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Ischemic ToleranceThe Mechanisms of Neuroprotective Strategy.

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THE ANATOMICAL RECORD 292:2002–2012 (2009)
Ischemic Tolerance: The Mechanisms of
Neuroprotective Strategy
Department of Medical Biochemistry, Jessenius Faculty of Medicine, Comenius
University, Centre of Excellence: Biomembranes, Martin, Slovakia
Institute of Neurobiology, Centre of Excellence, Košice, Slovakia
Jessenius Faculty of Medicine, Clinic of Anesthesiology and Intensive Medicine,
Comenius University, Martin, Slovakia
The phenomenon of ischemic tolerance perfectly describes this quote
‘‘What does not kill you makes you stronger.’’ Ischemic pre- or postconditioning is actually the strongest known procedure to prevent or reverse
neurodegeneration. It works specifically in sensitive vulnerable neuronal
populations, which are represented by pyramidal neurons in the hippocampal CA1 region. However, tolerance is effective in other brain cell populations as well. Although, its nomenclature is ‘‘ischemic’’ tolerance, the
tolerant phenotype can also be induced by other stimuli that lead to
delayed neuronal death (intoxication). Moreover, the recent data have
proven that this phenomenon is not limited to application of sublethal
stimuli before the lethal stress but reversed arrangement of events, sublethal stress after lethal insult, is rather equally effective. A very important
term is called ‘‘cross conditioning.’’ Cross conditioning is the capability of
one stressor to induce tolerance against another. So, since pre- or postconditioners can be used plenty of harmful stimuli, hypo- or hyperthermia
and some physiological compounds, such as norepinephrine, bradykinin.
Delayed neuronal death is the slow development of postischemic neurodegeneration. This allows an opportunity for a great therapeutic window of
2–3 days to reverse the cellular death process. Moreover, it seems that
the mechanisms of ischemic tolerance-delayed postconditioning could be
used not only after ischemia but also in some other processes leading to
C 2009 Wiley-Liss, Inc.
apoptosis. Anat Rec, 292:2002–2012, 2009. V
Key words: ischemic tolerance; neuroprotection; mechanisms
The third leading cause of death and disability is ischemic stroke. Ischemic stroke arises in humans as a
consequence of cardiac arrest or the stoppage of blood
flow to the brain, which can be due to embolic or thrombic occlusion of arteries. Both global or focal ischemia
are very severe pathogenic events with multiple, parallel, and sequential pathogenesis. Global forebrain ischemia leads to selective cell death of vulnerable pyramidal
neurons in the hippocampal CA1 region. It also leads to
death of cerebral cortex neurons (layers 3, 5, and 6) and
the dorsolateral striatum. When blood flow decreases
Grant sponsor: Ministry of Education (Slovak Republic);
Grant numbers: VEGA 0049/09, VEGA 2/141/09; Grant sponsor:
Ministry of Health (Slovak Republic); Grant numbers: EU
COST B30, APVV LPP 0235-06, VVCE 0064-07, 55-UK-16/2007.
*Correspondence to: Jan Lehotský, Department of Medical
Biochemistry, Jessenius Faculty of Medicine, Comenius University, Malá Hora 4, 036 01 Martin, Slovakia. Fax: 421-434136770. E-mail:
J. Lehotský and J. Burda contributed equally to this article.
Received 18 February 2009; Accepted 10 June 2009
DOI 10.1002/ar.20970
Published online in Wiley InterScience (www.interscience.wiley.
TABLE 1. Examples of anoxia-tolerant animals and natural neuroprotective
stimuli in humans (Kirino, 2002; Dirnagl et al., 2003; Gidday, 2006; Obrenovitch, 2008)
Inducing stimuli
Innate fetal and neonatal tolerance
High altitude
Transient ischemic attacks
Hibernation, hypoxia
Winter dormancy
Breath holding submersion
Breath holding submersion
during focal ischemia, the area known as ‘‘pneumbra’’
(surrounding necrotic core of ischemia) is perfused by
collateral vessels. It also undergoes the apoptotic final
fate of neurons (Endres et al., 2008).
Despite decades of intense research, no effective neuroprotective drugs are available yet to treat acute stroke
or cardiac arrest. For this reason, recent attention has
shifted to defining the brain’s own evolutionarily conserved endogenous neuroprotective mechanisms, which
occurs in ischemic tolerance (IT) or after ischemic preconditioning (IP). IT induced by several paradigms represents an important phenomenon of central nervous
system (CNS) adaptation to sublethal short-term ischemia. This results in increased tolerance of CNS to lethal
ischemia (Kirino, 2002, Dirnagl et al., 2003; Gidday,
2006). The molecular mechanisms underlying IT are not
yet fully understood because of its extreme complexity,
involving many signaling pathways and alterations in
gene expression. Additionally, a metabolic depression
has been suggested to play an important role in IT
(Yenari et al., 2008).
