Review
Palmitoylethanolamide and other anandamide congeners. Proposed role in the diseased brain

https://doi.org/10.1016/j.expneurol.2010.03.022Get rights and content

Abstract

Acylethanolamides are formed in the brain “on demand” from membrane phospholipids called N-acylated phosphatidylethanolamines. The acylethanolamides are signaling molecules of lipid nature, and this lipofilicity suggests an autocrine function. The acylethanolamides include palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamide (SEA), and several other quantitative minor species including anandamide (= arachidonoylethanolamide). PEA and OEA can activate several different receptors and inhibit some ion channels, e.g., PPARα, vanilloid receptor, K+ channels (Kv4.3, Kv1.5), and OEA can activate GPR119 and inhibit ceramidases. Targets for SEA are less clear, but it has some cannabimimetic actions in rats in vivo. All acylethanolamides accumulate during neuronal injury, and injected OEA has neuroprotective effects, and PEA has anti-inflammatory effects as studied in the peripheral system. Several of the pharmacological effects seem to be mediated via activation of PPARα. Recently, injected OEA has been found to consolidate memories in rats. Inhibitors of the acylethanolamide-degrading enzyme FAAH can increase levels of all acylethanolamides including annandamide, and some of the pharmacological effects caused by these inhibitors may be explained by increased cerebral levels of OEA and PEA, e.g., suppression of nicotine-induced activation of dopamine neurons. Furthermore, through activation of PPARα, OEA and PEA may stimulate neurosteroid synthesis, thereby modulating several biological functions mediated by GABA(A) receptors.

The existence of acylethanolamides in the mammalian brain has been known for decades, but it is first within the last few years that the putative biological functions of the three most abundant acylethanolamides species are starting to emerge.

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.

References (139)

  • J.A. Chavez et al.

    A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids

    J. Biol. Chem.

    (2003)
  • J.A. Chavez et al.

    Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling

    J. Biol. Chem.

    (2005)
  • B. Costa et al.

    The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB(1), TRPV1 and PPARgamma receptors and neurotrophic factors

    Pain

    (2008)
  • L. De Petrocellis et al.

    Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors

    FEBS Lett.

    (2001)
  • H.S. Hansen et al.

    N-Acylethanolamines and precursor phospholipids—relation to cell injury

    Chem. Phys. Lipids

    (2000)
  • H.S. Hansen et al.

    Putative neuroprotective actions of N-acyl-ethanolamines

    Pharmacol. Ther.

    (2002)
  • S.L. Hansen et al.

    Ketogenic diet is antiepileptogenic in pentylenetetrazole kindled mice and decrease levels of N-acylethanolamines in hippocampus

    Neurochem. Int.

    (2009)
  • H.A. Hostetler et al.

    Peroxisome proliferator-activated receptor α interacts with high affinity and is conformationally responsive to endogenous ligands

    J. Biol. Chem.

    (2005)
  • S.S. Hu et al.

    The biosynthesis of N-arachidonoyl dopamine (NADA), a putative endocannabinoid and endovanilloid, via conjugation of arachidonic acid with dopamine

    Prostaglandins Leukot. Essent. Fatty Acids

    (2009)
  • H. Khairy et al.

    Actions of ethanolamine on cultured sensory neurones from neonatal rats

    Neurosci. Lett.

    (2010)
  • P.J. Kingsley et al.

    Analysis of endocannabinoids, their congeners and COX-2 metabolites

    J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.

    (2009)
  • M. Maccarrone et al.

    Cannabimimetic activity, binding, and degradation of stearoylethanolamide within the mouse central nervous system

    Mol. Cell. Neurosci.

    (2002)
  • J.M. McCue et al.

    In vitro synthesis of arachidonoyl amino acids by cytochrome c

    Prostaglandins Other Lipid Mediat.

    (2009)
  • E.A. Mitchell et al.

    Neurosteroid modulation of GABAA receptors: molecular determinants and significance in health and disease

    Neurochem. Int.

    (2008)
  • B. Moesgaard et al.

    Accumulation of N-acyl-ethanolamine phospholipids in rat brains during post-decapitative ischemia: a 31P NMR study

    J. Lipid Res.

    (1999)
  • K. Monory et al.

