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endocannabinoid, lipase, 2-AG

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https://www.readbyqxmd.com/read/28213089/monoglyceride-lipase-as-a-drug-target-at-the-crossroads-of-arachidonic-acid-metabolism-and-endocannabinoid-signaling
#1
REVIEW
Gernot F Grabner, Robert Zimmermann, Rudolf Schicho, Ulrike Taschler
Monoglyerides (MGs) are short-lived, intermediary lipids deriving from the degradation of phospho- and neutral lipids, and monoglyceride lipase (MGL), also designated as monoacylglycerol lipase (MAGL), is the major enzyme catalyzing the hydrolysis of MGs into glycerol and fatty acids. This distinct function enables MGL to regulate a number of physiological and pathophysiological processes since both MGs and fatty acids can act as signaling lipids or precursors thereof. The most prominent MG species acting as signaling lipid is 2-arachidonoylglycerol (2-AG) which is the most abundant endogenous agonist of cannabinoid receptors in the body...
February 14, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28209735/the-epac-phospholipase-c%C3%AE%C2%B5-pathway-regulates-endocannabinoid-signaling-and-cocaine-induced-disinhibition-of-vta-dopamine-neurons
#2
Jiaqing Tong, Xiaojie Liu, Casey Vickstrom, Yan Li, Laikang Yu, Youming Lu, Alan V Smrcka, Qing-Song Liu
Exchange protein directly activated by cAMP (Epac) is a direct effector for the ubiquitous second messenger cAMP. Epac activates the phospholipase Cε (PLCε) pathway. PLCβ has been linked to the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Here, we report that Epac facilitates endocannabinoid-mediated retrograde synaptic depression through activation of PLCε. Intracellular loading of a selective Epac agonist 8-CPT-2Me-cAMP into ventral tegmental area (VTA) dopamine neurons enabled previously ineffective stimuli to induce depolarization-induced suppression of inhibition (DSI) and long-term depression of IPSCs (I-LTD) in the VTA...
February 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28193521/pharmacological-inhibition-of-magl-lipase-attenuates-experimental-colon-carcinogenesis
#3
Ester Pagano, Francesca Borrelli, Pierangelo Orlando, Barbara Romano, Martina Monti, Lucia Morbidelli, Gabriella Aviello, Roberta Imperatore, Raffaele Capasso, Fabiana Piscitelli, Lorena Buono, Vincenzo Di Marzo, Angelo A Izzo
Colorectal cancer (CRC) is a major health problem in Western countries. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) exerts antiproliferative actions in a number of tumoral cell lines, including CRC cells. Monoacylglycerol lipase (MAGL), a serine hydrolase that inactivates 2-AG, is highly expressed in aggressive human cancer cells. Here, we investigated the role of MAGL in experimental colon carcinogenesis. The role of MAGL was assessed in vivo by using the xenograft and the azoxymethane models of colon carcinogenesis; MAGL expression was evaluated by RT-PCR and immunohistochemistry; 2-AG levels were measured by liquid chromatography mass spectrometry; angiogenesis was evaluated in tumor tissues [by microvessel counting and by investigating the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) proteins] as well as in human umbilical vein endothelial cells (HUVEC); cyclin D1 was evaluated by RT-PCR...
February 10, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28192193/differential-expression-of-endocannabinoid-system-related-genes-in-the-dorsal-hippocampus-following-expression-and-reinstatement-of-morphine-conditioned-place-preference-in-mice
#4
Wei Li, Cong-Li Zhang, Zheng-Guo Qiu
The endocannabinoid signaling plays a critical role in mediating rewarding effects to morphine. The relative stability for the expression and reinstatement of morphine conditioned place preference (CPP) suggests the involvement of differential neuroadaptations in learned associations between environmental cues and morphine. Changes in gene expression in hippocampus through the endogenous cannabinoid system (eCB) may accompany and mediate the development of such neuroadaptations to repeated morphine stimulation...
February 10, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/27903595/lifelong-imbalanced-la-ala-intake-impairs-emotional-and-cognitive-behavior-via-changes-in-brain-endocannabinoid-system
#5
Erica Zamberletti, Fabiana Piscitelli, Valentina De Castro, Elisabetta Murru, Marina Gabaglio, Paola Colucci, Chiara Fanali, Pamela Prini, Tiziana Bisogno, Mauro Maccarrone, Patrizia Campolongo, Sebastiano Banni, Tiziana Rubino, Daniela Parolaro
Imbalanced dietary n-3 and n-6 PUFA content has been associated with a number of neurological conditions. Endocannabinoids are n-6 PUFA derivatives, whose brain concentrations are sensitive to modifications of fatty acid composition of the diet and play a central role in the regulation of mood and cognition. As such, the endocannabinoid system appears to be an ideal candidate for mediating the effects of dietary fatty acids on mood and cognition. Lifelong administration of isocaloric α-linolenic acid (ALA)-deficient and -enriched diets induced short-term memory deficits, whereas only dietary ALA enrichment altered emotional reactivity in adult male rats compared with animals fed a standard diet that was balanced in ALA/linoleic acid (LA) ratio...