Differences in intensity, duration, and frequency of
specific inducer/stressor determine the spectrum of
responses to noxious stimuli, that is, when the stimulus
is too weak to induce any response, when it is sufficient
to serve as a tolerance trigger, or when it is too strong
and harmful, resulting in apoptotic or necrotic damage.
It is symptomatic that there are no clear boundaries
between acquisition of tolerance and cellular apoptosis/
necrosis (Dirnagl et al., 2003).
Rodent and cell culture models serve as a basis for the
study of the tolerance phenomenon. To understand this,
mother nature serves as a model. In nature, we ubiquitously find adaptation to extreme environmental conditions, for example, hypoxic or anoxic tolerance.
Hibernation is another example of inherent adaptation
to extreme low-blood perfusion in animals. As such, IT
can be conceived as an evolutionary conserved form of
cerebral plasticity (Dirnagl et al., 2003; Gidday, 2006)
(Table 1).
It is not surprising that different animals have
evolved different molecular strategies to cope with anoxia and severe metabolic stress. This leads to the trigger of the neuroprotective tolerance state. A number of
common mechanisms with different relevance features
can be recognized:
i. depression of metabolic rate,
ii. modulation of glycolytic enzymes,
Fetus and neonates
Children, adults
Reptilia: snake, frog
Pisces: carp, shark
Reptilia: turtle
Mammalia: seal
Squirrel, bear
iii. reduction of ion channel fluxes,
iv. suppression of neural activity,
v. expression of chaperones and heat shock proteins
vi. activation of antioxidant defense systems,
vii. adaptation of blood rheology and others (for review,
see Gidday, 2006; Obrenovitch, 2008).
In the past decade, the phenomenon of IT has
attracted immense interest in experimental and clinical
fields as a potential and robust neuroprotective mechanism to the extreme metabolic stress, such as hypoxia/
anoxia/ischemia (Kirino, 2002; Dirnagl et al. 2003;
Gidday, 2006; Perez-Pinzon, 2007; Obrenovitch, 2008).
A large number of different activating mechanisms/
paradigms are used to induce IT, see Table 2. Although
preischemic challenge such as: (i) global ischemia (Kitagawa et al., 1991), or (ii) focal ischemia (Stagliano et al.,
1999), or (iii) cerebral hypoxia represents prototypical
preconditiong stimuli, IT can be induced by exposing
animals, cell cultures or tissue slices to various types of
endogenous or exogenous stimuli. For example, cortical
spreading depression (Kobayashi et al., 1995), chronic
hypoxia/hypoperfusion (Sharp and Bernaudin, 2004), or
hyperoxia or oxidative/nitrosative stress, hypothermia or
hyperthermia, and heat shock (Nishio et al., 2000) and
different pharmacological agents such as chemical preconditioning agents (e.g., metabolic inhibitors, lipopolysaccharides, inflammatory cytokines) or natural
regulators (erythropoietin, hormones) have been used to
induce IT. Brain cooling or therapeutic hypothermia
may also be used as factors, which induce IT, see recent
reviews (Gidday, 2006; Obrenovitch, 2008).
The concept of IP was introduced in the late 80s in
the heart by Murry et al. (1986) and later on in the
brain by Schurr et al. (1986) and Kitagawa et al. (1991).
Although the molecular mechanisms underlying IT
induced by IP are not yet fully understood, two windows
have been identified. One window represents very rapid
and short-lasting posttranslational changes, and the second window develops slowly (over days) after initial
insult. It develops as a robust and long-lasting transcriptional change involving de novo protein synthesis (Barone et al., 1998; Burda et al., 2003; Dirnagl et al., 2003;
Meller et al., 2005). Most stressors, including preischemia/hypoxia, induce both rapid and delayed tolerance
phenotypes (Gidday, 2006). Mechanisms that are prominent during the first phases of acute ischemic insults
such as excitoxicity are presumed to be induced during
rapid IT. In particular, elevation of adenosine and activation of adenosine receptor with the modulation of ATP
TABLE 2. Examples of inducing stimuli leading
to ischemic tolerant phenotype in different animals
and in vitro models (Kirino, 2002; Dirnagl et al., 2003;
Gidday, 2006; Obrenovitch, 2008)
Inducing stimuli
Sublethal preischemia/
Sublethal postischemia/
Remote ischemia
Hypoxia or HIF modifiers
Spreading depression/
pH/ion imbalance
Oxidative/nitrosative stress
inhibitors and dysfunction
Other factors (hormones,
agonists/antagonists, toxins)
Gerbils, rats, mice,
slices, cell cultures
Rats, gerbils, mice
Rats, mice
Gerbils, rats, mice,
slices, cell cultures
Rats, mice
Rats, mice, cell cultures
Gerbils, rats, mice
Gerbils, rats, cell cultures
Gerbils, rats, mice,
cell culture
Rats, mice, slices
Gerbils, rats, mice, slices,
cell cultures
Gerbils, rats, mice,
cell cultures
Gerbils, rats, mice,
Gerbils, rats, mice,
Gerbils, rats, mice,
cell cultures
sensitive Kþ channel are paralleled by the activation of
protein kinase C and other kinases in rapid tolerance. A
critical role for nitric oxide signaling pathways in IP and
tolerance was also suggested (Nandagopal et al., 2001).
