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endocannabinoid, lipase, 2-AG

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https://www.readbyqxmd.com/read/29171003/inhibition-of-monoacylglycerol-lipase-terminates-diazepam-resistant-status-epilepticus-in-mice-and-its-effects-are-potentiated-by-a-ketogenic-diet
#1
Gaetano Terrone, Alberto Pauletti, Alessia Salamone, Massimo Rizzi, Bianca R Villa, Luca Porcu, Mark J Sheehan, Edward Guilmette, Christopher R Butler, Justin R Piro, Tarek A Samad, Annamaria Vezzani
OBJECTIVE: Status epilepticus (SE) is a life-threatening and commonly drug-refractory condition. Novel therapies are needed to rapidly terminate seizures to prevent mortality and morbidity. Monoacylglycerol lipase (MAGL) is the key enzyme responsible for the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) and a major contributor to the brain pool of arachidonic acid (AA). Inhibiting of monoacylglycerol lipase modulates synaptic activity and neuroinflammation, 2 mediators of excessive neuronal activation underlying seizures...
November 24, 2017: Epilepsia
https://www.readbyqxmd.com/read/29148769/azetidine-and-piperidine-carbamates-as-efficient-covalent-inhibitors-of-monoacylglycerol-lipase
#2
Christopher R Butler, Elizabeth M Beck, Anthony R Harris, Zhen Huang, Laura A McAllister, Christopher W Am Ende, Kimberly F Fennell, Timothy L Foley, Kari R Fonseca, Steven J Hawrylik, Douglas S Johnson, John D Knafels, Scot Mente, Stephen Noell, Jayvardhan Pandit, Tracy B Phillips, Justin R Piro, Bruce N Rogers, Tarek A Samad, Jane Wang, Shuangyi Wan, Michael A Brodney
Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the pro-inflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient MAGL inhibitors, identified through a parallel medicinal chemistry approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL was aided by the generation of inhibitor-bound MAGL crystal structures...
November 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29145497/rare-genetic-variants-in-the-endocannabinoid-system-genes-cnr1-and-dagla-are-associated-with-neurological-phenotypes-in-humans
#3
Douglas R Smith, Christine M Stanley, Theodore Foss, Richard G Boles, Kevin McKernan
Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1), were found to be significantly associated with pain sensitivity (especially migraine), sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants...
2017: PloS One
https://www.readbyqxmd.com/read/29138223/effect-of-maternal-high-fat-diet-on-key-components-of-the-placental-and-hepatic-endocannabinoid-system
#4
Kushal Gandhi, Cun Li, Nadezhda German, Cezary Skobowiat, Maira Carrillo, Raja Reddy Kallem, Eneko Larumbe, Stacy Martinez, Marcel Chuecos, Gary Ventolini, Peter Nathanielsz, Natalia Schlabritz-Loutsevitch
INTRODUCTION: Involvement of endogenous cannabinoids (eCBs) in obesity is well-characterized. However, information regarding eCB physiology in obesity associated with pregnancy is sparse. METHODS: From at least 9 months before conception, non-pregnant baboons (Papio spp.) were fed a diet of either 45% fat (HFD; n=11) or 12% fat or a control diet (CTR; n=11), and dietary intervention continued through pregnancy. Maternal and fetal venous plasma samples were evaluated using liquid chromatography-mass spectrometry to quantify anandamide (AEA) and 2-arachidonoyl glycerol (2-AG)...
November 14, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29031792/control-of-myogenic-tone-and-agonist-induced-contraction-of-intramural-coronary-resistance-arterioles-by-cannabinoid-type-1-receptors-and-endocannabinoids
#5
Mária Szekeres, György L Nádasy, Eszter Soltész-Katona, László Hunyady
It was tested whether intrinsic CB1R activation modifies myogenic and agonist induced contraction of intramural coronary resistance arteries of the rat. CB1R protein was detected by immuno-histochemistry and by Western blot, its mRNA by qRT-PCR in their wall. Microsurgically prepared cylindrical coronary segments (∼100-150μm) developed myogenic contraction (∼20% of relaxed luminal diameter), from which a substantial relaxation (∼15%) in response to WIN55212 (a specific agonist of the CB1Rs) has been found...
