Distinct Roles of the Endocannabinoids Anandamide and 2-Arachidonoylglycerol in Social Behavior and Emotionality at Different Developmental Ages in Rats
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Modulation of Central Endocannabinoid System Results in Gastric Mucosal Protection in the Rat
Modulation of central endocannabinoid system results in gastric mucosal protection in the rat Tóth, V.E.1, Fehér, Á.1, Németh, J.2, Gyertyán, I.3, Zádori, Z.S.1, Gyires K.1 1 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4., 1089 Budapest, Hungary; 2 Department of Pharmacology and Pharmacotherapy, University of Debrecen, Nagyerdei krt. 98., 4032 Debrecen, Hungary; 3 MTA-SE NAP B Cognitive Translational Behavioural Pharmacology Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4., 1089 Budapest, Hungary *Corresponding author: Klára Gyires Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4., 1089, Budapest, Hungary Phone: 36-1-210-4416, Fax: 36-1-210-4412 e-mail: [email protected] 1 Abstract 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 be responsible for mucosal protective effect of FAAH, MAGL and uptake inhibitors. Methods: Gastric mucosal damage was induced by acidified ethanol. Gastric motility was measured in anesthetized rats. Catalepsy and the body temperature were also evaluated. Mucosal calcitonin gene- related peptide (CGRP), somatostatin concentrations and superoxide dismutase (SOD) activity were measured. The compounds were injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.). Results: 1. URB 597, JZL184 (inhibitors of FAAH and MAGL) and AM 404 (inhibitor of AEA uptake) decreased the mucosal lesions significantly given either i.c.v. -
Targeting the Endocannabinoid System to Reduce Nociception
Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2011 Targeting the endocannabinoid system to reduce nociception Lamont Booker Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medical Pharmacology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2419 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. Targeting the Endocannabinoid System to Reduce Nociception A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. By Lamont Booker Bachelor’s of Science, Fayetteville State University 2003 Master’s of Toxicology, North Carolina State University 2005 Director: Dr. Aron H. Lichtman, Professor, Pharmacology & Toxicology Virginia Commonwealth University Richmond, Virginia April 2011 Acknowledgements The author wishes to thank several people. I like to thank my advisor Dr. Aron Lichtman for taking a chance and allowing me to work under his guidance. He has been a great influence not only with project and research direction, but as an excellent example of what a mentor should be (always willing to listen, understanding the needs of each student/technician, and willing to provide a hand when available). Additionally, I like to thank all of my committee members (Drs. Galya Abdrakmanova, Francine Cabral, Sandra Welch, Mike Grotewiel) for your patience and willingness to participate as a member. Our term together has truly been memorable! I owe a special thanks to Sheryol Cox, and Dr. -
S41467-020-19780-Z.Pdf
ARTICLE https://doi.org/10.1038/s41467-020-19780-z OPEN Endocannabinoid signaling regulates the reinforcing and psychostimulant effects of ketamine in mice Wei Xu1,3, Hongchun Li1,3, Liang Wang1, Jiamei Zhang1, Chunqi Liu1, Xuemei Wan1, Xiaochong Liu1, Yiming Hu1, ✉ Qiyao Fang1, Yuanyuan Xiao1, Qian Bu1, Hongbo Wang2, Jingwei Tian2, Yinglan Zhao1 & Xiaobo Cen 1 The abuse potential of ketamine limits its clinical application, but the precise mechanism remains largely unclear. Here we discovered that ketamine significantly remodels the 1234567890():,; endocannabinoid-related lipidome and activates 2-arachidonoylglycerol (2-AG) signaling in the dorsal striatum (caudate nucleus and putamen, CPu) of mice. Elevated 2-AG in the CPu is essential for the psychostimulant and reinforcing effects of ketamine, whereas blockade of the cannabinoid CB1 receptor, a predominant 2-AG receptor, attenuates ketamine-induced remodeling of neuronal dendrite structure and neurobehaviors. Ketamine represses the transcription of the monoacylglycerol lipase (MAGL) gene by promoting the expression of PRDM5, a negative transcription factor of the MAGL gene, leading to increased 2-AG pro- duction. Genetic overexpression of MAGL or silencing of PRDM5 expression in the CPu robustly reduces 2-AG production and ketamine effects. Collectively, endocannabinoid signaling plays a critical role in mediating the psychostimulant and reinforcing properties of ketamine. 1 National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, People’s Republic of China. 2 Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, 264005 Yantai, People’s Republic of China. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Inhibition of Monoacylglycerol Lipase Reduces the Reinstatement Of
