U. Ito . C. Fieschi . F. Orzi . T. Kuroiwa I. Klatzo (Eds.)

Maturation Phenomenon in Cerebral Ischemia III Defensive Mechanisms Versus Apoptosis

Neuronal Recovery and Protection in Cerebral Infarction

Third International Workshop, April 20-22, 1998, Pozzili, Italy Istituto Neurologico Mediterraneo "Neuromed", Pozzilli (Isernia), Italy

With 67 Figures, some in Color, and 20 Tables

'SPringer

UMEO ITo Musashino Red Cross Hospital Department of Neurosurgery 1-26-1 Kyonan-cho, Musashino-shi Tokyo 180, )apan

CE SARE FIESCHI Universita di Roma "La Sapienza" Dipartimenti di Scienze Neurologiche Viale dell'University 30 00185 Roma, Italy

FRANCESCO ORZI Istituto Neurologico Mediterraneo NEUROMED Research Laboratories Via Atinense 18 86077 Pozzilli (Isernia), Italy

Third International Workshop, ApriI20-22, 1998

TOSHIHIKO KUROIWA Tokyo Medical and Dental University Department of Neuropathology Medical Research Institute 1-5-45 Yushima, Bunkyo-ku 113 Tokyo, )apan

IGOR KLATZO National Institutes of Health Laboratory of Neuropathology and Neuroanatomical Sciences, NINDS Bethesda, MD 20892-4128, USA

Istituto Neurologico Mediterraneo "Neuromed", Pozzilli (Isernia), Italy Chairmen: C. Fieschi and U. Ito. Cochairmen: F. Orzi and T. Kuroiwa Secretaries: U. Ito (general), F. Otzi (local) International Advisory Board: A. Baethmann, N. G. Bazan, D. W. Choi, K.-A. Hossmann, T. Kirino, I. Klatzo, K. Kogure, ). Krieglstein, F. Plum, F. R. Sharp, M. Tomita and T. Wieloch Local Organizers: F. Orzi, V. Colangelo, R. Di Grezia, G. Sette Secretariats: 1) General: Department of Neurosurgery, Musashino Red Cross Hospital, 1-26-1 Kyonan­cho, Musashino-shi. Tokyo 180, )apan, Tel: +81-422-32-3111, Fax: +81-422-32-9551, e-mail: umeo­ito@po.iijnet.or.jp 2) Local: INM Neuromed, Via Atinense 18, 86077 Pozzilli (IS), ItaI. Tel: +39-865-915266/91521, Fax: +39-865-927575, e-mail: forzi@tin.it

ISBN 978-3-540-65023-2 ISBN 978-3-642-58602-6 (eBook)

DOI 10.1007/978-3-642-58602-6 Library of Congress Cataloging-in-Publication Data. Maturation phenomenon in cerebral ischema III: defensive mechanisms versus apoptosis neuronal recovery and protection in cerebral infarction / U. Ito ... [et aL] (eds.) New York: Springer, 1999. p. cm. RC388.5.M3632 1999 616.8/1 21. 3540650237 (softcover). Proceedings of the 3rd International Symposium on Matuation Phenomenon in Cerebral Ischemia, held in Pozilly Italy in Apri! 1998. Includes bibliographical references and index. Cerebral ischemia - Pathophysiology - Congresses. Cerebral ischemia - Molecular aspects - Congresses. Apoptosis - Congresses. Neuroplasticity - Con­gresses. Nervous system - Regeneration - Congresses. Ito, U. (Umeo) International Symposium on Maturation Phenomenon in Cerebral Ischemia (3rd : 1998: Pozilly, Italy). 98044835

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specially the rights of translations, reprinting, reuse of illustrations, re citation, broad­casting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permis sion for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law.

