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Gerardo B. Ramírez-Rodríguez and Leonardo Ortiz-López. Chapter 15 ... Charanjit Kaur, Domenico De Berardis, Edward C. Lauterbach,. Samuel D. ... Raffaela Santoro, Maria Ferraiuolo, Giovanni Blandino,. Paola Muti ...... San Antonio, Texas.

MELATONIN

Therapeutic Value and Neuroprotection Venkatramanujan Srinivasan

Sri Sathya Sai Medical Educational and Research Foundation An International Medical Sciences Research Study Center Tamilnadu, India NHS Department of Mental Health, Hospital “G. Mazzini”, ASL Teramo Italy Department of Neurosciences; University “G.D Annunzio, Chiety, Italy

Gabriella Gobbi

Department of Psychiatry McGill University, and McGill University Health Center Montreal, Quebec, Canada

Samuel D. Shillcutt

Department of Psychiatry and Behavioural Sciences Mercer University School of Medicine Macon, Georgia, USA

Sibel Suzen

Departmental of Pharmaceutical Chemistry Faculty of Pharmacy, Ankara University Ankara, Turkey

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CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2015 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Version Date: 20140616 International Standard Book Number-13: 978-1-4822-2010-0 (eBook - PDF) This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urge to consult the relevant national drug formulary and the drug companies’ printed instructions, and their websites, before administering any of the drugs recommended in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

Contents Preface...............................................................................................................................................ix Acknowledgments..............................................................................................................................xi Editors............................................................................................................................................. xiii Contributors....................................................................................................................................xvii Chapter 1 Melatonin Production and Bioavailability.................................................................... 1

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Emel Öykü Çetin, Yiğit Uyanıkgil, Mehmet Turgut, and Meral Baka Chapter 2 Deviations of Melatonin Levels and Signaling in Aging and Diseases: Options and Limits of Treatment................................................................................ 11 Rüdiger Hardeland Chapter 3 Pineal Gland Volume and Melatonin.......................................................................... 19 Niyazi Acer, Süleyman Karademir, and Mehmet Turgut Chapter 4 Melatonin’s Beneficial Effects in Metabolic Syndrome with Therapeutic Applications.................................................................................... 29 Venkataramanujam Srinivasan, Yoshiji Ohta, Javier Espino, Rahimah Zakaria, and Mahaneem Mohamed Chapter 5 Therapeutic Applications of Melatonin in Pediatrics................................................. 49 Emilio J. Sanchez-Barcelo, Maria D. Mediavilla, and Russel J. Reiter Chapter 6 Neuroprotective Effect of Melatonin on Perinatal Hypoxia–Ischemia....................... 59 Daniel Alonso-Alconada, Antonia Alvarez, and Enrique Hilario Chapter 7 Melatonin as a Therapeutic Agent for Sepsis.............................................................. 71 Edward H. Sharman and Stephen C. Bondy Chapter 8 Melatonin’s Cardioprotective Role.............................................................................. 89 Alberto Dominguez-Rodriguez and Pedro Abreu-Gonzalez Chapter 9 Melatonin: Therapeutic Value and Neuroprotection in Stroke...................................97 Max Franzblau, Nick Franzese, Gabriel S. Gonzales-Portillo, Chiara Gonzales-Portillo, Meaghan Staples, Mia C. Borlongan, Naoki Tajiri, Yuji Kaneko, and Cesar V. Borlongan

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Chapter 10 Melatonin’s Antiapoptotic Activity in Neurodegenerative Diseases........................ 111 Xin Wang, Yingjun Guan, Wenyu Fu, Shuanhu Zhou, and Zheng-Hong Qin Chapter 11 MT2 Melatonin Receptors: Their Role in Sleep and Neuropsychiatric Disorders...... 133 Stefano Comai and Gabriella Gobbi Chapter 12 Melatonin: Its Hepatoprotective Actions and the Role of Melatonin Receptors....... 143 Alexander M. Mathes

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Chapter 13 Melatonin Signaling in the Control of Plasmodium Development and Replication....................................................................................................... 157 Alexandre Budu and Célia R. S. Garcia Chapter 14 Melatonin: Regulator of Adult Hippocampal Neurogenesis..................................... 167 Gerardo B. Ramírez-Rodríguez and Leonardo Ortiz-López Chapter 15 Comparison of Neuroprotective Effect of Melatonin in the Nigrostriatal and Mesolimbic Dopaminergic Systems of the Zitter Rat............................................... 179 Shuichi Ueda, Ayuka Ehara, Kenichi Inoue, Tomoyuki Masuda, Shin-ichi Sakakibara, and Kanji Yoshimoto Chapter 16 Melatonin’s Neuroprotective Role in Parkinson’s Disease....................................... 189 Venkataramanujam Srinivasan, Timo Partonen, Mahaneem Mohamed, Rahimah Zakaria, Asma Hayati Ahmad, Charanjit Kaur, Domenico De Berardis, Edward C. Lauterbach, Samuel D. Shillcutt, and U.S. Srinivasan Chapter 17 Neuroprotective Role of Melatonin in Glaucoma..................................................... 203 Ruth E. Rosenstein, María C. Moreno, Pablo Sande, Marcos Aranda, María F. González Fleitas, and Nicolás Belforte Chapter 18 Melatonin Receptors and Their Preventive Role in Carcinogenesis......................... 223 Raffaela Santoro, Maria Ferraiuolo, Giovanni Blandino, Paola Muti, and Sabrina Strano Chapter 19 Enhancement of Antitumor Activity of Ursolic Acid by Melatonin in Colon Cancer Cells............................................................................................... 233 Wei Guo, Jingshu Wang, and Wuguo Deng Chapter 20 Synthetic Melatonin Receptor Ligands..................................................................... 249 Silvia Rivara, Marco Mor, Annalida Bedini, and Gilberto Spadoni

