Phospholipids, eicosanoid derived

T FIGURE 10-18 Arachidonic acid and some eicosanoid derivatives. (a) In response to hormonal signals, phospholipase A2 cleaves arachidonic acid-containing membrane phospholipids to release arachidonic acid (arachidonate at pH 7), the precursor to various eicosanoids. (b) These compounds include prostaglandins such as PCE, in which C-8 and C-12 of arachidonate are joined to form the characteristic five-membered ring. In thromboxane A2/ the C-8 and... 

Lastly, eicosanoids are important pro-inflammatory mediators derived from membrane metabolism. PLA2 plays a key role in the production of eicosanoids, derived from arachi-donic acid of the phospholipids contained in the cell membrane (40,41). As mentioned earlier, arachidonic acid is liberated from the membrane-bound phospholipids by several forms of PLA2 and is the substrate for COX-1, COX-2, and 12-lipoxygenases (LOX) involved in vascular inflammation. 

Prostaglandins, thromboxanes and leucotrienes are eicosanoids deriving from oxidation of arachidonic acid. Arachidonic acid (deriving from PLA2 action on phospholipids) is cyclized by constitutive cyclooxygenase (COX-1) or inducible cyclooxygenase (COX-2) to yield... 

Eicosanoids, so named because they are all derived from 20-carbon fatty acids, are ubiquitous breakdown products of phospholipids. In response to appropriate stimuli, cells activate the breakdown of selected phospholipids (Figure 25.27). Phospholipase Ag (Chapter 8) selectively cleaves fatty acids from the C-2 position of phospholipids. Often these are unsaturated fatty acids, among which is arachidonic acid. Arachidonic acid may also be released from phospholipids by the combined actions of phospholipase C (which yields diacyl-glycerols) and diacylglycerol lipase (which releases fatty acids). 

There are three groups of eicosanoids that are synthesized from C20 eicosanoic acids derived from the essential fatty acids linoleate and a-linolenate, or directly from dietary arachidonate and eicosapentaenoate (Figure 23-5). Arachidonate, usually derived from the 2 position of phospholipids in the plasma membrane by the action of phospholipase Aj (Figure 24-6)—but also from the diet—is the substrate for the synthesis of the PG2, 1X2 series (prostanoids) by the cyclooxygenase pathway, or the LT4 and LX4 series by the lipoxygenase pathway, with the two pathways competing for the arachidonate substrate (Figure 23-5). 

This chapter surveys the neurochemistry of lipid messengers, as well as the mechanisms by which bioactive lipids accumulate upon stimulation in response to injury, cerebral ischemia, seizures, neurotrauma or neurodegen-erative diseases, and their significance in pathophysiology. Emphasis is placed on three groups of bioactive lipids AA and its metabolites, known collectively as eicosanoids PAF, a highly potent ether phospholipid and the newly identified DHA-derived mediator, neuroprotectin Dl. 

The eicosanoids, so called because of their derivation from a 20-carbon unsaturated fatty acid, arachidonic acid (eicosatetraenoic acid), are obtained from membrane phospholipids and synthesized de novo at the time of cellular stimulation. Arachidonic acid is cleaved from membrane-bound phosphatidylcholine by the enzyme phospholipase A2. Alternatively, arachidonic acid may be derived by the sequential actions of phospholipase C and diacylglyceryl lipase. Arachidonic acid can then follow either of two enzymatic pathways that result in the production of inflammatory mediators. The pathway initiated by cyclooxygenase (COX) produces prostaglandins the lipoxygenase pathway generates leukotrienes (Fig. 36.2). 

The biosynthetic pathway of prostaglandins and other eicosanoids is outlined in Figure 15-2. Basically, these compounds are derived from a 20-carbon essential fatty acid. In humans, this fatty acid is usually arachi-donic acid,68,73 which is ingested in the diet and stored as a phospholipid in the cell membrane. Thus, the cell has an abundant and easily accessible supply of this... 