© Springer-Verlag Berlin Heidelberg 1999

The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant pro­tective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information be consult ing the relevant literature. Production: PRO EDIT GmbH, Heidelberg Cover design: Design & Production GmbH, Heidelberg Typesetting: Mitterweger Werksatz GmbH, Plankstadt SPIN: 10663915 19/3133 - 5 4 3 2 1 0- Printed on acid-free paper

Preface

The Maturation Phenomenon, described by Ito et al. in 1975 [3) on the basis of his to­logical observations in the hippocampus as well as other portions of the cerebral hemisphere, refers to the hours or days of delay in the development of pathological changes in various parameters of ischemic injury following the restoration of blood flow to the ischemic brain. There is a direct relationship between the intensity of ischemic insult and the speed and rate of maturation of ischemic injury, a lesser intensity being associated with slower and less severe development of the lesions. The delayed neuronal death of CAl pyramidal cells of the hippocampus [8) is a classic example. In the cerebral cortex, with increasing intensity of the ischemic insult, the maturation phenomenon of ischemic injuries intensifies, seamlessly, from less exten­sive to more extensive disseminated selective neuronal necrosis (DSNN), and then further to cerebral infarction upon reaching a critical threshold [1,2,4,6,7). We also have found that following ischemic insults just under the threshold level required to induce infarction, only disseminated selective neuronal necrosis (DSNN) progresses, while following ischemic insults at the threshold level, initially only DSNN develops, followed by the evolution of a gradually enlarging infarcted focus [5, 7).

The reporting of this phenomenon boosted research in the field, as it became evi­dent that ischemic damage is not a sudden event, but a process potentially susceptible to therapeutic intervention. Since then a growing number of studies have improved our knowledge regarding the mechanisms of cell death and recovery following this event. In Septemer 1990, at the first international symposium on "Maturation Phe­nomenon in Cerebral Ischemia" in Tokyo, the nature and mechanisms of the phe­nomenon were discussed. The second symposium was organized in Tokyo in March­April 1996, with the subtitle "Neuronal Recovery and Plasticity". New development, particularly in the field of molecular biology, have been rapidly yielding information on the molecular nature and the dynamics of mechanisms of cell death and recovery.

It can be assumed that the Maturation Phenomenon represents a continuing strug­gle between the acceleration of tissue or neuronal death and the activation of defen­sive mechanisms leading to neuronal recovery. The elucidation of these mechanisms is important for developing the ability to manipulate them during a long-lasting "therapeutic window". This volume presents the third international symposium held in Pozzilli, Italy in April 1998, with the subtile. "Defensive Mechanisms Versus Apop­tosis and/or Necrosis, Neuronal Recovery and Protection in Cerebral Infarction." The book outlines the present status of investigations and provides further stimulation for research in this field.

The focus is on the elucidation of (1) genetic expression and neuronal apoptosis and/or necrosis in cerebral ischemia, (2) factors and mechanisms enhancing suscepti-

VI Preface

bility or tolerance (growth factors, etc.) in cerebral ischemia, (3) factors modulating neuronal plasticity and the course of maturation phenomenon (metabolic and inflammatory factors) in cerebral ischemia, and (4) ischemic infarction: threshold, experimental and clinical dynamics, and therapeutic designs for the prevention or reduction of its intensity.

December, 1998 Umeo Ito and coeditors

References

1. Hanyu, S, Ito U, Hakamata Y, Yoshida M (1995) Transition from ischemic neuronal necrosis to infarction in repeated ischemia. Brain Res 686:44-48

2. Hanyu S, Ito U, Hakamata Y, Nakano I (1997) Topographical analysis of cortical neuronal loss asso­ciated with dissemenated selective neuronal necrosis and infarction after repeated ischemia. Brain Res 767:154-157

3. Ito U, Spatz M, Walker J Jr, Klatzo I (1975) Experimental cerebral ischemia in mongolian gerbils. I. Light microscopic observations. Acta Neuropathol (Berl) 32:209-223

4. Ito U, Yamaguchi T, Tomita H, Tone 0, Shishido T, Hayashi H, Yoshida M (1992) Maturation phenomenon of ischemic injuries observed in Mongolian gerbils: introductory remarks. In: Ito U, Kirino T, Kuroiwa T, Klatzo I (eds) Maturation phenomenon in cerebral ischemia I. Springer, Berlin Heidelberg New York, pp 1-13

5. Ito U, Hanyu S, Hakamata Y, Nakamura, M, Arima K (1996) Ultrastructure of astrocytes associates with progressing selective neuronal death or impending infarction after repeated ischemia. In: Krieglstein J (ed) Pharmacology of cerebral ischemia. Medpharm, Stuttgart, pp 385-392

