Sensing, Signaling and Cell Adaptation

328 Pages·2002·12.369 MB·1-333\328

by  K.B. Storey and J.M. Storey (Eds.)

Preface
"Science is the game we play with God to find out what His rules are."
This quote from Albert Einstein has perhaps never been more appropriate than it is today, early in the new
millenium. Amazing recent advances in biochemistry and molecular biology have given rise to new fields
including genomics, proteomics and bioinformatics. Discoveries in interlocking areas are synthesizing prin-
ciples in the design and control of cellular functions including membrane transport, signal transduction,
gene expression, macromolecular synthesis, and others. We are certainly coming closer to figuring out what
the "rules" are. One clearly seems to be that protein kinases "mle"~the hundreds of protein kinases
encoded on the genome and the involvement of reversible protein phosphorylation as a means of regulatory
control in virtually every metabolic process show the universal importance of this mechanism.
This third and final volume of Cell and Molecular Responses to Stress has broad themes: sensing, signal-
ing and cellular adaptation. Every chapter provides a unique view of how cells and organisms deal with
stresses, great and small, on instantaneous versus evolutionary timelines, and provides examples of regula-
tory principles and their infinite variety that are used to preserve life on Earth. A group of chapters deals with
the molecular mechanisms of sensing of external signals: pain, heat, cold, radiation, and nutrient levels. The
many mechanisms of intracellular signal transduction and the regulation of gene expression are dealt with in
others, with a major emphasis on the roles of protein kinases. Chapters on metabolic control analysis and the
evolution of physiological adaptation consider important principles of metabolic regulation, whereas the
vast potential of emerging analytical technologies such as cDNA array screening are analyzed in others. The
adaptive significance of unique proteins such as uncoupling proteins and dehydrins are explored along with
metabolic adaptations for dealing with ischemia, temperature change, freezing and infrared radiation.
We extend our thanks to all of the authors who worked so hard to write the excellent chapters in this vol-
ume. Their marvelous stories of biochemical adaptation make every chapter a pleasure to read.
Kenneth B. Storey
Janet M. Storey
Ottawa, May 2002
iiv
List of Contributors
Ian M. Adcock
National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6LY, UK
E-mail: [email protected]; Tel: [phone] x 3061; Fax: +44 207 153 5675
Marie-Clotilde Alves-Guerra
Institut de Recherches Necker-Enfants Malades, rue de Vaugirard, 75015 Paris, France
Julien Averous
Unite de Nutrition Cellulaire et Moleculaire, INRA de Theix, 63122 Saint Genes Champanelle, France
Michael Bell
Center for Neuroscience Research, Children's Research Institute, Children' s National Medical Center, Washington, DC 20010,
USA
E-mail: [email protected]; Tel: 1+ 202 8843597; Fax: 1+ 202 884 5724
Manuel Benito
Departamento de Bioqufmica y Biologfa Molecular II, Universidad Complutensede Madrid, Ciudad Universitaria, 28040
Madrid, Spain
Tammie Bishop
MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK
E-mail: [email protected]; Tel: [phone]; Fax: [phone]
Jennifer K. Bonnington
Department of Pharmacology, University of Cambridge, Tennis Court Rd, Cambridge, CB2 1PD, UK
Frrdrric Bouillaud
Institut de Recherches Necker-Enfants Malades, rue de Vaugirard, 75015 Paris, France
Martin D. Brand
MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK
E-mail: [email protected]; Tel: [phone]; Fax: [phone]
Alain Bruhat
Unite de Nutrition Cellulaire et Moleculaire, INRA de Theix, 63122 Saint Genes Champanelle, France
Neff R. Chapman
Division of Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, DD 1 5EH, UK
Christine Clerici
Department of Physiology, Facult6 de Mrdecine Xavier Bichat, Universit6 Paris, 46 rue Henri Huchard, 75018 Paris, France
E-mail: [email protected]; Tel: [phone]; Fax: [phone]
Timothy J. Close
Department of Botany & Plant Sciences, University of California, Riverside, CA 92521-0124, USA
E-mail: [email protected]; Tel: + 1 909 7873318; Fax: + 1 909 7874437
Elodie Couplan
Institut de Recherches Necker-Enfants Malades, rue de Vaugirard, 75015 Paris, France
iiiv
Douglas L. Crawford
Division of Molecular Biology & Biochemistry, University of Missouri-Kansas City, Kansas City, MO 64110-2499, USA
E-mail: [email protected]; Tel: +l 816 2352565; Fax: 1+ 816 2355595
R. Keira Curtis
MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK
E-mail: [email protected]; Tel: [phone]; Fax: [phone]
Mafia Del Mar Gonzalez Barroso
Institut de Recherches Necker-Enfants Malades, me de Vaugirard, 75015 Paris, France
Kelly Drew
Department of Chemistry and Biochemsitry, Institute of Arctic Biology, Box 757000, University of Alaska Fairbanks,
Fairbanks, AK 99775-7000, USA
E-mail: [email protected]; Tel: + 1 907 4747190; Fax: + 1 907 474 6050
Peter F. Dubbelhuis
Department of Biochemistry, University of Amsterdam, Meibergdreef ,51 1105 AZ Amsterdam, The Netherlands
E-mail: [email protected]; Tel: 13+ 20 5665159; Fax: 13+ 20 6915519
Sean F. Eddy
Institute of Biochemistry and Department of Chemistry, Carleton University, 1125 Colonel By Drive, Ottawa, ON,
Canada K S1 5B6
E-mail: seddy @ccs.carleton.ca
Pierre Fafournoux
Unite de Nutrition Cellulaire et Moleculaire, INRA de Theix, 63122 Saint Genes Champanelle, France
E-mail: [email protected]; Tel: [phone]; Fax: [phone]
John Hallenbeck
Stroke Branch, NINDS, NIH, 36 Convent Drive MSC 4128, Bethesda, MD 20892-4128, USA
E-mail: [email protected]; Tel: 1+ 103 4966231; Fax: 1+ 103 4022769
Vidya Hebbar
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, 061 Frelinghuysen Road, Piscataway,
NJ 08854, USA
Norman P.A. Hurter
Department of Plant Sciences, University of Western Ontario, London, Canada N6A 5B7
E-mail: [email protected]; Tel: 1+ 519 6612111 x86638; Fax: 1+ 519 6613935
Abdelbagi M. Ismail
International Rice Research Institute, DAPO 7777, Metro Manila, Philippines
E-mail: [email protected]; Tel: [phone]; Fax: +63 2 167 2406
Alexander G. Ivanov
Department of Plant Sciences, University of Western Ontario, London, Canada N6A 5B7
E-mail: [email protected]; Tel: 1+ 519 6612111 x86488; Fax: 1+ 519 6613935
A.-N. Tony Kong
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, 061 Frelinghuysen Road, Piscataway,
NJ 08854, USA
E-mail: [email protected]; Tel: + 1 732 445 7335; Fax: + 1 732 445 3134
Marianna Krol
Department of Plant Sciences, University of Western Ontario, London, Canada N6A 5B7
E-mail: [email protected]; Tel: 1+ 519 6612111 x86638; Fax: 1+ 519 6613935
Kevin Larade
Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Canada K1S 5B6
E-mail: klarade @ ccs.carleton.ca
Lee Laurent-Applegate
Laboratory of Oxidative Stress and Aging, University Hospital-Lausanne, CH-1011 Lausanne, Switzerland
E-mail: [email protected]; Tel: +41 12 314 3169; Fax: +41 12 314 3499
Hon Cheung Lee
Department of Pharmacology, University of Minnesota, 123 Church .tS SE, 4-415 Jackson Hall, Minneapolis, MN 55455, USA
E-mail: [email protected]; Tel: 1+ 612 6257120; Fax: 1+ 612 6250991
Joel M. Linden
Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
E-mail: [email protected]; Tel: + 1 434 924 5600; Fax: + 1 434 924 2828
Dmitry A. Los
Institute of Plant Physiology, 35 Botanicheskaya Street, 127276 Moscow, Russia
E-mail: [email protected]: Tel/Fax: [phone]
Bruno Maresea
University of Salerno, Faculty of Pharmacy, Via Ponte don Melillo, 80084 Fisciano, Salerno, Italy
E-mail: [email protected]; Tel/Fax: [phone]
Michael Matthay
Cardiovascular Research Institute and Departments of Medicine and Anesthesia, University of California, San Francisco,
CA 94143-0624, USA
Peter A. MeNaughton
Department of Pharmacology, University of Cambridge, Tennis Court Rd, Cambridge, CB2 1PD, UK
E-mail: [email protected]; Tel: [phone]; Fax: [phone]
Alfred J. Meijer
Department of Biochemistry, University of Amsterdam, Meibergdreef ,51 1105 AZ Amsterdam, The Netherlands
E-mail: [email protected]; Tel: [phone]; Fax: [phone]
Bruno Miroux
Institut de Recherches Necker-Enfants Malades, rue de Vaugirard, 75015 Paris, France
E-mail: [email protected]; Tel: [phone]; Fax: [phone]
Ewa Miskiewiez
Department of Plant Sciences, University of Western Ontario, London, Canada N6A 5B7
E-mail: [email protected]; Tel: 1+ 519 6612111 x86475; Fax: 1+ 519 661 3935
Sylvie Mordier
Unite de Nutrition Cellulaire et Moleculaire, INRA de Theix, 63122 Saint Genes Champanelle, France
Norio Murata
National Institute for Basic Biology, 38 Nishigonaka, Myodaiji-cho, Okazaki 444 8585, Japan
E-mail: [email protected]; Tel: [phone]; Fax: [phone]
Aaron Ngocky Nguyen
Section of Microbiology, University of California, Davis, CA 95616, USA
Gunnar Oquist
Department of Plant Physiology, Umefi University, S-907 18 Umefi, Sweden
Tel: [phone]; Fax: [phone]
E. Tapio Palva
Department of Biosciences, Division of Genetics, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland
E-mail: [email protected]; Tel: [phone]; Fax: +358 9 191 59076
Claire Pecqueur
Institut de Recherches Necker-Enfants Malades, rue de Vaugirard, 75015 Paris, France
Neil D. Perkins
Division of Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, 1DD 5EH, UK
E-mail: [email protected]; Tel: [phone]; Fax: [phone]
Carole Plan~s
Department of Physiology, Facult6 de M6decine Xavier Bichat, Universit6 Paris, 46 rue Henri Huchard, 75018 Paris, France
Almudena Porras
Departamento de Bioqufmica y Biologfa Molecular II, Universidad Complutensede Madrid, Ciudad Universitaria, 28040
Madrid, Spain.
E-mail: [email protected]; Tel: +34 19 3941627; Fax: +34 19 3941779
Daniel Ricquier
Institut de Recherches Necker-Enfants Malades, rue de Vaugirard, 75015 Paris, France
David R. Robinson
Department of Pharmacology, University of Cambridge, Tennis Court Rd, Cambridge, CB2 1PD, UK
Sonia Rocha
Division of Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, DD 1 5EH, UK
St~phanie Roques
Laboratory of Oxidative Stress and Aging, University Hospital-Lausanne, CH-1011 Lausanne, Switzerland
Alison Shaw
EMBL, Meyerhofstrasse ,1 69012 Heidelberg, Germany
Kazuhiro Shiozaki
Section of Microbiology, University of California, Davis, CA 95616, USA
E-mail: [email protected]; Tel: + 1 530 7523628; Fax: + 1 530 7529014
Mark Smith
Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA
E-mail: mas21 @po.cwru.edu; Tel: + 1 216 863 3670; Fax: 216 863 8964
Janet B. Storey
Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario,
Canada S1K 5B6
E-mail: [email protected]; Tel: 1+ 613 520 3678; Fax: 1+ 316 520 2569
Kenneth B. Storey
Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario,
Canada K1S 5B6
E-mail: [email protected]; Tel: 1+ 316 520 3678; Fax: 1+ 316 520 2569
Gail W. Sullivan
Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