October 16, 2017: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/28970359/investigation-of-diacylglycerol-lipase-alpha-inhibition-in-the-mouse-lipopolysaccharide-inflammatory-pain-model
#6
Jenny L Wilkerson, Giulia Donvito, Travis W Grim, Rehab A Abdullah, Daisuke Ogasawara, Benjamin F Cravatt, Aron H Lichtman
Diacylglycerol lipase (DAGL) α and β, the major biosynthetic enzymes of the endogenous cannabinoid (endocannabinoid) 2-arachidonylglycerol (2-AG), are highly expressed in the nervous system and immune system, respectively. Genetic deletion or pharmacological inhibition of DAGL-β protects against lipopolysaccharide (LPS)-induced inflammatory responses in mouse peritoneal macrophages, and reverses LPS-induced allodynia in mice. In order to gain insight into the contribution of DAGL-α in LPS-induced allodynia, we tested global knockout mice as well as DO34, a dual DAGL-α/-β inhibitor...
October 2, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28947487/cannabinoid-cb1-discrimination-effects-of-endocannabinoids-and-catabolic-enzyme-inhibitors
#7
Michael Z Leonard, Shakiru O Alapafuja, Lipin Ji, Vidyanand G Shukla, Yingpeng Liu, Spyros P Nikas, Alexandros Makriyannis, Jack Bergman, Brian D Kangas
An improved understanding of the endocannabinoid system has provided new avenues of drug discovery and development toward the management of pain and other behavioral maladies. Exogenous cannabinoid type 1 (CB1) receptor agonists such as Δ(9)-tetrahydrocannabinol are increasingly used for their medicinal actions; however, their utility is constrained by concern regarding abuse-related subjective effects. This has led to growing interest in the clinical benefit of indirectly enhancing the activity of the highly labile endocannabinoids N-arachidonoylethanolamine [AEA (or anandamide)] and/or 2-arachidonoylglycerol (2-AG) via catabolic enzyme inhibition...
December 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28844762/2-arachidonoylglycerol-metabolism-is-differently-modulated-by-oligomeric-and-fibrillar-conformations-of-amyloid-beta-in-synaptic-terminals
#8
Ana C Pascual, Virginia L Gaveglio, Norma M Giusto, Susana J Pasquaré
Alzheimer's disease (AD) is the most prevalent disorder of senile dementia mainly characterized by amyloid-beta peptide (Aβ) deposits in the brain. Cannabinoids are relevant to AD as they exert several beneficial effects in many models of this disease. Still, whether the endocannabinoid system is either up- or down-regulated in AD has not yet been fully elucidated. Thus, the aim of the present paper was to analyze endocannabinoid 2-arachidonoylglycerol (2-AG) metabolism in cerebral cortex synaptosomes incubated with Aβ oligomers or fibrils...
August 24, 2017: Neuroscience
https://www.readbyqxmd.com/read/28826718/contrasting-effects-of-selective-magl-and-faah-inhibition-on-dopamine-depletion-and-gdnf-expression-in-a-chronic-mptp-mouse-model-of-parkinson-s-disease
#9
Noemi Pasquarelli, Christoph Porazik, Hanna Bayer, Eva Buck, Stefan Schildknecht, Patrick Weydt, Anke Witting, Boris Ferger
The modulation of the brain endocannabinoid system has been identified as an option to treat neurodegenerative diseases including Parkinson's disease (PD). Especially the elevation of endocannabinoid levels by inhibition of hydrolytic degradation represents a valuable approach. To evaluate whether monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) inhibition could be beneficial for PD, we examined in parallel the therapeutic potential of the highly selective MAGL inhibitor KML29 elevating 2-arachidonoylglyerol (2-AG) levels and the highly selective FAAH inhibitor PF-3845 elevating anandamide (AEA) levels in a chronic methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/probenecid) mouse model of PD...
November 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28820005/inhibition-of-endocannabinoid-metabolizing-enzymes-in-peripheral-tissues-following-developmental-chlorpyrifos-exposure-in-rats
#10
Robert W Buntyn, Navatha Alugubelly, Rachel L Hybart, Afzaal N Mohammed, Carole A Nail, Greta C Parker, Matthew K Ross, Russell L Carr
Repeated developmental exposure to the organophosphate (OP) insecticide chlorpyrifos (CPF) inhibits brain fatty acid amide hydrolase (FAAH) activity at low levels, whereas at higher levels, it inhibits brain monoacylglycerol lipase (MAGL) activity. FAAH and MAGL hydrolyze the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG), respectively. Peripherally, AEA and 2-AG have physiological roles in the regulation of lipid metabolism and immune function, and altering the normal levels of these lipid mediators can negatively affect these processes...
