Table Of ContentSpringer Series in Translational Stroke Research
Jun Chen
John H. Zhang
Xiaoming Hu Editors
Non-Neuronal
Mechanisms of
Brain Damage
and Repair
After Stroke
Springer Series in Translational Stroke Research
Series Editor
John Zhang
More information about this series at h ttp://www.springer.com/series/10064
Jun Chen • John H. Zhang • Xiaoming Hu
Editors
Non-Neuronal Mechanisms
of Brain Damage and Repair
After Stroke
Editors
Jun Chen John H. Zhang
Department of Neurology Department of Anesthesiology
University of Pittsburgh Loma Linda University School of Medicine
Pittsburgh, PA , USA Loma Linda , CA , USA
Pittsburgh Institute of Brain Disorders Department of Pharmacology
and Recovery Loma Linda University School of Medicine
University of Pittsburgh Loma Linda , CA , USA
Pittsburgh , PA , USA
Department of Physiology
State Key laboratory of Medical Loma Linda University School of Medicine
Neurobiology Loma Linda , CA , USA
Fudan University
Center for Neuroscience Research
Shanghai , China
Loma Linda University School of Medicine
Loma Linda , CA , USA
Xiaoming Hu
Department of Neurology
University of Pittsburgh
Pittsburgh , PA, USA
Pittsburgh Institute of Brain Disorders
and Recovery
University of Pittsburgh
Pittsburgh , PA , USA
State Key laboratory of Medical
Neurobiology
Fudan University
Shanghai , China
ISSN 2363-958X ISSN 2363-9598 (electronic)
Springer Series in Translational Stroke Research
ISBN 978-3-319-32335-0 ISBN 978-3-319-32337-4 (eBook)
DOI 10.1007/978-3-319-32337-4
Library of Congress Control Number: 2016944470
© Springer International Publishing Switzerland 2016
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Introduction: Nonneuronal Mech anisms
and Targets for Stroke
For several decades now, clinically effective neuroprotection has been an elusive
goal. Although much progress has been made in terms of dissecting molecular path-
ways and cellular mechanisms, true translation has not succeeded for patients suf-
fering from stroke, brain trauma, and neurodegeneration. Excitotoxicity, oxidative
stress, and programmed cell death all represent logical targets for preventing neuro-
nal demise. But it is now increasingly apparent that saving neurons alone may not
be enough.
B ased on these challenges, the neurovascular unit was proposed as a conceptual
framework for reassessing neuroprotection, the fundamental premise being that
central nervous system (CNS) function is not solely based on neuronal activity. The
brain is more than just action potentials! For neurotransmission to work, release–
reuptake kinetics must be coordinated between neurons and astrocytes. For myelin-
ated signals to connect different brain networks, axons need to be in constant
homeostatic communication with oligodendrocytes. For the blood–brain barrier to
be manifested, crosstalk is required between glial endfeet and cerebral endothelium.
Altogether, CNS function is based on cell–cell signaling between multiple cells.
Therefore, neuroprotection requires one to do much more than just prevent neuronal
death. Rescuing function and cell–cell crosstalk between all cell types in neuronal,
glial, and vascular compartments should be required. It is in this context that this
monograph N onneuronal Mechanisms of Brain Damage and Repair After Stroke
represents a signifi cant addition to the literature and fi eld.
This monograph is divided into fi ve well-integrated sections. The fi rst section
focuses on microvascular integrity. Chapters here include analyses of the structural
biology of tight junctions, the role of pericytes, glial regulation of barrier function,
blood–brain barrier damage in neonatal stroke, and a reconsideration of angiogen-
esis after stroke. The second section covers the complex actions of glial cells and
includes chapters on astrocyte protection, biphasic effects of microglia, and cross-
talk between cerebral endothelium and oligodendrocyte precursor cells. The third
section then goes on to examine the multifactorial pathways in stroke neuroinfl am-
mation, with analyses of peripheral immune activators, monocyte/macrophage
responses, T cells, B cells, mast cells and neutrophils, and the web of cytokines that
v
vi Introduction: Nonneuronal Mechanisms and Targets for Stroke
all contribute to stroke pathophysiology. A critical part of stroke that is relatively
less investigated comprises white matter response, and this is the focus of the fourth
section of the monograph. In this section, chapters are devoted to assessing the age
dependence of white matter injury and subsequently investigating the role of oligo-
dendrogenesis for white matter plasticity. Finally, the last collection of chapters
builds on the mechanistic themes explored thus far to develop potential therapeutic
approaches. In this fi nal section, chapters span a comprehensive range, including
the targeting of leukocyte–endothelial interactions, methods to repair the entire neu-
rovascular unit, immune-based treatments, and cell-based therapies that all seek to
achieve neuroprotection by restoring crosstalk amongst the nonneuronal population
of CNS cells.
T aken together, the chapters here represent the very best in cutting-edge hypoth-
eses and translational ideas. The mechanisms dissected herein may eventually lead
us to testable targets for stroke patients. Curated by editors and authors who are
experts in their fi eld, this is an impressive collection of stroke science.
Eng H. Lo, Ph.D.
