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Dai Lu, Sri Sujana Immadi, Zhixing Wu, Debra A Kendall
The cannabinoid type-1 (CB1 ) receptor, a G-protein-coupled receptor, is an attractive target for drug discovery due to its involvement in many physiological processes. Historically, drug discovery efforts targeting the CB1 receptor have focused on the development of orthosteric ligands that interact with the active site to which endogenous cannabinoids bind. Research performed over the last several decades has revealed substantial difficulties in translating CB1 orthosteric ligands into druggable candidates...
October 17, 2018: Acta Pharmacologica Sinica
Kenji Yoshida, Yoshihiro Kita, Suzumi M Tokuoka, Fumie Hamano, Maya Yamazaki, Kenji Sakimura, Masanobu Kano, Takao Shimizu
Excess energy intake causes obesity, which leads to insulin resistance and various other complications of metabolic syndrome, including diabetes, atherosclerosis, dyslipidemia, and nonalcoholic fatty liver disease. Although recent studies have depicted altered lipid metabolism as an underlying feature, the detailed mechanisms are still unclear. Here we describe a possible role in high-fat diet (HFD)-induced obesity for monoacylglycerol lipase (MGL), an enzyme that is also known to hydrolyze the endocannabinoid 2-arachidonoylglycerol in brain...
September 28, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Yan-Chen Guo, Ti-Fei Yuan
No abstract text is available yet for this article.
2018: Frontiers in Pharmacology
Gemma Navarro, Irene Reyes-Resina, Rafael Rivas-Santisteban, Verónica Sánchez de Medina, Paula Morales, Salvatore Casano, Carlos Ferreiro-Vera, Alejandro Lillo, David Aguinaga, Nadine Jagerovic, Xavier Nadal, Rafael Franco
Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal-regulated kinases (ERK1/2), ß-arrestin recruitment and label-free/DMR) in HEK-293T cells expressing cannabinoid receptors, CB1 or CB2 , or CB1 -CB2 heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to the orthosteric center of either receptor, was measured...
September 5, 2018: Biochemical Pharmacology
Zoltán Hegyi, Tamás Oláh, Áron Kőszeghy, Fabiana Piscitelli, Krisztina Holló, Balázs Pál, László Csernoch, Vincenzo Di Marzo, Miklós Antal
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
September 7, 2018: Scientific Reports
Arnau Busquets-Garcia, José F Oliveira da Cruz, Geoffrey Terral, Antonio C Pagano Zottola, Edgar Soria-Gómez, Andrea Contini, Hugo Martin, Bastien Redon, Marjorie Varilh, Christina Ioannidou, Filippo Drago, Federico Massa, Xavier Fioramonti, Pierre Trifilieff, Guillaume Ferreira, Giovanni Marsicano
By priming brain circuits, associations between low-salience stimuli often guide future behavioral choices through a process known as mediated or inferred learning. However, the precise neurobiological mechanisms of these incidental associations are largely unknown. Using sensory preconditioning procedures, we show that type 1 cannabinoid receptors (CB1 R) in hippocampal GABAergic neurons are necessary and sufficient for mediated but not direct learning. Deletion and re-expression of CB1 R in hippocampal GABAergic neurons abolishes and rescues mediated learning, respectively...
September 19, 2018: Neuron
Jussi Hirvonen, Paolo Zanotti-Fregonara, David A Gorelick, Chul Hyoung Lyoo, Denise Rallis-Frutos, Cheryl Morse, Sami S Zoghbi, Victor W Pike, Nora D Volkow, Marilyn A Huestis, Robert B Innis
BACKGROUND: Previous studies showed reduction of brain cannabinoid CB1 receptors in adults with cannabis and alcohol use disorders. Preclinical data suggest that these receptors also contribute to nicotine reward and dependence. Tobacco smoking may confound clinical studies of psychiatric disorders because many patients with such disorders smoke tobacco. Whether human subjects who smoke tobacco but are otherwise healthy have altered CB1 receptor binding in brain is unknown. METHODS: We measured CB1 receptors in brains of 18 healthy men who smoke tobacco (frequent chronic cigarette smokers), and 28 healthy men who do not smoke tobacco, using positron emission tomography and [18 F]FMPEP-d2 , a radioligand for CB1 receptors...
July 21, 2018: Biological Psychiatry
Susana Mato, Fuencisla Pilar-Cuéllar, Elsa M Valdizán, Javier González-Maeso, Rafael Rodríguez-Puertas, Javier Meana, Joan Sallés, Benedicto Crespo-Facorro, Ángel Pazos
Brain endocannabinoid system is proposed to play a role in the pathogenesis of affective disorders. In the present study, we analyzed the functionality of the cannabinoid receptor type 1 (CB1 receptor) at different transduction levels in prefrontal cortex (PFC) of depressed suicide victims. We examined stimulation of [35 S]GTPγS binding, activation of Gα protein subunits and inhibition of adenylyl cyclase by the cannabinoid agonist WIN55,212-2, as well as [3 H]CP55,940 binding, in PFC homogenates from suicide victims with major depression (MD) and matched control subjects...