6. Ito U, Hanyu S, Hakamata Y, Kuroiwa T, Yoshida M (1997) Features and threshold of infarct devel­opment in ischemic maturation phenomenon. In: Ito U, Kirino T, Kuroiwa T, Klatzo I (eds) Matu­ration phenomenon in cerebral ischemia II. Springer, Berlin Heidelberg New York, pp 115-121

7. Ito U, Hanyu S, Hakamata Y, Arima K, Oyanagi K, Kuroiwa T, Nakano I (1999) Temporal profIle of cortical injury following ischemic insult just below and at the threshold level for induction of infarction-light and electron microscopic study. In: Ito U, Fieschi C, Orzi F, Kuroiwa T, Klatzo I (eds) Maturation phenomenon in cerebral ischemia III. Springer, Berlin, Heidelberg New York (this volume)

8. Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:57-69

Contents

I Role of Genetic Expression and Neuronal Apoptosis and/or Necrosis

Multiple Molecular Penumbras Associated with Focal Ischemia in Brain F. R. SHARP, M. BERGERON, J. HONKANIEMI, A. MANUSCO, S. MASSA, and P. R. WEINSTEIN .................................................. 3

Aspects of Maturation Phenomenon Observed by the TUNEL Method W. C. GORDON, V. COLANGELO, N. G. BAZAN, and I. KLATZO ................ 15

Delayed Gene Expression and Ischemic Brain Injury C. IADECOLA, M. E. Ross, F. ZHANG, S. NOGAWA, M. NAGAYAMA, and T. NAGAYAMA ..................................................... 25

The Role of Programmed Cell Death in Cerebral Ischemia F. GILLARDON, M. SPRANGER, R. HATA, C. TIESLER, and K.-A. HOSSMANN .... 33

The Role of Caspase-3 Like Protease in the Hippocampus After Transient Global Ischemia J. CHEN and R. P. SIMON ............................................... 41

Alterations in Translation Initiation Following Global Brain Ischemia D. J. DEGRACIA, B. C. WHITE, and G. S. KRAUSE .......................... 47

Studies of Neuronal Necrosis and Apoptosis after Global Cerebral Ischemia in Superoxide Dismutase Transgenic and Knockout Mutants M. KAWASE, K. MURAKAMI, M. FUJIMURA, T. KONDO, Y. MORITA-FuJIMURA, S. F. CHEN, R. W. SCOTT, C. J. EpSTEIN, and P. H. CHAN .................... 53

Apoptosis-Related Genes Are Expressed in the Rat Model of Subarachnoid Hemorrhage K. YAMADA, M. NAKATSUKA, A. MAS AGO, and H. TAKI ..................... 65

No Morphological Evidence of Apoptosis Following Mild to Severe Episodes of Four-Vessel-Occlusion Ischemia in Rats F. COLBOURNE, H. LI, and A. BUCHAN ................................... 69

VIlI

II Factors and Mechanisms Enhancing Susceptibility or Tolerance (Growth Factors)

Stimulation of ~2-Adrenoceptors Induces Nerve Growth Factor and Inhibits Apoptosis in Rat Brain After Ischemia

Contents

J. KRIEGLSTEIN, C. CULMSEE, Y. ZHU, and I. SEMKOVA ..................... 77

Ischemia-Induced Dynamic Cellular Response in the Brain M. MATSUMOTO, K. KITAGAWA, M. HORI, and T. YANAGIHARA .............. 87

Oxygen Free Radicals and Ischaemic Preconditioning in the Brain: Preliminary Data and a Hypothesis P. SCHUMANN, K. PRASS, F. WIEGAND, M. AHRENS, D. MEGOW, and U. DIRNAGL ...................................................... 95

Ischemic Tolerance in the Maturation of Disseminated Selective Neuronal Necrosis and Cerebral Infarction After Repetitive Ischemia S. HANYU, U. ITO, T. KUROIWA, Y. HAKAMATA, and I. NAKANO ............... 105

Upregulation of Vascular Endothelial Growth Factor Protein Levels in Global Ischemia Induced by Cardiac Arrest and Resuscitation in Rat Brain P. PICHIULE, J. C. CHAVEZ, K. XU, and J. C. LAMANNA ..................... III

