Physiol Rev 88: 211–247, 2008;
doi:10.1152/physrev.00039.2006.
Molecular Physiology of Preconditioning-Induced Brain
Tolerance to Ischemia
TIHOMIR PAUL OBRENOVITCH
Division of Pharmacology, School of Life Sciences, University of Bradford, Bradford, United Kingdom
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I. Introduction
II. Cellular “House- and Health-Keeping” Mechanisms in the Tolerant Brain
A. Cellular ionic homeostasis and energy metabolism
B. Transport systems across the cellular membrane
C. Defense mechanisms against oxidative stress
D. Heat shock proteins
E. Control of cell death/survival
F. DNA repair
G. Self-repair and plasticity (neurogenesis/synaptogenesis and growth factors)
III. Synaptic Transmission in the Tolerant Brain
A. Balance between glutamatergic and GABAergic transmission
B. Role of adenosine
C. Nicotinic-cholinergic transmission
D. Other changes in ion channels, exocytotic mechanisms, and receptors
IV. Features of Brain Tolerance At Tissue Level
A. Inflammatory mechanisms
B. Cerebrovascular adaptation (vascular remodeling and reactivity)
C. BBB integrity
V. Concluding Remarks
Obrenovitch TP. Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia. Physiol Rev 88:
211–247, 2008; doi:10.1152/physrev.00039.2006.—Ischemic tolerance describes the adaptive biological response of
cells and organs that is initiated by preconditioning (i.e., exposure to stressor of mild severity) and the associated
period during which their resistance to ischemia is markedly increased. This topic is attracting much attention
because preconditioning-induced ischemic tolerance is an effective experimental probe to understand how the brain
protects itself. This review is focused on the molecular and related functional changes that are associated with, and
may contribute to, brain ischemic tolerance. When the tolerant brain is subjected to ischemia, the resulting insult
severity (i.e., residual blood flow, disruption of cellular transmembrane gradients) appears to be the same as in the
naive brain, but the ensuing lesion is substantially reduced. This suggests that the adaptive changes in the tolerant
brain may be primarily directed against postischemic and delayed processes that contribute to ischemic damage, but
adaptive changes that are beneficial during the subsequent test insult cannot be ruled out. It has become clear that
multiple effectors contribute to ischemic tolerance, including: 1) activation of fundamental cellular defense mechanisms such as antioxidant systems, heat shock proteins, and cell death/survival determinants; 2) responses at tissue
level, especially reduced inflammatory responsiveness; and 3) a shift of the neuronal excitatory/inhibitory balance
toward inhibition. Accordingly, an improved knowledge of preconditioning/ischemic tolerance should help us to
identify neuroprotective strategies that are similar in nature to combination therapy, hence potentially capable of
suppressing the multiple, parallel pathophysiological events that cause ischemic brain damage.
I. INTRODUCTION
Preconditioning/ischemic tolerance of the brain,
heart, and other organs refers to a natural adaptive process that can be induced by a variety of sublethal insults
(e.g., transient hypoxia), and which increases the tissue
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tolerance to a subsequent, potentially lethal ischemia.
This adaptive cytoprotection is a fundamental capability
of living cells, allowing them to survive exposure to potentially recurrent stressors. Preconditioning induces two
different time windows of tolerance. The first phase
(often named “rapid preconditioning”) occurs rapidly af-
0031-9333/08 $18.00 Copyright © 2008 the American Physiological Society
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TIHOMIR PAUL OBRENOVITCH
Physiol Rev • VOL
mission, which may also alter brain tolerance, are assembled in section III. Finally, changes in mechanisms that
involve multiple systems (e.g., inflammation) constitute
section IV. This organization is imperfect at times, because
some biological changes (e.g., mitochondrial preservation) are involved in several mechanisms that may underlie ischemic tolerance. Indeed, it has become clear that
ischemic tolerance results from interrelated, multifactorial processes, and this key feature is the primary rationale for this review. The complexity of the biological
responses underlying ischemic tolerance may reflect a
fundamental reprogramming of the brain tissue genomic
response to injury, a notion proposed by Stenzel-Poor,
Simon, and colleagues from their microarray analyses of
changes in gene expression (386, 387). In accordance with
the purpose of this review, subsections covering topics
that have been extensively investigated (e.g., inflammation and ischemic tolerance) are less comprehensive and
detailed than previous reviews dedicated to the corresponding topic; such more specialized reviews are cited
whenever appropriate.