August 10, 2018: Biochemical Pharmacology
Ester Aso, Pol Andrés-Benito, Isidre Ferrer
Activating CB1 cannabinoid receptor has been demonstrated to produce certain therapeutic effects in animal models of Alzheimer's disease (AD). In this study, we evaluated the specific contribution of CB1 receptor to the progression of AD-like pathology in double transgenic APP/PS1 mice. A new mouse strain was generated by crossing APP/PS1 transgenic mice with CB1 knockout mice. Genetic deletion of CB1 drastically reduced the survival of APP/PS1 mice. In spite that CB1 mutant mice bearing the APP/PS1 transgene developed normally, they suddenly died within the first two months of life likely due to spontaneous seizures...
August 7, 2018: Biochemical Pharmacology
Sjoerd W Westra, Stijn P G van Vugt, Sümeyye Sezer, Reinder Evertz, Martin E Hemels, Rypko J Beukema, Carlo de Asmundis, Marc A Brouwer, Gian-Battista Chierchia
PURPOSE: Currently, information on the optimal approach of redo procedures for paroxysmal atrial fibrillation (PAF) is limited. Radiofrequency ablation is the preferred technique, with reported success rates of 50-70% at 1-2 years, whereas only few reports exist on redo cryoballoon (CB) ablations. We describe outcomes on a systematic approach of repeat procedures with a second-generation cryoballoon (CB-2) after a successful index CB ablation. METHODS: Cohort study of 40 consecutive patients with recurrent PAF (55% male), median CHA2 DS2 -VASc score 1 (IQR 0-3)...
August 8, 2018: Journal of Interventional Cardiac Electrophysiology: An International Journal of Arrhythmias and Pacing
Edgar Angelats, Marta Requesens, David Aguinaga, Michael R Kreutz, Rafael Franco, Gemma Navarro
Endocannabinoids are important players in neural development and function. They act via receptors, whose activation inhibits cAMP production. The aim of the paper was to look for calcium- and cAMP-signaling cross-talk mediated by cannabinoid CB1 receptors (CB1 R) and to assess the relevance of EF-hand CaM-like calcium sensors in this regard. Using a heterologous expression system, we demonstrated that CB1 R interacts with calneuron-1 and NCS1 but not with caldendrin. Furthermore, interaction motives were identified in both calcium binding proteins and the receptor, and we showed that the first two sensors competed for binding to the receptor in a Ca2+ -dependent manner...
2018: Frontiers in Cell and Developmental Biology
Zoltán Hegyi, Tamás Oláh, Áron Kőszeghy, Fabiana Pisticelli, Krisztina Holló, Balázs Pál, László Csernoch, Vincenzo Di Marzo, Miklós Antal
Accumulating evidence supports the role of astrocytes in endocannabinoid mediated modulation of neural activity. It has been reported that some astrocytes express the cannabinoid type 1 receptor (CB1 -R), the activation of which is leading to Ca2+ mobilization from internal stores and a consecutive release of glutamate. It has also been documented that astrocytes have the potential to produce the endocannabinoid 2-arachidonoylglycerol, one of the best known CB1 -R agonist. However, no relationship between CB1 -R activation and 2-arachidonoylglycerol production has ever been demonstrated...
July 12, 2018: Scientific Reports
Gemma Navarro, Katia Varani, Irene Reyes-Resina, Verónica Sánchez de Medina, Rafael Rivas-Santisteban, Carolina Sánchez-Carnerero Callado, Fabrizio Vincenzi, Salvatore Casano, Carlos Ferreiro-Vera, Enric I Canela, Pier Andrea Borea, Xavier Nadal, Rafael Franco
Cannabigerol (CBG) is one of the major phytocannabinoids present in Cannabis sativa L. that is attracting pharmacological interest because it is non-psychotropic and is abundant in some industrial hemp varieties. The aim of this work was to investigate in parallel the binding properties of CBG to cannabinoid CB1 (CB1 R) and CB2 (CB2 R) receptors and the effects of the compound on agonist activation of those receptors and of CB1 -CB2 heteroreceptor complexes. Using [3 H]-CP-55940, CBG competed with low micromolar K i values the binding to CB1 R and CB2 R...
2018: Frontiers in Pharmacology
Xiang-Hu He, Chloe J Jordan, Kiran Vemuri, Guo-Hua Bi, Jia Zhan, Eliot L Gardner, Alexandros Makriyannis, Yan-Lin Wang, Zheng-Xiong Xi
Cannabinoid CB1 receptors (CB1 Rs) have been shown to be a promising target in medication development for the treatment of addiction. However, clinical trials with SR141716A (rimonabant, a selective CB1 R antagonist/inverse agonist) for the treatment of obesity and smoking cessation failed due to unwanted side effects, such as depression, anxiety, and suicidal tendencies. Recent preclinical studies suggest that the neutral CB1 R antagonist AM4113 may retain the therapeutic anti-addictive effects of SR141716A in nicotine self-administration models and possibly has fewer unwanted side effects...