E-mail: [email protected]; Tel: + 1 434 9249665; Fax: + 1 434 9242828
Jan Svensson
Department of Biosciences, Division of Genetics, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland
E-mail: [email protected]; Tel: [phone]; Fax: +358 9 191 59076
Tokujiro Uchida
Department of Physiology, Facult6 de M6decine Xavier Bichat, Universit6 Paris, 46 rue Henri Huchard, 75018 Paris, France
Vittorio Vellani
Department of Pharmacology, University of Cambridge, Tennis Court Rd, Cambridge, CB2 1PD, UK
6lzsi~L Vigh
Institute of Biochemistry, Hungarian Academy of Sciences, Temesv~iri krt. 62, H-6726 Szeged, Hungary
E-mail: [email protected]; Tel/Fax: [phone]
Kenneth E. Wilson
Department of Molecular Biology, University of Geneva, CH-1211 Geneva, Switzerland
E-mail: [email protected]; Tel: [phone]; Fax: [phone]
Zhanguo Xin
Plant Stress and Germplasm Development Unit, USDA, Agricultural Research Service, 3810 4th Street, Lubbock, TX 79415,
USA
E-mail: [email protected]; Tel: + 1 806 7495560; Fax: + 1 806 7235272
Sensing, Signaling and Cell Adaptation. Edited by K.B. Storey and J.M. Storey
(cid:14)9 2002 Elsevier Science B. .V All rights reserved.
CHAPTER 1
Ischemic Tolerance in the Brain: Models and Mechanisms
Michael Bell ,4'1 Kelly Drew ,2 Mark Smith 3 and John Hallenbeck ~
retneC~ for Neuroscience Research, Children's Research Institute, ChiMren's National Medical ,retneC
,notgnihsaW DC 20010, ASU
naksalA2 Basic Neuroscience Program and Department of Chemistry and Biochemistry, Institute of Arctic
Biology, University of Alaska Fairbanks, Fairbanks, AK 99775-7000, ASU
etutitsnI3 of Pathology, Case Western Reserve University, Cleveland, 0H44106, ASU
ekortS4 Branch, NINDS, NIH, Bethesda, MD 20892-4128, ASU
.1 Introduction neuroprotective mechanisms associated with toler-
ance to brain ischemia could guide the search for
Ischemic brain cells produce a wide array of medi- effective stroke therapy through this morass of
ators that participate in progression of ischemic interlaced mechanisms.
brain injury. As a noncomprehensive example, Preconditioning is the phenomenon whereby a
there is evidence for the participation of excito- stressful non-lethal stimulus sets in motion a cas-
toxins (Rothman and Olney, 1995), free radicals cade of biochemical events that renders cells, tis-
(Hall and Braughler, 1989), activated endothelium sues or the whole organism tolerant to a future,
(Hallenbeck, 1996), leukocytes (del Zoppo et al., more lethal stimulus. Ischemia has proven a potent
1991), cytokines (Giulian and Robertson, 1990), primary stimulus for preconditioning both in the
platelets (Dougherty et al., 1977), platelet activat- myocardium, where it was first described and in
ing factor (Lindsberg et al., 1991), eicosanoids the brain. This chapter will begin with a review of
(Walker and Pickard, 1985), endothelin (Green- myocardial preconditioning that emphasizes cellu-
berg et al., 1992), altered gene expression (Nowak, lar mechanisms since these studies stimulated
1990), edema (Klatzo, 1985), nitric oxide studies of preconditioning within neurological sys-
(Samdani et al., 1997), poly(ADP-ribose) poly- tems. Models of brain preconditioning in animals
merase (PARP) (Eliasson et al., 1997), growth fac- and cell cultures will then be reviewed with
tors (Finklestein et al., 1990), apoptosis (Choi, emphasis on the molecular mechanisms involved
1996), matrix metalloproteinases (Mun-Bryce and in the development of the neuroprotection. Finally
Rosenberg, 1998) and mitochondrial permeability a "natural model of tolerance", hibernation, will be
pore transition (Duchen et al., 1993) in evolving discussed.