In the numerous studies reviewed herein, preconditioning was induced by stressors as diverse as brief
period(s) of hypoxia or ischemia, cortical spreading depression, and administration of bacterial lipopolysaccharides (LPS). Therefore, it is pertinent to outline here the
notion of cross-tolerance, i.e., one stressor induces tolerance against a different stressor (127, 201, 316). The efficacy of cross-tolerance, relative to the classic ischemic
preconditioning (i.e., brief, sublethal cerebral ischemia,
with subsequent test ischemia that would damage the
naı̈ve brain; Ref. 372) may be more modest, and it appears
to vary with the nature and intensity of the first challenge
(201). The window of ischemic tolerance may be also
shifted or different; for example, the “tolerizing” effect or
LPS needed more time for maturation, starting at 48 h
after LPS injection and reaching full potential at 72 h in
the study of Tasaki et al. (407). For more details on
cross-tolerance, ischemic tolerance dependency on de
novo protein synthesis, and kinetics of increased brain
resistance to ischemia induced by preconditioning, see
Kirino (201).
There are two notes of caution. Cross-tolerance is an
important feature, but potentially misleading by suggesting that different preconditioning stimuli result ultimately
in similar mechanisms of tolerance. That may be only
partially true, and dependent on the nature of the stimuli
considered. Comparison of the genomic profiles of brain
responses to ischemia from mice preconditioned with
either brief ischemia or low-dose LPS revealed that a
substantial subset of the differentially expressed genes
were unique to each preconditioning stimulus (385).
This suggests that the nature of the preconditioning
stimulus may determine a specific neuroprotective phenotype (385).
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ter the stimulus used for induction of preconditioning and
only lasts for ⬃1 h, whereas the delayed phase corresponds to a robust state of tolerance that is usually detectable 24 h after preconditioning induction, peaks at 3
days, and fades after 7 days. For clarity sake, in this
review, “preconditioning” describes which initial stimulus
or treatment (e.g., chemical preconditioning) was used
for the induction of increased resistance to ischemia
and/or other stressors. “Ischemic tolerance” is restricted
to define the period of increased resistance of the brain to
ischemic injury, whereas the terms brain tolerance or
tolerant brain define the wider notion of increased cerebral resistance to ischemia and other stressors.
Clearly identified in the heart by Murry et al. in 1986
(262), preconditioning and subsequent ischemic tolerance
were then demonstrated in the brain (203), and attracted
rapidly the interest of clinical and basic neuroscientists
for several reasons. First, this biological process became
widely recognized as a pertinent and effective experimental probe to understand how the brain protects itself
against ischemia, thereby providing an innovative approach for the discovery of novel cerebroprotective strategies. Second, retrospective case-control studies showed
a clinical correlate of the phenomenon discovered experimentally. Patients with a history of transient ischemic
attack (TIA) have a decreased morbidity after stroke (284,
432). Finally, other findings suggested that brain tolerance
may be induced, or mimicked pharmacologically (39).
This review focuses on brain tolerance which, as
defined above, lasts several days after preconditioning
induction. Its purpose is to provide an integrated account
of the adaptive modifications that are associated with
brain tolerance, with emphasis placed on effector mechanisms (i.e., the molecular and related functional changes
that may increase tolerance). In all studies, preconditioning is used to induce a state of tolerance prior to the
subsequent, potentially lethal “test” ischemia (i.e., a procedure equivalent to a neuroprotective pretreatment) and,
therefore, the molecular changes underlying ischemic tolerance may be effective against deleterious processes that
occur during or after the lethal ischemia. This review was
written for investigators who are new to this field of
study, and to help experts including and interpreting their
findings within a more complex and integrated picture.
Several previous reviews provide a broader coverage of
brain preconditioning and ischemic tolerance (94, 136,
201), and readers should refer to those for information on
complementary issues such as 1) Which molecular sensors are activated by preconditioning and initiate the
biological responses that ultimately lead to ischemic tolerance? 2) Which signaling cascades and transducers contribute to the development of ischemic tolerance?