International Journal of Neuropsychopharmacology (2019) 22(2): 165–172 doi:10.1093/ijnp/pyy086 Advance Access Publication: November 27, 2018 Regular Research Article regular research article Inhibition of Monoacylglycerol Lipase Reduces the Reinstatement of Methamphetamine-Seeking and Anxiety-Like Behaviors in Methamphetamine Self-Administered Rats Yoko Nawata, Taku Yamaguchi, Ryo Fukumori, Tsuneyuki Yamamoto Department of Pharmacology, Faculty of Pharmaceutical Science, Nagasaki International University, Nagasaki, Japan Correspondence: Tsuneyuki Yamamoto, PhD, Department of Pharmacology, Faculty of Pharmaceutical Science, Nagasaki International University, 2825–7 Huis Ten Bosch Sasebo, Nagasaki 859–3298, Japan ([email protected]). Abstract Background: Methamphetamine is a highly addictive psychostimulant with reinforcing properties. Our laboratory previously found that Δ8-tetrahydrocannabinol, an exogenous cannabinoid, suppressed the reinstatement of methamphetamine- seeking behavior. The purpose of this study was to determine whether the elevation of endocannabinoids modulates the reinstatement of methamphetamine-seeking behavior and emotional changes in methamphetamine self-administered rats. Methods: Rats were tested for the reinstatement of methamphetamine-seeking behavior following methamphetamine self- administration and extinction. The elevated plus-maze test was performed in methamphetamine self-administered rats during withdrawal. We investigated the effects of JZL184 and URB597, 2 inhibitors of endocannabinoid hydrolysis, on the reinstatement of methamphetamine-seeking and anxiety-like behaviors. Results: JZL184 (32 and 40 mg/kg, i.p.), an inhibitor of monoacylglycerol lipase, significantly attenuated both the cue- and stress-induced reinstatement of methamphetamine-seeking behavior. Furthermore, URB597 (3.2 and 10 mg/kg, i.p.), an inhibitor of fatty acid amide hydrolase, attenuated only cue-induced reinstatement. AM251, a cannabinoid CB1 receptor antagonist, antagonized the attenuation of cue-induced reinstatement by JZL184 but not URB597. -
The Selective Reversible FAAH Inhibitor, SSR411298, Restores The
www.nature.com/scientificreports OPEN The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive Received: 22 September 2017 Accepted: 26 January 2018 behaviors to acute and chronic Published: xx xx xxxx stress in rodents Guy Griebel1, Jeanne Stemmelin2, Mati Lopez-Grancha3, Valérie Fauchey3, Franck Slowinski4, Philippe Pichat5, Gihad Dargazanli4, Ahmed Abouabdellah4, Caroline Cohen6 & Olivier E. Bergis7 Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-efects (memory defcit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like efects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profle positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors. Te endocannabinoid (eCB) system is formed by two G protein-coupled receptors, CB1 and CB2, and their main transmitters, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoyglycerol (2-AG)1. -
Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System
International Journal of Molecular Sciences Review Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System Ana Lago-Fernandez , Sara Zarzo-Arias, Nadine Jagerovic * and Paula Morales * Medicinal Chemistry Institute, Spanish Research Council, Juan de la Cierva 3, 28006 Madrid, Spain; [email protected] (A.L.-F.); [email protected] (S.Z.-A.) * Correspondence: [email protected] (N.J.); [email protected] (P.M.); Tel.: +34-91-562-2900 (P.M.) Abstract: Cannabinoids have shown to exert their therapeutic actions through a variety of targets. These include not only the canonical cannabinoid receptors CB1R and CB2R but also related orphan G protein-coupled receptors (GPCRs), ligand-gated ion channels, transient receptor potential (TRP) channels, metabolic enzymes, and nuclear receptors. In this review, we aim to summarize reported compounds exhibiting their therapeutic effects upon the modulation of CB1R and/or CB2R and the nuclear peroxisome proliferator-activated receptors (PPARs). Concomitant actions at CBRs and PPARα or PPARγ subtypes have shown to mediate antiobesity, analgesic, antitumoral, or neuroprotective properties of a variety of phytogenic, endogenous, and synthetic cannabinoids. The relevance of this multitargeting mechanism of action has been analyzed in the context of diverse pathologies. Synergistic effects triggered by combinatorial treatment with ligands that modulate the aforementioned targets have also been considered. This literature overview provides structural and pharmacological insights for the further development of dual cannabinoids for specific disorders. Citation: Lago-Fernandez, A.; Zarzo-Arias, S.; Jagerovic, N.; Keywords: PPAR; cannabinoids; CB1R; CB2R; FAAH; multitarget; endocannabinoid system Morales, P. Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System. -
Cannabinoid Interventions for PTSD: Where to Next?