brain injury. Disappointingly, clinical trials of
agonists or antagonists of many of these mediators
of brain injury have uniformly failed to confer sig- 2. Myocardial preconditioning
nificant cytoprotection in acute stroke. As an ex-
ample, more than 80 clinical trials of over 30 Myocardial preconditioning in animal models has
different neuroprotective agents had been pub- been studied since the mid-1980s and recent clini-
lished by 1996 in the therapy of stroke and none cal studies suggest it may be operative in humans
has shown clear evidence of a benefit (Dorman and (Bahr et al., 2000; Noda et al., 1999; Ottani et al,,
Sandercock, 1996). Study of endogenous 1995). Murry and colleagues were the first to
2 Ch. .1 Ischemic tolerance in the brain
develop a preconditioning paradigm and used which the protection was afforded suggested that
infarct size as a measure of injury (Muny et al., substances released from the ischemic myo-
1986). Their paradigm involved four episodes of cardium were likely responsible for the cardio-
brief ischemia consisting of 5-min occlusion of cir- protection observed rather than de novo synthesis
cumflex coronary artery followed by 5-min of of mediators. Adenosine, bradykinin and opioid
reperfusion. A longer ischemic insult was imposed peptides were identified as agents that were
immediately thereafter for varying amounts of released from ischemic myocardium and could
time in separate groups of dogs (group 1 for 40 min independently substitute for the brief periods of
and group 2 for 3 hours). Preconditioned dogs had ischemia as an early preconditioning stimulus.
a 75% reduction in infarct size in group 1 com- Adenosine was found to exert its effects via bind-
pared to shams while no protection was conferred ing to its A1 or A3 receptors within the myo-
to the preconditioned animals in group .2 This sug- cardium in isolated cardiac myocytes (Eliasson et
gested that several brief episodes of ischemia cre- al., 1997), animal studies (Tracey et al., 1997) and
ated a brief time period of protection from more human cardiac tissue (Cart et al., 1997). Binding of
lethal ischemia. Other groups (Cohen et al., 1991; bradykinin to its B2 receptor protected cardiac
Shiki and Hearse, 1987) have used contractility, myocytes (Parratt et al., 1995; Wall et al., 1994),
incidence of ischemia-induced arrhythmia or mag- although its marked hemodynamic effects make it
nitude of ST-segment elevation as measures of difficult to exclude effects not related to precondi-
injury and similarly found that brief precondition- tioning. Opioid peptides precondition by binding
ing stimuli can confer immediate protection. to their &receptor subtype and selective ~-opioid
In 1993, two independent groups demonstrated receptor agonists have been shown to induce
that the protection achieved from brief episodes of cardioprotecfion in experimental models (Schultz
ischemia is biphasic. A second "window" of pro- et al., 1998).
tection from ischemia was found 24 h after the ini- With these mediators identified, efforts contin-
tial preconditioning stimuli (Kuzuya et al., 1993; ued to define the intracellular events responsible
Marber et al., 1993). Marber and colleagues found for cardioprotecfion. Currently, a working theory
that a similar preconditioning stimulus of 4 epi- of cardioprotecfion after preconditioning involves
sodes of 5 min coronary artery occlusion provided the ATP-sensitive potassium channel .)PTAK( This
approximately 30% protection to a 30 min channel, thought to link myocardial metabolism to
ischemic insult given 24 h after the preconditioned membrane electrical activity, is present in the
stimulus. This phenomenon was termed "late" pre- sarcoplasmic reticulum membrane (sarc )prAK as
conditioning in contrast to "classic" or "early" pre- well as the mitochondrial membrane (mt KA~ ). A
conditioning described above. Initial hypotheses role in preconditioning was postulated soon after
were formulated suggesting that products of its discovery (Noma, 1983). Noma noted that brief
metabolism immediately released after ischemia periods of ischemia caused an opening of sarc rAK p
may mediate "early" preconditioning while newly channels and suggested a prominent role of sarc
synthesized proteins may be required for "late" yAK P channels in preconditioning. He theorized that