As outlined in the table of contents, alterations occurring at the cellular level and their functional consequences constitute section II. Changes in synaptic trans-
BRAIN ISCHEMIC TOLERANCE
When a specific variable (gene expression, level of a
specific protein, etc.) is found to be altered in animals
subjected to both preconditioning stimulus and test insult, this change may be causally related to the mechanism of protection, and this interpretation is often favored
by authors. However, as the fundamental nature of preconditioning is to protect the brain against a subsequent
insult, an alternative and valid interpretation may be that
the identified change simply reflects, or is an epiphenomenon of, the reduced damage. This potential pitfall should
be kept in mind.
A. Cellular Ionic Homeostasis
and Energy Metabolism
As brain preconditioning implies the induction of
biological processes prior to a potentially lethal insult, it
is rational to examine whether brain cell tolerance to
ischemia is actually strengthened during the test insult.
Among other mechanisms, this could be achieved by improved brain energy metabolism under low oxygen and/or
glucose, or a prolonged latency for anoxic depolarization
after the ischemia onset. With regard to the latter, cellular
depolarization is clearly detrimental to the ultimate outcome in models of cerebral ischemia. 1) Ischemic neuronal damage subsequent to transient global ischemia or
hypoxia correlates closely with the duration of anoxic
depolarization (20, 187, 283, 374), and 2) the size of infarct
in stroke models increases with the number and total
duration of peri-infarct depolarizing events (250, 408). In
addition, brain cells appear to have the ability to adapt to
hypoxia by reducing their energy demand through modulation of ion channels, which delays anoxic depolarization
(150, 162, 419, 437). Reduced brain energy demand is also
a feature of hibernation and hypothermia, two other conditions that reduce the brain vulnerability to energy deprivation (22, 118).
In mice subjected to preconditioning alone (induced
by 15 min of middle cerebral artery occlusion, MCAO) or
followed 3 days later by damaging ischemia (60-min
MCAO), the profile of changes in gene expression suggested metabolic depression and attenuation of ion-channel activity (387). Follow-up experiments with cultured
rat cortical neurons showed that preconditioning induced
by brief noninjurious oxygen and glucose deprivation decreased voltage-gated potassium currents (387). However, most of the data reviewed next do not support the
notion that reduced energy demand and ion channel
“arrest” are determinant factors for ischemic tolerance.
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1. Ischemic tolerance and latency of
anoxic/ischemic depolarization
When brain preconditioning was produced by a standardized ischemic insult to the forebrain (i.e., transient
4-vessel occlusion to produce anoxic depolarization for
2–3.5 min) in rats, at the time for maximum neuroprotection in these experiments (i.e., 2 days postpreconditioning), anoxic depolarization was delayed by ⬃1 min during
the subsequent ischemic insult (417). This indicated that
the severity of the subsequent test insult was reduced
slightly by preconditioning in this rat model, but such an
effect was not observed when the same experimental
strategy was applied to gerbils (1), nor in mice with
cortical spreading depression (CSD) preconditioning and
bilateral carotid occlusion as subsequent test insult
(Godukhin OV, Jackson G, Obrenovitch TP, unpublished
data). Furthermore, other data in the rat study suggested
that the delayed anoxic depolarization in the preconditioned group only played a minor contribution toward
ischemic tolerance, because the ischemic thresholds for
hippocampal neuron loss, measured 1 wk after the test
insult, increased from 4 min of ischemic depolarization in
controls to 15 min in the preconditioned group, i.e., far
more than the 1-min increase of the anoxic depolarization
latency (417). Finally, the anoxic depolarization latency
was not significantly different between slices from gerbils
subjected to ischemic preconditioning and those from
sham-operated gerbils, when these slices were exposed to
anoxia (191). The experimental strategy used in this latter
study was pertinent because it ruled out a potential, interfering cerebrovascular effect of preconditioning (see
sect. IVB).