Accepted Manuscript Cannabinoid interventions for PTSD: Where to next? Luke Ney, Allison Matthews, Raimondo Bruno, Kim Felmingham PII: S0278-5846(19)30034-X DOI: https://doi.org/10.1016/j.pnpbp.2019.03.017 Reference: PNP 9622 To appear in: Progress in Neuropsychopharmacology & Biological Psychiatry Received date: 14 January 2019 Revised date: 20 March 2019 Accepted date: 29 March 2019 Please cite this article as: L. Ney, A. Matthews, R. Bruno, et al., Cannabinoid interventions for PTSD: Where to next?, Progress in Neuropsychopharmacology & Biological Psychiatry, https://doi.org/10.1016/j.pnpbp.2019.03.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT 1 Cannabinoid interventions for PTSD: Where to next? Luke Ney1, Allison Matthews1, Raimondo Bruno1 and Kim Felmingham2 1School of Psychology, University of Tasmania, Australia 2School of Psychological Sciences, University of Melbourne, Australia ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT 2 Abstract Cannabinoids are a promising method for pharmacological treatment of post- traumatic stress disorder (PTSD). Despite considerable research devoted to the effect of cannabinoid modulation on PTSD symptomology, there is not a currently agreed way by which the cannabinoid system should be targeted in humans. In this review, we present an overview of recent research identifying neurological pathways by which different cannabinoid-based treatments may exert their effects on PTSD symptomology. -
The Expanded Endocannabinoid System/Endocannabinoidome As a Potential Target for Treating Diabetes Mellitus
Current Diabetes Reports (2019) 19:117 https://doi.org/10.1007/s11892-019-1248-9 OBESITY (KM GADDE, SECTION EDITOR) The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus Alain Veilleux1,2,3 & Vincenzo Di Marzo1,2,3,4,5 & Cristoforo Silvestri3,4,5 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review The endocannabinoid (eCB) system, i.e. the receptors that respond to the psychoactive component of cannabis, their endogenous ligands and the ligand metabolic enzymes, is part of a larger family of lipid signals termed the endocannabinoidome (eCBome). We summarize recent discoveries of the roles that the eCBome plays within peripheral tissues in diabetes, and how it is being targeted, in an effort to develop novel therapeutics for the treatment of this increasingly prevalent disease. Recent Findings As with the eCB system, many eCBome members regulate several physiological processes, including energy intake and storage, glucose and lipid metabolism and pancreatic health, which contribute to the development of type 2 diabetes (T2D). Preclinical studies increasingly support the notion that targeting the eCBome may beneficially affect T2D. Summary The eCBome is implicated in T2D at several levels and in a variety of tissues, making this complex lipid signaling system a potential source of many potential therapeutics for the treatments for T2D. Keywords Endocannabinoidome . Bioactive lipids . Peripheral tissues . Glucose . Insulin Introduction: The Endocannabinoid System cannabis-derived natural product, Δ9-tetrahydrocannabinol and its Subsequent Expansion (THC), responsible for most of the psychotropic, euphoric to the “Endocannabinoidome” and appetite-stimulating actions (via CB1 receptors) and immune-modulatory effects (via CB2 receptors) of marijuana, The discovery of two G protein-coupled receptors, the canna- opened the way to the identification of the endocannabinoids binoid receptor type-1 (CB1) and − 2 (CB2) [1, 2], for the (eCBs). -
Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model
Glaucoma Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model Sally Miller,1 Emma Leishman,1 Sherry Shujung Hu,2 Alhasan Elghouche,1 Laura Daily,1 Natalia Murataeva,1 Heather Bradshaw,1 and Alex Straiker1 1Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States 2Department of Psychology, National Cheng Kung University, Tainan, Taiwan Correspondence: Alex Straiker, De- PURPOSE. Cannabinoids, such as D9-THC, act through an endogenous signaling system in the partment of Psychological and Brain vertebrate eye that reduces IOP via CB1 receptors. Endogenous cannabinoid (eCB) ligand, 2- Sciences, Indiana University, Bloom- arachidonoyl glycerol (2-AG), likewise activates CB1 and is metabolized by monoacylglycerol ington, IN 47405, USA; lipase (MAGL). We investigated ocular 2-AG and its regulation by MAGL and the therapeutic [email protected]. potential of harnessing eCBs to lower IOP. Submitted: February 16, 2016 Accepted: May 16, 2016 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 Citation: Miller S, Leishman E, Hu SS, cord of MAGL knockout (MAGLÀ/À) mice using high performance liquid chromatography/ et al. Harnessing the endocannabinoid tandem mass spectrometry (HPLC/MS/MS). We also examined the protein distribution of 2-arachidonoylglycerol to lower intra- ocular pressure in a murine model. MAGL in the mouse anterior chamber. Invest Ophthalmol Vis Sci. RESULTS. 2-Arachidonoyl glycerol reliably lowered IOP in a CB1- and concentration-dependent 2016;57:3287–3296. DOI:10.1167/ manner. Monoacylglycerol lipase is expressed prominently in nonpigmented ciliary iovs.16-19356 epithelium. -
Assessment of Anandamide's Pharmacological Effects in Mice Deficient of Both Fatty Acid Amide Hydrolase and Cannabinoid CB1 Receptors
European Journal of Pharmacology 557 (2007) 44–48 www.elsevier.com/locate/ejphar Short communication Assessment of anandamide's pharmacological effects in mice deficient of both fatty acid amide hydrolase and cannabinoid CB1 receptors Laura E. Wise a, Christopher C. Shelton a, Benjamin F. Cravatt b, ⁎ Billy R. Martin a, Aron H. Lichtman a, a Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, United States b The Skaggs Institute for Chemical Biology and Departments of Cell Biology and Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037, United States Received 12 September 2006; received in revised form 2 November 2006; accepted 6 November 2006 Available online 10 November 2006 Abstract In the present study, we investigated whether anandamide produces its behavioral effects through a cannabinoid CB1 receptor mechanism of action. The behavioral effects of anandamide were evaluated in mice that lacked both fatty acid amide hydrolase (FAAH) and cannabinoid CB1 receptors (DKO) as compared to FAAH (−/−), cannabinoid CB1 (−/−), and wild type mice. Anandamide produced analgesia, catalepsy, and hypothermia in FAAH (−/−) mice, but failed to elicit any of these effects in the other three genotypes. In contrast, anandamide decreased locomotor behavior regardless of genotype, suggesting the involvement of multiple mechanisms of action, including its products of degradation. These findings indicate that the cannabinoid CB1 receptor is the predominant target mediating anandamide's behavioral effects. © 2006 Elsevier B.V. All rights reserved. Keywords: Cannabinoid CB1 receptor; FAAH [Fatty acid amide hydrolase]; N-arachidonoyl ethanolamine (anandamide); Pain; Analgesia; Marijuana 1. -
Inhibition of Fatty Acid Amide Hydrolase (FAAH) by Macamides
Molecular Neurobiology (2019) 56:1770–1781 https://doi.org/10.1007/s12035-018-1115-8 Inhibition of Fatty Acid Amide Hydrolase (FAAH) by Macamides M. Alasmari1 & M. Bӧhlke1 & C. Kelley1 & T. Maher1 & A. Pino-Figueroa1 Received: 25 October 2017 /Accepted: 11 May 2018 /Published online: 20 June 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract The pentane extract of the Peruvian plant, Lepidium meyenii (Maca), has been demonstrated to possess neuroprotective activity in previous in vitro and in vivo studies (Pino-Figueroa et al. in Ann N Y Acad Sci 1199:77–85, 2010; Pino-Figueroa et al. in Am J Neuroprot Neuroregener 3:87–92, 2011). This extract contains a number of macamides that may act on the endocannabinoid system (Pino-Figueroa et al. in Ann N Y Acad Sci 1199:77–85, 2010; Pino-Figueroa et al., 2011; Dini et al. in Food Chem 49:347–349, 1994). The aim of this study was to characterize the inhibitory activity of four of these maccamides (N- benzylstearamide, N-benzyloleamide, N-benzyloctadeca-9Z,12Z-dienamide, and N-benzyloctadeca-9Z,12Z,15Z-trienamide) on fatty acid amide hydrolase (FAAH), an enzyme that is responsible for endocannabinoid degradation in the nervous system (Kumar et al. in Anaesthesia 56:1059–1068, 2001). The four compounds were tested at concentrations between 1 and 100 μM, utilizing an FAAH inhibitor screening assay. The results demonstrated concentration-dependent FAAH inhibitory activities for the four macamides tested. N-Benzyloctadeca-9Z,12Z-dienamide demonstrated the highest FAAH inhibitory activ- ity whereas N-benzylstearamide had the lowest inhibitory activity.