Novel Eicosanoid and Docosanoid Mediators: Resolvins, Docosatrienes, and Neuroprotectins Charles N

Novel eicosanoid and docosanoid mediators: resolvins, docosatrienes, and neuroprotectins Charles N. Serhan Purpose of review Abbreviations It is well known that arachidonic acid is the precursor to COX cyclooxygenase potent mediators. Many clinical studies suggest that DHA docosahexaenoic acid EPA eicosapentaenoic acid omega-3 polyunsaturated fatty acids such as HEPE hydroxyeicosapentaenoic acid eicosapentaenoic acid and docosahexaenoic acid have PMN polymorphonuclear neutrophils PUFA polyunsaturated fatty acids beneficial actions in human diseases. The molecular basis of these actions remains of interest. Recent findings # 2005 Lippincott Williams & Wilkins These demonstrate that eicosapentaenoic acid and 1363-1950 docosahexaenoic acid are precursors to potent (nM range) bioactive mediators that possess both anti-inflammatory Introduction and protective properties. These mediators were coined Beneficial actions of essential omega-3 polyunsaturated resolvins, docosatrienes, and protectins as general classes, fatty acids (PUFA) were noted as early as 1929 [1] and since each possesses unique chemical structures that are have been studied until the present [2–5]. In parallel, it features of the new chemical classes and are has emerged that inflammation plays a central role in biosynthesized by new pathways. Resolvins, discovered many prevalent diseases not previously known to involve first, were identified during the resolution phase of acute inflammation, including Alzheimer’s disease, cardiovas- inflammation; hence the term resolution interaction cular disease [6], and cancer [7], in addition to those well products, because they are also biosynthesized by human known to be associated with inflammation, such as arthri- cells via cell–cell interactions. Docosatrienes contain tis and periodontal disease [8,9]. The molecular mechan- conjugated triene structures generated from ism(s) underlying the many reports of the beneficial docosahexaenoic acid as a defining feature. The protectins actions of omega-3 PUFA remains an exciting and impor- comprise docosatrienes and resolvins of the D series that tant challenge for molecular medicine. Also, attributing are both neuroprotective and anti-inflammatory. Aspirin beneficial responses to these fatty acids per se may not be impacts on these new pathways by triggering formation of appropriate because pharmaceutical eicosapentaenoic their epimers (i.e. R isomers). acid (EPA) and docosahexaenoic acid (DHA) have not Summary been widely available for study. Along these lines, we In view of the many beneficial actions attributed to omega-3 recently identified novel oxygenated products generated dietary supplementation, identification of novel potent by enzymatic processes from the precursors EPA and mediators from omega-3 that are both anti-inflammatory and DHA. These new compounds possess potent actions in protective may have wide implications. the resolution of inflammatory exudates [10,11, 12 ] and have neuroprotective properties [13,14]. The terms Keywords resolvin (resolution phase interaction products) and docosa- aspirin, inflammation, polyunsaturated fatty acids, triene were introduced from initial studies, since the new resolution compounds displayed both potent anti-inflammatory and immunoregulatory properties, reducing neutrophil traffic Curr Opin Clin Nutr Metab Care 8:115–121. # 2005 Lippincott Williams & Wilkins. and the magnitude of the inflammatory response [10,11]. The term neuroprotectin was introduced, given the Center for Experimental Therapeutics and Reperfusion Injury, Department of protective actions of 10,17-docosatriene in neural and Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA retinal systems [14 ], as well as in stroke [13 ] and animal models of Alzheimer’s disease (N.G. Bazan, et al., unpub- Correspondence to Professor Charles N. Serhan, Director, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, 75 Francis lished data). St., Thorn Building for Medical Research, Room 724, Boston, MA 02115, USA Tel: +1 617 732 8822; fax: +1 617 582 6141; e-mail: [email protected] Unlike some of the other products characterized earlier as potentially being formed from omega-3 PUFA that are Current Opinion in Clinical Nutrition and Metabolic Care 2005, 8:115–121 similar in structure to eicosanoids but either less potent or devoid of bioactions [15,16], the resolvins, docosatrienes, and neuroprotectins evoke potent biological actions in the nanomolar or picomolar range in vitro and in vivo 115 116 Lipid metabolism and therapy Figure 1. Essential polyunsaturated fatty acids are precursors anti-inflammation and pro-resolution. This is a sharp to bioactive lipid mediators departure from the well