Neuroprotective Effect of Hepatocyte Growth Factor T. MIYAZAWA, K. MATSUMOTO, N. TSUZUKI, H. NAKAU, T. YAMASHIMA, K. SHIMA, and T. NAKAMURA ........................................... 117

III Factors Modulating Neuronal Plasticity and the Course of Maturation Phenomenon in Cerebral Ischemia (Metabolic and Inflammatory Factors)

Tumor Necrosis Factor-a-Induced Ischemic Tolerance as Manifested by Microvascular and Endothelial Cell Responses D. DAWSON, I. GINIS, J. LIU, M. SPATZ, and J. M. HALLENBECK .............. 127

The Role of Glial and Inflammatory Reactions in Cerebral Ischemia H. KATO ............................................................. 135

Effect of EndothelinA Receptor Antagonist on Neuronal Injury in Global and Focal Ischemia Y. OHARA, D. DAWSON, H. SUGANO, C. RUETZLER, N. AZZAM, J. M. HALLENBECK, R. M. MCCARRON, and M. SPATZ ...................... 143

Lowering of Ameboid Microglial Resistance to Hydrogen Peroxide by Propentofylline M. TOMITA, Y. FUKUUCHI, M. TANAHASHI, M. KOBARI, H. TAKEDA, and M. YOKOYAMA .................................................... 151

Contents

Combination Therapy: A Promising Treatment Strategy for Cerebral Ischemia E. HUNGERHUBER, S. ZAUSINGER, A. BAETHMANN, H.-J. REULEN,

IX

and R. SCHMID-ELSAESSER ............................................. 159

Another Facet of Nitric Oxide: Reduction of Toxis Zinc Influx Through Voltage-Gated Channels B. J. SNIDER, J.-Y. CHOI, D. M. TURETSKY, 1. M. T. CANZONIERO, S. 1. SENSI, C. T. SHELINE, and D. W. CHOI ......................................... 169

Slowly Progressive Neuronal Degeneration in Remote Areas After Focal Cerebral Ischemia A. TAMURA, M. NAKANE, T. KUROIWA, T. NAGAOKA, H. NAKANISHI, T. NAKAGOMI, T. MATSUI, and K. SANO .................................. 175

Metabolic Disturbance and Gene Responses Following Cortical Injury in Rats: Relationship to Spreading Depression D. M. HERMANN, G. MIEs, and K.-A. HOSSMANN .......................... 183

Protein Expression and Brain Plasticity After Transient Middle Cerebral Artery Occlusion in the Rat M. CHOPP, Y. LI, and Z. G. ZHANG ...................................... 193

Alteration of Cyclic Adenosine Monophosphate Binding in Ischemic Brain: Sensitive Metabolic Marker for Early Ischemic Tissue Damage K. TANAKA, Y. FUKUUCHI, T. SHIRAI, H. NOZAKI, E. NAGATA, S. SUZUKI, and T. DEMBO ........................................................ 203

IV Ischemic Infarction: Threshold, Experimental and Clinical Dynamics and Therapeutic Design for Prevention or Reduction of Intensity

Role of Mitochondria in Immediate and Delayed Reperfusion Damage B. K. SIESJO, Y. OUYANG, T. KRISTI.~.N, E. ELMER, P.-A. LI, and H. UCHINO .... 217

Temporal Profile of Cortical Injury Following Ischemic Insult Just Below and at the Threshold Level for Induction of Infarction - Light and Electron Microscopic Study U. ITO, S. HANYU, Y. HAKAMATA, K. ARIMA, K. OYANAGI, T. KOROIWA, and 1. NAKANO ....................................................... 227

Mitochondrial Dysfunction and Maturation Phenomenon in Ischemic Gerbil Cortex T. KUROIWA, G. MIES, Y. HAKAMATA, S. HANYU, R. OKEDA, and U. ITO ....... 237

Metabolic Ca2+ Signalling and Refilling of Ca2+ Stores in Hippocampal Astrocytes Are Driven by Adenosine Triphosphate Supplied by Glycolysis G. REISER and M. BERNSTEIN .......................................... 243

x

Brain-Derived Neurotrophic Factor and Ciliary Neurotrophic Factor Treatment of Focal Cerebral Ischemia in Rat K.-A. HOSSMANN, K. YAMASHITA, C. WIESSNER, and D. LINDHOLM

