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CHAPTER 64 Pharmacological Aspects of Anandamide and 2-Arachidonoyglycerol As Bioactive Lipids M

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CHAPTER 64 Pharmacological Aspects of Anandamide and 2-Arachidonoyglycerol As Bioactive Lipids M CHAPTER 64 Pharmacological Aspects of Anandamide and 2-Arachidonoyglycerol as Bioactive Lipids M. Alhouayek, G.G. Muccioli Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium SUMMARY POINTS 2-arachidonoylglycerol (2-AG) that do not bind • The endocannabinoids N- cannabinoid receptors. arachidonoylethanolamine (AEA) and • They have long been considered as acting 2-arachidonoylglycerol (2-AG) are involved in via an “entourage effect,” by protecting many pathophysiological processes. endocannabinoids from degradation, and potentiating their actions; however, they also • Classically, endocannabinoids exert their actions have receptor-specific effects. by activating the CB and CB cannabinoid 1 2 • Among N-acylethanolamines: N- receptors, and their actions are terminated by palmitoylethanolamine (PEA) exerts antiinflammatory, their hydrolysis by specific hydrolases. analgesic, and neuroprotective effects, and is a • More receptors mediating the effects of AEA and PPAR-α agonist, while N-oleoylethanolamine (OEA) 2-AG have been added over the years. is a GPR119 and a PPAR-α ligand known for its • Endocannabinoids can also be metabolized by anorexigenic properties, and the control of glucagon cyclooxygenase (COX)-2, which leads to the secretion. synthesis of other bioactive lipids. • 2-Oleoylglycerol (2-OG) is a monoacylglycerol related • Endocannabinoids and their COX-2 derived to 2-AG that acts as a GPR119 agonist to increase metabolites can exert different effects in some secretion of glucagon-like peptide 1 (GLP-1). settings, a fact that increases the complexity of endocannabinoid signaling. LIST OF ABBREVIATIONS • Interfering with the metabolism of endocannabinoids opens up a lot of therapeutic 2-AG 2-Arachidonoylglycerol opportunities. ABHD6 α/β Hydrolase domain 6 ABHD12 α/β Hydrolase domain 12 AEA N-arachidonoylethanolamine or anandamide KEY FACTS ABOUT ENDOCANNABINOID- CB1 and CB2 Cannabinoid receptor 1 and 2 RELATED COMPOUNDS COX-2 Cyclooxygenase-2 • They are bioactive lipids belonging to the families cPLA2 Cytosolic phospholipase A2 of N-arachidonoylethanolamine (AEA) or CYP450 Cytochrome P450 DAGL Diacylglycerol lipase Handbook of Cannabis and Related Pathologies. http://dx.doi.org/10.1016/B978-0-12-800756-3.00074-0 Copyright © 2017 Elsevier Inc. All rights reserved. 616 CLASSICAL METABOLISM OF ANANDAMIDE AND 2-ARACHIDONOYLGLYCEROL 617 EET Epoxyeicosatrienoic acid modulators of endocannabinoid signaling, as well as the EET-EA Epoxyeicosatrienoic acid-ethanolamide potential therapeutic opportunities of such modulators. EET-G Epoxyeicosatrienoic acid-glycerol ester FAAH Fatty acid amide hydrolase GDE1 Glycerophosphodiester OVERVIEW OF THE EFFECTS phosphodiesterase 1 OF ANANDAMIDE AND HETE Hydroxyeicosatetraenoic acid 2-ARACHIDONOYLGLYCEROL HETE-EA Hydroxyeicosatetraenoic acid- ethanolamine These endocannabinoids have several beneficial effects HETE-G Hydroxyeicosatetraenoic acid-glycerol that could be used in potential treatments. For instance, ester endocannabinoids have antiinflammatory effects, which LOX Lipoxygenase can be beneficial in diseases such as inflammatory bowel MAGL Monoacylglycerol lipase diseases and arthritis (Alhouayek & Muccioli, 2012; Mecs, NAAA N-acylethanolamine-hydrolyzing acid Tuboly, Toth, Nagy, & Nyari, 2010). They are also valuable amidase in neurodegenerative diseases such as multiple sclerosis, NAE N-acylethanolamine or following cerebral trauma, due to their antiinflam- NAPE N-acylphosphatidylethanolamine matory and neuroprotective properties (Lourbopoulos, NAPE-PLD N-acylphosphatidylethanolamine Grigoriadis, Lagoudaki, Touloumi, & Polyzoidou, 2011; phospholipase D Panikashvili, Shein, Mechoulam, Trembovler, & Kohen, PG-EA Prostaglandin-ethanolamine or 2006). Endocannabinoids also exert analgesic effects prostamide in many settings (Guindon & Hohmann, 2009), modu- PG-G Prostaglandin-glycerol ester late the stress response, reduce anxiety and depression PPAR Peroxisome proliferator activated (Ruehle et al., 2012), promote sleep (Murillo-Rodriguez, receptor Poot-Ake, Arias-Carrion, Pacheco-Pantoja, & Fuente- TRPV1 Transient receptor potential vanilloid 1 Ortegon, 2011), and decrease nausea and vomiting (Sharkey, Darmani, & Parker, 2014). Generally, increas- ing endocannabinoid levels is thought to be beneficial, INTRODUCTION therefore endocannabinoid degradation enzymes con- stitute interesting targets, and many inhibitors of these The concept of bioactive lipids stems from the recog- enzymes have been developed. However, the endocan- nition that lipids are not only involved in cell membrane nabinoid system also