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Chapter 21 Evaluation of Synthetic Melatonin Analog Antioxidant Compounds....................... 259 Sibel Suzen Chapter 22 Melatonin’s Analogues in Glaucoma........................................................................ 269 Hanan Awad Alkozi and Jesús Pintor Chapter 23 Melatonergic Drugs as Therapeutic Agents for Insomnia and Depressive Disorders.......................................................................................... 289

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Venkataramanujam Srinivasan, Domenico De Berardis, Amnon Brzezinski, Rahimah Zakaria, Zahiruddin Othman, Samuel D. Shillcutt, Edward C. Lauterbach, Gregory M. Brown, and Timo Partonen Chapter 24 Agomelatine: A Neuroprotective Agent with Clinical Utility beyond Depression and Anxiety............................................................................................309 Cecilio Álamo, Francisco López-Muñoz, and Pilar García-García Chapter 25 Melatonergic Antidepressant Agomelatine in Depressive and Anxiety Disorders...... 325 Domenico De Berardis, Michele Fornaro, Venkataramanujam Srinivasan, Stefano Marini, Nicola Serroni, Daniela Campanella, Gabriella Rapini, Luigi Olivieri, Felice Iasevoli, Alessandro Valchera, Giampaolo Perna, Maria Antonia Quera-Salva, Monica Mazza, Marilde Cavuto, Ida Potena, Giovanni Martinotti, and Massimo Di Giannantonio Chapter 26 Effects of Melatonin and Melatonergic Drugs in Transgenic Mouse Models of Alzheimer’s Disease..................................................................... 339 Beatriz B. Otalora, M. Angeles Rol, and Juan A. Madrid Chapter 27 Melatonin’s Mitochondrial Protective Role in Alzheimer’s Mice: Role of Melatonin Receptors................................................................................................. 353 Vedad Delic and Patrick C. Bradshaw Chapter 28 Melatonin and Its Therapeutic Implications in Injuries of the Developing Brain and Retina........................................................................................................ 375 Gurugirijha Rathnasamy, Eng-Ang Ling, and Charanjit Kaur Chapter 29 Melatonin’s Protection against Human Prion-Mediated Neurotoxicity.................... 389 Jae-Kyo Jeong and Sang-Youel Park Chapter 30 Melatonin’s Protection against Methamphetamine Toxicity in Neuroblastoma Cells............................................................................................. 397 Banthit Chetsawang

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Chapter 31 Melatonin’s Beneficial Effects on Dopaminergic Neurons in the Rat Model of Parkinson’s Disease..................................................................409 Manisha Gautam, Reshu Gupta, Ravinder Kumar Saran, and Bal Krishana Chapter 32 Antiepileptic Effects of Melatonin............................................................................ 421 M. Hakan Seyithanoğlu, Mehmet Turgut, Meliha Gündağ Papaker, Mustafa Ayyıldız, Süleyman Kaplan, and Saffet Tüzgen Chapter 33 Analgesic Effects of Melatonin................................................................................. 431

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Selçuk Yavuz, Mehmet Turgut, Özlem Yalçınkaya Yavuz, and Teoman Aydın Chapter 34 Effects of Melatonin on the Proliferative and Differentiative Activity of Neural Stem Cells........................................................... 441 Saime İrkören, Heval Selman Özkan, and Mehmet Turgut Chapter 35 Role of Melatonin in Collagen Synthesis.................................................................. 447 Özgür Taşpınar, Mehmet Turgut, Engin Taştaban, and Teoman Aydın Chapter 36 Melatonin Use in Peripheral Nerve Injury................................................................ 457 Mehmet Emin Önger, Süleyman Kaplan, Ebru Elibol, Ömür Gülsüm Deniz, and Berrin Zühal Altunkaynak Chapter 37 Neuroprotective Role of Melatonin and Its Agonists: Neuroprotective Role of Melatonin against Dexamethasone-Induced Neurotoxicity...................................... 463 Aziza B. Shalby and Hanaa H. Ahmed Chapter 38 Does Melatonin Have a Protective Role against Side Effects of Nonsteroidal Anti-Inflammatory Drugs?........................................................................................469 Ebru Elibol, Berrin Zühal Altunkaynak, Ömür Gülsüm Deniz, Mehmet Emin Önger, and Süleyman Kaplan Chapter 39 Melatonin: Pharmacological Aspects and Clinical Trends....................................... 485 Emiliano Ricardo Vasconcelos Rios Chapter 40 Protective Effects of Melatonin in Radiation-Induced Nephrotoxicity.................... 493 Eda Kucuktulu and Uzer Kucuktulu Chapter 41 Melatonin and Familial Mediterranean Fever.......................................................... 499 Engin Taştaban, Mehmet Turgut, and Teoman Aydın