preconditioning cardioprotection. opening of the sarc TAK P channels would enhance
the shortening of the cardiac action potential by
2.1. Early preconditioning mechanisms accelerating phase 3 repolarization. This enhanced
repolarization could inhibit calcium influx into the
Early preconditioning was observed in several spe- myocyte, prevent calcium overload within the cell
cies including swine, rabbit, rat and dogs (Cohen et and, therefore, enhance cellular viability. Evidence
al., 1991; Murphy et al., 1993; Schott et al., 1990; for a role of these channels in preconditioning was
Yao and Gross, 1993) and investigators strove to furnished by a series of studies. First, selective ~AK
determine the biochemical mechanisms underly- antagonists (glibenclamide and sodium 5-hydr-
ing this protective response. The rapidity with oxydecanoate) blocked the protection while a TAK e
Brain preconditioning 3
opener (aprilkam) augmented the protection of subsequent events. In their initial study, Marber
preconditioning (Auchampach et al., 1992; Gross and colleagues noted that the cardioprotection of
and Auchampach, 1992). Also, multiple mediators preconditioning was coincident with an upregula-
associated with ischemic preconditioning, includ- tion of an inducible 70-kDa heat shock protein
ing adenosine, regulate TAK p channel function (Yao (HSP 70) (Marber et al., 1993) and this finding has
and Gross, 1994). Most convincingly, the develop- been replicated by others. Moreover, over-
ment of specific openers of mt WAK channels, spe- expression of HSP 70 in transgenic mice also
cifically diazoxide, demonstrated that opening of increases resistance to myocardial ischemia
mt TAK p channels can confer cardioprotection with- (Marber et al., 1995).
out involvement of sarc ~AK v channels (Garlid et
al., 1997). While the regulation of mt KAT e channel 3. Brain preconditioning
opening appears complex, preliminary studies sug-
gest that multiple ligands can bind to a trans- Groups have attempted to replicate the precondi-
membrane G-protein leading to intracellular tioned responses to ischemia observed in the myo-
activation of protein kinase C. This ubiquitous cardium in neurologic models. The similarities
intracellular messenger can lead to a conform- between the organs include the necessity of ion
ational change in the mt TAK e channel although fur- channels for function, the need for high-energy
ther study is needed to fully define the mechanism substrates to maintain homeostasis and a common-
underlying the cardioprotection (Marber, 2000). ality of mediators known to alter the organ's func-
This work has culminated in clinical trials using tion (adenosine, nitric oxide, for example).
nicorandil, a ~AK v channel opener with nitrate-like Important differences include the heterogeneity of
hemodynamic properties. Nicorandil improves left cell types within the CNS (neurons, astrocytes,
ventricular wall motion in ischemic heart disease oligodendrocytes, microglia, in addition to blood
and has improved EKG findings in patients under- vessels) compared to the relatively homogeneous
going angioplasty (Markham et al., 2000). population of myocardial myocytes within the
heart. In work spanning more than a decade,
2.2. Late preconditioning mechanisms groups of investigators have successfully demon-
strated that the principles of preconditioning can be
Examination of the mechanisms involved in late applied within the CNS and that ischemia need not
preconditioning is in its infancy compared to the be the sole initiating stimulus.
detailed delineation of key processes in early pre-
conditioning. While some have cited adenosine 3.1. Ischemic preconditioning--clinical
release leading to protein kinase C activation as a experience and animal models
potential mechanism of late preconditioning
(Baxter et al., 1997), still others have suggested Clinical evidence for preconditioning neuro-
that the gradual onset and persistence of the protec- protection from transient ischemic attacks (TIA)
tion suggests that de novo protein synthesis occur- exists (Moncayo et al., 2000) in that prior TIA has
ring subsequent to the initial stimulus represents a been associated with milder stroke symptoms after
more probable mechanism. The heat shock controlling for other cardiovascular risk factors.