July 2, 2018: Acta Pharmacologica Sinica
Hong-Le Wang, Xi Cheng, Shan-Wen Ding, Dong-Wei Wang, Chun Chen, Chun-Ling Xu, Hui Xie
The rice white tip nematode, Aphelenchoides besseyi, is widely distributed in rice planting areas worldwide and causes serious economic losses. Cathepsin genes have been demonstrated to have importance in studying the reproduction, development, pathogenicity, and control methods of plant nematodes. In this paper, a novel cathepsin B gene, Ab-cb-1, was found and cloned. The Ab-cb-1 gene was 1347 bp in length and encodes 369 amino acids. The Ab-CB-1 protein contains characteristic occluding loops but no signal peptide...
2018: PloS One
Lucia Recinella, Annalisa Chiavaroli, Claudio Ferrante, Adriano Mollica, Giorgia Macedonio, Azzurra Stefanucci, Marilisa Pia Dimmito, Szabolcs Dvorácskó, Csaba Tömböly, Luigi Brunetti, Giustino Orlando, Sheila Leone
BACKGROUND: The endocannabinoid (eCB) system is strongly involved in the regulation of anxiety and feeding behavior. RVD-hemopressin(α) [RVD-hp(α)], a N-terminally extended form of hemopressin, is a negative allosteric modulator of the cannabinoid (CB) 1 receptor and a positive allosteric modulator of CB2 receptor which has been recently reported to exert anxiolytic/antidepressant and anorexigenic effects after peripheral administration in rats. Pharmacological evidences reported a possible link between brain hypocretin/orexin, monoamine and eCB systems, as regards appetite and emotional behavior control...
August 2018: Pharmacological Reports: PR
Chelsey George, Alan M Ducatman, Baqiyyah N Conway
AIMS: Diabetes is linked with decreases in lung elasticity and in capacity to transfer carbon monoxide. Systemic inflammation, a common concern with diabetes, may contribute to airflow obstruction. We examined the association of self-reported diabetes with self-reported respiratory diseases (RDs) among 53,146 adults from the C8 Health Project. METHODS: Participants were categorized into three groups: Type 1 (T1D, n = 781), Type 2 (T2D, n = 4277), or no diabetes (n = 48,088)...
August 2018: Diabetes Research and Clinical Practice
Mohammed I Khan, Anna A Sobocińska, Klaudia K Brodaczewska, Katarzyna Zielniok, Malgorzata Gajewska, Claudine Kieda, Anna M Czarnecka, Cezary Szczylik
BACKGROUND: The anti-tumor properties of cannabinoids have been investigated in many in vitro and in vivo studies. Many of these anti-tumor effects are mediated via cannabinoid receptor types 1 and 2 (CB1 and CB2 ), comprising the endocannabinoid system (ECS). In this study, we investigated the ECS based on CB 1 and CB 2 receptor gene and protein expression in renal cell carcinoma (RCC) cell lines. In view of their further use for potential treatments, we thus investigated the roles of CB1 and CB2 receptors in the anti-proliferative action and signal transduction triggered by synthetic cannabinoid agonists [such as JWH-133 and WIN 55,212-2 (WIN-55)] in RCC cell lines...
May 23, 2018: BMC Cancer
Malliga R Iyer, Resat Cinar, Nathan J Coffey, George Kunos
Cannabinoid-1 receptor (CB1 R) antagonists/inverse agonists have great potential in the treatment of metabolic disorders like dyslipidemia, type 2 diabetes, and nonalcoholic steatohepatitis. Cannabinoid-1 receptor inverse agonists have also been reported to be effective in mitigating fibrotic disorders in murine models. Inducible nitric oxide synthase is another promising target implicated in fibrotic and inflammatory disorders. We have disclosed MRI-1867 as a potent and selective, peripherally acting dual-target inhibitor of the CB1 R and inducible nitric oxide synthase (iNOS)...
May 23, 2018: Journal of Labelled Compounds & Radiopharmaceuticals
Laurie M Robin, José F Oliveira da Cruz, Valentin C Langlais, Mario Martin-Fernandez, Mathilde Metna-Laurent, Arnau Busquets-Garcia, Luigi Bellocchio, Edgar Soria-Gomez, Thomas Papouin, Marjorie Varilh, Mark W Sherwood, Ilaria Belluomo, Georgina Balcells, Isabelle Matias, Barbara Bosier, Filippo Drago, Ann Van Eeckhaut, Ilse Smolders, Francois Georges, Alfonso Araque, Aude Panatier, Stéphane H R Oliet, Giovanni Marsicano
Bidirectional communication between neurons and astrocytes shapes synaptic plasticity and behavior. D-serine is a necessary co-agonist of synaptic N-methyl-D-aspartate receptors (NMDARs), but the physiological factors regulating its impact on memory processes are scantly known. We show that astroglial CB1 receptors are key determinants of object recognition memory by determining the availability of D-serine at hippocampal synapses. Mutant mice lacking CB1 receptors from astroglial cells (GFAP-CB1 -KO) displayed impaired object recognition memory and decreased in vivo and in vitro long-term potentiation (LTP) at CA3-CA1 hippocampal synapses...
June 6, 2018: Neuron
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