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Chapter 42 Effects of Melatonin on Osteoblastic and Osteoclastic Activities of Bone Tissue......................................................................................... 505 Meliha Gündağ Papaker, M. Hakan Seyithanoğlu, Mehmet Turgut, Süleyman Kaplan, and Saffet Tüzgen Chapter 43 Phyto-Melatonin: A Novel Therapeutic Aspect of Melatonin in Nature’s Way....... 515 Chandana Haldar, Somenath Ghosh, and Amaresh Kumar Singh

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Index............................................................................................................................................... 523

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Preface Melatonin was first isolated from the bovine pineal gland in 1958 by the dermatologist Aaron B. Lerner. Since then, thousands of papers have been published on melatonin function, but its action remains to be clarified. However, the nature of melatonin and its diverse physiological actions, ranging from sleep initiation to control of mood and behavior, has greatly increased during the last two decades, primarily due to the impetus that has been given to the identification and cloning of melatonin receptors and the studies related to altered functional receptorial status seen in neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and cancer. In addition, the discovery of several selective and nonselective melatonergic agonists, displaying a better pharmacokinetic profile compared to melatonin itself, has also allowed us to expand our knowledge of melatonin functions. A number of clinical trials conducted on the use of these drugs in neurological and psychiatric disorders have testified to the successful therapeutic application of some of these melatonergic agonists in treating brain disorders. Altogether, these preclinical and clinical studies have opened up new vistas in melatonin research, especially in relation to its nature, receptor binding function, and its therapeutic potential. The aim of this book is to bring together a comprehensive synopsis of the functional importance of melatonin and its receptors with regard to human health as well as the possible mechanisms by which melatonin and its agonists are able to exert their therapeutic effects in diseases like cancer, Alzheimer’s disease, Parkinson’s disease, epilepsy, stroke, and cardiovascular disorders. The chapters focusing on these themes have been written by experts in specific melatonin fields and/or clinical investigators working with the therapeutic use of either melatonin or melatonergic derivates such as the hypnotic ramelteon or the antidepressant agomelatine. This book will be useful not only for graduates and research scientists pursuing research studies on melatonin but also for clinical investigators, neurologists, psychiatrists, and physicians with an interest in the field. More importantly, this book will motivate researchers and clinicians to further investigate the therapeutic potential of melatonin.

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Acknowledgments

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It is our pleasure to acknowledge Lance Wobus, senior editor, Taylor & Francis Group, who showed keen interest in this project and supported it throughout the production process. But for his timely help, this book could not have been published. We are grateful to Prof. Stephan C. Bondy, Prof. Aberto-Dominguez-Rodriguez, Prof. Cesar V. Borlongan, Doz Dr. Alexander M. Mathes, Prof. Gerado B. Ramirez-Rodriguez, Prof. Shuichi-Ueda, Prof. Domenico De Berardis, Prof. Francisco López-Muñoz, Prof. Patrick B. Bradshaw, Prof. Suleyman Kaplan, Dr. Gerardo B. Ramirez Rodriguez, and Prof. Timo Partonen for their unfailing support and encouragement. Our thanks also to all authors for their valuable contributions. Finally, we acknowledge Rachael Panthier, project editor, Taylor & Francis Group, who coordinated this project successfully from beginning to end.