As was recently shown by Meller et al. (2008), the selective ubiquitin–proteasome degradation of a cell deathassociated protein, Bcl-2-interacting mediator of cell
death (Bim) with the reduced activation of programmed
cell death-associated caspases (caspase 3) could play an
important role in rapid tolerance to ischemia.
As mentioned earlier, IT can be induced by various
stimuli that are not necessarily ischemic or hypoxic (Fig.
1). Thus, the phenomenon of cross-tolerance implies that
noxious stress can initiate cellular tolerance to subsequent stress that is different in nature from the first
one. Therefore, one stressor can promote cross-tolerance
to another; however, the efficacy of this tolerance may be
more modest, and it appears to vary with the nature
and intensity of the first challenge. Additionally, the
window of evolved IT may also be shifted. However, the
nature of the stimulus may determine the specific protective or in worse meaning the reduced damage
HIF, hypoxia inducing factor.
Numerous studies have investigated the overall signaling cascades and key molecules in various in vitro
and in vivo models of IT. As mentioned earlier, most of
the stressors induce both rapid and delayed tolerance.
However, interrelated, multifactorial processes are responsible for adaptive changes leading to IT. As
reviewed recently by Obrenovitch (2008), the features of
IT partially resemble naturally occuring adaptive mechanisms, including at cellular levels (Fig. 2):
Fig. 1. Time scale of injured phenomena induced by ischemic insult
without previous preconditioning leading to ischemic/reperfusion
injured phenotype. Cerebroprotection can be induced by different
types of preconditioning or postconditioning stimuli (ischemic, immu-
nological, pharmacological and anesthetic). Temporary defined
responses during therapeutical window may induce protective
response with which subsequent ischemia serve as basis of the ischemic-tolerant phenotype.
Fig. 2. Overview of the cellular components that are activated by
different pre- and postconditioning stimuli leading to ischemic tolerant
phenotype. Akt, serine/threonine protein kinase; AP1, activating protein 1; BCl-2, B cell/lymphoma protein 2; BDNF, brain-derived neurotrophic factor; CREB, cAMP response element binding protein; COX2, cyclooxygenase 2; ERK1,2, extracellular signal regulated kinase;
GRP 78, glucose-regulated protein 78; HIF1, hypoxia inducing factor
1; HO-1, heme oxygenase 1; HSP 70, heat shock protein 70; ICAM,
intercellular adhesion molecules; JAK-STAT, Janus thyrosine kinasesignal transducer and activator of transduction; JNK, c-jun terminal kinase; MAPK, mitogen-activated protein kinase; MMP-9, matrix metalloproteinase-9; NOS, nitric oxide synthase; NMDA, N-methyl Daspartate; NFjB, nuclear factor kappa B; NGF, nerve growth factor;
ORP 150, oxygen-regulated protein; p53, tumor suppressor p53; PI3K,
phosphatidyl inositol 3-kinase; SOD, superoxiddismutase; VEGF, vascular endothelial growth factor; TNF, tumor necrosis factor.
i. Alterations in energy cellular metabolism (metabolic
depression). Although anoxic energy producing
pathways cannot be increased during ischemia (limitation of substrate), preconditioning preserves
mitochondrial function and membrane integrity
(Dave et al., 2001; Racay et al., 2007). Additionally,
IP induces upregulation of genes involved in energy
ii. Preservation of mitochondrial membrane potential
and possibly the opening of ATP sensitive Kþ channels with protection against the deficits affecting respiratory complexes and protecting mitochondrial
oxidative phosphorylation and antioxidant enzymes
such as superoxide dismutases (SODs), catalase,
glutathione peroxidase, and thioredoxin system
(Danielisova et al., 2006; Racay et al., 2007).
iii. Amelioration of different aspects of neuronal excitotoxicity and latency of anoxic/ischemic depolarisation, which leads to a shift of excitatory to
inhibitory neurotransmission, such as suppression
of glutamate release, downregulation of glutamate
AMPA and NMDA receptors and increases in GABA
release and downregulation of the glial glutamate
transporter isoforms (EAAT1 and EAAT2) and upregulation of GABAA receptors (Dave et al., 2005).
Improved capacity to preserve cellular ionic and pH
homeostasis by ion transport systems (Ca2þ-ATPase,
Naþ, Kþ-ATPase and Naþ/Ca2þ exchanger) and
transporters for metabolites.