response involves the production of novel proteins Yet most simply regard the occurrence of TIA as a
in response to a stress and was first described as a risk factor for the development of stroke (Weih et
response of cells to thermal injury. Other stimuli al., 1999). The paucity of definitive clinical evi-
including ischemia and oxidative stress have been dence of preconditioning notwithstanding, a num-
shown to elicit this response and it has been con- ber of animal models demonstrated that sublethal
served through evolution in species as diverse as doses of ischemia could protect against a future,
fruit flies, yeast, plants and mammals. The synthe- more lethal dose. As in the myocardium, multiple
sis of these proteins protects the organism from small preconditioning stimuli were found to be
4 Ch. 1. Ischemic tolerance in the brain
more effective than single stimuli and the interval middle cerebral artery (MCA) was occluded for
between the preconditioned stimulus and the sub- 20-min followed by 24 hours of reperfusion. The
sequent insult was found to be critical. However, rats were then subjected to bilateral common caro-
brain models of preconditioning revealed key dif- tid artery occlusion with hemorrhagic hypotension
ferences. Mainly, the interval between the precon- and preconditioned animals showed decreased
ditioning and lethal stimuli needed to be longer and damage in ipsilateral and contralateral hippocampi.
the duration of the neuroprotection was increased Others have observed essentially the same results
relative to the observations in the myocardium. using gerbils (Miyashita et al., 1994).
Furthermore, either global or focal preconditioning
stimuli were found to induce protection against 3.2. Alternative preconditioning stimuli
both global and focal lethal insults. These findings
have led investigators to postulate novel mecha- The study of preconditioning in animals has
nisms of protection within the brain. expanded to include models using altemative pre-
Global preconditioning stimuli can protect conditioning stimuli. Hypoxia, defined as
against both global and focal injuries. Kitigawa decreased oxygen delivery with no alteration in
and colleagues showed that a 5-min episode of blood flow, is distinct from conditions in which
bilateral carotid artery occlusion in gerbils caused blood flow is reduced. Using neonatal rats, 4 h of
selective damage to the CA1 region of the hippo- hypoxia (8% 02 environment) administered 24 h
campus, a region of brain selectively vulnerable to prior to a hypoxic-ischemic insult (left carotid
ischemia (Kitagawa et al., 1990). They demon- artery occlusion, 8% 02 environment for 2 h) led to
strated that two episodes of sublethal ischemia decreases in infarct volume and hippocampal cell
(2-min duration) performed at 24 h intervals for loss (Ota et al., 1998). Inflammatory mediators
two days prior to the lethal ischemic injury pro- including cytokines, particularly tumor necrosis
vided almost complete protection of this vulnera- factor-t~ (TNF-t~), can also serve as a precondition-
ble region. They also found that a single dose of the ing stimulus in animal models. Systemic injection
preconditioning stimulus was partially effective in of lipopolysaccharide (LPS) induced protection
providing protection but multiple smaller doses of from permanent MCA occlusion in spontaneously
preconditioning ischemia (1-min duration) were hypertensive rats and pharmacological blockade of
ineffective. Simon and colleagues found that 48 the effects of TNF-t~ nullified this protection
hours after a global ischemia, rats were protected (Tasaki et al., 1997). In a follow-up study, precon-
against permanent middle cerebral artery occlu- ditioning with intracistemal injection of TNF-ct 24
sion, a focal injury, manifested as a decrease in the h prior to ischemia decreased infarct size in mice
overall infarct size (Simon et al., 1993). after secondary permanent MCA occlusion in a
Similarly, focal preconditioning stimuli can dose- and time-dependent manner (Nawashiro et
protect against both focal and global injuries. Chen al., 1997 .)a
and colleagues used three 10-min episodes of
MCA occlusion (separated by 45 min of reper- 3.3. Proposed mechanisms of ischemic
fusion) as a preconditioning stimulus and showed preconditioning ni animal models
decreased infarct size after a subsequent 100 min
occlusion of the MCA in rats (Chen et al., 1996). Several mechanisms have been postulated for pre-
Interestingly, the protection was only elicited 2-5 conditioning neuroprotection. Some evidence sug-
days after the preconditioning stimulus. At day 1 gests that mediators released coincident with
and day 7 after preconditioning, the protective ischemia, such as excitatory amino acids and
effects of the preconditioning were not observed. adenosine, may be involved in the ischemic pre-
Glazier and colleagues demonstrated that a focal conditioning. Excitatory amino acids such as gluta-
preconditioning stimulus could protect against a mate are released after ischemic injury and interact
global injury (Glazier et al., 1994). Using rats, the with the N-methyl-D-aspartate (NMDA) receptor.