ADVANCES IN THE PRECLINICAL STUDY OF ISCHEMIC STROKE Edited by Maurizio Balestrino Advances in the Preclinical Study of Ischemic Stroke Edited by Maurizio Balestrino Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2012 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. 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Publishing Process Manager Maja Bozicevic Technical Editor Teodora Smiljanic Cover Designer InTech Design Team First published March, 2012 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Advances in the Preclinical Study of Ischemic Stroke, Edited by Maurizio Balestrino p. cm. ISBN 978-953-51-0290-8 Contents Preface IX Part 1 Animal Models and Techniques 1 Chapter 1 Ischemic Neurodegeneration in Stroke-Prone Spontaneously Hypertensive Rats and Its Prevention with Antioxidants Such as Polyphenols 3 Kazuo Yamagata Chapter 2 Frameless Stereotaxy in Sheep – Neurosurgical and Imaging Techniques for Translational Stroke Research 21 Antje Dreyer, Albrecht Stroh, Claudia Pösel, Matthias Findeisen, Teresa von Geymüller, Donald Lobsien, Björn Nitzsche and Johannes Boltze Chapter 3 A Master Key to Assess Stroke Consequences Across Species: The Adhesive Removal Test 47 Valentine Bouet and Thomas Freret Chapter 4 Variations in Origin of Arteries Supplying the Brain in Rabbit and Their Impact on Total Cerebral Ischemia 65 David Mazensky, Jan Danko, Emil Pilipcinec, Eva Petrovova and Lenka Luptakova Part 2 Pathophysiology of Ischemic or Anoxic Damage 83 Chapter 5 Cerebral Ischemia Induced Proteomic Alterations: Consequences for the Synapse and Organelles 85 Willard J. Costain, Arsalan S. Haqqani, Ingrid Rasquinha, Marie-Soleil Giguere and Jacqueline Slinn Chapter 6 Delayed Neuronal Death in Ischemic Stroke: Molecular Pathways 117 Victor Li, Xiaoying Bi, Paul Szelemej and Jiming Kong VI Contents Chapter 7 The Matrix Metalloproteinases and Cerebral Ischemia 145 Wan Yang and Guangqin Li Chapter 8 Folate Deficiency Enhances Delayed Neuronal Death in the Hippocampus After Transient Cerebral Ischemia 155 Jun Hyun Yoo Chapter 9 Glial Cells, Inflammation and Heat Shock Proteins in Cerebral Ischemia 177 Vivianne L. Tawfik, Robin E. White and Rona Giffard Chapter 10 Role of Creatine Kinase – Hexokinase Complex in the Migration of Adenine Nucleotides in Mitochondrial Dysfunction 193 Elena Erlykina and Tatiana Sergeeva Chapter 11 Diabetes-Mediated Exacerbation of Neuronal Damage and Inflammation After Cerebral Ischemia in Rat: Protective Effects of Water-Soluble Extract from Culture Medium of Ganoderma lucidum Mycelia 215 Naohiro Iwata, Mari Okazaki, Rika Nakano, Chisato Kasahara, Shinya Kamiuchi, Fumiko Suzuki, Hiroshi Iizuka, Hirokazu Matsuzaki and Yasuhide Hibino Chapter 12 Mechanisms of Ischemic Induced Neuronal Death and Ischemic Tolerance 241 Jan Lehotsky, Martina Pavlikova, Stanislav Straka, Maria Kovalska, Peter Kaplan and Zuzana Tatarkova Chapter 13 Mitochondrial Ceramide in Stroke 269 Tatyana I. Gudz and Sergei A. Novgorodov Part 3 Novel Approaches to Neuroprotection 303 Chapter 14 Neuroprotection in Animal Models of Global Cerebral Ischemia 305 Miguel Cervantes, Ignacio González-Burgos, Graciela Letechipía-Vallejo, María Esther Olvera-Cortés and Gabriela Moralí Chapter 15 Nrf2 Activation, an Innovative Therapeutic Alternative in Cerebral Ischemia 347 Carlos Silva-Islas, Ricardo A. Santana, Ana L. Colín-González and Perla D. Maldonado Chapter 16 Preconditioning and Postconditioning 379 Joseph T. McCabe, Michael W. Bentley and Joseph C. O’Sullivan Contents VII Chapter 17 Could Mannitol-Induced Delay of Anoxic Depolarization be Relevant in Stroke Patients? 399 Maurizio Balestrino, Enrico Adriano and Patrizia Garbati Chapter 18 Fasudil (a Rho Kinase Inhibitor) Specifically Increases Cerebral Blood Flow in Area of Vasospasm After Subarachnoid Hemorrhage 409 Masato Shibuya, Kenko Meda and Akira Ikeda Chapter 19 Endogenous Agents That Contribute to Generate or Prevent Ischemic Damage 419 Ornella Piazza and Giuliana Scarpati Chapter 20 Time-Window of Progesterone Neuroprotection After Stroke and Its Underlying Molecular Mechanisms 479 Weiyan Cai, Masahiro Sokabe and Ling Chen Chapter 21 The Na + /H + Exchanger-1 as a New Molecular Target in Stroke Interventions 497 Vishal Chanana, Dandan Sun and Peter Ferrazzano Chapter 22 PPAR Agonism as New Pharmacological Approach to the Management of Acute Ischemic Stroke 511 Elisa Benetti, Nimesh Patel and Massimo Collino Preface In the last part of the 20th century scientists discovered drugs that made the brain more resistant to ischemia, to such an extent that cerebral tissue treated with them was only little damaged, or was not damaged at all, by an ischemic insult that badly damaged control, untreated tissue. It was the beginning of a very exciting era in neuroscience research, a period when academic and industrial scientists all pursued the research of a “neuroprotectant” that could defend the ischemic brain from irreversible damage. As most people know, the search turned out to be mostly unsuccessful because the drugs that in the animal models were effective were not so effective in the clinics. Frustratingly enough, one compound after another failed in clinical trials of stroke patients. The easiest and most common explanation given was that something was wrong with animal studies, and this is still the