Environmental Influence on Neurotrophic Gene Expression After Experimental Brain Infarction in the Rat

Contents

251

B. B. JOHANSSON, L.-R. ZHAO, and B. MATTSSON .......................... 261

Delayed Neuronal Death in Experimental Ischemic Stroke J. H. GARCIA, Z.-R. YE, K.-F. Lru, and J. A. GUTIERREZ ..................... 267

A Rat Model to Study Damage and Defense Mechanisms Under Penumbra Conditions T. SEIWERT, A. HEIMANN, and O. KEMPSKI ............................... 275

Instrumental Diagnosis and Treatment of Acute Ischemic Stroke: The Clinician's Perspective C. FIESCHI, C. ARGENTINO, A. FALCOU, M. FIORELLI, M. L. SACCHETTI, G. SETTE, and D. TONI ................................................. 281

V Special Lecture

Mechanisms of Regulation of Cerebral Blood Flow L. SOKOLOFF ......................................................... 291

VI Poster Presentations (Abstracts)

The Protective Effect of DY9760e, a Novel Calmodulin Antagonist, on Rat Permanent Middle Cerebral Artery Occlusion K. TAGAKI, A. TAMURA, H. NAKAYAMA, K. NARITA, M. AOKI, T. SATO, and Y. SHIRA SAKI ..................................................... 311

Amelioration of Brain Damage Following Transient Focal Ischemia in Rats by ONO-2506: Relevance of Its Modulating Action on Astroglial Functions N. TATEISHI, Y. KAGAMIISHI, T. SHIMODA, K. SHINTAKU, S. SATOH, and K. KONDO ........................................................ 313

The Effect of ONO-2506 on Permanent Focal Ischemia in Rats T. ASANO, T. MATSUI, E. MORI, A. TAMURA, N. TATEISHI, Y. KAGAMIISHI, S. SATOH, and K. KONDO ............................................... 315

Preconditioning with 5 Min Forebrain Ischemia Ameliorated Mortality and Brain Edema Caused by 15Min Forebrain Ischemia in the Gerbil T. MIMA, M. FUKuoKA, and M. MORI .................................... 317

Contents

Alteration of Control Mechanisms of Endoplasmic Reticulum Calcium Pools in Focal Cerebral Ischemia T. DEMBO, K. FUKUUCHI, K. TANAKA, T. SHIRAI, E. NAGATA, D. ITO,

XI

S. SUZUKI, and A. FUTATSUGI ........................................... 319

Global Ischemia Induces Downregulation of GluR2 mRNA and Increases AMPA Receptor-Mediated Ca2+ Influx in Hippocampal CAl Neurons J. A. GORTER, E. M. ARONICA, T. OPITZ, M. V. L. BENNETT, J. A. CONNOR, and R. S. ZUKIN ...................................................... 321

SPD 502 (NS 1209), a New Selective AMPA Antagonist, Reduces the Infarct Size in Rats Following Permanent Occlusion of the Middle Cerebral Artery T. N. SAGER, A. M0LLER, F. WXTJEN, O. B. PAULSON, and J. DREJER .......... 323

Neuroprotective Effects of Magnesium and Tirilazad in Rats Subjected to Transient Focal Cerebral Ischemia R. SCHMID-ELSAESSER, E. HUNGERHUBER, S. ZAUSINGER, A. BAETHMANN, and H.-J. REULEN ..................................................... 325

Do Natural Antioxidants Protect Neurons from Oxidative Stress Due to Their Anti-Radical Activity? A. BOLDYREV, P. JOHNSON, Y. WEI, Y. TAN, and D. CARPENTER .............. 327

Carnosine Prevents Neurons from Excitoxic Effects of NMDA and Kainate A. BOLDYREV, D. CARPENTER, Z. KOVALENKO, N. KULEVA, D. LAWRENCE, and R. SONG ......................................................... 329

Aspects of Tolerance and Apoptosis: Cell and Molecular Biological Studies V. COLANGELO, W. C. GORDON, W. J. LUKIW, P. K. MUKHERJEE, I. KLATZO, and N. BAZAN ........................................................ 331