February 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/27890602/the-endocannabinoid-hydrolysis-inhibitor-sa-57-intrinsic-antinociceptive-effects-augmented-morphine-induced-antinociception-and-attenuated-heroin-seeking-behavior-in-mice
#6
Jenny L Wilkerson, Sudeshna Ghosh, Mohammed Mustafa, Rehab A Abdullah, Micah J Niphakis, Roberto Cabrera, Rafael L Maldonado, Benjamin F Cravatt, Aron H Lichtman
Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class...
March 1, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/27784678/oxyradical-stress-increases-the-biosynthesis-of-2-arachidonoylglycerol-involvement-of-nadph-oxidase
#7
Anberitha T Matthews, Jung Hwa Lee, Abdolsamad Borazjani, Lee C Mangum, Xiang Hou, Matthew K Ross
NADPH oxidase (Nox)-derived oxyradicals contribute to atherosclerosis by oxidizing low-density lipoproteins (LDL), leading to their phagocytosis by vascular macrophages. Endocannabinoids, such as 2-arachidonoylglycerol (2-AG), might be an important link between oxidative stress and atherosclerosis. We hypothesized that 2-AG biosynthesis in macrophages is enhanced following ligation of oxidized LDL by scavenger receptors via a signal transduction pathway involving Nox-derived ROS that activates diacylglycerol lipase-β (DAGL-β), the 2-AG biosynthetic enzyme...
December 1, 2016: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/27775008/coordinated-regulation-of-endocannabinoid-mediated-retrograde-synaptic-suppression-in-the-cerebellum-by-neuronal-and-astrocytic-monoacylglycerol-lipase
#8
Xiaojie Liu, Yao Chen, Casey R Vickstrom, Yan Li, Andreu Viader, Benjamin F Cravatt, Qing-Song Liu
The endocannabinoid 2-arachidonoylglycerol (2-AG) mediates retrograde synaptic depression including depolarization-induced suppression of excitation (DSE) and inhibition (DSI). 2-AG is degraded primarily by monoacylglycerol lipase (MAGL), which is expressed in neurons and astrocytes. Using knockout mice in which MAGL is deleted globally or selectively in neurons or astrocytes, we investigated the relative contribution of neuronal and astrocytic MAGL to the termination of DSE and DSI in Purkinje cells (PCs) in cerebellar slices...
October 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27630088/beyond-the-direct-activation-of-cannabinoid-receptors-new-strategies-to-modulate-the-endocannabinoid-system-in-cns-related-diseases
#9
Andrea Chicca, Chiara Arena, Clementina Manera
BACKGROUND: Anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are signalling lipids which belong to the class of endocannabinoids (ECs) and exert their actions by activating cannabinoid receptor type-1 (CB1) and type-2 (CB2). These receptors are involved in many physiological and pathological processes in the central nervous system (CNS) and in peripheral organs. Despite many potent and selective ligands for cannabinoid receptors have been generated over the last two decades, this class of compounds achieved only a very limited therapeutic success, mainly because of the CB1- mediated side effects...
2016: Recent Patents on CNS Drug Discovery
https://www.readbyqxmd.com/read/27595600/regulated-endosomal-trafficking-of-diacylglycerol-lipase-alpha-dagl%C3%AE-generates-distinct-cellular-pools-implications-for-endocannabinoid-signaling
#10
Ya Zhou, Fiona V Howell, Oleg O Glebov, David Albrecht, Gareth Williams, Patrick Doherty
Diacylglycerol lipase alpha (DAGLα) generates the endocannabinoid (eCB) 2-arachidonylglycerol (2-AG) that regulates the proliferation and differentiation of neural stem cells and serves as a retrograde signaling lipid at synapses. Nothing is known about the dynamics of DAGLα expression in cells and this is important as it will govern where 2-AG can be made and released. We have developed a new construct to label DAGLα at the surface of live cells and follow its trafficking. In hippocampal neurons a cell surface pool of DAGLα co-localizes with Homer, a postsynaptic density marker...
