serine residues. In contrast, inflammatory arachidonic acid is generated by the action of a family of low-molecular-weight secretory PLA2 (sPLA2) proteins (14-18 kDa), which appear to be ubiquitous and are found in high concentrations in snake venom and pancreatic juices. In addition, arachidonic acid can be generated by DAG lipase.
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