appreciated pro-inflammatory roles of lipid mediators in general and particularly the Prostaglandins roles of prostaglandins and leukotrienes. The recognition Pro-inflammatory Arachidonic acid Eicosanoids Leukotrienes C20:4 that resolution is an active process and that activation of EETs p450 the lipoxin biosynthetic circuit and lipoxins themselves, cell cell Anti-inflammatory as well as aspirin-triggered lipoxins and their stable Lipoxins pro-resolution analogs, are potent agonists of anti-inflammation in vivo Resolvins and in many disease models [22] has now turned our Eicosapentaenoic acid (EPA) Eicosanoids E series C20:5 attention to understanding the biochemical events that Resolvins are activated during the resolution of local inflammatory Docosahexaenoic acid (DHA) Docosanoids D series responses. C20:6 Docosatrienes Protectins Neuroprotectins The omega-3 connection See text for details. EET, epoxyeicosatetraenoic acid. In view of the compelling results from the GISSI study, which showed improvements in >11 000 cardiovascular patients [24,25]: namely, reduction in sudden death by 45% by taking almost a gram of omega-3 per day; we [10,11,12,13,14]. This review gives a brief overview of addressed the role of omega-3 PUFA. Inspection of the the novel biosynthetic pathways from EPA that carry GISSI protocols revealed that all the patients in each arm potent biological actions, the resolvins of the E series of the study also took aspirin daily, but the contribution of (Resolvin E1 or RvE1), and those from DHA, the resolvins ongoing aspirin therapy to the beneficial outcome of of the D series (Resolvin D1 or RvD1), as well as bio- omega-3 PUFA was not accounted for in the analysis. synthesis pathways that form novel conjugated triene An abundant literature on omega-3 PUFA at doses of structures denoted as docosatrienes that are also both anti- milligrams to grams daily suggests beneficial actions in inflammatory [10,11,12] and neuroprotective [13,14], many human diseases including periodontal disease [26], termed neuroprotectins (see Ref. [14] and Fig. 1). inflammatory diseases and cancer [2,27]. The three major Chemical mediators of resolution: lipoxygenases (5-LO, 12-LO, 15-LO) can each convert recognizing that resolution is an active DHA to various monohydroxy-containing products. process However, the in-vivo functions of these products were either not apparent or they did not display bioactivity From the early studies of Bergstro¨m, Samuelsson, and [16,28,29]. Also, DHA can be non-enzymatically oxyge- colleagues, it is clear that arachidonic acid is transformed nated to isoprostane-like compounds termed neuro- into many potent bioactive compounds such as prosta- prostanes that reflect oxidative stress in the brain [30], glandins, leukotrienes, and lipoxins. The departure of or autooxidized to products that are monohydroxy fatty acids from simply playing structural roles in cell racemates [31] of the compounds that are now known membranes and/or as energy stores came largely from to be enzymatically produced during biosynthesis of the recognition of the rapid transformation of arachidonic resolvins and docosatrienes [11,12,13,14]. Despite acid to these potent eicosanoids by both cyclooxygenase the many years of research on omega-3 PUFA, it is and lipoxygenase mechanisms (see Refs [17–19]). Many noteworthy that the molecular basis and mechanisms of the classic prostaglandins and leukotriene mediators underlying their immunoprotective actions remained to are pro-inflammatory and play a decisive role in inflam- be established, and their direct connection to human mation and/or in systems such as the reproductive system, disease and treatment are still important biomedical where prostaglandins are key physiologic regulators. In challenges [32]. sharp contrast, in recent years it has become clear that counter-regulatory substances, such as the lipoxins, are generated during the resolution of acute inflammation, The impact of aspirin treatment: and that these serve as agonists for endogenous anti- discovery of the aspirin-triggered lipid inflammatory mechanisms. This constitutes the first mediators evidence that the resolution of inflammation, which Aspirin is an active ingredient in more than 60 over-the- was once thought to be a passive process [20], is actually counter remedies, making it a difficult substance to an active process that involves turning on of specific control completely in many human studies. To address pro-resolution circuits [21,22,23]. this in an experimental setting, we used murine dorsal skin pouches [10,11] that were known to spontaneously It is now clear from an abundance of emerging litera- resolve in rats [23]. We adapted them for study in mice ture that the lipoxins

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