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Editors Professor Venkataramanujam Srinivasan, PhD, MAMS, started his professional career as an assistant professor at the Institute of Physiology, Madurai Medical College, Madurai, Tamil Nadu, India, where he served for 24 years. During his tenure there, he was engaged in both teaching and research studies. Besides teaching physiology to undergraduate medical students, he undertook various collaborative research studies with the Department of Psychiatry and published a number of papers on lithium, catecholamine metabolism, the pineal gland, and melatonin in both national and international medical and life sciences journals. He has also served as one of the advisory council members for the International Society of Psychoneuroendocrinology (ISPNE) for 10 years. Professor Srinivasan then undertook teaching assignments as associate professor of physiology at the School of Medical Sciences, University Sains Malaysia (USM), Kubang Kerian, Kelantan, Malaysia, after which he continued with his teaching and research activities. He collaborated on research publications with a number of professors and research scientists working in different universities in Argentina, Canada, the United States, the Netherlands, and Spain, which were published and indexed in PubMed. After leaving USM, he continued to work on his collaborative research projects on melatonin with professors working in different universities in Spain, the United States, Italy, Finland, Japan, Germany, Malaysia, and Singapore as well as from Sri Sathya Sai Medical Educational and Research Foundation, an International Medical Sciences Research Study Center located in KOVAI Coimbatore, Tamil Nadu, India. He has also published papers in international medical journals, which can be viewed in PubMed. Professor Srinivasan has served as guest lecturer and has presented papers in national and international conferences/congresses organized by the Association of Physiologists and Pharmacologists of India (APPI), Federation of the Asian and Oceanian Physiological Societies (FAOPS), International Union of Physiological Sciences (IUPS), British Lithium Congress, Malaysian Society of Pharmacology and Physiology (MSPP), and International Society of Psychoneuroendocrinology (ISPNE) Biotechnology Conference (Tokyo) in addition to numerous symposia and workshops organized in India, Malaysia, Japan, and Singapore. He has also contributed chapters in books published by Springer and Informa Health Care and NOVA Publishers, among others. Recently, he has coedited the book entitled Melatonin and Melatonergic Drugs in Clinical Practice along with Prof. A Brzezinski (Israel), Prof. Sukru Oter (Turkey), and Prof. Samuel D. Shillcutt (USA), which was published by Springer in January 2014. Professor Srinivasan is also a life member of the Association of Physiologists and Pharmacologists of India (APPI) and the National Academy of  Medical Sciences, India. Dr. Gabriella Gobbi is an associate professor in the Department of Psychiatry, McGill University; staff psychiatrist at the McGill University Health Center (MUHC), Montreal, Canada; and coleader of Mental Illness and Addiction Axis of the Research Institute of the MUHC. Dr. Gobbi earned her MD in 1991 and her specialty in psychiatry and psychotherapy in 1995 from the Catholic University of Rome, Italy. She also earned a PhD in neuroscience at the University of Cagliari, Italy. She then moved to McGill University, Montreal, Canada, in 1998, where she initially worked as a postdoc with Drs. Blier, De Montigny, and Debonnel. She then joined the University of Montreal as an assistant professor in 2002 and became associate professor at McGill University in 2008. She leads a laboratory of basic science and works as a psychiatrist at the mood disorder clinic of the MUHC. Dr. Gobbi’s research interests include understanding the pathophysiology of major depression and related disorders and discovering new treatments for them. xiii

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In particular, her laboratory conducts research on the short- and long-term effects of cannabis use in mood and anxiety and the potential beneficial effects of drugs acting on the endocannabinoid system (endogenous cannabis) to cure mental diseases. Her lab also conducts research on the effect of melatonin in alleviating mood disorders and anxiety, and sleep regulation in an effort to understand how novel selective ligands for melatonin receptors (called MT1 and MT2 receptors) can be used to treat seasonal depression, major depression, sleep disorders, and other neuropsychiatric conditions. The laboratory research ranges from bench to bedside, bridging the gaps between fundamental and clinical research. The techniques employed in the lab include in vivo electrophysiology, behavioral pharmacology, and neurochemistry. Dr. Gobbi is the author of more than 50 highly cited manuscripts in international journals, including Proceedings of the National Academy of Sciences of the United States of America (PNAS), Nature Neuroscience, and the Journal of Neuroscience and holds two international patents in psychopharmacology. She has received several fellowships, awards, and grants from the Canadian Institutes of Health Research (CIHR), Fonds de la Recherche en Santé du Québec (FRSQ, Junior 1, Junior 2, Senior), the Canadian Psychiatric Research Foundation (CPRF), and the Canadian Foundation for Innovation (CFI), as well as from multinational pharmaceutical companies. She won the Canadian College of Neuropsychopharmacology (CCNP) Young Investigator Award in 2012. Dr. Gobbi has served as a reviewer/editor for many journals and international grant agencies and has been invited to speak at conferences worldwide. Dr. Samuel D. Shillcutt is a tenured professor and director of neuropsychopharmacology research in the Department of Psychiatry, Mercer University School of Medicine, and a clinical pharmacology consultant for the Medical Center of Central Georgia. He is also the director of the Medical Center of Central Georgia/Mercer University School of Medicine, Psychiatry Research Fellowship Program. Dr. Shillcutt earned degrees in chemistry (BA), pharmacy (BS), clinical pharmacy (PharmD), and neuropharmacology (PhD) and completed postdoctoral training in clinical neuropsychopharmacology. He has held positions at the University of Nebraska Medical Center, Creighton University School of Medicine, the Veterans Administration Medical Center (Omaha, Nebraska), Southern Illinois University (SIU) School of Medicine, and Mercer University School of Medicine (MUSM). He was the director of the Schizophrenia Research Program with SIU and MacFarland Psychiatric Hospital, Springfield, Illinois, and director of the Center for Clinical Studies at Central State Hospital, Milledgeville, Georgia, and the Medical Center of Central Georgia, Macon, Georgia. For 20 years at MUSM, Dr. Shillcutt was the director of the Neuro-Psychopharmacology Research Laboratory, conducting cerebrovascular, receptor, and neurochemical analysis research, and established collaboration with Harvard University and the University of Arkansas brain banks for pathophysiological investigation of schizophrenia, Alzheimer’s disease, and Huntington’s disease. Dr. Shillcutt’s 38 years of research have focused on translational studies connecting interpretation of basic science and clinical trials data to lead to effective treatment modalities. His interest in understanding the pathology and treatment of neuropsychiatric disorders has led him to establishing the efficacy and safety of atypical antipsychotics, antidepressants, and medications used for Alzheimer’s disease. His research techniques involve using clinical investigation of psychopharmaceuticals, neurochemistry, and electrophysiology to determine human responses and using human tissue in cell culture to establish models for basic science investigation of potential novel compounds. His most current studies investigated the effects of melatonin-like substances in regulation of mood and sleep disorders in dementias. Dr. Shillcutt has numerous national and international peer-reviewed publications, books, book chapters, and abstracts. He is a member of ten national and international professional societies. He is also a reviewer/editor for several journals, books, and granting agencies and has been an invited speaker at many national and international colloquia and conferences.

