Colloquium Series on Integrated Systems Physiology KELLY • ET AL • ET KELLY Colloquium Lectures on Series ISSN: 2154-560X The Endocannabinoid System in Integrated Systems Physiology From Molecule to Function to Disease Local and Systemic Inflammation THE ENDOCANNABINOID SYSTEM IN LOCAL AND SYSTEMIC INFLAMMATION THE ENDOCANNABINOID SYSTEM IN LOCAL Series Editors: D. Neil Granger, LSU Health Sciences, Shreveport Joey Granger, University of Mississippi Medical Center Regulation of Gastrointestinal Mucosal Growth, Second Edition Rao N. Jadalanki, University of Maryland School of Medicine, Baltimore Veterans Affairs Medical Center Jian-Ying Wang, University of Maryland School of Medicine, Baltimore Veterans Affairs Medical Center The mammalian gastrointestinal mucosa is a rapidly self-renewing tissue in the body, and its homeostasis is preserved through the strict regulation of epithelial cell proliferation, growth arrest, and apoptosis. The control of the growth of gastrointestinal mucosa is unique and, compared with most other tissue in the body, complex. Mucosal growth is regulated by the same hormones that alter metabolism in other tissues, but the gastrointestinal mucosa also responds to host events triggered by the ingestion and presence of food within the digestive tract. These gut hormones and peptides regulate the growth of the exocrine pancreas, gallbladder epithelium, and the mucosa of the oxyntic gland region of the stomach and the small and large intestines. Luminal factors, including nutrients or other dietary factors, secretions, and microbes that occur within the lumen and distribute over a proximal-to-distal gradient, are also crucial for maintenance of normal gut mucosal regeneration and could explain the villous-height-crypt-depth gradient and variety of adaptation, since these factors are diluted, absorbed, and destroyed as they pass down the digestive tract. Recently, intestinal stem cells, cellular polyamines, and noncoding RNAs are shown to play an important role in the regulation of gastrointestinal mucosal growth under physiological and various pathological conditions. In this book, we highlight key issues and factors that control gastrointestinal mucosal growth and homeostasis, with special emphasis on the mechanisms through which epithelial renewal and apoptosis are regulated at the cellular and molecular levels. About Morgan & Claypool Publishers This volume is a printed version of a work that appears in the Colloquium Digital Library of Life Sciences. Colloquium books provide concise, original presentations of important research topics, authored by invited experts. All books are available in digital & print formats. For more information, visit store.morganclaypool.com morgan & store.morganclaypool.com claypool MELANIE E.M. KELLY • CHRISTIAN LEHMANN • JUAN ZHOU The Endocannabinoid System in Local and Systemic Inflammation ii Colloquium Digital Library of Life Sciences TheColloquium Digital Library of Life Sciences is an innovative information resource for researchers, instructors, and students in the biomedical life science community, including clinicians. Each PDF e-book available in the Colloquium Digital Library is an accessible overview of a fast-moving basic science research topic, authored by a prominent expert in the field. They are intended as time-sav- ing pedagogical resources for scientists exploring new areas outside of their specialty. They are also excellent tools for keeping current with advances in related fields, as well as refreshing one’s under- standing of core topics in biomedical science. For the full list of available books, please visit: colloquium.morganclaypool.com Each book is available on our website as a PDF download. Access is free for readers at institutions that license the Colloquium Digital Library. Please e-mail [email protected] for more information. iii Colloquium Series on Integrated Systems Physiology: From Molecule to Function to Disease Editors D. Neil Granger Louisiana State University Health Sciences Center Joey P. Granger University of Mississippi Medical Center Physiology is a scientific discipline devoted to understanding the functions of the body. It addresses function at multiple levels, including molecular, cellular, organ, and system. An appreciation of the processes that occur at each level is necessary to understand function in health and the dysfunction associated with disease. Homeostasis and integration are fundamental principles of physiology that account for the relative constancy of organ processes and bodily function even in the face of substantial environmental changes. This constancy results from integrative, cooperative interactions of chemical and electrical signaling processes within