ReviewPalmitoylethanolamide and other anandamide congeners. Proposed role in the diseased brain
Introduction
Amides of fatty acids and ethanolamine, called N-Acylethanolamines or acylethanolamides (Fig. 1), attracted attention as bioactive lipids for the first time in 1957 when it was discovered that palmitoylethanolamide (PEA) isolated from soybeans, peanuts, and egg yolk has anti-inflammatory activity in guinea pigs (Kuehl et al., 1957). In 1965, it was shown that acylethanolamides also existed in mammalian tissues, especially the brain (Bachur et al., 1965). A great deal of work on formation and catabolism of acylethanolamides was done in the 1980s by the group of Harald Schmid (Schmid et al., 1990). However, it was first by the discovery of anandamide (Devane et al., 1992), which is an arachidonic acid-containing acylethanolamide, that major focus was put on these compounds (Hansen et al., 2006). Anandamide appears to be a partial agonist for cannabinoid receptor-1, while 2-arachidonoyl glycerol is a full agonist for both cannabinoid receptor-1 and cannabinoid receptor-2 (Sugiura et al., 1999, Sugiura et al., 2000). Docosatetraenoylethanolamide, eicosatrienoylethanolamide, eicosapentaenoylethanolamide, and docosahexaenoylethanolamide can also bind to the cannabinoid receptor-1 (Hanus et al., 1993, Sheskin et al., 1997) although with lower affinity than anandamide. Discussion of these polyunsaturated acylethanolamides as well as their metabolites generated via cycloxygenase-2 (Kingsley and Marnett, 2009) is not within the scope of this review, which will focus on possible roles in the brain of PEA, oleoylethanolamide (OEA), and stearoylethanolamide (SEA). Linoleoylethanolamide in the brain is only found in minute amounts as opposed to its presence in other tissues (Artmann et al., 2008), and this compound will not be discussed further.
Section snippets
Formation and catabolism of palmitoylethanolamide and congeners
PEA and its congeners are formed from the unusual phospholipid, N-acylated phosphatidylethanolamine (NAPE) by several enzymatic pathways (Fig. 1) (Hansen & Diep, 2009, Ahn et al., 2008, Wang & Ueda, 2009). The major pathway is catalyzed by a membrane-associated NAPE-phospholipase D (NAPE-PLD) generating the acylethanolamide and phosphatidic acid (Leung et al., 2006, Okamoto et al., 2004). This NAPE-phospholipase D can in vitro be inhibited by some lactamase inhibitors (Petersen et al., 2009).
Targets for palmitoylethanolamide and congeners
Initially, it was found that in some cases, PEA and OEA could potentiate the effect of anandamide on cannabinoid receptor or vanilloid receptor (VR1) (De Petrocellis et al., 2001, Mechoulam et al., 1997, Smart et al., 2002). This so-called “entourage effect” could be mediated by competitive inhibition of anandamide hydrolysis by FAAH (Jonsson et al., 2001) and/or direct allosteric effect of PEA on TRPV1 (De Petrocellis et al., 2004, Ho et al., 2008). PEA, OEA, and SEA are found in much higher
Possible role in diseased brain
A clear physiological role in the brain of OEA, PEA, and SEA is not apparent. However, available data point to several possible roles of the acylethanolamides in the diseased brain.
Since it is known that the acylethanolamide precursors, NAPEs (Hansen et al., 2001a, Moesgaard et al., 1999), as well as all the acylethanolamides (Degn et al., 2007, Hansen et al., 2001b) (Berger et al., 2004) accumulate in the tissue during brain injury, it has been speculated that some of these lipid molecules
Acknowledgments
This work has been supported by the Novonordisk Foundation and by the research project “UNIK: Food, Fitness & Pharma for Health and Disease”. The UNIK project is supported by the Danish Ministry of Science, Technology and Innovation.
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