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Dr. Sibel Süzen currently serves as a professor of pharmaceutical chemistry in the Faculty of Pharmacy, Ankara University, Turkey, and institutional coordinator of the European Union (EU) student exchange programme (Erasmus Programme). Dr. Süzen pursued her studies at Ankara University and earned her pharmacy degree in 1985 and master’s degree in pharmaceutical chemistry in 1989 from the same university. She earned a PhD (1997) from the University of Swansea, Department of Chemistry (United Kingdom), where she worked on the synthesis and hydrazinolysis of dehydroalanine and glycoproteins. She has been involved in several medicinal chemistry projects supported by the government and Ankara University. These projects are related to the synthesis and investigation of biological activity of aldose reductase inhibitory compounds, antioxidant compounds, indole derivatives, in vitro drug metabolisms by electroanalytical, and, most importantly, the synthesis and antioxidant investigation of melatonin derivatives. Dr. Süzen is the author of more than 50 highly cited manuscripts in international journals. She has organized and participated in a number of international pharmaceutical chemistry meetings. She is on the editorial board and has served as a reviewer for many pharmaceutical and medicinal chemistry journals and has been invited to speak at conferences. Her research interest focuses on the synthesis and biological evaluation of melatonin- and peptide-related antioxidant compounds as well as aldose reductase inhibitors and electrochemical investigations.

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Contributors

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Pedro Abreu-Gonzalez Department of Physiology Universidad de La Laguna Tenerife, Spain Niyazi Acer Department of Anatomy School of Medicine Erciyes University Kayseri, Turkey Asma Hayati Ahmad Department of Physiology School of Medical Sciences Universiti Sains Malaysia Kelantan, Malaysia Hanaa H. Ahmed Department of Hormones National Research Centre Cairo, Egypt Cecilio Álamo Faculty of Medicine and Health Sciences Department of Biomedical Sciences (Pharmacology Area) University of Alcalá Madrid, Spain Hanan Awad Alkozi Department of Biochemistry and Molecular Biology IV Faculty of Optics and Optometry University Complutense de Madrid Madrid, Spain Daniel Alonso-Alconada Department of Cell Biology and Histology School of Medicine and Dentistry University of the Basque Country Bizkaia, Spain

Berrin Zühal Altunkaynak Department of Histology and Embryology School of Medicine Ondokuz Mayıs University Samsun, Turkey Antonia Alvarez Department of Cell Biology and Histology School of Medicine and Dentistry University of the Basque Country Bizkaia, Spain Marcos Aranda Department of Human Biochemistry School of Medicine/CEFyBO University of Buenos Aires/CONICET Buenos Aires, Argentina Teoman Aydın Department of Physical Therapy and Rehabilitation School of Medicine Bezmialem Vakıf University İstanbul, Turkey Mustafa Ayyıldız Department of Physiology School of Medicine Ondokuz Mayıs University Samsun, Turkey Meral Baka Department of Histology and Embryology School of Medicine Ege University Izmir, Turkey Annalida Bedini Department of Biomolecular Sciences University of Urbino “Carlo Bo” Urbino, Italy

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Nicolás Belforte Department of Human Biochemistry School of Medicine/CEFyBO University of Buenos Aires/CONICET Buenos Aires, Argentina

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Giovanni Blandino Translational Oncogenomics Unit Molecular Medicine Area Regina Elena National Cancer Institute Rome, Italy Stephen C. Bondy Department of Medicine Center for Occupational and Environmental Health University of California, Irvine Irvine, California Cesar V. Borlongan Department of Neurosurgery and Brain Repair Center of Excellence for Aging and Brain Repair Morsani College of Medicine University of South Florida Tampa, Florida Mia C. Borlongan Department of Neurosurgery and Brain Repair Center of Excellence for Aging and Brain Repair Morsani College of Medicine University of South Florida Tampa, Florida Patrick C. Bradshaw Department of Cell Biology, Microbiology, and Molecular Biology University of South Florida Tampa, Florida Gregory M. Brown Department of Psychiatry University of Toronto and Centre for Addiction and Mental Health Toronto, Ontario, Canada

Contributors

Amnon Brzezinski Department of Obstetrics and Gynecology Hadassah Medical Center The Hebrew University Jerusalem, Israel