[email protected]
Neuroprotection Research Laboratory
Department of Radiology
Massachusetts General Hospital and
Harvard Medical School
149 13th Street , Charlestown , MA , 02129 , USA
Contents
Part I Microvascular Integrity in Stroke
Structural Alterations to the Endothelial Tight Junction
Complex During Stroke .................................................................................. 3
Anuska V. Andjelkovic and Richard F. Keep
Role of Pericytes in Neurovascular Unit and Stroke ................................... 25
Turgay Dalkara , Luis Alarcon-Martinez , and Muge Yemisci
Glial Support of Blood–Brain Barrier Integrity: Molecular Targets
for Novel Therapeutic Strategies in Stroke................................................... 45
Patrick T. Ronaldson and Thomas P. Davis
Barrier Mechanisms in Neonatal Stroke ...................................................... 81
Zinaida S. Vexler
Angiogenesis: A Realistic Therapy for Ischemic Stroke ............................. 93
Ke-Jie Yin and Xinxin Yang
Part II Glial Cells in Stroke
Astrocytes as a Target for Ischemic Stroke ................................................... 111
Shinghua Ding
Microglia: A Double-Sided Sword in Stroke ................................................ 133
Hong Shi , Mingyue Xu , Yejie Shi , Yanqin Gao , Jun Chen ,
and Xiaoming Hu
Crosstalk Between Cerebral Endothelium and Oligodendrocyte
After Stroke ..................................................................................................... 151
Akihiro Shindo , Takakuni Maki , Kanako Itoh , Nobukazu Miyamoto ,
Naohiro Egawa , Anna C. Liang , Takayuki Noro , Josephine Lok ,
Eng H. Lo , and Ken Arai
vii
viii Contents
Part III Peripheral Immune Cells in Stroke
The Peripheral Immune Response to Stroke ................................................ 173
Josef Anrather
The Role of Spleen-Derived Immune Cells in Ischemic Brain Injury ....... 189
Heng Zhao
Regulatory T Cells in Ischemic Brain Injury ............................................... 201
Arthur Liesz
B-Cells in Stroke and Preconditioning- Induced Protection
Against Stroke ................................................................................................. 217
Uma Maheswari Selvaraj , Katie Poinsatte , and Ann M. Stowe
Mast Cell as an Early Responder in Ischemic Brain Injury ....................... 255
Perttu J. Lindsberg , Olli S. Mattila , and Daniel Strbian
Roles of Neutrophils in Stroke ....................................................................... 273
Glen C. Jickling and Frank R. Sharp
The Function of Cytokines in Ischemic Stroke ............................................ 303
Christopher C. Leonardo and Keith R. Pennypacker
Part IV White Matter Injury and Repair in Stroke
Ischemic Injury to White Matter: An Age- Dependent Process .................. 327
Sylvain Brunet , Chinthasagar Bastian , and Selva Baltan
Part V Emerging Therapies to Target Non- neuronal
Mechanisms After Stroke
Neurovascular Repair After Stroke .............................................................. 347
Sherrefa R. Burchell , Wing-Mann Ho , Jiping Tang , and John H. Zhang
The Role of Nonneuronal Nrf2 Pathway in Ischemic Stroke:
Damage Control and Potential Tissue Repair .............................................. 377
Tuo Yang , Yang Sun , and Feng Zhang
Stem Cell Therapy for Ischemic Stroke ........................................................ 399
Hung Nguyen , Naoki Tajiri , and Cesar V. Borlongan
Contributors
Luis Alarcon-Martinez , B.Sc., M.Sc., Ph.D. Institute of Neurological Sciences
and Psychiatry , Hacettepe University , Ankara , Turkey
Anuska V. Andjelkovic , M.D., Ph.D. Department of Pathology , University of
Michigan , Ann Arbor , MI , USA
D epartment of Neurosurgery, U niversity of Michigan Health System, A nn Arbor,
MI , USA
Josef Anrather Feil Family Brain and Mind Research Institute, Weill Cornell
Medical College , New York , NY , USA
Ken Arai Neuroprotection Research Laboratory, Departments of Radiology and
Neurology, M assachusetts General Hospital and Harvard Medical School,
Charlestown , MA , USA
Selva Baltan , M.D., Ph.D. Department of Molecular Medicine , Cleveland Clinic
Lerner College of Medicine of Case Western Reserve University , Cleveland , OH ,
USA
D epartment of Neurosciences, L erner Research Institute, Cleveland Clinic
Foundation , Cleveland , OH , USA
Chinthasagar Bastian , M.B.B.S., Ph.D. Department of Neurosciences , Lerner
Research Institute, Cleveland Clinic Foundation , Cleveland , OH , USA
Cesar V. Borlongan D epartment of Neurosurgery and Brain Repair, U niversity of
South Florida Morsani College of Medicine , Tampa , FL , USA
Sylvain Brunet , B.Sc., Ph.D. Department of Molecular Medicine , Cleveland
Clinic Lerner College of Medicine of Case Western Reserve University,, C leveland,
OH , USA
D epartment of Neurosciences, L erner Research Institute, Cleveland Clinic
Foundation , Cleveland , OH , USA
ix