and between cells, organs and systems. This eBook series on the broad field of physiology covers the major organ systems from an integrative perspective that addresses the molecular and cellular processes that contribute to homeostasis. Material on pathophysiology is also included throughout the eBooks. The state-of the-art treatises were produced by leading experts in the field of physiology. Each eBook includes stand-alone information and is intended to be of value to students, scientists, and clinicians in the biomedical sciences. Since physiological concepts are an ever-changing work-in-progress, each contributor will have the opportunity to make periodic updates of the covered material. Published titles (for future titles please see the website, www.morganclaypool.com/toc/isp/1/1) iv Copyright © 2017 by Morgan & Claypool All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means—electronic, mechanical, photocopy, recording, or any other except for brief quotations in printed reviews, without the prior permission of the publisher. The Endocannabinoid System in Local and Systemic Inflammation Melanie E. M. Kelly, Christian Lehmann, and Juan Zhou www.morganclaypool.com ISBN: 9781615047482 paperback ISBN: 9781615047499 ebook DOI: 10.4199/C00151ED1V01Y201702ISP074 A Publication in the Morgan & Claypool series COLLOQUIUM SERIES ON INTEGRATED SYSTEMS PHYSIOLOGY: FROM MOLECULE TO FUNCTION TO DISEASE Lecture #74 Series Editors: D. Neil Granger, LSU Health Sciences Center, and Joey P. Granger, University of Mississippi Medical Center ISSN 2154-560X print ISSN 2154-5626 electronic The Endocannabinoid System in Local and Systemic Inflammation Melanie E. M. Kelly Dalhousie University Christian Lehmann Dalhousie University Juan Zhou Dalhousie University COLLOQUIUM SERIES ON INTEGRATED SYSTEMS PHYSIOLOGY: FROM MOLECULE TO FUNCTION TO DISEASE #74 &MC MORGAN & CLAYPOOL LIFE SCIENCES vi ABSTRACT This book focuses on the role of the endocannabinoid system in local and systemic inflammation, with individual chapters written by experts in the field of cannabinoid research and medicine. The topics explore the actions of the endocannabinoid system on the immune system, including neu- roinflammation in autoimmune disorders such as multiple sclerosis, and in neurodegenerative dis- orders such as Huntington’s and Alzheimer’s, as well as local and systemic inflammatory conditions affecting organs including the eye (uveitis and corneal inflammation), the bladder (interstitial cys- titis), pancreas (diabetes), cardiovascular system (stroke), joints (arthritis), and sepsis. The objective of this book is to provide knowledge transfer on the use of cannabinoids in inflammatory disease by critically examining preclinical and clinical research on the immunomodulatory actions of the endocannabinoid system, with specific emphasis on the actions of cannabinoids in diseases where inflammation is a prominent component. By drawing these results together, we seek to provide fur- ther understanding of the complexities of endocannabinoid system modulation of immune function and identify potential uses and limitations for cannabinoid-based therapeutics. KEY WORDS Alzheimer’s disease, amyloid β, arthritis, cannabinoids, cannabinoid receptors, cannabis, CNS injury, diabetic retinopathy, dronabinol, endocannabinoids, endocannabinoid system, endotox- in-induced uveitis, experimental autoimmune encephalomyelitis, experimental autoimmune uve- oretinitis, Huntington’s disease, immune system, immune cells, inflammation, marijuana, multiple sclerosis, Nabiximols, neuroinflammation, neurodegeneration, neuroprotection, ocular inflamma- tion, pain, phytocannabinoids, proliferative vitreoretinopathy, spasticity, Sativex® vii Contents Preface . xi 1 Inflammation and the Endocannabinoid System . 1 1.1 Introduction . 1 1.2 Cannabinoid Type 1 Receptor . 2 1.3 Cannabinoid Type 2 Receptor . 4 1.4 Other Receptors and Ligands . 6 1.5 Modulation of the Inflammatory Immune Response by the Endocannabinoid System . 7 1.6 Conclusions . 8 2 Cannabinoids in Multiple Sclerosis . 9 2.1 Multiple Sclerosis. 10 2.1.1 Etiology �������������������������������������������������������������������������������������������� 10 2.1.2 Pathology and Symptoms of Multiple Sclerosis . 11 2.1.3 Current Treatments for Multiple Sclerosis . 12 2.2 Cannabinoids in Multiple Sclerosis . 13 2.2.1 Experimental Autoimmune Encephalomyelitis Animal Models . 13 2.2.2 Clinical Data . 15 2.2.3 Tolerability of Cannabinoids . 17 2.3 Concluding Remarks and Future Directions . 18 3 Huntington’s Disease and the Endocannabinoid System . 19 3.1 Huntington’s Disease . 21 3.2 Neuroinflammation in Huntington’s Disease . 22 3.3 The Management of euroinflammationN in Huntington’s