Alexandre Budu Departamento de Fisiologia Instituto de Biociências Universidade de São Paulo São Paulo, Brazil

Daniela Campanella Department of Mental Health Psychiatric Service of Diagnosis and Treatment Hospital “G. Mazzini” Teramo, Italy

Marilde Cavuto Istituto Abruzzese di Storia Musicale L’Aquila, Italy

Emel Öykü Çetin Department of Biopharmaceutics and Pharmacokinetics and Department of Pharmaceutical Technology Ege University İzmir, Turkey Banthit Chetsawang Research Center for Neuroscience Institute of Molecular Biosciences Mahidol University Nakhonpathom, Thailand

Stefano Comai Department of Psychiatry McGill University and McGill University Health Centre Montreal, Québec, Canada

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Domenico De Berardis Department of Mental Health Psychiatric Service of Diagnosis and Treatment Hospital “G.Mazzini” Teramo, Italy and Department of Neurosciences and Imaging University “G.D” Annunzio Chieti, Italy Vedad Delic Department of Cell Biology, Microbiology, and Molecular Biology University of South Florida Tampa, Florida Wuguo Deng Institute of Cancer Stem Cell Dalian Medical University Cancer Center Dalian, Liaodong, People’s Republic of China and State Key Laboratory of Oncology in South China Sun Yat-Sen University Cancer Center Guangzhou, Guangdong, People’s Republic of China Ömür Gülsüm Deniz Department of Histology and Embryology Medical School Ondokuz Mayıs University Samsun, Turkey Massimo Di Giannantonio Department of Neuroscience and Imaging University “G. D’Annunzio” Chieti, Italy Alberto Dominguez-Rodriguez Department of Cardiology Hospital Universitario de Canarias Tenerife, Spain Ayuka Ehara Department of Histology and Neurobiology School of Medicine Dokkyo Medical University Tochigi, Japan

Ebru Elibol Department of Histology and Embryology School of Medicine Ondokuz Mayıs University Samsun, Turkey Javier Espino Department of Physiology University of Extremadura Badajoz, Spain Maria Ferraiuolo Molecular Chemoprevention Group Molecular Medicine Area Regina Elena National Cancer Institute Rome, Italy María F. González Fleitas Department of Human Biochemistry School of Medicine/CEFyBO University of Buenos Aires/CONICET Buenos Aires, Argentina Michele Fornaro Department of “Scienze della Formazione” University of Catania Catania, Italy Max Franzblau Department of Neurosurgery and Brain Repair Center of Excellence for Aging and Brain Repair Morsani College of Medicine University of South Florida Tampa, Florida Nick Franzese Department of Neurosurgery and Brain Repair Center of Excellence for Aging and Brain Repair Morsani College of Medicine University of South Florida Tampa, Florida

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Wenyu Fu Department of Histology and Embryology Weifang Medical University Weifang, Shandong, People’s Republic of China

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Manisha Gautam Department of Physiology Maulana Azad Medical College New Delhi, India

Célia R. S. Garcia Departamento de Fisiologia Instituto de Biociências Universidade de São Paulo São Paulo, Brazil

Pilar García-García Faculty of Medicine and Health Sciences Department of Biomedical Sciences (Pharmacology Area) University of Alcalá Madrid, Spain

Somenath Ghosh Department of Zoology Banaras Hindu University Uttar Pradesh, India

Gabriella Gobbi Department of Psychiatry McGill University and McGill University Health Center Montreal, Québec, Canada

Chiara Gonzales-Portillo Department of Neurosurgery and Brain Repair Center of Excellence for Aging and Brain Repair Morsani College of Medicine University of South Florida Tampa, Florida

Contributors

Gabriel S. Gonzales-Portillo Department of Neurosurgery and Brain Repair Center of Excellence for Aging and Brain Repair Morsani College of Medicine University of South Florida Tampa, Florida Yingjun Guan Department of Histology and Embryology Weifang Medical University Weifang, Shandong, People’s Republic of China Wei Guo Institute of Cancer Stem Cell Dalian Medical University Cancer Center Dalian, Liaoning, People’s Republic of China Reshu Gupta Department of Physiology SMS Medical College Jaipur, Rajasthan, India Chandana Haldar Department of Zoology Banaras Hindu University Uttar Pradesh, India Rüdiger Hardeland Johann Friedrich Blumenbach Institute of Zoology and Anthropology University of Göttingen Göttingen, Germany Enrique Hilario Department of Cell Biology and Histology School of Medicine and Dentistry University of the Basque Country Bizkaia, Spain Felice Iasevoli Department of Neuroscience University School of Medicine “Federico II” Naples, Italy

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Kenichi Inoue School of Medicine Dokkyo Medical University Tochigi, Japan