Eicosanoid mediators are derived from araehidonie aeid (eieosatetraenoie) and related poly-unsaturated fatty aeids, sueh as aeid eieosapentanoic acid. These fatty acids are mainly found as constituents of phospholipids in cellular membranes (Figure 12. la), and it is from there that they are mobilized for eicosanoid mediator synthesis. The major classes of eicosanoids are prostaglandins, thromboxanes, and leukotrienes. Eicosanoids are very widespread in the mammalian organism - most cells synthesize them. 

Figure 12.1. Overview of eicosanoid metabolism, a Stmetures of eicosanoid precursor fatty acids, and their occurrence in membrane phospholipids (PC is shown as an example). Araehidonie acid is the prototypic precursor eicosatrienoic and eicosapen-tanoic acid differ from it by the a lackingor an additional double bond, respectively, b Conversion of preemsor fatty acids occurs by various enzymes, notably cyclooxygenases and lipoxygenases. Isoprostanes are non-enzymahe derivatives that may form in vivo at appreciable rates one characterishc featme is that they occur as racemic mixtures. Their physiological significance is not entirely clear.

The family of compounds referred to as eicosanoids, which includes the prostaglandins (PCs), leukotrienes (LTs) and thromboxanes (TXs), have been shown to play key roles in the inflammatory process (Flower et al 1985). Eicosanoids are derived from 20-carbon essential fatty acids, with arachidonic acid being the most common precursor. Perturbations of cell membranes, whether chemical, physical or immune-mediated, release phospholipids, which are rapidly converted to arachidonic acid by phospholipase A2 and other acylhydrolases. Once released, arachidonic acid and its congeners form the substrates for a number of enzyme systems (Fig. 14.1). Products that contain ring structures (PCs and TXs) are the result of metabolism by the cyclooxygenase (COX) enzymes, while the hydroxylated derivatives of straight-chain fatty acids (LTs) result from the action of various lipoxygenases (Flower et al 1985). 

LEUKOTRIENE RECEPTOR AGONISTS act at receptors recognizing leukotrienes and analogues. The lipoxygenase system forms the leukotrienes, which are members of the eicosanoid family of phospholipid mediators. Their name derives from the fact that leukotrienes are found in leucocytes and contain a triene system of double bonds. The other members of the eicosanoid family are the prostanoids (thromboxanes and the prostaglandins), and these are formed by the cyclooxygenase system see cyclooxygenase INHIBITORS. All the eicosanoids are derived mainly from arachidonic acid. These mediators are synthesized on demand, and in some cases their half-lives are short. The... 

Recently Liu and Weller [84] have reviewed the arachidonic acid metabolism in filarial parasites and other helminths. Arachidonic acid (AA) is a 20 carbon polyunsaturated fatty acid derived from dietary fatty acids. In human tissues, AA is usually present in the esterified form such as glycerolipids, phospholipids and neutral lipids. The free AA, released by phospholipases, undergoes various enzymatic oxygenations to form local mediators such as prostaglandins and leukotrienes, which are collectively known as eicosanoids (Chart 9). These eicosanoids are associated with platelet aggregation, vasodilation, leukocyte inflammatory and immune functions and cellular adhesion [85]. 

Eicosanoids Oxygenated lipid signaling molecules containing 20 carbons derived from polyunsaturated fatty acids released from membrane phospholipids by the action of phospholipase A. These include the prostanoids produced by the cyclooxygenase pathway and the leukotrienes produced by the lipoxygenase pathway. 

Fatty acids are monocarboxylic acids that occur primarily in triacylglycerols, phospholipids, and sphingolipids. The eicosanoids are a group of powerful hormonelike molecules derived from long chain fatty acids. The eicosanoids include the prostaglandins, thromboxanes, and the leukotrienes. 

For a phospholipid to move from one side of the bilayer to the other, the polar head must move through the hydrophobic portion of the phospholipid membrane. This process requires a significant amount of energy and is therefore relatively slow. 11. Eicosanoids are derived from arachidonic acid. Medical conditions in which it is advantageous to suppress the synthesis of eicosanoids are anaphylaxis, allergies, pain, the inflammation caused by injury, and fever. 

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