exerts some unwanted effects. As structure and energy storage. Indeed, some lipids bind an example, cannabis use is associated with psychotropic to specific receptors, leading to signal transduction and effects that are reproduced following a chronic increase biological effects. Accordingly, variations in the levels of 2-AG levels in animals (Long, Li, Booker, Burston, & of such lipids lead to pathophysiological consequences. Kinsey, 2009a; Schlosburg, Blankman, Long, Nomura, & These are considered bioactive lipids. Eicosanoids, such Pan, 2010). Moreover, cannabis use is associated with im- as the arachidonic acid-derived prostaglandins, are com- paired memory, and this is also observed with adminis- monly known bioactive lipids. tration of cannabinoid receptor agonists to mice. Finally, The endocannabinoids N-arachidonoylethanolamine endocannabinoids have been shown to exert deleterious (anandamide or AEA) and 2-arachidonoylglycerol effects in some settings, such as obesity. Indeed, AEA and (2-AG) are bioactive lipids that are involved in many 2-AG are orexigenic and adipogenic agents (Bisogno, physiological processes, such as the regulation of food Mahadevan, Coccurello, Chang, & Allara, 2013; Muccioli, intake, the control of anxiety, and the modulation of pain Naslain, Backhed, Reigstad, & Lambert, 2010). In this and inflammation (Borrelli & Izzo, 2009; Ruehle, Rey, context, inhibitors of endocannabinoid biosynthesis seem Remmers, & Lutz, 2012; Guindon & Hohmann, 2009; to be interesting therapeutic tools. Alhouayek & Muccioli, 2012). As for many bioactive lip- ids, the activity of endocannabinoids is regulated by their tissue levels and, therefore by the balance between their CLASSICAL METABOLISM biosynthesis and their degradation (Muccioli, 2010). In OF ANANDAMIDE AND this context, pharmacological modulation of endocan- 2-ARACHIDONOYLGLYCEROL nabinoid levels represents an attractive therapeutic av- enue for many diseases. Although both 2-AG and AEA are arachidonic acid This chapter presents an overview of endocannabinoid derivatives synthetized from membrane phospholipids, metabolism, with many of the intricacies that character- their biosynthetic and degradation routes are quite dif- ize it, in order to describe the available pharmacological ferent, with diverse enzymes implicated. V. PHARMACOLOGY AND CELLULAR ACTIVITIES OF CANNABINOIDS AND ENDOCANNABINOIDS 618 64. PHARMACOLOGICAL ASPECTS OF ANANDAMIDE AND 2-ARACHIDONOYGLYCEROL AS BIOACTIVE LIPIDS The most described biosynthetic route for 2-AG and diacylglycerol lipases (DAGLα and DAGLβ) to pro- (Fig. 64.1A) is through the sequential actions of an duce 2-AG. However, DAGLs do not constitute the only activity-dependent phospholipase C-β (releasing diacyl- biosynthesis pathway for 2-AG, as this bioactive lipid is glycerols from phosphatidylinositols-4,5-bisphosphate) synthetized in DAGL-knockout mice (Aaltonen, Riera, FIGURE 64.1 Biosynthesis of the endocannabinoids 2-AG and AEA. (A) 2-AG is produced through the sequential action of either a phos- pholipase C (PLC) and diacylglycerol lipase (sn-1-DAGL), or a phospholipase A (PLA1) and a lysophospholipase C (LysoPLC). Diacylglycerol (DAG) levels are also regulated by a phosphatidic acid hydrolase (PA hydrolase) and a diacylglycerol kinase (DAG kinase); (B) N-acylphosphati- dylethanolamine (NAPE), the key intermediate in the synthesis of AEA, is synthesized from phosphatidylcholine (PC) and phosphatidylethanol- amine (PE) by a calcium-dependent N-acyltransferase activity (NAT). Several pathways are responsible for the production of AEA from NAPE: (1) directly via a N-acylphosphatidylethanolamine preferring phospholipase D (NAPE-PLD); (2) or through a phosphate intermediate (P-NAE) generated by a phospholipase C (PLC) and hydrolyzed by the phosphatase PTPN22; (3) or through a lyso-N-acylphosphatidylethanolamine (lyso-NAPE), produced by ABHD4, and which in turn can be hydrolyzed into AEA by a lyso-phospholipase D (lyso-PLD), or converted into the glycerophosphate intermediate (GP-NAE) before its conversion into AEA by glycerophosphodiester phosphodiesterase 1 (GDE1). V. PHARMACOLOGY AND CELLULAR ACTIVITIES OF CANNABINOIDS AND ENDOCANNABINOIDS CLASSICAL METABOLISM OF ANANDAMIDE AND 2-ARACHIDONOYLGLYCEROL 619 Lehtonen, Savinainen, & Laitinen, 2014). 2-AG is then N-acyltransferase (to generate N-acylphosphatidyleth- inactivated through its hydrolysis by several lipases into anolamines or NAPEs), and a NAPE-preferring phos- arachidonic acid and glycerol (Fig. 64.2). Monoacylglyc- pholipase D (NAPE-PLD) that leads to the production erol lipase (MAGL) was the first enzyme described as of N-acylethanolamines (NAEs), including AEA hydrolyzing 2-AG. This enzyme plays a prevalent role in (Muccioli, 2010). While NAPE-PLD was first described the brain, where it controls around 80% of 2-AG hydro- as
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