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endocannabinoid, lipase, 2-AG

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https://www.readbyqxmd.com/read/29896156/analysis-of-endocannabinoid-system-in-rat-testis-during-the-first-spermatogenetic-wave
#1
Marina Migliaccio, Giulia Ricci, Antonio Suglia, Francesco Manfrevola, Ken Mackie, Silvia Fasano, Riccardo Pierantoni, Teresa Chioccarelli, Gilda Cobellis
Endocannabinoids are lipid mediators, enzymatically synthesized and hydrolyzed, that bind cannabinoid receptors. Together with their receptors and metabolic enzymes, they form the "endocannabinoid system" (ECS). Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the main endocannabinoids studied in testis. In this study, using the first wave of spermatogenesis as an in vivo model to verify the progressive appearance of germ cells in seminiferous tubules [i.e., spermatogonia, spermatocytes, and spermatids], we analyzed the expression of the main enzymes and receptors of ECS in rat testis...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29890144/ischemia-reperfusion-model-impairs-endocannabinoid-signaling-and-na-k-atpase-expression-and-activity-in-kidney-proximal-tubule-cells
#2
Luzia S Sampaio, Fabio A Iannotti, Luciana Veneziani, Rosa T Borelli-Tôrres, Fabrizia De Maio, Fabiana Piscitelli, Ricardo A M Reis, Vincenzo Di Marzo, Marcelo Einicker-Lamas
LLC-PK1 cells, an immortalized epithelial cell line derived from pig renal proximal tubules, express all the major players of the endocannabinoid system (ECS) such as CB1, CB2 and TRPV1 receptor, as well as the main enzymes involved in the biosynthesis and degradation of the major endocannabinoids named 2-arachidonoylglycerol, 2-AG and anandamide, AEA. Here we investigated whether the damages caused by ischemic insult either in vitro using LLC-PK1 cells exposed to antimycin A (an inductor of ATP-depletion) or in vivo using Wistar rats in a classic renal ischemia and reperfusion (IR) protocol, lead to changes in AEA and 2-AG levels, as well as altered expression of genes from the main enzymes involved in the regulation of the ECS...
June 8, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29867382/potential-of-endocannabinoids-to-control-bladder-pain
#3
REVIEW
Dale E Bjorling, Zun-Yi Wang
Bladder-related pain is one of the most common forms of visceral pain, and visceral pain is among the most common complaints for which patients seek physician consultation. Despite extensive studies of visceral innervation and treatment of visceral pain, opioids remain a mainstay for management of bladder pain. Side effects associated with opioid therapy can profoundly diminish quality of life, and improved options for treatment of bladder pain remain a high priority. Endocannabinoids, primarily anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are endogenously-produced fatty acid ethanolamides with that induce analgesia...
2018: Frontiers in Systems Neuroscience
https://www.readbyqxmd.com/read/29842858/pharmacological-inhibiton-of-2-arachidonoilglycerol-hydrolysis-enhances-memory-consolidation-in-rats-through-cb2-receptor-activation-and-mtor-signaling-modulation
#4
Patrizia Ratano, Carla Petrella, Fabrizio Forti, Pamela Petrocchi Passeri, Maria Morena, Maura Palmery, Viviana Trezza, Cinzia Severini, Patrizia Campolongo
The endocannabinoid system is a key modulator of memory consolidation for aversive experiences. We recently found that the fatty acid amide hydrolase (FAAH) inhibitor URB597, which increases anandamide levels by inhibiting its hydrolysis, facilitates memory consolidation through a concurrent activation of both cannabinoid receptor type 1 (CB1) and 2 (CB2). Here, we investigated the role played on memory consolidation by the other major endocannabinoid, 2-arachidonoylglycerol (2-AG). To this aim, we tested the effects of pharmacological inhibition of monoacylglycerol lipase (MAGL) through systemic administration of the MAGL inhibitor JZL184 to rats immediately after training of the inhibitory avoidance task...