Expression of Hsps as one form of a universal feature of the cellular response to insult.
Suppression of cell death and apoptotic mechanisms, such as reduction of cytochrome c release, inhibition of caspases and proapoptotic genes, and
activation of survival pathways such as serine/threonine activated kinases (Akt) and extracellular signal-regulated kinases (ERK) and trophic factors.
Activation of DNA repair and self-repair/plasticity
mechanisms including increasing activity of growth/
neurotrophic factors such as nerve growth factor
(NGF) and brain-derived neurotrophic factor
viii. Reduction of inflammatory response initiated by activation of Toll-like receptor and suppression of induced
proinflammatory cytokines [(tumor necrosis factors
(TNFs) and interleukins and activation of transcription
nuclear factor jB (NFjB)].
ix. Cerebrovascular adaptation by vascular remodeling
as a result of vascular endothelial growth factors
(VEGF) activity, a key angiogenic regulator, and
activation of erythropoietin and heme oxygenase 1
as targets of hypoxia inducing factor a1 (HIFa1).
The preservation of the blood–brain barrier acts as
a result of the attenuated activity of matrix metalloproteinases and cell adhesion molecules.
For a comprehensive review of the signaling pathways
activated by different types of IT, see the review by Gidday (2006).
In 1991, our laboratory results (Burda et al., 1991)
showed that graded postischemic reoxygenation could be
used as a simple and effective neuroprotective tool
diminishes secondary postischemic damage in nervous
tissue. This also includes the newly synthesized proteins
(Burda et al., 1991). Later, we have documented that duration of the sublethal ischemic episode (for 3–8 min)
(IP) and the time that had elapsed between the second
ischemia is important not only for the acquisition of IT
(at least in the most vulnerable CA1 hippocampal sector), but it also determines the expression of the 72-kDa
Hsp as a proposed molecular transducer of tolerance
(Burda et al., 2003). In addition, the following articles
presented evidence that the repression of global proteosynthesis induced during reperfusion of the ischemic
brain is significantly attenuated by IP. Detailed analysis
of translational machinery showed that the translation
attenuation occurs through multiple molecular targets.
We have also shown that IP affects the activity of several translational initiation factors. Additionally, IP
affects activities of the Akt, extracellular signal-regulated protein kinase phosphorylation, expression of glucose-regulated protein (GRP78) and growth arrest DNA
damage-inducible protein 34 (GADD34) proteins. However, the role eEF2 (translational elongation factor)
plays in different phosphorylation states during preconditioning-induced derepression of proteosynthesis was
not proven in the hippocampal or cortical areas (Garcı́a
et al., 2004a,b). Matrix-assisted laser desorption ionization time of flight (MALDI TOF) and mass spectrometry
(MS) were further used in animal models of IT. This was
done to analyze complexes of serine/threonine phosphatase 1 (PP1) with the substrates. These substrates are
presumably influenced by IT (Cid et al., 2007). As shown
before, inhibition of the PP1 expression is associated
with the early ischemic/reperfusion damage and PP1
inhibitors prevent protection evolved by preconditioning
(Martin de la Vega et al., 2001; Horiguchi et al., 2002).
Moreover, expression of the PP1c positive modulator and
GADD34 is induced by IT (Garcı́a et al., 2004a). Ischemic/reperfusion injury altered the interaction of heat
shock cognate 71 kDa-protein (HSC), creatine kinase B,
and dopamine- and cAMP-regulated phosphoprotein 32
kDa (DARPP32) with both PP1a and PP1c, and the
interaction of phosphodiesterase-6B, transitional ER
ATPase, lamin-A, GRP78, c-enolase, neurofilament-L,
and ubiquitin ligase with PP1c. Remarkably, preconditioning prevented most of the ischemia-induced effects,
which points to the potential role of PP1; it acts as a
target of the endogenous protective mechanisms induced
by IT.
In addition, translational attenuation occurring rapidly during the first minutes of reperfusion after ischemic episode is linked with the phosphorylation of the a
subunit of eukaryotic translation initiation factor 2
(eIF2a). eIF2a is one of the substrates of protein phosphatase 1. As we have shown by microcystin chromatography and 2D fluorescence difference gel electrophoresis
(2D DIGE), the highest levels of phosphorylated eIF2a
correlated with increased levels in PP1 immunoprecipitates of the inhibitor DARPP32 as well as GRP78 and
heat shock cognate protein (HSC70) proteins. They
returned to control values in the later reperfusion period. Remarkably, IT promoted a decrease in eIF2a phosphorylated levels. It also induced association of GADD34
with PP1c while preventing DARPP32, GRP78, and
HSC70. Different levels of HSC70 and DARPP32 associated with PP1a and PP1c isoforms were detected.
