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Methods in Molecular Biology 982 Pietro Ghezzi Anthony Cerami Editors Tissue-Protective Cytokines Methods and Protocols M M B ™ ETHODS IN OLECULAR IOLOGY Series Editor John M. Walker School of Life Sciences University of Hertfordshire Hat fi eld, Hertfordshire, AL10 9AB, UK For further volumes: http://www.springer.com/series/7651 Tissue-Protective Cytokines Methods and Protocols Edited by Pietro Ghezzi Brighton and Sussex Medical School, Falmer, UK Anthony Cerami Leiden University Medical Center, Leiden, The Netherlands Editors Pietro Ghezzi Anthony Cerami Brighton and Sussex Medical School Leiden University Medical Center Falmer, UK Leiden, The Netherlands ISSN 1064-3745 ISSN 1940-6029 (electronic) ISBN 978-1-62703-307-7 ISBN 978-1-62703-308-4 (eBook) DOI 10.1007/978-1-62703-308-4 Springer New York Heidelberg Dordrecht London Library of Congress Control Number: 2013932704 © Springer Science+Business Media, LLC 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Humana Press is a brand of Springer Springer is part of Springer Science+Business Media (www.springer.com) Preface In 2004, Pietro Ghezzi asked me to write a short introductory chapter for a book on TNF he was putting together for this very same series. The focus of what I wrote then was on TNF as an infl ammatory agent. In fact, our fi nding, in the 1980s, that cachexia associated with in fl ammatory and infectious diseases was due to TNF opened the way to the develop- ment of anti-TNF drugs that are now standard treatment for chronic infl ammatory disease. Now, I am asked again to write about the continuation of this saga. In 1998, with Mike Brines and Carla Hand, I started investigating why patients who receive EPO feel well soon after the fi rst treatment. That led to the discovery, published in 2000, that systemically administered EPO is neuroprotective in animal models of ischemic and traumatic brain injury. That paper opened the fi eld of the neuroprotective action of EPO. The protective action of EPO was soon demonstrated in other tissues, hence the use of the term “tissue- protective cytokine” (1). As in the case of TNF, we had to fi ght the commonplace that EPO has only erythropoietic actions, that its receptor is present only in erythroid progenitor cells, and that EPO is produced only by the kidney (2). As in the case of TNF, originally identifi ed for its antitumor activities, we had to work against the common belief that EPO is solely an erythropoietic cytokine acting solely on erythroid progenitors. Several investigators also documented the expression of EPO in the central nervous system and other tissues, against the common belief that only the kidney and the foetal liver produce EPO. From the perspective of pharmacological use, the erythropoietic action of EPO, by increasing the haematocrit and activating platelets, has some undesired side effects as a tis- sue-protectant, and this led to the development of novel non-erythropoietic EPO-derived tissue-protective molecules some of which are described here. I believe that tissue-protection will be a new fi eld of interest of cytokine biology, both in discovering novel actions of known cytokines and in developing new drugs. In this con- text, this book is a valuable collection of methodological papers that describe in detail the key models that have been used to characterize the tissue-protective actions of EPO and derivatives and will, hopefully, be of use in the discovery of new tissue-protective molecules. Leiden, The Netherlands Anthony Cerami References 1. Cerami A (2011) The value of failure: the discovery of TNF and its natural inhibitor erythropoietin. J Intern Med 269(1):8–15 2. Ghezzi P, Bernaudin M, Bianchi R, Blomgren K, Brines M, Campana W, Cavaletti G, Cerami A, Chopp M, Coleman T, Digicaylioglu M, Ehrenreich H, Erbayraktar S, Erbayraktar Z, Gassmann M, Genc S, Gokmen N, Grasso G, Juul S, Lipton SA, Hand CC, Latini R, Lauria G, Leist M, Newton SS, Petit E, Probert L, Sfacteria A, Siren AL, Talan M, Thiemermann C, Westenbrink D, Yaqoob M, Zhu C (2010) Erythropoietin: not just about erythropoiesis. Lancet 375(9732):2142 v Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix 1 Erythropoietin and Engineered Innate Repair Activators. . . . . . . . . . . . . . . . 1 Michael Brines and Anthony Cerami 2 Epo and Non-hematopoietic Cells: What Do We Know?. . . . . . . . . . . . . . . . 13 Omolara O. Ogunshola and Anna Yu. Bogdanova 3 Tissue-Protective Cytokines: Structure and Evolution . . . . . . . . . . . . . . . . . . 43 Pietro Ghezzi and Darrell Conklin 4 The Regenerative Activity of Interleukin-6 . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Eithan Galun and Stefan Rose-John 5 Brain Ischemic Injury in Rodents: The Protective Effect of EPO. . . . . . . . . . 79 Annelise Letourneur, Edwige Petit, Simon Roussel, Omar Touzani, and Myriam Bernaudin 6 Experimental Traumatic Spinal Cord Injury . . . . . . . . . . . . . . . . . . . . . . . . . 