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endocannabinoid, lipase, 2-AG

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...
June 3, 2016: Recent Patents on CNS Drug Discovery
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
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
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
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
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
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
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
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
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
Iram P Rodriguez-Sanchez, Josee Guindon, Marco Ruiz, Maria E Tejero, Gene Hubbard, Laura E Martinez-de-Villarreal, Hugo A Barrera-Saldaña, Edward J Dick, Anthony G Commuzzie, 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)...
June 17, 2016: Neurotoxicology and Teratology
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
Caron Dean, Cecilia J Hillard, Jeanne L Seagard, Francis A Hopp, Quinn H Hogan
The present study was undertaken to examine whether variations in endocannabinoid signaling in the dorsal periaqueductal gray (dPAG) are associated with baseline autonomic nerve activity, heart rate, and blood pressure. Blood pressure was recorded telemetrically in rats, and heart rate and power spectral analysis of heart rate variability were determined. Natural variations from animal to animal provided a range of baseline values for analysis. Transcript levels of endocannabinoid signaling components in the dPAG were analyzed, and endocannabinoid content and catabolic enzyme activity were measured...
August 1, 2016: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Lu Wang, Wakana Mori, Ran Cheng, Joji Yui, Akiko Hatori, Longle Ma, Yiding Zhang, Benjamin H Rotstein, Masayuki Fujinaga, Yoko Shimoda, Tomoteru Yamasaki, Lin Xie, Yuji Nagai, Takafumi Minamimoto, Makoto Higuchi, Neil Vasdev, Ming-Rong Zhang, Steven H Liang
Monoacylglycerol lipase (MAGL) is a 33 kDa member of the serine hydrolase superfamily that preferentially degrades 2-arachidonoylglycerol (2-AG) to arachidonic acid in the endocannabinoid system. Inhibition of MAGL is not only of interest for probing the cannabinoid pathway but also as a therapeutic and diagnostic target for neuroinflammation. Limited attempts have been made to image MAGL in vivo and a suitable PET ligand for this target has yet to be identified and is urgently sought to guide small molecule drug development in this pathway...
2016: Theranostics
Juha R Savinainen, Dina Navia-Paldanius, Jarmo T Laitinen
Despite great progress in identifying and deorphanizing members of the human metabolic serine hydrolase (mSH) family, the fundamental role of numerous enzymes in this large protein class has remained unclear. One recently found mSH is α/β-hydrolase domain containing 12 (ABHD12) enzyme, whose natural substrate in vivo appears to be the lysophospholipid lysophosphatidylserine (LPS). In vitro, ABHD12 together with monoacylglycerol lipase (MAGL) and ABHD6 hydrolyzes also monoacylglycerols (MAGs) such as the primary endocannabinoid 2-arachidonoyl glycerol (2-AG)...
2016: Methods in Molecular Biology
Kwang-Mook Jung, Daniele Piomelli
Monoacylglycerol lipase (MGL) is a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). 2-AG is one of the main endogenous lipid agonists for cannabinoid receptors in the brain and elsewhere in the body. In the central nervous system (CNS), MGL is localized to presynaptic nerve terminals of both excitatory and inhibitory synapses, where it helps control the regulatory actions of 2-AG on synaptic transmission and plasticity. In this chapter, we describe an in vitro method to assess MGL activity by liquid chromatography/mass spectrometry (LC/MS)-based quantitation of the reaction product...
2016: Methods in Molecular Biology
Tiziana Bisogno
The endocannabinoid 2-arachidonoylglycerol (2-AG) exerts its physiological action by binding to and functionally activating type-1 (CB1) and type-2 (CB2) cannabinoid receptors. It is thought to be produced through the action of sn-1 selective diacylglycerol lipase (DAGL) that catalyzes 2-AG biosynthesis from sn-2-arachidonate-containing diacylglycerols. Since 2-AG biosynthetic enzymes have been identified only recently, little information on methodological approaches for measuring DAGL activity is as yet available...
2016: Methods in Molecular Biology
Bárbara S Pinheiro, Cristina Lemos, Fernanda Neutzling Kaufmann, Joana M Marques, Carla S da Silva-Santos, Eugénia Carvalho, Ken Mackie, Ricardo J Rodrigues, Rodrigo A Cunha, Attila Köfalvi
Here we asked if insulin activation of the nucleus accumbens in vitro is reflected by an increase in (3)H-deoxyglucose ([(3)H]DG) uptake, thus subserving a new model to study molecular mechanisms of central insulin actions. Additionally, we investigated the dependence of this insulin effect on endocannabinoids and corticosteroids, two major culprits in insulin resistance. We found that in acute accumbal slices, insulin (3 and 300nM but not at 0.3nM) produced an increase in [(3)H]DG uptake. The synthetic cannabinoid agonist, WIN55212-2 (500nM) and the glucocorticoid dexamethasone (10μM), impaired insulin (300nM) action on [(3)H]DG uptake...
June 2016: Brain Research Bulletin
Yao Chen, Xiaojie Liu, Casey R Vickstrom, Michelle J Liu, Li Zhao, Andreu Viader, Benjamin F Cravatt, Qing-Song Liu
Endocannabinoids are diffusible lipophilic molecules that may spread to neighboring synapses. Monoacylglycerol lipase (MAGL) is the principal enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Using knock-out mice in which MAGL is deleted globally or selectively in neurons and astrocytes, we investigated the extent to which neuronal and astrocytic MAGL limit the spread of 2-AG-mediated retrograde synaptic depression in cerebellar slices. A brief tetanic stimulation of parallel fibers in the molecular layer induced synaptically evoked suppression of excitation (SSE) in Purkinje cells, and both neuronal and astrocytic MAGL contribute to the termination of this form of endocannabinoid-mediated synaptic depression...
May 2016: ENeuro
Ziliang Zou, Yongli Lu, Yunhong Zha, Hongwei Yang
Inflammation plays a pivotal role in the pathogenesis of many diseases in the central nervous system. Caudate nucleus (CN), the largest nucleus in the brain, is also implicated in many neurological disorders. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from some proinflammatory stimuli. However, the neuroprotective mechanism of 2-AG is complex and has not been fully understood. A-type K(+) channels critically regulate neuronal excitability and have been demonstrated to be associated with some nervous system diseases...
August 2016: Journal of Molecular Neuroscience: MN
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