October 2016: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/27542344/mglur1-5-activation-in-the-lateral-hypothalamus-increases-food-intake-via-the-endocannabinoid-system
#11
Asai Sánchez-Fuentes, Bruno A Marichal-Cancino, Mónica Méndez-Díaz, Alline L Becerril-Meléndez, Alejandra E Ruiz-Contreras, Oscar Prospéro-Garcia
Mounting evidence has shown that glutamatergic and endocannabinoid systems in the hypothalamus regulate mammalian food intake. Stimulation of hypothalamic mGluR1/5 and CB1 receptors induces hyperphagia suggesting a possible interaction between these systems to control food intake. In addition, synthesis of endocannabinoids has been reported after mGluR1/5 stimulation in the brain. The aim of this study was to examine the potential cannabinergic activity in the food intake induction by lateral hypothalamic stimulation of mGluR1/5...
September 19, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/27501482/robust-anti-nociceptive-effects-of-monoacylglycerol-lipase-inhibition-in-a-model-of-osteoarthritis-pain
#12
James J Burston, Paul I Mapp, Sarir Sarmad, David A Barrett, Micah J Niphakis, Benjamin F Cravatt, David A Walsh, Victoria Chapman
BACKGROUND AND PURPOSE: Chronic pain is often a symptom of knee osteoarthritis (OA) for which current analgesics are either inadequate or are associated with serious side effects. The endocannabinoid system may offer alternative targets for pain relief. We evaluated the effects of a potent and selective monoacylglycerol (MAG) lipase inhibitor (MJN110) on OA pain behaviour, spinal mechanisms of action and joint histopathology in the rat. EXPERIMENTAL APPROACH: Intra-articular injection of monosodium iodoacetate (MIA) models OA pain and mimics clinical joint pathology...
November 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27452464/crucial-roles-of-the-endocannabinoid-2-arachidonoylglycerol-in-the-suppression-of-epileptic-seizures
#13
Yuki Sugaya, Maya Yamazaki, Motokazu Uchigashima, Kenta Kobayashi, Masahiko Watanabe, Kenji Sakimura, Masanobu Kano
Endocannabinoid signaling is considered to suppress excessive excitability of neural circuits and to protect the brain from seizures. However, the precise mechanisms of this effect are poorly understood. Here, we report that 2-arachidonoylglycerol (2-AG), one of the two major endocannabinoids, is crucial for suppressing seizures. We found that kainate-induced seizures in mice lacking the 2-AG synthesizing enzyme, diacylglycerol lipase α, were much more severe compared with those in cannabinoid CB1 receptor knockout mice and were comparable to those in mice lacking both CB1- and CB2-receptor-mediated signaling...
August 2, 2016: Cell Reports
https://www.readbyqxmd.com/read/27451409/in-vivo-characterization-of-the-ultrapotent-monoacylglycerol-lipase-inhibitor-4-bis-benzo-d-1-3-dioxol-5-yl-methyl-piperidin-1-yl-1h-1-2-4-triazol-1-yl-methanone-jjkk-048
#14
Niina Aaltonen, Ewa Kedzierska, Jolanta Orzelska-Górka, Marko Lehtonen, Dina Navia-Paldanius, Hermina Jakupovic, Juha R Savinainen, Tapio Nevalainen, Jarmo T Laitinen, Teija Parkkari, Mikko Gynther
Monoacylglycerol lipase (MAGL) is a serine hydrolase that acts as a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). In addition to terminating the signaling function of 2-AG, MAGL liberates arachidonic acid to be used as a primary source for neuroinflammatory prostaglandin synthesis in the brain. MAGL activity also contributes to cancer pathogenicity by producing precursors for tumor-promoting bioactive lipids. Pharmacological inhibitors of MAGL provide valuable tools for characterization of MAGL and 2-AG signaling pathways...
October 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27448020/orexins-contribute-to-restraint-stress-induced-cocaine-relapse-by-endocannabinoid-mediated-disinhibition-of-dopaminergic-neurons
#15
Li-Wei Tung, Guan-Ling Lu, Yen-Hsien Lee, Lung Yu, Hsin-Jung Lee, Emma Leishman, Heather Bradshaw, Ling-Ling Hwang, Ming-Shiu Hung, Ken Mackie, Andreas Zimmer, Lih-Chu Chiou
Orexins are associated with drug relapse in rodents. Here, we show that acute restraint stress in mice activates lateral hypothalamic (LH) orexin neurons, increases levels of orexin A and 2-arachidonoylglycerol (2-AG) in the ventral tegmental area (VTA), and reinstates extinguished cocaine-conditioned place preference (CPP). This stress-induced reinstatement of cocaine CPP depends on type 1 orexin receptors (OX1Rs), type 1 cannabinoid receptors (CB1Rs) and diacylglycerol lipase (DAGL) in the VTA. In dopaminergic neurons of VTA slices, orexin A presynaptically inhibits GABAergic transmission...