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Saime İrkören Department of Plastic and Reconstructive Surgery School of Medicine Adnan Menderes University Aydın, Turkey Jae-Kyo Jeong Bio Safety Research Institute College of Veterinary Medicine Chonbuk National University Jeonju, Republic of Korea Yuji Kaneko Department of Neurosurgery and Brain Repair Center of Excellence for Aging and Brain Repair Morsani College of Medicine University of South Florida Tampa, Florida Süleyman Kaplan Department of Histology and Embryology Medical School Ondokuz Mayıs University Samsun, Turkey Süleyman Karademir Department of Histology and Embryology School of Medicine Adnan Menderes University Aydın, Turkey Charanjit Kaur Department of Anatomy Yong Loo Lin School of Medicine National University of Singapore Singapore, Singapore Bal Krishana Department of Physiology Maulana Azad Medical College New Delhi, India

Eda Kucuktulu Department of Radiation Oncology Trabzon Kanuni Training and Research Hospital Trabzon, Turkey Uzer Kucuktulu Department of General Surgery Trabzon Kanuni Training and Research Hospital Trabzon, Turkey Edward C. Lauterbach Department of Psychiatry and Behavioural Sciences and Department of Internal Medicine (Neurology Section) School of Medicine Mercer University Macon, Georgia Eng-Ang Ling Department of Anatomy Yong Loo Lin School of Medicine National University of Singapore Singapore, Singapore Francisco López-Muñoz Faculty of Health Sciences Camilo José Cela University and Faculty of Medicine and Health Sciences Department of Biomedical Sciences (Pharmacology Area) University of Alcalá and Hospital 12 de Octubre Research Institute Madrid, Spain Juan A. Madrid Faculty of Biology Chronobiology Laboratory Department of Physiology University of Murcia Murcia, Spain

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Stefano Marini Department of Mental Health Psychiatric Service of Diagnosis and Treatment Hospital “G. Mazzini” Teramo, Italy

María C. Moreno Department of Human Biochemistry School of Medicine/CEFyBO University of Buenos Aires/CONICET Buenos Aires, Argentina

and

Paola Muti Department of Oncology Juravinski Cancer Center McMaster University Hamilton, Ontario, Canada

Department of Neuroscience and Imaging University “G. D’Annunzio” Chieti, Italy

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Contributors

Giovanni Martinotti Department of Neuroscience and Imaging University “G. D’Annunzio” Chieti, Italy Tomoyuki Masuda Department of Neurobiology School of Medicine University of Tsukuba Tsukuba, Japan Alexander M. Mathes Department of Anesthesiology Düsseldorf University Hospital Düsseldorf, Germany Monica Mazza Department of Life, Health and Environmental Sciences University of L’Aquila L’Aquila, Italy Maria D. Mediavilla Department of Physiology and Pharmacology School of Medicine and Research Institute “Marqués de Valdecilla” (IDIVAL) University of Cantabria Santander, Spain Mahaneem Mohamed Department of Physiology School of Medical Sciences Universiti Sains Malaysia Kelantan, Malaysia Marco Mor Department of Pharmacy University of Parma Parma, Italy

Yoshiji Ohta School of Medicine Fujida Health University Toyoake, Japan Luigi Olivieri Department of Mental Health Psychiatric Service of Diagnosis and Treatment Hospital “G. Mazzini” Teramo, Italy Mehmet Emin Önger Department of Histology and Embryology Medical School Ondokuz Mayıs University Samsun, Turkey Leonardo Ortiz-López Division of Clinical Investigations National Institute of Psychiatry “Ramón de la Fuente Muñiz” México, México Beatriz B. Otalora Department of Physiology University of Murcia Murcia, Spain Zahiruddin Othman Department of Psychiatry School of Medical Sciences Universiti Sains Malaysia Kelantan, Malaysia

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Contributors

Heval Selman Özkan Department of Plastic and Reconstructive Surgery School of Medicine Adnan Menderes University Aydın, Turkey

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Meliha Gündağ Papaker Department of Neurosurgery School of Medicine Bezmialem Vakıf University İstanbul, Turkey Sang-Youel Park Bio Safety Research Institute College of Veterinary Medicine Chonbuk National University Jeonju, Republic of Korea Timo Partonen Department of Mental Health and Substance Abuse Services National Institute for Health and Welfare Helsinki, Finland Giampaolo Perna Department of Clinical Neurosciences Villa San Benedetto Menni Hermanas Hospitalarias, FoRiPsi Como, Italy and Department of Psychiatry and Behavioral Sciences Leonard Miller School of Medicine University of Miami Miami, Florida and Department of Psychiatry and Neuropsychology University of Maastricht Maastricht, the Netherlands Jesús Pintor Department of Biochemistry and Molecular Biology IV Faculty of Optics and Optometry University Complutense de Madrid Madrid, Spain

Ida Potena Department of Mental Health Center of Mental Health Teramo, Italy Zheng-Hong Qin Department of Pharmacology School of Pharmaceutical Science Soochow University Suzhou, Jiangsu, People’s Republic of China Maria Antonia Quera-Salva AP-HP Sleep Unit Department of Physiology Raymond Poincaré Hospital Garches, France Gerardo B. Ramírez-Rodríguez Laboratory of Neurogenesis Division of Clinical Investigations National Institute of Psychiatry “Ramón de la Fuente Muñiz” México, México Gabriella Rapini Department of Mental Health Psychiatric Service of Diagnosis and Treatment Hospital “G. Mazzini” Teramo, Italy Gurugirijha Rathnasamy Department of Anatomy Yong Loo Lin School of Medicine National University of Singapore Singapore, Singapore Russel J. Reiter Department of Cellular and Structural Biology University of Texas Health Science Center San Antonio, Texas Emiliano Ricardo Vasconcelos Rios Laboratory of Neuropharmacology Federal University of Ceará Ceará, Brazil