leading belief of mainstream neurologists. So, skepticism grew among clinicians, and nowadays it is very rare to find a clinician that gets excited by the idea of trying or studying a “neuroprotective” compound in stroke. However, I think that such a dismissal is plain wrong. It is unconceivable that hundreds of scientists throughout the world have for 30 years all carried out flawed or even fraudulent research demonstrating that several compounds improve the resistance of the brain to ischemic damage. Granted, that may have happened sometimes, but hundreds of laboratories around the world cannot have been run during 30 years by incompetent or criminal scientists. At least, all successful animal research in neuroprotection must be seen as having provided a “proof-of-concept” demonstrating that it is possible to use drugs to protect the brain from ischemic damage. And in fact, that neuroprotection is indeed possible is demonstrated beyond doubt by the neglected survivor of that host of neuroprotectant agents: hypothermia. Hypothermia was demonstrated to be effective in a score of animal experiments, and it has now become recommended intervention in out-of-hospital cardiac arrest. Hypothermia is not a drug, but it demonstrates that neuroprotection is a reality, not a myth. Besides, it obviously shows that animal experiments were right, humans treated with hypothermia fare better than untreated ones, just like animal studies had predicted. Thus, the fact that hypothermia is now successful in clinical practice, at least in out-of- hospital cardiac arrest, tells us one simple truth: neuroprotection is possible. Another X Preface demonstration that neuroprotection is possible may be edaravone, a neuroprotective compound that has been used for years in Japan and China, and that has been declared reasonably effective in ischemic stroke, at least pending larger trials, by a recent Cochrane Review (S. Feng, et al. Edaravone for acute ischaemic stroke. Cochrane Database Syst. Rev. 12:CD007230, 2011). Why, then, have scores of drugs, previously found to be effective in animal models, failed clinical trials? The average clinician will answer this question by saying that animal experiments are useless, that they do not reflect the human situation, that they are badly designed and carried out, and so forth. Meetings and committees have even been celebrated to declare this truth, and to teach preclinical neuroscientists how to properly carry out their experiments, see for example the “STAIR” (Stroke Therapy Academic Industry Roundtable) meetings in the US. Of course, there is some truth in this answer, and probably much more than “some”. We are in the 21 st century, and even animal experiments must be updated and modernized. I am perfectly convinced that preclinical scientists (among whom I proudly list myself) must learn, as they have done for a couple of centuries, new ways of designing and carrying out their experiments. “Blind” treatment and evaluation, use of older animals (more similar to stroke patients), reliance on permanent rather than on transient models of ischemia are just the simplest and most obvious improvements that should be implemented in the laboratory, at least for those experiments that are meant to build the foundation for a clinical translation of the treatment. All these modifications, and much more, will certainly improve the reliability and the usefulness of animal experiments, much in the same way as the use of statistics has greatly improved animal experimentation in the 20 th century (remember those very old days when statistics were not required to publish an experiment?). But I believe that other truths must be told, too. First, clinicians have not been able to grasp the true conditions under which neuroprotection is possible. Clinicians (or maybe the drug industry?) have been blinded by the illusion that a simple cure to all ischemic strokes was at hand, and they simply treated all patients with stroke, irrespective, for example, of age, infarct size and comorbidity. Sometimes the neuroprotective treatment was administered one day after stroke onset, an obvious nonsense that was not justified by animal data. With these and other behaviors, clinicians lost the opportunity of neuroprotection by applying it to patients that were not apt to benefit from it. I was very happy in reading that this truth has finally been recognized even in published science: Reza et al. (Neuroprotection in acute ischemic stroke. J Neurosurg Sci. 55 (2):127-138, 2011) wrote that “Previous clinical studies have failed to show benefit [of neuroprotection] likely due to poor patient selection, altering time windows that had shown benefit in bench models and failure to link treatments with reperfusion”. Alas, animal scientists must . ADVANCES IN THE PRECLINICAL STUDY OF ISCHEMIC STROKE Edited by Maurizio Balestrino Advances in the Preclinical Study of Ischemic Stroke Edited by Maurizio Balestrino. detected in the astrocytes of SHRSP/Izm rats compared with those of WKY/Izm rats (Yamagata et al., 2010a). Advances in the Preclinical Study of Ischemic Stroke 4 Epidemiologic study indicated. advanced in the past decade, mainly due to the study of novel pathways of damage and of novel techniques to investigate them. Better knowledge of how brain tissue becomes damaged in stroke will