September 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28771697/effects-of-centrally-administered-endocannabinoids-and-opioids-on-orofacial-pain-perception-in-rats
#11
Marek Zubrzycki, Anna Janecka, Andreas Liebold, Mechthild Ziegler, Maria Zubrzycka
BACKGROUND AND PURPOSE: Endocannabinoids and opioids play a vital role in mediating pain-induced analgesia. The specific effects of these compounds within the orofacial region are largely unknown. In this study, we tried to determine whether an increase in cannabinoid and opioid concentration in the CSF affects impulse transmission between the motor centres localized in the vicinity of the third and fourth cerebral ventricles. EXPERIMENTAL APPROACH: The study objectives were realized on rats using a method that allows the recording of the amplitude of evoked tongue jerks (ETJ) in response to noxious tooth pulp stimulation...
November 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28733897/alleviation-of-neuropathology-by-inhibition-of-monoacylglycerol-lipase-in-app-transgenic-mice-lacking-cb2-receptors
#12
Jian Zhang, Chu Chen
Inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, produces profound anti-inflammatory and neuroprotective effects and improves synaptic and cognitive functions in animal models of Alzheimer's disease (AD). However, the molecular mechanisms underlying the beneficial effects produced by inhibition of 2-AG metabolism are still not clear. The cannabinoid receptor type 2 (CB2R) has been thought to be a therapeutic target for AD...
July 21, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28726298/faah-but-not-magl-inhibition-modulates-acute-tlr3-induced-neuroimmune-signaling-in-the-rat-independent-of-sex
#13
Lisa E Flannery, Rebecca J Henry, Daniel M Kerr, David P Finn, Michelle Roche
Toll-like receptor (TLR)3 is a key component of the innate immune response to viral infection. The present study firstly examined whether sex differences exist in TLR3-induced inflammatory, endocrine, and sickness responses. The data revealed that TLR3-induced expression of interferon- or NFkB-inducible genes (IFN-α/β, IP-10, or TNF-α), either peripherally (spleen) or centrally (hypothalamus), did not differ between male and female rats, with the exception of TLR3-induced IFN-α expression in the spleen of female, but not male, rats 8 hr post TLR3 activation...
July 20, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28673548/inhibition-of-the-endocannabinoid-regulating-enzyme-monoacylglycerol-lipase-elicits-a-cb1-receptor-mediated-discriminative%C3%A2-stimulus-in-mice
#14
Robert A Owens, Mohammed A Mustafa, Bogna M Ignatowska-Jankowska, M Imad Damaj, Patrick M Beardsley, Jenny L Wiley, Micah J Niphakis, Benjamin F Cravatt, Aron H Lichtman
Substantial challenges exist for investigating the cannabinoid receptor type 1 (CB1)-mediated discriminative stimulus effects of the endocannabinoids, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), compared with exogenous CB1 receptor agonists, such as Δ(9)-tetrahydrocannabinol (THC) and the synthetic cannabinoid CP55,940. Specifically, each endocannabinoid is rapidly degraded by the respective hydrolytic enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH)...
June 30, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28611585/role-of-n-arachidonoyl-serotonin-aa-5-ht-in-sleep-wake-cycle-architecture-sleep-homeostasis-and-neurotransmitters-regulation
#15
Eric Murillo-Rodríguez, Vincenzo Di Marzo, Sergio Machado, Nuno B Rocha, André B Veras, Geraldo A M Neto, Henning Budde, Oscar Arias-Carrión, Gloria Arankowsky-Sandoval
The endocannabinoid system comprises several molecular entities such as endogenous ligands [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], receptors (CB1 and CB2), enzymes such as [fatty acid amide hydrolase (FAHH) and monoacylglycerol lipase (MAGL)], as well as the anandamide membrane transporter. Although the role of this complex neurobiological system in the sleep-wake cycle modulation has been studied, the contribution of the blocker of FAAH/transient receptor potential cation channel subfamily V member 1 (TRPV1), N-arachidonoyl-serotonin (AA-5-HT) in sleep has not been investigated...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28404744/the-role-of-cb1-in-intestinal-permeability-and-inflammation
#16
Mustafa A Karwad, Daniel G Couch, Elena Theophilidou, Sarir Sarmad, David A Barrett, Michael Larvin, Karen L Wright, Jonathan N Lund, Saoirse E O'Sullivan
The endocannabinoid system has previously been shown to play a role in the permeability and inflammatory response of the human gut. The goal of our study was to determine the effects of endogenous anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) on the permeability and inflammatory response of intestinal epithelium under normal, inflammatory, and hypoxic conditions. Human intestinal mucosa was modeled using Caco-2 cells. Human tissue was collected from planned colorectal resections. Accumulation of AEA and 2-AG was achieved by inhibiting their metabolizing enzymes URB597 (a fatty acid amide hydrolase inhibitor) and JZL184 (a monoacylglycerol lipase inhibitor)...