VII Round Table Discussion

Round Table Summary ...................... . . . . . . . . . . . . . . . . . . . . . . . . . .. 335

Subject Index .................................................... 341

NEUR"mED

Chairmen "-,- ... \(.,1" ...... 111 ",t,,:.lf.1I11

L'lln·h.· l,,..to. I .. ".,:

Co-Chairmen I t.lIl ..... ~,' \ }r,1

~

h'..!lIh:",· .... 11I.·I~\.l ·k.,·

Advisory Boord \ 1,-\,111.1,'1 U.I." III1I.lIm \fl. ''''I 'Ip '/"" ~ H,I.I,III ,. I" l~ \

1",""\I1I ... l h •• , }-

.... \UU\.I ... I.~Uh·

1...1' '0 h"'"\'l,h "'1,,'-.:1":"11\ \! I R~

I r,lII" ~ "'h,ltl' '. I It a,l

\!tn"HI h'III1I •• I ~I}'

1.1.I,u ..... \\"'I,,,1a ".1 ..

l " ... I:.· .~ .. T"t I,'; \".11'"

1I.,"'l"' ,

;..

List of First-Named Authors

ASANO, T. Department of Neurosurgery, Saitama Medical Center/School, Kamoda, Kawagoe, Saitama 350, Japan

BOLDYREV, A.

Institute of Neurology, Russian Academy of Medical Sciences, 123367 Moscow, Russia

CHEN, J.

Department of Neurology, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15217, USA

CHOPP, M. Henry Ford Health Science Center, Henry Ford Hospital, Neurology Department, 2799 West Grand Boulevard, Detroit, MI 48202, USA

COLANGELO, V. LSUMC Neuroscience Center of Excellence, 2020 Gravier St., Suite D, New Orleans, LA 70112, USA

COLBOURNE, F. Alberta Stroke Program, Department of Pathology, Faculty of Medicine, Health Sciences Center, University of Calgary, 3330 Hospital Dr. NW, Calgary, AB, Canada T2N 4N1

DAWSON, D.

Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bldg. 36, Rm. 4A03, 36 Convent Drive MSC 4128, Bethesda, MD 20982 - 4128, USA

DEGRACIA, D.J.

Department of Emergency Medicine, Wayne State University, Detroit, MI 48202, USA

DEMBO, T. Department of Neurology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, 160-8582 Tokyo, Japan

XIV List of First-Named Authors

FlESCH I, e. Department of Neurological Sciences, University "La Sapienza", Viale dell' Universita 30, 00185, Rome, Italy

GARCIA, J.H.

Department of Pathology, Henry Ford Hospital, K-6 2799W Grand Boulevard, Detroit, MI 48202-2689, USA

GILLARDON, F. Max Planck Institute for Neurological Research, Department of Experimental Neurology, Gleueler StraBe 50, 50931 Cologne, Germany

GORDON, W.e. LSUMC Neuroscience Center of Excellence, 2020 Gravier St., Suite D, New Orleans, LA 70112, USA

GORTER, J.A.

Department of Experimental Dierkunde, University of Amsterdam, Kruislaan 320, 1098 SM Amsterdam, The Netherlands

HANYU, S. Department of Neurology, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi­machi, Kawachi, Tochigi, 329-04 Japan

HERMANN, D.M. Max Planck Institute for Neurological Research, Department of Experimental Neurology, Gleueler StraBe 50, 50931 Cologne, Germany

HOSSMANN, K.-A.

Max Planck Institute for Neurological Research, Department of Experimental Neurology, Gleueler StraBe 50, 50931 Cologne, Germany

HUNGERHUBER, E. Institute for Surgical Research, Klinikum Grosshadern, Ludwig-Maximilians­Universitat, MarchioninistraBe 15, 81377 Munich, Germany

IADECOLA, C. Laboratory of Cerebrovascular Biology and Stroke, Department of Neurology, University of Minnesota Medical School, Box 295 UMHC, 420 Delaware St. S.E., Minneapolis, MN 55455, USA

ITO, U. Department of Neurosurgery, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo 180, Japan

JOHANSSON, B.B. Section for Experimental Neurology, Wallenberg Neuroscience Center, Lund University, University Hospital, 221 85 Lund, Sweden

List of First-Named Authors xv

KATO, H. Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai 980-8574, Japan

KAWASE, M.

