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endocannabinoid, lipase, 2-AG

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https://www.readbyqxmd.com/read/29662438/cannabinoid-receptor-type-1-expression-in-the-developing-avian-retina-morphological-and-functional-correlation-with-the-dopaminergic-system
#1
Luzia da Silva Sampaio, Regina C C Kubrusly, Yolanda P Colli, Priscila P Trindade, Victor T Ribeiro-Resende, Marcelo Einicker-Lamas, Roberto Paes-de-Carvalho, Patricia F Gardino, Fernando G de Mello, Ricardo A De Melo Reis
The avian retina has been used as a model to study signaling by different neuro- and gliotransmitters. It is unclear how dopaminergic and cannabinoid systems are related in the retina. Here we studied the expression of type 1 and 2 cannabinoid receptors (CB1 and CB2 ), as well as monoacylglycerol lipase (MAGL), the enzyme that degrades 2-arachidonoylglycerol (2-AG), during retina development. Our data show that CB1 receptor is highly expressed from embryonic day 5 (E5) until post hatched day 7 (PE7), decreasing its levels throughout development...
2018: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29551907/contribution-of-diacylglycerol-lipase-%C3%AE-to-pain-after-surgery
#2
Jennifer Luk, Yong Lu, Amanda Ackermann, Xiaoxue Peng, Diane Bogdan, Michelino Puopolo, David E Komatsu, Simon Tong, Iwao Ojima, Mario J Rebecchi, Martin Kaczocha
Background: Metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG) yields arachidonic acid (AA), the precursor to proalgesic eicosanoids including prostaglandin E2 (PGE2 ). Diacylglycerol lipase β (DAGLβ) is an enzyme that synthesizes 2-AG and its inhibition reduces eicosanoid levels and produces antinociceptive effects in models of inflammatory pain. Here we test whether inhibition of DAGLβ produces antinociceptive effects in a model of postoperative pain. Methods: Rats were administered the selective DAGLβ inhibitor KT109 or vehicle and underwent plantar incision...
2018: Journal of Pain Research
https://www.readbyqxmd.com/read/29524763/glucocorticoid-endocannabinoid-uncoupling-mediates-fear-suppression-deficits-after-early-life-stress
#3
Piray Atsak, Maria Morena, Chantal Schoenmaker, Emma Tabak, Charlotte A Oomen, Sara Jamil, Matthew N Hill, Benno Roozendaal
Early-life stress (ELS) creates life-long vulnerability to stress-related anxiety disorders through altering stress and fear systems in the brain. The endocannabinoid system has emerged as an important regulator of the stress response through a crosstalk with the glucocorticoid system, yet whether it plays a role in the persistent effects of ELS remains unanswered. By combining, behavioral, pharmacological and biochemical approaches in adult male rats, we examined the impact of ELS on the regulation of endocannabinoid function by stress and glucocorticoids...
February 21, 2018: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/29504066/anticonvulsive-effects-of-endocannabinoids-an-investigation-to-determine-the-role-of-regulatory-components-of-endocannabinoid-metabolism-in-the-pentylenetetrazol-induced-tonic-clonic-seizures
#4
Parisa Zareie, Mehdi Sadegh, Mohammad Reza Palizvan, Homeira Moradi-Chameh
2-Arachidonoylglycerol (2-AG) and anandamide are two major endocannabinoids produced, released and eliminated by metabolic pathways. Anticonvulsive effect of 2-AG and CB1 receptor is well-established. Herein, we designed to investigate the anticonvulsive influence of key components of the 2-AG and anandamide metabolism. Tonic-clonic seizures were induced by an injection of Pentylenetetrazol (80 mg/kg, i.p.) in adult male Wistar rats. Delay and duration for the seizure stages were considered for analysis. Monoacylglycerol lipase blocker (JJKK048; 1 mg/kg) or alpha/beta hydroxylase domain 6 blocker (WWL70; 5 mg/kg) were administrated alone or with 2-AG to evaluate the anticonvulsive potential of these enzymes...