GRP78 was only detected in PP1c immunoprecipitates.
Thus, we suggest that PP1 through different signaling
complexes with their interacting proteins, modulates the
phosphorylation states of eIF2a, and affects tolerance acquisition with the important role of GADD34/PP1c complexes (Garcı́a-Bonilla et al., 2007).
The effect of preconditioning was further studied on
functional states of two substrates of Ca2þ-dependent
cysteine protease calpain. These are protein p35 and eukaryotic translational elongation factor eEF4G (GarciaBonilla et al., 2006). Although the induced tolerance did
not promote significant changes in p35 and p25 levels, it
stimulated a slight increase in calpastatin (calpain inhibitor) and eIF4G levels in the hippocampal subregions
after 4 hr of reperfusion.
Remarkably, the iron deposition in the hippocampus
CA1 area and the corpus striatum pars dorsolateralis
reflects ischemic damage. Recirculation in rats was significantly attenuated by IP. It also prevented neuronal
destruction of the hippocampal CA1 region induced by a
20-min ischemia (Danielisova et al., 2004). In accordance
with this evidence, we observed activity of the main
antioxidant enzymes, SOD and catalase (CAT) in the
hippocampus, striatum, and cortex. After induced IT by
IP, SOD and CAT were significantly increased after 5 hr,
1 and 2 days of reperfusion. The observed increased levels of antioxidant enzymes can be ascribed to the de
novo proteosynthesis. However, in spite of upregulation,
a large number of CA1 hippocampal neurons underwent
neurodegeneration within 7 days after ischemia (Danielisova et al., 2005).
Mechanisms that potentially caused protection against
Ca2þ toxicity in IT were studied in CA1 hippocampal
neurons by the analysis of the level of plasma membrane
Ca2þ-ATPase (PMCA) in ischemia-tolerant gerbils. We
showed in our laboratory that ischemic-reperfusion
insult selectively decreases the level of PMCA1 isoform
in hippocampal cells (Lehotsky et al., 1999). This
decrease can be ascribed to the activity of calpain proteases (Lehotsky et al., 2002). As was shown in another
study by Garcia-Bonilla et al. (2006), IT increases activity of calpastatin, an inhibitor of calpain. This is in line
with the results of Ohta et al. (1996). By histochemical
methodology, Ohta determined that IP significantly
increased the Ca2þATPase level before the start of lethal
ischemia. It remained at a higher level subsequently,
compared with ischemia-nontolerant CA1 neurons.
These results strongly resemble data on CA3 neurons,
which are constitutively resistant to periods of ischemia.
It also signifies the role of Ca2þ-ATPase in the process of
acquired tolerance. This view has been supported by the
experiments of Kato et al. (2005), which indicates IT acquisition. PMCA is not essential; however, PMCA1 plays
an important role in the enhancement of IT. A recent article of Sun et al. (2007) describing the effect of preconditioning on the heart identified that S-nitrosylation of
Ca2þ-ATPase is involved in the protective role against
Brain ischemia/reperfusion (IRI) initiates a catastrophic cascade in which many subcellular organelles
play an important role. In our own experiments, we
have evaluated the effect of IP on ischemic brain injury.
This was done by examining the endoplasmic reticulum
(ER) stress response (UPR/unfolded protein response) on
mRNA and protein levels of specific genes such as,
ATF6, GRP78, and XBP and expression of the Golgi apparatus (secretory pathways) Ca2þATPases (SPCA1)
after global ischemia/reperfusion. Ischemia/reperfusion
initiated time-dependent differences in ER gene expression at both the mRNA and protein levels. ER gene
expression is affected by preischemic treatment. The differences between naı̈ve ischemic and IP animals were
detected in both the mRNA and protein levels of all
products of ER stress response (Lehotsky et al., 2008,
2009; Urban et al., 2009). In addition, IP partially suppresses the extent of lipo- and protein oxidation in hippocampal membranes initiated by ischemia. IP also
leads to partial recovery of the ischemia-induced depression of SPCA activity. At the molecular level, IP initiates
an earlier cellular response to the injury by significant
elevation of mRNA expression and SPCA protein levels
(Pavlikova et al., 2009). This suggests that preischemic
treatment may exert a role in the attenuation of ER
stress response and in the correlation of SPCA-Golgi
function; specifically, in the neuroprotective phenomenon
of acquired IT. Changes in the gene expression of the
key proteins provide insight into ER stress pathways. It
might suggest possible targets of future therapeutic
interventions to enhance recovery after stroke (Lehotsky
et al., 2009; Urban et al., 2009).
Ischemic insult leads to severe disturbance in the
energy metabolism and general mitochondrial functions,
such as mitochondrial protein synthesis and inhibition of
respiratory chain complexes. Mitochondrial dysfunction
is considered one of the key events in ischemic neuronal
cell death, because of its capacity of releasing apoptogenic
proteins. As shown in this laboratory by Racay et al.