Department of Neurosurgery, Neurology & Neurological & Sciences, Stanford University School of Medicine, Palo Alto, CA 94304, USA

KRIEGLSTEIN, J. Institut fUr Pharmakologie und Toxikologie, Fachbereich Pharmazie und Lebensmittelchemie, Philipps-Universitat, Ketzerbach 63, 35032 Marburg, Germany

KUROIWA, T. Deparment of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan

MATSUMOTO, M.

Division of Strokology, First Department of Medicine, Osaka University School of Medicine, 2 - 2 Yamada-oka, Suita, Osaka 565-0871, Japan

MIMA, T. Deparment of Neurosurgery, Kochi Medical School, Kohasu, Okatoyo-cho, Nanngoku City, Kochi, 738 Japan

MIYAZAWA, T. Deparment of Neurosurgery, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama 359, Japan

OHARA, Y. Naval Medical Research Institute, Bethesda, Maryland, USA

PICHIULE, P.

Department of Anatomy, Case Western Reserve University, School of Medicine, Cleveland, OH 44106 - 4938, USA

REISER, G. Institut fUr Neurobiochemie, Medizinische Fakultat der Universitat Magdeburg, Leipziger StraBe 44, 39120 Magdeburg, Germany

SAGER, T.N. Dept. of Pharmacology, 26B Smedeland, 2600 Glostrup, Denmark

SCHMID-ELSAESSER, R.

Department of Neurosurgery, Klinikum Grosshadern, Ludwig-Maximilians­Universitat, MarchioninistraBe 15,81377 Munich, Germany

XVI List of First-Named Authors

SCHUMANN, P. Division of Experimental Neurology, Department of Neurology, Charite Hospital, 10098 Berlin, Germany

SEIWERT, T.

Institute for Neurosurgical Pathophysiology, Johannes Gutenberg University, LangenbeckstraBe 1,55101 Mainz, Germany

SHARP, ER. Department of Neurology, University of California at San Francisco, and Department of Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA

SIESJO, B.K. Center for the Study of Neurological Disease, The Neuroscience Institute, Queen's Medical Center, 1356 Lusitana Street, 8th Floor, Honolulu, HI 96813, USA

SNIDER, B.J. Center for the Study of Nervous System Injury, and Department of Neurology, Washington University Medical School, st. Louis, MO 63110, USA

SOKOLOFF, L. Laboratory of Cerebral Metabolism, National Institute of Mental Health, Building No. 36, Room lA-05, Bethesda, MD 20892, USA

TAKAGI, K. Department of Neurosurgery, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, 173 - 8605, Japan

TAMURA, A. Department of Neurosurgery, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, 173 - 8605, Japan

TANAKA, K. Department of Neurology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160 - 8582, Japan

TATEISHI, N. Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka 618, Japan

TOMITA, M. Department of Neurology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160 - 8582 Tokyo, Japan

YAMADA, K. Department of Neurosurgery, Nagoya City University Medical School, 1 Kawasumi, Mizuho-ku, Nagoya 467-0001, Japan

Author Index

Ahrens, M. 95 Aoki, M. 311 Argentino, C. 281 Arima, K. 227 Aronica, E. M. 321 Asano, T. 315 Azzam, N. 143 Baethmann, A. 159,325 Bazan, N. G. 15, 331 Bennett, M. V. L. 321 Bergeron, M. 3 Boldyrev, A. 327, 329 Buchan, I. 69 Canzoniero, L. M. T. 169 Carpenter, D. 327, 329 Chan, P. H. 53 Chavez, J. c. 111 Chen, J. 41 Chen, S. F. 53 Choi, D. W. 169 Choi, J.-Y 169 Chopp, M. 193 Colangelo, V. 15, 331 Colbourne, F. 69 Connor, J. A. 321 Culmsee, Y. 77 Dawson, D. 127, 143 DeGracia, D. J. 47 Dembo, T. 203,319 Dirnagel, U. 95 Drejer, J. 323 Elmer, E. 217 Epstein, C. J. 53 Falcou, A. 281 Fieschi, C. 281 Fiorelli, M. 281 Fujimura, M. 53 Fukuoka, M. 317 Fukuuchi, K. 319 Fukuuchi, Y. 151, 203 Futatsugi, A. 319 Garcia, J.H. 267