    The endocannabinoid system controls key epileptogenic circuits in the hippocampus

    Neuron

    (2006)
  • S. Moreno et al.

    Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS

    Neuroscience

    (2004)
  • P. Movahed et al.

    Endogenous unsaturated C18N-acylethanolamines are vanilloid receptor (TRPV1) agonists

    J. Biol. Chem.

    (2005)
  • E. Murillo-Rodriguez et al.

    Dirunal variation of arachidonoylethanolamine, palmitoylethanolamide and oleoylethanolamide in the brain of the rat

    Life Sci.

    (2006)
  • V.A. Narkar et al.

    AMPK and PPARdelta agonists are exercise mimetics

    Cell

    (2008)
  • S. Oddi et al.

    Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins

    Chem. Biol.

    (2009)
  • Y. Okamoto et al.

    Molecular characterization of a phospholipase D generating anandamide and its congeners

    J. Biol. Chem.

    (2004)
  • H.A. Overton et al.

    Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents

    Cell Metab.

    (2006)
  • M. Oz

    Receptor-independent actions of cannabinoids on cell membranes: focus on endocannabinoids

    Pharmacol. Ther.

    (2006)
  • U. Pannasch et al.

    The potassium channels Kv1.5 and Kv1.3 modulate distinct functions of microglia. Mol

    Cell Neurosci.

    (2006)
  • K. Ahn et al.

    Enzymatic pathways that regulate endocannabinoid signaling in the nervous system

    Chem. Rev.

    (2008)
  • A. Ambrosini et al.

    Oleoylethanolamide protects human sperm cells from oxidation stress: studies on cases of idiopathic infertility

    Biol. Reprod.

    (2006)
  • A. Barana et al.

    Endocannabinoids and cannabinoid analogues block cardiac hKv1.5 channels in a cannabinoid receptor-independent manner

    Cardiovasc. Res.

    (2010)
  • R.P. Bazinet et al.

    Rapid high-energy microwave fixation is required to determine the anandamide (N-arachidonoylethanolamine) concentration of rat brain

    Neurochem. Res.

    (2006)
  • A. Bento-Abreu et al.

    Peroxisome proliferator-activated receptor-alpha is required for the neurotrophic effect of oleic acid in neurons

    J. Neurochem.

    (2007)
  • C. Berger et al.

    Massive accumulation of N-acylethanolamines after stroke. Cell signalling in acute cerebral ischemia?

    J. Neurochem.

    (2004)
  • L.M. Boland et al.

    Inhibitory effects of polyunsaturated fatty acids on Kv4/KCh1P potassium channels

    Am. J. Physiol. Cell. Physiol.

    (2009)
  • Bonini, J. A. 2002. Methods of identifying compounds that binds to SNORF25 receptors. US Patent...
  • M.L. Bourdeau et al.

    Kv4.3-mediated A-type K+ currents underlie rhythmic activity in hippocampal interneurons

    J. Neurosci.

    (2007)
  • A. Burkhalter et al.

    Differential expression of I(A) channel subunits Kv4.2 and Kv4.3 in mouse visual cortical neurons and synapses

    J. Neurosci.

    (2006)
  • P. Campolongo et al.

    Fat-induced satiety factor oleoylethanolamide enhances memory consolidation

    Proc. Natl. Acad. Sci. U. S. A.

    (2009)
  • Y. Chen et al.

    The protective effect of ceramide in immature rat brain hypoxia–ischemia involves up-regulation of Bcl-2 and reduction of TUNEL-positive cells

    J. Cereb. Blood Flow Metab.

    (2001)
  • S.J. Chmura et al.

    Down-regulation of ceramide production abrogates ionizing radiation-induced cytochrome c release and apoptosis

    Mol. Pharmacol.

    (2000)
  • Z.L. Chu et al.

    N-oleoyldopamine enhances glucose homeostasis through the activation of GPR119

    Mol. Endocrinol.

    (2010)
  • B.F. Cravatt et al.

    Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides

    Nature

    (1996)
  • Cited by (0)

    View full text