2016: Nature Communications
https://www.readbyqxmd.com/read/27441413/involvement-of-endocannabinoid-neurotransmission-in-the-bed-nucleus-of-stria-terminalis-in-cardiovascular-responses-to-acute-restraint-stress-in-rats
#16
Lucas Gomes-de-Souza, Leandro A Oliveira, Ricardo Benini, Patrícia Rodella, Willian Costa-Ferreira, Carlos C Crestani
BACKGROUND AND PURPOSE: Endocannabinoid signalling has been reported as an important neurochemical mechanism involved in responses to stress. Previous studies provided evidence of endocannabinoid release in the bed nucleus of the stria terminalis (BNST) during aversive stimuli. Nevertheless, a possible involvement of this neurochemical mechanism in stress responses has never been evaluated. Therefore, in the present study we investigated the involvement of BNST endocannabinoid neurotransmission, acting via local CB1 receptors, in the cardiovascular responses to acute restraint stress in rats...
October 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27394666/inhibitors-of-diacylglycerol-lipases-in-neurodegenerative-and-metabolic-disorders
#17
REVIEW
Freek J Janssen, Mario van der Stelt
2-Arachidonoylglycerol (2-AG) is an endocannabinoid that activates the cannabinoid receptors type 1 and 2. It also serves as an important lipid precursor for the eicosanoid signaling pathway. Consequently, 2-AG is involved in many physiological functions, including anxiety, food intake, inflammation, memory, pain sensation and neurotransmission. Diacylglycerol lipases (DAGLs) are the main biosynthetic enzymes for 2-AG and their role in several pathophysiological conditions is currently under investigation. In this Digest we review all DAGL inhibitors reported to date and their effects in preclinical models of neurodegeneration and metabolic disorders...
August 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27333182/harnessing-the-endocannabinoid-2-arachidonoylglycerol-to-lower-intraocular-pressure-in-a-murine-model
#18
Sally Miller, Emma Leishman, Sherry Shujung Hu, Alhasan Elghouche, Laura Daily, Natalia Murataeva, Heather Bradshaw, Alex Straiker
PURPOSE: Cannabinoids, such as Δ9-THC, act through an endogenous signaling system in the vertebrate eye that reduces IOP via CB1 receptors. Endogenous cannabinoid (eCB) ligand, 2-arachidonoyl glycerol (2-AG), likewise activates CB1 and is metabolized by monoacylglycerol lipase (MAGL). We investigated ocular 2-AG and its regulation by MAGL and the therapeutic potential of harnessing eCBs to lower IOP. METHODS: We tested the effect of topical application of 2-AG and MAGL blockers in normotensive mice and examined changes in eCB-related lipid species in the eyes and spinal cord of MAGL knockout (MAGL-/-) mice using high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS)...
June 1, 2016: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/27327781/the-endocannabinoid-system-in-the-baboon-papio-spp-as-a-complex-framework-for-developmental-pharmacology
#19
Iram P Rodriguez-Sanchez, Josee Guindon, Marco Ruiz, M Elizabeth Tejero, Gene Hubbard, Laura E Martinez-de-Villarreal, Hugo A Barrera-Saldaña, Edward J Dick, Anthony G Comuzzie, Natalia E Schlabritz-Loutsevitch
INTRODUCTION: The consumption of marijuana (exogenous cannabinoid) almost doubled in adults during last decade. Consumption of exogenous cannabinoids interferes with the endogenous cannabinoid (or "endocannabinoid" (eCB)) system (ECS), which comprises N-arachidonylethanolamide (anandamide, AEA), 2-arachidonoyl glycerol (2-AG), endocannabinoid receptors (cannabinoid receptors 1 and 2 (CB1R and CB2R), encoded by CNR1 and CNR2, respectively), and synthesizing/degrading enzymes (FAAH, fatty-acid amide hydrolase; MAGL, monoacylglycerol lipase; DAGL-α, diacylglycerol lipase-alpha)...
November 2016: Neurotoxicology and Teratology
https://www.readbyqxmd.com/read/27307500/discriminative-stimulus-properties-of-the-endocannabinoid-catabolic-enzyme-inhibitor-sa-57-in-mice
#20
Robert A Owens, Bogna Ignatowska-Jankowska, Mohammed Mustafa, Patrick M Beardsley, Jenny L Wiley, Abdulmajeed Jali, Dana E Selley, Micah J Niphakis, Benjamin F Cravatt, Aron H Lichtman
Whereas the inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the respective major hydrolytic enzymes of N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), elicits no or partial substitution for Δ(9)-tetrahydrocannabinol (THC) in drug-discrimination procedures, combined inhibition of both enzymes fully substitutes for THC, as well as produces a constellation of cannabimimetic effects. The present study tested whether C57BL/6J mice would learn to discriminate the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) from vehicle in the drug-discrimination paradigm...
August 2016: Journal of Pharmacology and Experimental Therapeutics
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