103 Zübeyde Erbayraktar, Necati Gökmen, Osman Yılmaz, and Serhat Erbayraktar 7 Erythropoietin as a Neuroprotectant for Neonatal Brain Injury: Animal Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Christopher M. Traudt and Sandra E. Juul 8 Evaluating Effects of EPO in Rodent Behavioral Assays Related to Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Catharine H. Duman and Samuel S. Newton 9 Erythropoietin and Cytoprotective Cytokines in Experimental Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Samson Kumar Gaddam, Jovany Cruz, and Claudia Robertson 10 Therapeutic Efficacy of Erythropoietin in Experimental Autoimmune Encephalomyelitis in Mice, a Model of Multiple Sclerosis . . . . . . . . . . . . . . . 163 Ilaria Cervellini, Pietro Ghezzi, and Manuela Mengozzi 11 Deciphering the Intracellular Signaling of Erythropoietin in Neuronal Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 Murat Digicaylioglu 12 Assessment of Allodynia Relief by Tissue-Protective Molecules in a Rat Model of Nerve Injury-Induced Neuropathic Pain. . . . . . . . . . . . . . . . . . . . . . . . . . 187 Maarten Swartjes, Marieke Niesters, and Albert Dahan 13 Intra-epidermal Nerve Fibers Density and Nociception in EPO-Treated Type 1 Diabetic Rats with Peripheral Neuropathy. . . . . . . . . . . . . . . . . . . . . 197 Bianchi Roberto, Lombardi Raffaella, Porretta-Serapiglia Carla, and Lauria Giuseppe vii viii Contents 14 ARA290 in a Rat Model of Inflammatory Pain . . . . . . . . . . . . . . . . . . . . . . . 213 Andrew Dilley 15 In Vivo Angiogenic Activity of Erythropoietin. . . . . . . . . . . . . . . . . . . . . . . . 227 Domenico Ribatti 16 Photoreceptor Degeneration in Mice: Adeno-Associated Viral Vector-Mediated Delivery of Erythropoietin . . . . . . . . . . . . . . . . . . . . . . . . . 237 Pasqualina Colella and Alberto Auricchio 17 Myocardial Infarction: Cardioprotection by Erythropoietin. . . . . . . . . . . . . . 265 Mark I. Talan and Roberto Latini 18 Using Plethysmography to Determine Erythropoietin’s Impact on Neural Control of Ventilation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Tommy Seaborn, Max Gassmann, and Jorge Soliz 19 Cerebral Malaria: Protection by Erythropoietin. . . . . . . . . . . . . . . . . . . . . . . 315 Anne-Lise Bienvenu and Stephane Picot Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 Contributors ALBERTO AURICCHIO (cid:129) Telethon Institute of Genetics and Medicine (TIGEM), Naples , Italy; Medical Genetics, Department of Medical Translational Science, Federico II University, Naples , Italy MYRIAM BERNAUDIN (cid:129) CERVOxy team “Hypoxia, cerebrovascular and tumoral pathophysiologies”, UMR 6301-ISTCT, CNRS, CEA, Université de Caen Basse-Normandie, CYCERON, Caen , France ANNE-LISE BIENVENU (cid:129) Malaria Research Unit, SMITH ICBMS UMR CNRS, UCBL, INSA Lyon, Lyon , France ANNA YU. BOGDANOVA (cid:129) Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich , Switzerland MICHAEL BRINES (cid:129) Araim Pharmaceuticals, Inc., Ossining, NY , USA PORRETTA-SERAPIGLIA CARLA (cid:129) Neuromuscular Diseases Unit, IRCCS Foundation, “Carlo Besta” Neurological Institute, Milan, Italy ANTHONY CERAMI (cid:129) Araim Pharmaceuticals, Ossining, NY , USA; Leiden University Medical Center, Leiden, The Netherlands ILARIA CERVELLINI (cid:129) Brighton & Sussex Medical School, Falmer , UK PASQUALINA COLELLA (cid:129) Telethon Institute of Genetics and Medicine (TIGEM), Naples , Italy DARRELL CONKLIN (cid:129) Department of Computer Science and Artifi cial Intelligence, University of the Basque Country UPV/EHU, San Sebastián , Spain; IKERBASQUE, Basque Foundation for Science, Bilbao , Spain JOVANY CRUZ (cid:129) Baylor College of Medicine, Houston, TX , USA ALBERT DAHAN (cid:129) Department of Anesthesiology , Leiden University Medical Center, Leiden, The Netherlands MURAT DIGICAYLIOGLU (cid:129) Departments of Neurosurgery and Physiology, University of Texas Health Science Center, San Antonio, TX , USA ANDREW DILLEY (cid:129) Brighton and Sussex Medical School, Falmer , UK CATHARINE H. DUMAN (cid:129) Department of Psychiatry , Yale University School of Medicine, New Haven, CT , USA SERHAT ERBAYRAKTAR (cid:129) Department of Neurosurgery , School of Medicine, Dokuz Eylul University, İnciralti, İzmir , Turkey ZÜBEYDE ERBAYRAKTAR (cid:129) Department of Medical Biochemistry , School of Medicine, Dokuz Eylul University, İnciralti, İzmir , Turkey SAMSON KUMAR GADDAM (cid:129) Baylor College of Medicine, Houston, TX , USA EITHAN GALUN (cid:129) Goldyne Savad Inst. of Gene Therapy, Hadassah Hebrew University Hospital , Jerusalem, Israel MAX GASSMANN (cid:129) Institute of Veterinary Physiology , Vetsuisse Faculty and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich , Switzerland ix

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