March 4, 2018: Metabolic Brain Disease
https://www.readbyqxmd.com/read/29503395/inhibition-of-2-arachydonoylgycerol-degradation-attenuates-orofacial-neuropathic-pain-in-trigeminal-nerve-injured-mice
#5
Rantaro Kamimura, Mohammad Z Hossain, Shumpei Unno, Hiroshi Ando, Yuji Masuda, Kojiro Takahashi, Masanori Otake, Isao Saito, Junichi Kitagawa
Current therapeutics are not effective for orofacial neuropathic pain, and better options are needed. The present study used inferior orbital nerve (ION)-injured mice to investigate the effect of inhibiting monoacylglycerol lipase (MAGL), an enzyme that degrades the major endocannabinoid 2-arachydonoylgycerol (2-AG) in orofacial neuropathic pain. The head-withdrawal threshold to mechanical stimulation of the whisker pad was reduced on days 3, 5, and 7 after ION injury. Injection of JZL184, a selective inhibitor of MAGL, on day 7 after ION injury attenuated the reduction in head-withdrawal threshold at 2 h after administration...
March 2, 2018: Journal of Oral Science
https://www.readbyqxmd.com/read/29498843/discovery-of-trifluoromethyl-glycol-carbamates-as-potent-and-selective-covalent-monoacylglycerol-lipase-magl-inhibitors-for-treatment-of-neuroinflammation
#6
Laura A McAllister, Christopher R Butler, Scot Mente, Steven V O'Neil, Kari R Fonseca, Justin R Piro, Julie A Cianfrogna, Timothy L Foley, Adam M Gilbert, Anthony R Harris, Christopher J Helal, Douglas S Johnson, Justin I Montgomery, Deane M Nason, Stephen Noell, Jayvardhan Pandit, Bruce N Rogers, Tarek A Samad, Christopher L Shaffer, Rafael Guimaraes da Silva, Daniel P Uccello, Damien Webb, Michael A Brodney
Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway, and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group which confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups...
March 2, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29481079/in-vitro-and-in-vivo-evaluation-of-11-c-labeled-azetidine-carboxylates-for-imaging-monoacylglycerol-lipase-by-pet-imaging-studies
#7
Ran Cheng, Wakana Mori, Longle Ma, Mireille Alhouayek, Akiko Hatori, Yiding Zhang, Daisuke Ogasawara, Gengyang Yuan, Zhen Chen, Xiaofei Zhang, Hang Shi, Tomoteru Yamasaki, Lin Xie, Katsushi Kumata, Masayuki Fujinaga, Yuji Nagai, Takafumi Minamimoto, Mona Svensson, Lu Wang, Yunfei Du, Mary Jo Ondrechen, Neil Vasdev, Benjamin F Cravatt, Christopher Fowler, Ming-Rong Zhang, Steven H Liang
Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing the endogenous cannabinoid ligand, 2-arachidonylglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including 11C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination...
February 26, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29477030/association-between-alcoholism-and-the-gene-encoding-the-endocannabinoid-synthesizing-enzyme-diacylglycerol-lipase-alpha-in-the-japanese-population
#8
Hiroki Ishiguro, Susumu Higuchi, Tadao Arinami, Emmanuel S Onaivi
The endocannabinoid system has been recognized to be involved in neuropsychiatric diseases. 2-arachidonoyl glycerol (2-AG) is one of the two main endocannabinoids, and their regulation could play roles in disorders under environmental influence. This study investigated the involvement of the 2-AG biosynthesizing enzyme diacylglycerol lipase alpha (DAGLA) in the pathogenesis of alcoholism. We investigated a possible association between alcoholism and single nucleotide polymorphisms (SNPs) of the human DAGLA gene in the Japanese population...