August 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28380440/monoglyceride-lipase-deficiency-affects-hepatic-cholesterol-metabolism-and-lipid-dependent-gut-transit-in-apoe-mice
#17
Nemanja Vujic, Melanie Korbelius, Christina Leopold, Madalina Duta-Mare, Silvia Rainer, Stefanie Schlager, Madeleine Goeritzer, Dagmar Kolb, Thomas O Eichmann, Clemens Diwoky, Andreas Zimmer, Robert Zimmermann, Achim Lass, Branislav Radovic, Dagmar Kratky
Monoglyceride lipase (MGL) hydrolyzes monoglycerides (MGs) to glycerol and fatty acids. Among various MG species MGL also degrades 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid and potent activator of cannabinoid receptors (CBR) 1 and 2. MGL-knockout (-/-) mice exhibit pronounced 2-AG accumulation, but lack central cannabimimetic effects due to CB1R desensitization. We have previously shown that MGL affects plaque stability in apolipoprotein E (ApoE)-/- mice, an established animal model for dyslipidemia and atherosclerosis...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28373073/evaluation-of-monoacylglycerol-lipase-as-a-therapeutic-target-in-a-transgenic-mouse-model-of-als
#18
Noemi Pasquarelli, Michael Engelskirchen, Johannes Hanselmann, Sascha Endres, Christoph Porazik, Hanna Bayer, Eva Buck, Meliha Karsak, Patrick Weydt, Boris Ferger, Anke Witting
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system with limited therapeutic options. While an increasing number of ALS patients can be linked to a small number of autosomal-dominantly inherited cases, most cases are termed sporadic. Both forms are clinically and histopathologically indistinguishable, raising the prospect that they share key pathogenic steps, including potential therapeutic intervention points. The endocannabinoid system is emerging as a versatile, druggable therapeutic target in the CNS and its dysregulation is an early hallmark of neurodegeneration...
March 31, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28284861/biological-evaluation-of-pyridone-alkaloids-on-the-endocannabinoid-system
#19
Andrea Chicca, Regina Berg, Henning J Jessen, Nicolas Marck, Fabian Schmid, Patrick Burch, Jürg Gertsch, Karl Gademann
Naturally occurring pyridone alkaloids as well as synthetic derivatives were previously shown to induce neurite outgrowth. However, the molecular basis for this biological effect remains poorly understood. In this work, we have prepared new pyridones, and tested the effect of thirteen 4-hydroxy-2-pyridone derivatives on the components of the endocannabinoid system. Investigation of binding affinities towards CB1 and CB2 receptors led to the identification of a compound binding selectively to CB1 (12). Compound 12 and a closely related derivative (11) also inhibited anandamide (AEA) hydrolysis by fatty acid amide hydrolase...
February 17, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28262417/cell-autonomous-excitation-of-midbrain-dopamine-neurons-by-endocannabinoid-dependent-lipid-signaling
#20
Stephanie C Gantz, Bruce P Bean
The major endocannabinoid in the mammalian brain is the bioactive lipid 2-arachidonoylglycerol (2-AG). The best-known effects of 2-AG are mediated by G-protein-coupled cannabinoid receptors. In principle, 2-AG could modify neuronal excitability by acting directly on ion channels, but such mechanisms are poorly understood. Using a preparation of dissociated mouse midbrain dopamine neurons to isolate effects on intrinsic excitability, we found that 100 nM 2-AG accelerated pacemaking and steepened the frequency-current relationship for burst-like firing...
March 22, 2017: Neuron
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