(2007, 2008, 2009), IP affects ischemia-induced dysfunction of hippocampal mitochondria in two different ways.
Similar to global proteosynthesis, IP also attenuated the
repression of mitochondrial translation induced during
reperfusion time in hippocampus. However, the activity
of respiratory complex IV was protected by IP only
slightly and the activity of complex I remained depressed.
Despite this, IP partially reduced changes in the integrity
of the mitochondrial membrane, as shown by fluorescent
probe measurement. Apoptotic changes initiated by ischemic insult in the CA1 sector of the hippocampus were
detected by the Fluoro-Jade C staining, detection of the
genomic DNA breaks, translocation of apoptoptic proteins
p53 and Bax. Interestingly, preconditioning abolished mitochondrial apoptosis initiation and translocation of p53
protein largely in the hippocampus but not in the cerebral cortex. The results indicate that both the initiation
and execution of mitochondrial apoptosis can be abolished by preconditioning in the CA1 hippocampal sector
(Racay et al., 2008, 2009).
Ischemic postconditioning is a phenomenon that intermits interruptions of blood flow in the early phase of
reperfusion which can protect an organ from ischemia/
reperfusion injury. These brief periods of ischemia performed just at the time of reperfusion can reduce the
volume of injured tissue. This ‘‘rapid’’ postconditioning is
an effective protective treatment in the case of a heart
infarct (Zhao et al., 2003; Galagudza et al., 2004; Kin
et al., 2004), ischemia of liver (Sun et al., 2004), kidney
(Liu et al., 2007), muscles (McAllister et al., 2008), skin
(Moon et al., 2008) as well as intestinal mucosa (Santos
et al., 2008).
In the CNS, postconditioning increases the neuronal
survival rate and decreases the size of an infarct area
after transient global cerebral ischemia (Pateliya et al.,
2008; Wang et al., 2008), focal ischemia (Zhao et al.,
2006; Xing et al., 2008), spinal cord ischemic injury and
is effective in a rat hippocampal slice model of cerebral
ischemia, too (Scartabelli et al., 2008). Gao et al. (2008)
found that the protective properties of postconditioning
depend on the number of cycles and on the duration of
each cycle of reperfusion and occlusion and the onset
time of postconditioning; and that they are comparable
to those of rapid preconditioning but not as robust as
those of delayed preconditioning (Gao et al., 2008).
Although this method is quite new, it largely resembles
a 20-year-olds attempt to prevent postischemic burst of
free oxygen radicals by ‘‘graded (controlled) reoxygenation’’ (Marsala et al., 1989; Burda et al., 1991, 1995).
As usual in a novel neuroprotective approach, very little is known about the mechanism of postconditioning
effects. Wang et al. (2008) provided the evidence that an
appropriate ischemic postconditioning strategy had neuroprotective effects, which are associated with its ability
to improve disturbed cerebral blood flow (partial prevention of reactive hyperemia and subsequent hypoperfusion) and prevent cytochrome c translocation. An equal
effect mediated by mitochondrial pore transition was
suggested in a postconditioned rabbit heart (Argaud
et al., 2005). Pignataro et al. (2008) documented the activation of the protein kinase Akt. Activation of the phosphoinositide 3-kinase-linked pathway has been described
in postconditioned mice (Rehni and Singh, 2007).
A new approach to adopt the postconditioning phenomenon is based on the idea to induce the mechanism
of IT by application of drugs known as inducers of IT
(O’Sullivan et al., 2007). Authors used diazoxide known
to induce preconditioning through its effect as a
mitochondrial potassium ATP channel opener and succinate dehydrogenase inhibitor. This treatment resulted in
significantly increased Hsps HSP25 and HSP70 expression and induction of tolerance.
mechanisms of IT-delayed postconditioning can be
exploited not only after ischemia but also in some other
processes leading to apoptosis.
In clinical settings, where the interruption of reperfusion cannot be performed immediately at the end of ischemia, the therapeutic window is extremely short. This
inspired Ren et al. (2008). He explored that if delayed
postconditioning is conducted a few hours after reperfusion, it offers protection against stroke. In rats, after 3–6
hr of focal ischemia, he applied six cycles of 15 min
occlusion/15 min release of the ipsilateral common carotid arteries which resulted in a robust reduction of the
infarction size.
