Eicosanoids in Cerebrovascular Diseases

Introduction

Eicosanoids have long been known to participate in cerebrovascular injury, starting in the early 1970s . Eicosanoids are derivatives of the 20-carbon polyunsaturated fatty acid (PUFA) arachidonic acid (AA); the more generalized term for oxidized versions of PUFAs is oxylipins. Nonetheless, because of the physiological importance of AA-derived prostaglandins and leukotrienes, as well as the hydroxyeicosanoic acids (HETEs), eicosanoids is sometimes used as a blanket term for the enzyme-generated oxidation products of PUFAs. Although there are several important oxylipins with shorter or longer chains, e.g., the 18-carbon linoleic acid derivative 13-HODE and the 22-carbon docosahexaenoic acid protectins, the main focus of this review will be on the eicosanoids as oxidation products of AA, and the enzymes that generate them. A great number of eicosanoids has been identified, and novel functions continue to be discovered. They can be pro- or antiinflammatory, vasoconstrictive or vasodilatory, or can serve as intracellular second messengers. Because of this dizzying array of substances with sometimes overlapping, sometimes counteractive activities, the enzymes leading to the production of eicosanoids have received increased attention. The reasons for this are threefold. One, there is a limited number of enzymes contributing to the generation and consumption of eicosanoids; two, these enzymes and their activities are upregulated following experimental stroke and several are implicated in causing neurovascular injury; three, as enzymes they are potentially very promising drug targets.

Production of Eicosanoids

AA is not produced in the human body, and thus must be taken up exogenously from various food sources. Once processed, most AA is not present as the free acid, but incorporated into phospholipids, typically in the sn-2 position. These AA-containing phospholipids are especially abundant in the brain, where they make up around 30% of all phospholipids. Under conditions of ischemia, phospholipases A2 (PLA2s) are activated, which liberate AA from the membrane phospholipids. Chief among these is the cytosolic calcium-dependent PLA2, but others may contribute.

With its four double bonds, free AA is highly reactive and prone to oxidation. This is especially relevant in stroke, because oxidative stress is known to be a major injury mechanism.

The Eicosanoid-Producing Enzymes

Three classes of enzymes oxidize free arachidonic acid in the brain (see Fig. 16.1 ): the lipoxygenases, which generate leukotrienes, HETEs, and lipoxins as major oxidation products ; the cyclooxygenases I and II, which lead to the production of inflammatory prostaglandins ; and cytochromes P450, which generate vasoactive substances including 20-HETE and various protective epoxides, the epoxyeicosatrienoic acids (EETs) .