Arachidonic acid isoprostanes from

Glutamate-mediated calcium influx results in stimulation arachidonic acid release from neural membrane glycerophospholipids. This release is catalyzed by CPLA2 and PLC/DAG-lipase pathway (McIntosh et al., 1998 Schuhmann et al., 2003 Shohami et al., 1987, 1989 Wei et al., 1982 Dhillon et al., 1996 Homayoun et al., 1997, 2000). Arachidonic acid release occurs in traumatic as well as fluid percussion models of brain injury (FPI). Enzymic oxidation of arachidonic acid generates prostaglandins, leukotrienes, and thromoboxanes whereas non-enzymic oxidation produces isoprostanes and ROS which include superoxide and hydroxyl radicals (Farooqui and Horrocks, 2007). 

Although the acute vasodilator effects, as shown in in vitro studies (see above), may participate in the antihypertensive effects, the reduced blood pressure persisted even 42-48 h after the last administration of quercetin, when the plasma quercetin concentration and its metabolites fell bellow 25% of the peak post-administration levels [43]. Furthermore, the antihypertensive effects of quercetin did not appear to be related to its antioxidant properties since quercetin did not lower the urinary isoprostane F20 excretion, a prostaglandin-like compound produced in a non enzymatic reaction of arachidonic acid in membrane lipids and superoxide, which is currently used as a reliable marker of oxidative stress. The mechanisms involved in the antihypertensive effects and protection from organ damage... 

Hydroxyhept-6-enoates have been key intermediates in the synthesis of a variety of natural products, especially of the arachidonic acid metabolic pathway, including prostaglandins, leukotrienes, and isoprostanes [105, 113-118]. The usage of two enantiocomplementary enzymes allowed convenient access to both enantiomers via an ADH-catalyzed reduction of 5-oxo-hept-6-enoate. Alcohol dehydrogenase from Lactobacillus brevis (ADH-LB) furnished the (S )-enantiomer, Thermoanaerobacter sp. ADH (ADH-T) the (7 )-enantiomer in excellent enantiomeric access respectively [119]. A cross-metathesis reaction followed by cyclopropanation led to the formal synthesis of constanolactones C and D (Fig. 16) [86, 120, 121]. 

The isoprostanes are a unique series of prostaglandin-like compounds formed in vivo via a nonenzymatic mechanism involving the free radical-initiated peroxidation of arachidonic acid. This article summarizes our current knowledge of these compounds. Herein, a historical account of their discovery and the mechanism of their formation are described. Methods by which these compounds can be analyzed and quantified are also discussed, and the use of these molecules as biomarkers of in vivo oxidant stress is summarized. In addition to being accurate indices of lipid peroxidation, some isoprostanes possess potent biological activity. This activity will be discussed in detail. Finally, in more recent years, isoprostane-like compounds have been shown to be formed from polyunsaturated fatty acids, including eicosapentaenoic acid and docosahexaenoic acid. These findings will be summarized as well. 

A relatively new class of oxidized arachidonic acid derivatives with potential relevance to atherosclerosis are F2 isoprostanes [24] (Fig. 6) (Chapter 12). These compounds form as a result of non-enzymatic, free-radical attack of the fatty acid moieties of cellular or lipoprotein phospholipids, followed by release of the isoprostanes from the phospholipids by a phospholipase. 8-wo-prostaglandin-F2 may also be formed by the action of COX-1 or -2 in platelets or monocytes, respectively, but the significance of COX-dependent 8-W0-PGF2 formation in vivo is unproven. Fj isoprostanes circulate in the plasma and appear in the urine as free compounds or esterified to phospholipids, and... 

F. 35.14. Generation of an isoprostane. Radical damage to a phospholipid on the arachidonic acid residue at position 2 generates an isoprostane, which is then removed from the damaged phospholipid by phospholipase A2. The example of an isoprostane shown in this figure is just one of many that can be produced. 

The complex mixture of regioisomers and stereoisomers structurally related to the endoperoxides and thromboxanes (prostaglandin-like compounds) produced from arachidonic acid and esterified to phospholipids and cholesterol are classified as isoprostanes. These compounds are used as markers of in vivo oxidative injury in biological systems and considered reliable because they are specific, stable and not affected by the lipid content of the diet (Chapter 13. E.4). However, these secondary oxidation products are produced in relatively small concentrations because they are derived from arachidonic acid, which is a minor polyunsaturated lipid compared to linoleic acid in biological samples. Very sensitive gas chromatography-mass spectrometric (GC-MS) and liquid chromatography-MS techniques are required to analyse isoprostanes in biological samples. 

Figure 1. Mechanism of formation of isoprostanes by free radical catalysis of arachidonic acid. (With kind permission from Morrow et al, Anal Biochem, 1990b.)...

The first chapter of the book deals with the properties and activities of fatty acids. This is followed by detailed discussions of diacylglycerols and phosphoinositides. The lysolipids are represented by sphingosine 1-phosphate and lysophosphatidic acid, followed by an overview of the properties of ether lipids. Ceramides and glycosphingolipids are covered in two chapters. The metabolites of the arachidonic acid cascade are discussed in a further two chapters on prostanoids, leukotrienes and lipoxins, followed by the last two chapters of the book which focus on endocannabinoids and isoprostanes. The authors come from several European countries and North America, each one of them bringing on board their individual research and teaching experience, and insight of their expertise. 

Useful intermediates for the synthesis of a variety of arachidonic acid metabolites were prepared (Figure 11.10a). (R)-5-Hydroxyhept-6-enonoate was obtained from the reduction of ethyl 5-oxo-6-heptenoate by Thermoanaerobacter sp. alcohol dehydrogenase (ADH) expressed in E. coli [56]. The opposite enantiomer, (S)-5-hydroxyhept-6-enonoate, was obtained by using Lactobacillus brevis ADH. These chiral alcohols are important intermediates for prostaglandins, leukotrienes, isoprostanes, and atractyligenin. 

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