Substantially different is the delayed protein synthesis
dependent approach used in Burda’s laboratory. This
method is based on discovery that the end effector of IT
is activated by lethal ischemia itself (Burda et al., 2005)
and full strength tolerance consists of the combination of
events occurring after first stress with those activated
by the repeated stress (Burda et al., 2006). Delayed postconditioning applied 2 days after lethal ischemia exploits
the fact that death of most sensitive pyramidal neurons
in hippocampal CA1 region is a slow process lasting 2–3
days before the first morphological changes can be
observed (Kirino, 1982; Pulsinelli et al., 1982). Coincidentally, the process of IT maturation lasts the same
time. Thus, application of the second sublethal stress 2
days after lethal stress, outruns irreversible changes
leading to apoptosis like delayed neuronal death. All
compounds commonly used as preconditioners (short ischemia, hypoxia, norepinephrine, 3-nitropropionic acid,
bradykinin) would be effective if used as postconditioners too (Burda et al., 2005, 2006; Danielisova et al.,
2006, 2008; Nemethova et al., 2008). With regard to the
mechanism of postconditioning, a common feature of all
compounds (conditioners) is the activation of SOD and
catalase immediately after administration regardless of
whether they are used as preconditioners (Danielisova
et al., 2005) or postconditioners (Danielisova et al., 2006,
2008). If a postconditioner is used 2 days after the first
stress when the activity of antioxidant enzymes
decreases, but the level of other possible protective proteins (e.g., HSP72) increases (Burda et al., 2003), postconditioner provokes de novo synthesis and increases
the activity of endogenous antioxidant enzymes. However, application of the second stress does not exclude
occurrence of another protecting compound with antiapoptotic/antidegenerative attributes.
Paradigm of delayed postconditioning can be effectively
utilized also after kainic acid intoxication (Burda et al.,
2007). Number of degenerated CA1 hippocampal neurons, assessed by analysis of neuronal density by Fluoro
Jade B-staining, exceeded 64% after 7 days after kainic
acid injection. In rats treated 2 days after kainate by i.p.
injection of norepinephrine or bradykinin, neurodegeneration in CA1 subfield significantly reduced to 6%.
These results support the therapeutical value of postconditioning in neuronal protection. Monitoring the
interval between ischemia and the first signs of delayed
neuronal death opens up a broad potential therapeutic
window for reversal of cellular death process. Moreover,
Since the seminal work of Murry et al. (1986) on the
protective effect of preconditioning in the heart, this endogenous response has been reproduced in all species
including humans and in a variety of organs. Other than
the heart, these also include the kidneys, liver, and
brain. In a clinical setting, when an acute myocardial infarction is preceded by preinfarction angina, the resulting infarction is milder. The heart has fewer cardiac
arrhythmias and a better left ventricular function compared to hearts without preceding angina (Rezkalla and
Kloner, 2007). This observation has promoted the therapeutic application of brief balloon inflations instead of
longer coronary interventions. This allows protection of
the heart (early preconditioning approach) and promotes
the development of delayed preconditioning mimetic
compounds such as nitro glycerin. Both strategies have
been successfully tested in randomized controlled trials
(Argaud et al., 2005; Jneid et al., 2005).
Nevertheless, the demonstration of adaptation to ischemia in patients in the setting of coronary bypass surgery (Perrault et al., 1996) strongly suggests that IP
occurs in humans. However, whether the myocardium in
patients with acute myocardial infarct (MI) can be preconditioned independently of collateral flow development
still remains a controversial issue. Earlier studies
(Ottani et al., 1995) suggested the possible occurrence of
IP in patients with acute MI undergoing thrombolytic
therapy. However, later studies (Tomoda and Aoki, 1999)
questioned this beneficial effect of preinfarction angina
and instead suggested that earlier recanalization of
occluded coronary arteries and myocardial reperfusion
may be a more likely explanation for the limited infarction size seen in those patients.
A more recent study (Takahashi et al., 2002) suggested that a protective effect of preinfarction angina is
mediated by inhibition of microcirculatory damage after
reperfusion. Thus, the available evidence in the clinical
setting of IP indicates that cardiomyocytes are not effectively preconditioned in human subjects (Otani, 2008).
Indeed, IT of the CNS has also been shown to have
consistent and robust neuroprotective effects in the laboratory. Although the clinical importance of IT is obvious,
the resulting protective manipulations have so far not
yet been transferred into the clinical environment. In
clinical settings, it might have practical use for cardiopulmonary bypass surgery, cardiac transplantation, and
other types of brain surgeries; where necessary, periods
of ischemia are provoked in healthy tissue and possibly
also in the management of brain tumors and trauma.
Importantly, the multimodal nature of tolerance
described in experimental studies indicates that protective pathways are probably highly evolutionary conserved and that harnessing endogenous protecting
pathways could potentially allow us to develop therapies
that would be well tolerated and capable of reducing
multiple types of injuries (Dirnagl et al., 2009). Even in
safe strategies, an additional factor needs to be understood; especially, when the target population for
preventive neuroprotection is usually elderly patients.
Protective stimuli might be specific to sex, dependent on
age and affected by diet and clinical comorbidities. In
addition, it is still unknown whether cumulative neuroprotection can be achieved by the combination of tolerance and pharmacological protection in the risk stroke
patients and patients with transient ischemic attacks
(Pignataro et al., 2009).