October 12, 2017: Alcohol
https://www.readbyqxmd.com/read/29458998/role-of-striatal-direct-pathway-2-arachidonoylglycerol-signaling-in-sociability-and-repetitive-behavior
#9
Brian C Shonesy, Walker P Parrish, Hala K Haddad, Jason R Stephenson, Rita Báldi, Rebecca J Bluett, Christian R Marks, Samuel W Centanni, Oakleigh M Folkes, Keeley Spiess, Shana M Augustin, Ken Mackie, David M Lovinger, Danny G Winder, Sachin Patel, Roger J Colbran
BACKGROUND: Endocannabinoid signaling plays an important role in regulating synaptic transmission in the striatum, a brain region implicated as a central node of dysfunction in autism spectrum disorder. Deficits in signaling mediated by the endocannabinoid 2-arachidonoylglycerol (2-AG) have been reported in mouse models of autism spectrum disorder, but a causal role for striatal 2-AG deficiency in phenotypes relevant to autism spectrum disorder has not been explored. METHODS: Using conditional knockout mice, we examined the electrophysiological, biochemical, and behavioral effects of 2-AG deficiency by deleting its primary synthetic enzyme, diacylglycerol lipase α (DGLα), from dopamine D1 receptor-expressing or adenosine A2a receptor-expressing medium spiny neurons (MSNs) to determine the role of 2-AG signaling in striatal direct or indirect pathways, respectively...
December 28, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/29438780/modulation-of-central-endocannabinoid-system-results-in-gastric-mucosal-protection-in-the-rat
#10
V E Tóth, Á Fehér, J Németh, I Gyertyán, Z S Zádori, K Gyires
Previous findings showed that inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), degrading enzymes of anandamide (2-AEA) and 2-arachidonoylglycerol (2-AG), reduced the nonsteroidal anti-inflammatory drug-induced gastric lesions. The present study aimed to investigate: i./whether central or peripheral mechanism play a major role in the gastroprotective effect of inhibitors of FAAH, MAGL and AEA uptake, ii./which peripheral mechanism(s) may play a role in mucosal protective effect of FAAH, MAGL and uptake inhibitors...
February 10, 2018: Brain Research Bulletin
https://www.readbyqxmd.com/read/29310667/wwl70-protects-against-chronic-constriction-injury-induced-neuropathic-pain-in-mice-by-cannabinoid-receptor-independent-mechanisms
#11
Jie Wen, Melissa Jones, Mikiei Tanaka, Prabhuanand Selvaraj, Aviva J Symes, Brian Cox, Yumin Zhang
BACKGROUND: Targeting the endocannabinoid system has emerged as an effective strategy for the treatment of inflammatory and neurological diseases. Unlike the inhibition of the principal 2-arachidonyl glycerol (2-AG) hydrolytic enzyme monoacylglycerol lipase (MAGL), which leads to 2-AG overload and cannabinoid receptor desensitization, selective inhibition of the minor 2-AG hydrolytic enzyme alpha, beta-hydrolase domain 6 (ABHD6) can provide therapeutic benefits without producing cannabimimetic side effects...
January 8, 2018: Journal of Neuroinflammation
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
#12
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...
January 2018: Epilepsia
https://www.readbyqxmd.com/read/29148769/azetidine-and-piperidine-carbamates-as-efficient-covalent-inhibitors-of-monoacylglycerol-lipase
#13
Christopher R Butler, Elizabeth M Beck, Anthony Harris, Zhen Huang, Laura A McAllister, Christopher W Am Ende, Kimberly Fennell, Timothy L Foley, Kari Fonseca, Steven J Hawrylik, Douglas S Johnson, John D Knafels, Scot Mente, G 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 proinflammatory 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 were aided by the generation of inhibitor-bound MAGL crystal structures...
December 14, 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
#14
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
#15
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
Maternal obesity in pregnancy has been linked to a spectrum of adverse developmental changes. Involvement of eCBs in obesity is well characterized. However, information regarding eCB physiology in obesity associated with pregnancy is sparse. This study evaluated fetomaternal hepatic, systemic, and placental eCB molecular changes in response to maternal consumption of a HFD. From ≥9 mo before conception, nonpregnant baboons ( Papio spp.) were fed a diet of either 45 (HFD; n = 11) or 12% fat or a control diet (CTR; n = 11), and dietary intervention continued through pregnancy...
April 1, 2018: 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
#16
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
#17
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. 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...
December 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28947487/cannabinoid-cb-1-discrimination-effects-of-endocannabinoids-and-catabolic-enzyme-inhibitors
#18
COMPARATIVE STUDY
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 Δ9 -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
#19
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
#20
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
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