May 26, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29813086/elevated-levels-of-2-arachidonoylglycerol-promote-atherogenesis-in-apoe-mice
#5
Julian Jehle, Benedikt Schöne, Sayeh Bagheri, Elina Avraamidou, Melina Danisch, Imke Frank, Philipp Pfeifer, Laura Bindila, Beat Lutz, Dieter Lütjohann, Andreas Zimmer, Georg Nickenig
BACKGROUND: The endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) is a known modulator of inflammation and ligand to both, pro-inflammatory cannabinoid receptor 1 (CB1) and anti-inflammatory CB2. While the role of both receptors in atherogenesis has been studied extensively, the significance of 2-AG for atherogenesis is less well characterized. METHODS: The impact of 2-AG on atherogenesis was studied in two treatment groups of ApoE-/- mice. One group received the monoacylglycerol lipase (MAGL)-inhibitor JZL184 [5 mg/kg i...
2018: PloS One
https://www.readbyqxmd.com/read/29786643/controlled-deactivation-cb1-receptor-ligands-as-a-novel-strategy-to-lower-intraocular-pressure
#6
Sally Miller, Shashank Kulkarni, Alex Ciesielski, Spyros P Nikas, Ken Mackie, Alexandros Makriyannis, Alex Straiker
Nearly half a century has passed since the demonstration that cannabis and its chief psychoactive component Δ⁸-THC lowers intraocular pressure (IOP). Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a condition that places millions at risk of blindness. It is likely that Δ⁸-THC exerts much of its IOP-lowering effects via the activation of CB1 cannabinoid receptors. However, the initial promise of CB1 as a target for treating glaucoma has not thus far translated into a credible therapeutic strategy...
May 22, 2018: Pharmaceuticals
https://www.readbyqxmd.com/read/29748627/deficient-endocannabinoid-signaling-in-the-central-amygdala-contributes-to-alcohol-dependence-related-anxiety-like-behavior-and-excessive-alcohol-intake
#7
Antonia Serrano, Francisco J Pavon, Matthew W Buczynski, Joel Schlosburg, Luis A Natividad, Ilham Y Polis, David G Stouffer, Eric P Zorrilla, Marisa Roberto, Benjamin F Cravatt, Rémi Martin-Fardon, Fernando Rodriguez de Fonseca, Loren H Parsons
Negative emotional states that are associated with excessive alcohol intake, particularly anxiety-like states, have been linked to opponent processes in the central nucleus of the amygdala (CeA), affecting stress-related transmitters and monoamines. This study extends these observations to include endocannabinoid signaling in alcohol-dependent animals. Rats and mice were exposed to chronic intermittent alcohol with vapor inhalation or liquid diet to induce dependence. In vivo microdialysis was used to estimate interstitial concentrations of endocannabinoids [N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG)] and amino acids (glutamate and GABA) in rat CeA...
April 5, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29695817/therapeutic-endocannabinoid-augmentation-for-mood-and-anxiety-disorders-comparative-profiling-of-faah-magl-and-dual-inhibitors
#8
Gaurav Bedse, Rebecca J Bluett, Toni A Patrick, Nicole K Romness, Andrew D Gaulden, Philip J Kingsley, Niels Plath, Lawrence J Marnett, Sachin Patel
Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions...
April 26, 2018: Translational Psychiatry
https://www.readbyqxmd.com/read/29662438/cannabinoid-receptor-type-1-expression-in-the-developing-avian-retina-morphological-and-functional-correlation-with-the-dopaminergic-system
#9
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
#10
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
#11
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...
May 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
#12
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...
June 2018: Metabolic Brain Disease
https://www.readbyqxmd.com/read/29503395/inhibition-of-2-arachydonoylgycerol-degradation-attenuates-orofacial-neuropathic-pain-in-trigeminal-nerve-injured-mice
#13
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 24, 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
#14
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 G 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 that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups...
April 12, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29481079/in-vitro-and-in-vivo-evaluation-of-11-c-labeled-azetidinecarboxylates-for-imaging-monoacylglycerol-lipase-by-pet-imaging-studies
#15
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 endogenous cannabinoid ligand 2-arachidonoyglycerol (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 11 C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination...
March 22, 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
#16
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...
May 2018: Alcohol
https://www.readbyqxmd.com/read/29458998/role-of-striatal-direct-pathway-2-arachidonoylglycerol-signaling-in-sociability-and-repetitive-behavior
#17
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
#18
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
#19
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
#20
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
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