Gillardon, F. 33 Ginis, I. 127 Gordon, W. C. 15,331 Gorter, J. A. 321 Gutierrez, J. A. 267 Hakamata, Y. 105,227,237 Hallenbeck, J. M. 127, 143 Hanyu, S. 105, 227, 237 Hata, R. 33 Heimann, A. 275 Honkaniemi, J. Hori, M. 87 Hossmann, K.-A. 33,251 Hungerhuber, E. 159, 325 Iadecola, C. 25 Ito, D. 319 Ito, U. 105,227, 237 Johansson, B. B. 261 Johnson, P. 327 Kagamiishi, Y. 313,315 Kato 135 Kawase, M. 53 Kempski, O. 275 Kitagawa, K. 87 Klatzo, I. 25, 331 Kobari, M. 151 Kondo, K. 313, 315 Kondo, T. 53 Kovalenko, Z. 329 Krause, G. S. 47 Krieglstein, J. 77 Kristian, T. 217 Kuleva, N. 329 Kuroiwa, T. 105, 175, 227, 237 LaManna, J. C. 111 Lawrence, D. 329 Li, P.-A. 217 Lindholm, D. 251 Liu, J. 127 Liu, K.-F. 267 Lukiw, W. 331 Mancuso, A. 3

XVIII

Masago, A. 65 Massa, S. 3 Matsui, T. 175,315 Matsumoto, K. 87,117 Mattsson, B. 261 McCarron, R. M. 143 Megow, D. 95 Mies, G. 237 Mirna, T. 317 Miyazawa, T. 117 M011er, A. 323 Mori, E. 315 Mori, K. 317 Morita-Fujimura, Y. 53 Mukherjee, P. K. 331 Murakami, K. 53 Nagaoka, T. 175 Nagata, E. 203,319 Nagayama, T. 25,27 Nakagomi, T. 175 Nakamura, T. 117 Nakane, M. 175 Nakanishi, H. 175 Nakano, I. 105, 227 Nakatsuka, M. 65 Nakau, H. 117 Nakayama, H. 311 Narita, K. 311 Nogawa, S. 25 Nozaki, H. 203 Ohara, Y. 143 Okeda, R. 237 Opitz, T. 321 Ouyang, Y. 217 Oyanagi, K. 227 Paulson, O. B. 323 Pichiule, P. 111 Prass, K. 9S Reulen, H.-J. 159,325 Ross, M. E. 25 Ruetzler, C. 143 Sacchetti, M. L. 281 Sager, T. N. 323 Sano, K. 175 Sato, T. 311 Satoh, S. 313,315 Schmid-Elsaesser, R. 159,325 Schumann, P. 95 Scott, R. W. 53 Seiwert, T. 27S Semkova, I. 77

Sensi, S. L. 169 Sette, G. 281 Sharp, F. R. 3 Sheline, C. T. 169 Shim, K. 117 Shimoda, T. 313 Shintaku, K. 313 Shirai, T. 203,319 Shirasaki, Y. 311 Siesjo, B. K. 217 Simon, R. P. 41 Snider, B. J. 169 Sokoloff, L. 291 Song, E. 329 Spatz, M. 127, 143 Spranger, M. 33 Sugano, H. 143 Suzuki, S. 203, 319 Takagi, K. 311 Taked, H. 151 Taki, H. 65 Tamura, A. 175,311,315 Tan, Y. 327 Tanahashi, N. 151 Tanaka, K. 203,319 Tateishi, N. 313,315 Tiesler, C. 33 Tomita, M. 151 Toni, D. 281 Tsuzuki, N. 117 Turetsky, M. 169 Uchino, H. 217 Watjen, F. 323 Wei, Y. 327 Weinstein, P. R. 3 White, B. C. 47 Wiegand, F. 9S Wiessner, C. 251 Xu, K. III Yamada, K. 65 Yamashima, T. 117 Yamashita, K. 251 Yanagihara, T. 87 Ye, Z.-R. 267 Yokoyama, M. 151 Zausinger, S. 159, 325 Zhang,F. 25 Zhao, 31 261 Zhu, Y. 77 Zukin, R. S. 321

Author Index