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Silvia Rivara Department of Pharmacy University of Parma Parma, Italy

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M. Angeles Rol Department of Physiology University of Murcia Murcia, Spain Ruth E. Rosenstein Department of Human Biochemistry School of Medicine/CEFyBO University of Buenos Aires/CONICET Buenos Aires, Argentina Shin-ichi Sakakibara Laboratory of Molecular Neurobiology Institute of Applied Brain Sciences Waseda University Saitama, Japan Emilio J. Sanchez-Barcelo Department of Physiology and Pharmacology School of Medicine and Research Institute “Marqués de Valdecilla” (IDIVAL) University of Cantabria Santander, Spain Pablo Sande Department of Human Biochemistry School of Medicine/CEFyBO University of Buenos Aires/CONICET Buenos Aires, Argentina Raffaela Santoro Molecular Chemoprevention Group Molecular Medicine Area Regina Elena National Cancer Institute Rome, Italy Ravinder Kumar Saran Department of Pathology G B Pant Hospital New Delhi, India

Contributors

Nicola Serroni Department of Mental Health Psychiatric Service of Diagnosis and Treatment Hospital “G. Mazzini” Teramo, Italy M. Hakan Seyithanoğlu Department of Neurosurgery School of Medicine Bezmialem Vakıf University İstanbul, Turkey Aziza B. Shalby Department of Hormones National Research Centre Cairo, Egypt Edward H. Sharman Department of Neurology University of California, Irvine Irvine, California Samuel D. Shillcutt Department of Psychiatry and Behavioral Sciences School of Medicine Mercer University Macon, Georgia Amaresh Kumar Singh Department of Zoology Banaras Hindu University Uttar Pradesh, India Gilberto Spadoni Department of Biomolecular Sciences University of Urbino “Carlo Bo” Urbino, Italy U.S. Srinivasan Fortis Malar Hospital Chennai, Tamil Nadu, India

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Contributors

Venkataramanujam Srinivasan International Medical Sciences Research Study Center Sri Sathya Sai Medical Educational and Research Foundation Coimbatore, Tamil Nadu, India and

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Department of Mental Health Psychiatric Service of Diagnosis and Treatment Hospital “G. Mazzini” National Health Service Teramo, Italy and Department of Neurosciences and Imaging University “G. d’Annunzio” Chieti, Italy

Meaghan Staples Department of Neurosurgery and Brain Repair Center of Excellence for Aging and Brain Repair Morsani College of Medicine University of South Florida Tampa, Florida

Sabrina Strano Molecular Chemoprevention Group Molecular Medicine Area Regina Elena National Cancer Institute Rome, Italy and

Naoki Tajiri Department of Neurosurgery and Brain Repair Center of Excellence for Aging and Brain Repair Morsani College of Medicine University of South Florida Tampa, Florida Özgür Taşpınar Department of Physical Therapy and Rehabilitation School of Medicine Bezmialem Vakıf University İstanbul, Turkey Engin Taştaban Department of Physical Therapy and Rehabilitation School of Medicine Adnan Menderes University Aydın, Turkey Mehmet Turgut Department of Neurosurgery School of Medicine Adnan Menderes University Aydin, Turkey Saffet Tüzgen Department of Neurosurgery School of Medicine Bezmialem Vakıf University İstanbul, Turkey

Department of Oncology Juravinski Cancer Center McMaster University Hamilton, Ontario, Canada

Shuichi Ueda Department of Histology and Neurobiology School of Medicine Dokkyo Medical University Tochigi, Japan

Sibel Suzen Department of Pharmaceutical Chemistry Faculty of Pharmacy Ankara University Ankara, Turkey

Yiğit Uyanıkgil Department of Histology and Embryology School of Medicine Ege University Izmir, Turkey

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Alessandro Valchera Hermanas Hospitalarias, FoRiPsi Villa S. Giuseppe Hospital Ascoli Piceno, Italy

Contributors

Selçuk Yavuz Department of Physical Therapy and Rehabilitation Edirne State Hospital Edirne, Turkey

Jingshu Wang State Key Laboratory of Oncology in South China Sun Yat-Sen University Cancer Center Guangzhou, Guangdong, People’s Republic of China

Kanji Yoshimoto Department of Food Sciences and Biotechnology Hiroshima Institute of Technology Hiroshima, Japan

Xin Wang Department of Neurosurgery Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts

Rahimah Zakaria Department of Physiology School of Medical Sciences Universiti Sains Malaysia Kelantan, Malaysia

Özlem Yalçınkaya Yavuz Department of Physiology School of Medicine Trakya University Edirne, Turkey

Shuanhu Zhou Department of Orthopedic Surgery Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts