The Endocannabinoid System
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Régulation De L'inflammation Par Les Lipides Bioactifs : Interactions Biosynthétiques Et Fonctionnelles Entre Les Endocannabinoïdes Et Les Éicosanoïdes
Régulation de l'inflammation par les lipides bioactifs : interactions biosynthétiques et fonctionnelles entre les endocannabinoïdes et les éicosanoïdes Thèse Caroline Turcotte Doctorat en microbiologie-immunologie Philosophiæ doctor (Ph. D.) Québec, Canada © Caroline Turcotte, 2019 Régulation de l’inflammation par les lipides bioactifs : interactions biosynthétiques et fonctionnelles entre les endocannabinoïdes et les éicosanoïdes Thèse Caroline Turcotte Sous la direction de : Nicolas Flamand, directeur de recherche Marie-Renée Blanchet, codirectrice de recherche Résumé Les maladies inflammatoires chroniques sont un fardeau de santé important à travers le monde. Les traitements actuellement disponibles soulagent la douleur et l’inflammation, mais leurs effets secondaires rendent leur utilisation à long terme risquée. À la lumière de cette problématique, la communauté scientifique s’intéresse au potentiel d’anti-inflammatoires naturels comme les endocannabinoïdes. Les endocannabinoïdes sont des lipides endogènes qui activent les récepteurs cannabinoïdes (CB1 et CB2). Ils régulent ainsi divers processus physiologiques tels l’appétit, l’adipogénèse et la nociception. Les deux endocannabinoïdes les mieux caractérisés, le 2-AG et l’AEA, peuvent également moduler l’inflammation en activant le récepteur CB2 à la surface des cellules immunitaires. Les souris déficientes pour le récepteur CB2 présentent un phénotype inflammatoire exacerbé, suggérant que ce récepteur est anti-inflammatoire. Cependant, le rôle des endocannabinoïdes dans l’inflammation est beaucoup plus complexe puisqu’ils peuvent être métabolisés en une grande variété de médiateurs lipidiques de l’inflammation. Leur voie de dégradation principale est leur hydrolyse en acide arachidonique (AA), qui sert de précurseur à la biosynthèse d’éicosanoïdes pro-inflammatoires comme le leucotriène B4 et la prostaglandine E2. Ils peuvent également être métabolisés directement par certaines enzymes impliquées dans la synthèse d’éicosanoïdes, pour générer des médiateurs comme les prostaglandines-glycérol (PG-G). -
Cannabinoids and Endocannabinoid System Changes in Intestinal Inflammation and Colorectal Cancer
cancers Review Cannabinoids and Endocannabinoid System Changes in Intestinal Inflammation and Colorectal Cancer Viktoriia Cherkasova, Olga Kovalchuk * and Igor Kovalchuk * Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 7X8, Canada; [email protected] * Correspondence: [email protected] (O.K.); [email protected] (I.K.) Simple Summary: In recent years, multiple preclinical studies have shown that changes in endo- cannabinoid system signaling may have various effects on intestinal inflammation and colorectal cancer. However, not all tumors can respond to cannabinoid therapy in the same manner. Given that colorectal cancer is a heterogeneous disease with different genomic landscapes, experiments with cannabinoids should involve different molecular subtypes, emerging mutations, and various stages of the disease. We hope that this review can help researchers form a comprehensive understanding of cannabinoid interactions in colorectal cancer and intestinal bowel diseases. We believe that selecting a particular experimental model based on the disease’s genetic landscape is a crucial step in the drug discovery, which eventually may tremendously benefit patient’s treatment outcomes and bring us one step closer to individualized medicine. Abstract: Despite the multiple preventive measures and treatment options, colorectal cancer holds a significant place in the world’s disease and mortality rates. The development of novel therapy is in Citation: Cherkasova, V.; Kovalchuk, critical need, and based on recent experimental data, cannabinoids could become excellent candidates. O.; Kovalchuk, I. Cannabinoids and This review covered known experimental studies regarding the effects of cannabinoids on intestinal Endocannabinoid System Changes in inflammation and colorectal cancer. In our opinion, because colorectal cancer is a heterogeneous Intestinal Inflammation and disease with different genomic landscapes, the choice of cannabinoids for tumor prevention and Colorectal Cancer. -
Marijuana: Drug of Abuse Or Therapeutic Option? Learning Objectives
Handout for the Neuroscience Education Institute (NEI) online activity: Marijuana: Drug of Abuse or Therapeutic Option? Learning Objectives • Explain how cannabinoids affect the body and the brain • Educate patients about: – Evidence of efficacy for mental health and other conditions – Potential risks of cannabis use Timeline 1989? 90?: Discovery of ~2000 BC: binding site 2015: Elimination of Chinese 1943: Marijuana for THC— 1992: US Public Health emperors removed from CB1 Endogenous Service oversight cannabinoid recommend listing as a 1963: 1964: THC receptor for obtaining anandamide marijuana as medication in US Cannabidiol isolated marijuana for discovered medicine Pharmacopeia isolated research purposes 1995: 1851: Marijuana 1961: United 1970: Marijuana is Endogenous Aug 11 2016: listed as a Nations Single labeled Schedule I cannabinoid 2-AG DEA declines to medication in US Convention on by the US discovered reschedule Pharmacopeia Narcotic Drugs: Substance Abuse marijuana marijuana said to Act; this restricts be dangerous with both personal use no medical value and access for research purposes THE INTERSECTION OF THE HEALTHCARE AND CANNABIS INDUSTRIES What is Cannabis? 500 chemicals 100 cannabinoids Best understood: THC and CBD Scheduling of Controlled Substances No medicinal value, high Moderate to Lower High potential Low potential potential for low potential potential for for abuse for abuse abuse for abuse abuse Schedule I Schedule II Schedule III Schedule IV Schedule V Marijuana Cocaine Tylenol w/ Tramadol Robitussin AC Heroin -
Cannabinoid-Induced Hypotension and Bradycardia in Rats Is 1 Mediated by CB1-Like Cannabinoid Receptors
0022-3565/97/2813-1030$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 281, No. 3 Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 281:1030–1037, 1997 Cannabinoid-Induced Hypotension and Bradycardia in Rats Is 1 Mediated by CB1-Like Cannabinoid Receptors KRISTY D. LAKE, DAVID R. COMPTON, KAROLY VARGA, BILLY R. MARTIN and GEORGE KUNOS Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia Accepted for publication February 19, 1997 ABSTRACT 9 Previous studies indicate that the CB1 cannabinoid receptor an- potency was (-)-11-OH-D -THC dimethylheptyl $ (-)-3-[2- tagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophe- hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]cy- nyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A), in- clohexan-1-ol . (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]- hibits the anandamide- and D9-tetrahydrocannabinol- (THC) 4-[3-hydroxy-propyl]cyclohexan-1-ol . THC . anandamide $ induced hypotension and bradycardia in anesthetized rats with a (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy- potency similar to that observed for SR141716A antagonism of propyl]cyclohexan-1-ol, which correlated well with CB1 receptor THC-induced neurobehavioral effects. To further test the role of affinity or analgesic potency (r 5 0.96-0.99). There was no hypo- CB1 receptors in the cardiovascular effects of cannabinoids, we tension or bradycardia after palmitoylethanolamine or (1)-11-OH- examined two additional criteria for receptor-specific interactions: D9-THC dimethylheptyl. -
In Vitro Immunopharmacological Profiling of Ginger (Zingiber Officinale Roscoe)
Research Collection Doctoral Thesis In vitro immunopharmacological profiling of ginger (Zingiber officinale Roscoe) Author(s): Nievergelt, Andreas Publication Date: 2011 Permanent Link: https://doi.org/10.3929/ethz-a-006717482 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH Nr. 19591 In Vitro Immunopharmacological Profiling of Ginger (Zingiber officinale Roscoe) ABHANDLUNG zur Erlangung des Titels DOKTOR DER WISSENSCHAFTEN der ETH ZÜRICH vorgelegt von Andreas Nievergelt Eidg. Dipl. Apotheker, ETH Zürich geboren am 18.12.1978 von Schleitheim, SH Angenommen auf Antrag von Prof. Dr. Karl-Heinz Altmann, Referent Prof. Dr. Jürg Gertsch, Korreferent Prof. Dr. Michael Detmar, Korreferent 2011 Table of Contents Summary 6 Zusammenfassung 7 Acknowledgements 8 List of Abbreviations 9 1. Introduction 13 1.1 Ginger (Zingiber officinale) 13 1.1.1 Origin 14 1.1.2 Description 14 1.1.3 Chemical Constituents 15 1.1.4 Traditional and Modern Pharmaceutical Use of Ginger 17 1.1.5 Reported In Vitro Effects 20 1.2 Immune System and Inflammation 23 1.2.1 Innate and Adaptive Immunity 24 1.2.2 Cytokines in Inflammation 25 1.2.3 Pattern Recognition Receptors 29 1.2.4 Toll-Like Receptors 30 1.2.5 Serotonin 1A and 3 Receptors 32 1.2.6 Phospholipases A2 33 1.2.7 MAP Kinases 36 1.2.8 Fighting Inflammation, An Ongoing Task 36 1.2.9 Inflammation Assays Using Whole Blood 38 1.3 Arabinogalactan-Proteins 39 1.3.1 Origin and Biological Function of AGPs 40 1.3.2 Effects on Animals 41 1.3.3 The ‘Immunostimulation’ Theory 42 1/188 2. -
Supporting Information
Supporting Information Blankman et al. 10.1073/pnas.1217121110 SI Materials and Methods RT-PCR. Total RNA was isolated from brain tissue of 6-wk-old −/− +/+ Materials. We purchased 2-arachidonoylglycerol (2-AG) from ABHD12 and ABHD12 mice using TRIzol (Invitrogen). Cayman Chemicals; 2-oleoylglycerol, pentadecanoic acid (PDA), First-strand cDNA was synthesized using the SuperScript III and dodecylmonoalkylglycerol ether (C12:0 MAGE) were pur- Reverse Transcriptase kit (Invitrogen) according to the manu- chased from Sigma-Aldrich. Monopentadecanoin (C15:0 MAG) facturer’s protocol. PCR amplification (25 cycles) of a 259 bp fragment of the ABHD12 cDNA was performed with primers 50- and monoheptadecanoin (C17:0 MAG) were purchased from Nu- 0 0 Chek-Prep. Phospholipids and lysophospholipids were purchased CTCAGTAGGAACACCATCGGAGC-3 and 5 -GCCAGGG- AAGTATCGGTATATCACTG-3. Amplification of a 245-bp from Avanti Polar Lipids. Fluorophosphonate (FP)-rhodamine 0 (1) and JZL184 (2) were synthesized as described previously. GAPDH product was performed as a control with primers 5 - GGTGAAGGTCGGTGTGAACGG-30 and 50-CCCATTTGA- 0 Generation of ABHD12−/− Mice. The α/β-hydrolase domain-con- TGTTAGTGGGGTCTCG-3 . Both sets of primers were de- taining (ABHD)12-targeting construct was generated by ampli- signed to span a >2-kb region of genomic DNA. fying 3.4- and 4.4-kb regions of the Abhd12 gene adjacent to the Untargeted liquid chromatography–mass spectrometry proteomic analysis. catalytic exon 8 from a BAC clone containing the Abhd12 locus Mouse brain membrane proteomes were prepared from 6-mo-old − − + + (clone ID RP23-193L22 from BACPAC Resources Center at ABHD12 / and ABHD12 / mice (n = 3 per genotype). -
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. -
Cannabinoid Receptor and Inflammation
Cannabinoid Receptor and Inflammation Newman Osafo1, Oduro Yeboah1, Aaron Antwi1, and George Ainooson1 1Kwame Nkrumah University of Science and Technology September 11, 2020 Abstract The eventual discovery of endogenous cannabinoid receptors CB1 and CB2 and their endogenous ligands has generated interest with regards to finally understanding the endocannabinoid system. Its role in the normal physiology of the body and its implication in pathological states such as cardiovascular diseases, neoplasm, depression and pain have been subjects of scientific interest. In this review the authors focus on the endogenous cannabinoid pathway, the critical role of cannabinoid receptors in signaling and mediation of neurodegeneration and other inflammatory responses as well as its potential as a drug target in the amelioration of some inflammatory conditions. Though the exact role of the endocannabinoid system is not fully understood, the evidence found leans heavily towards a great potential in exploiting both its central and peripheral pathways in disease management. Cannabinoid therapy has already shown great promise in several preclinical and clinical trials. 1.0 Introduction Ethnopharmacological studies have shown the use of Cannabis sativa in traditional medicine for over a thousand years, with its widespread use promoted by its psychotropic effects (McCoy, 2016; Turcotte et al., 2016). The discovery of a receptor within human body, that is selectively activated by cannabinoids suggested the presence of at least one endogenous ligand for this receptor. This is confirmed by the discovery of two endogenously synthesized lipid mediators, 2-arachidonoyl-glycerol and arachidonoylethanolamide, which function as high-affinity ligands for a subfamily of cannabinoid receptors ubiquitously distributed in the central nervous system, known as the CB1 receptors (Turcotte et al., 2016). -
A Dissertation Entitled Uncovering Cannabinoid Signaling in C. Elegans
A Dissertation Entitled Uncovering Cannabinoid Signaling in C. elegans: A New Platform to Study the Effects of Medicinal Cannabis By Mitchell Duane Oakes Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biology ________________________________________ Dr. Richard Komuniecki, Committee Chair _______________________________________ Dr. Bruce Bamber, Committee Member ________________________________________ Dr. Patricia Komuniecki, Committee Member ________________________________________ Dr. Robert Steven, Committee Member ________________________________________ Dr. Ajith Karunarathne, Committee Member ________________________________________ Dr. Jianyang Du, Committee Member ________________________________________ Dr. Amanda Bryant-Friedrich, Dean College of Graduate Studies The University of Toledo August 2018 Copyright 2018, Mitchell Duane Oakes This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Uncovering Cannabinoid Signaling in C. elegans: A New Platform to Study the Effects of Medical Cannabis By Mitchell Duane Oakes Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biology The University of Toledo August 2018 Cannabis or marijuana, a popular recreational drug, alters sensory perception and exerts a range of medicinal benefits. The present study demonstrates that C. elegans exposed to -
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. -
Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer’S Disease
Molecular Neurobiology https://doi.org/10.1007/s12035-019-1637-8 Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer’s Disease David Schubert1 & Devin Kepchia1 & Zhibin Liang1 & Richard Dargusch1 & Joshua Goldberg & Pamela Maher1 Received: 30 January 2019 /Accepted: 6 May 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Finding a therapy for Alzheimer’s disease (AD) is perhaps the greatest challenge for modern medicine. The chemical scaffolds of many drugs in the clinic today are based upon natural products from plants, yet Cannabis has not been extensively examined as a source of potential AD drug candidates. Here, we determine if a number of non-psychoactive cannabinoids are neuroprotective in a novel pre-clinical AD and neurodegeneration drug-screening platform that is based upon toxicities associated with the aging brain. This drug discovery paradigm has yielded several compounds in or approaching clinical trials for AD. Eleven cannabinoids were assayed for neuroprotection in assays that recapitulate proteotoxicity, loss of trophic support, oxidative stress, energy loss, and inflammation. These compounds were also assayed for their ability to remove intraneuronal amyloid and subjected to a structure-activity relationship analysis. Pairwise combinations were assayed for their ability to synergize to produce neuropro- tective effects that were greater than additive. Nine of the 11 cannabinoids have the ability to protect cells in four distinct phenotypic neurodegeneration screening assays, including those using neurons that lack CB1 and CB2 receptors. They are able to remove intraneuronal Aβ, reduce oxidative damage, and protect from the loss of energy or trophic support. -
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.