In cardiology and nephrology, the tolerance phenomenon is under active clinical investigation with ongoing
trials. In neurology, by contrast, only a few clinical studies have been conducted on this topic to test the safety
and efficacy of preconditioning strategies. In addition, a
consensus has not yet been developed that transient ischemic attack (TIA) provides protection against stroke
(Yenari et al., 2008). TIA is defined as a brief episode of
neurological dysfunction caused by focal brain ischemia
without evidence of acute infarction. Several studies
(clinical retrospective reports) support the hypothesis
that induced neuroprotection is important in patients
with TIA who have a subsequent ischemic stroke. In
early 1999, Weih et al. (1999) analyzed 148 ischemic
stroke patients with TIA (n ¼ 37) and without TIA (n ¼
111) and showed that TIA was an independent predictor
of mild stroke. Additional studies in humans are consistent with the view that acute stroke preceded by prodromal TIA results in fewer neurological deficits than
strokes do without a preceding TIA. Moncayo et al.
(2000) reported that brief TIA episodes lasting 10–20
min experienced less than 1 week before infarction have
a higher proportion of favorable outcome than those
with TIA 1–4 weeks before stroke. Similarly, as shown
by Castillo et al. (2003) in patients with ischemic stroke
including atherothrombotic and cardioembolic infarcts,
groups were significantly lower in patients with relevant
TIA. In a group of nonlacunar stroke with TIA, Arboix
et al. (2004) demonstrated a significantly higher favorable outcome with a history of stroke. Interestingly, in
the group of lacunar stroke patients, the percentage
with neurological deficits was similar and suggested that
the previous TIA has some distinctive clinical features.
More recently, Schaller (2005) revealed that strokes with
the prodromal TIA showing a similar clinical pictures
(NIHSS scores) on admission had better outcome than
those lacking prodromal TIA. The very recent article of
Fu et al. (2008) documented no significant effect of prodromal TIA on the outcome in a group of all ischemic
stroke patients. However, when they subdivided patients
according to the NIHSS difference scores on (i) prodromal TIA lasting up to 4 min; (ii) two prodromal TIA
attacks and/or; (iii) prodromal TIA-stroke interval within
7 days separately, they conclusively showed that
patients in subgroups 1 and 2 exhibited significantly better outcomes. However, no significant effect was found in
subgroup three, although this TIA group did show better
outcome when considering the NIHSS changes. The
authors suggested that the neuroprotection conferred by
the TIA may be associated with the duration and the
frequency of the TIA, although the relationship between
the TIA-stroke interval and prognosis is not clear. Based
on the above findings, it seems that TIAs have a protective effect in patients with nonlacunar cerebral infarction when TIAs occur weeks before cerebral infarction
and last for more than 10 min. On the other hand, Johnston (2004) failed to show correlation between the occurrence of TIA and reduced disability attributable to
subsequent stroke in a cohort study of more than 1,707
patients with prodromal TIA within 1 day, 1–7 days, and
90 days of a stroke. The reasons for these discrepancies
are unclear, but it is difficult to control certain factors in
clinical settings such as the duration and timing of TIAs
relative to the occurrence of stroke. However, previous
work leads to better insights. The spatial and temporal
limitations of the protective window provided by preconditioning reminds us of the need to increase our understanding of the nature and consequences of TIAs at least
because of limited duration of protection. The previous
studies mentioned earlier and study of Schaller and
Graf (2002) documented that several TIAs within the
week prior to a stroke were strongly associated with a
better outcome. Because nobody will prescribe a TIA for
a patient prior to experiencing a stroke, the other important question is how to imitate TIA protective effect by
introduction of small molecule therapies that regulate
targets like Hsps that play a critical role in as we may
learn to mimic the biochemical effects of a TIA (Obrenovitch, 2008). However, without a definite biomarker of
TIA, the strong debate over TIA constitutes will continue. Although the recent EXPRESS studies suggested
that up to 80% of strokes can be prevented by the emergent evaluation and treatment of patients with TIA
(Rothwell et al., 2007, Luengo-Fernandez et al., 2009),
the rapid response systems for TIA are just now being
Several clinical trials are ongoing to test the safety
and efficacy of other precondioning strategies. For example, remote preconditioning (tight cuff inflation) was
shown to decrease cerebral damage in patients undergoing carotid endarterectomy, or preconditioned effectors
such as erythropoietin, NO, and interleukin 1 receptor
agonist or induction of mucosal tolerance against E
selectin via nasal spray to lower stroke events and
reduce effect of cerebral ischemia (see; http:, and for review, see
Dirnagl et al., 2009). The results of postconditioned neuroprotection seem promising in this respect.
Authors thank Yasmeen Ahmed for help in the manuscript preparation.
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