2. Ischemic tolerance and peri-infarct
depolarizing events
Electrical stimulation of the cerebellar fastigial
nucleus (FN) for 1 h was found to elicit a marked and
long-lasting increase in the brain tolerance to insults, with
features suggesting that the resulting tolerance was similar to that achieved by other preconditioning methods:
1) effective protection against different insults, including
global and focal ischemia (141, 333) and excitotoxicity
(139); 2) delayed protection against MCAO was maximal
3 days after FN stimulation; 3) decreased susceptibility of
brain cells to apoptosis in vitro (462); and 4) decreased
inflammatory reactivity in the brain (129). However, the
most interesting finding within the context of this subsection was that FN stimulation at 3 days before MCAO also
markedly reduced the development of peri-infarct depolarizations (142). It would be pertinent to test whether
this effect occurs with other preconditioning methods,
because peri-infarct depolarizations are known to contribute to lesion progression in MCAO models (250, 408)
as well as in humans with acute brain injuries (107). In
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II. CELLULAR “HOUSE- AND HEALTHKEEPING” MECHANISMS IN THE
TOLERANT BRAIN
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3. Cellular ionic homeostasis in the ischemiatolerant brain
Ischemic preconditioning, induced 24 h before global
forebrain ischemia in rats, prevented the inhibitory effect
of ischemia/reperfusion on Na⫹-K⫹-ATPase activity in
cytoplasmic membrane fractions of hippocampus and cerebral cortex (92), but this was probably a consequence of
cytoprotection as N-methyl-D-aspartate (NMDA) receptor
block with dizocilpine (MK-801) had similar effects (258).
Given the potentially lethal consequences of intracellular Ca2⫹ overload (32), it is relevant to examine whether
Ca2⫹ homeostasis is altered in ischemic-tolerant brain
cells. When ischemic preconditioning preceded a lethal 5
min of forebrain ischemia in gerbils, several potentially
beneficial changes were found in hippocampal CA1 neurons, including the following: plasma membrane Ca2⫹ATPase activities were elevated before the test ischemia,
and remained subsequently at a higher level, and mitochondrial sequestration Ca2⫹ was enhanced (285). In line
with these data, imaging of intracellular Ca2⫹ ([Ca2⫹]i)
showed that its elevation in hippocampal CA1 neurons
after an anoxic-aglycemic episode was markedly inhibited
in the ischemia-tolerant gerbil (367). Furthermore, also in
the hippocampus of gerbils, the expression of the plasma
membrane Ca2⫹-ATPase isoform 1 (PMCA1) was increased, together with that of inducible 72-kDa heat
shock protein (HSP70), when brain ischemic tolerance
was enhanced by 3-nitropropionic acid preconditioning
(190). It is relevant to mention that the Na⫹/Ca2⫹ exchanger (NCX) gene was upregulated after transient
global ischemia in rats (235). However, the duration of the
recirculation period was only 6 h in this study (235), and
more recent experiments suggested that NCX gene expression after permanent MCAO in rats is regulated in a
differential manner, depending on the exchanger isoform
(NCX1, -2, or -3) and the region involved in the insult (i.e.,
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ischemic core, peri-infarct areas or spared regions)
(42, 313).
Na⫹/H⫹ exchange and Na⫹-K⫹-2Cl⫺ cotransport are
also critical ion transporters as they contribute to the
regulation of intracellular pH and cell volume (305). This
dual role, however, makes it difficult to predict whether a
change in the efficacy of these transporters may promote
or impair the survival of cells to ischemia; for example,
enhanced Na⫹/H⫹ exchange would help to reduce intracellular pH but promote cell swelling and further Ca2⫹
influx through Na⫹/Ca2⫹ exchange. Comparison of cortical astrocyte cultures from wild-type and Na⫹/H⫹ exchanger isoform 1 deficient [NHE1(⫺/⫺)] mice suggested
that NHE1 deficiency actually attenuated the disruption
of ionic regulation and swelling induced by 2 h of oxygen
and glucose deprivation (200), and this notion was confirmed in vivo (234). In wild-type mice treated with the
Na⫹/H⫹ exchange inhibitor HOE 642 and in NHE1(⫺/⫺)
mice, the size of infarct measured 24 h after 2h of MCAO
was reduced by around one-third. (65). Similar data were
obtained with genetic manipulations of the Na⫹-K⫹-2Cl⫺
cotransporter isoform 1 (NKCC1) in mice and inhibition
of NKCC1 by bumetanide (65). According to these data,
one could expect ischemic tolerance to be associated
with a downregulation of NHE1 and/or NKCC1, but no
report of such an association could be found for either
central nervous system (CNS) or myocardium.
4. Glucose consumption, ATP levels, and lactic
acid accumulation/clearance
As the delay for anoxic/ischemic depolarization is, to
some extent, related to the cerebral metabolic rate during
the ischemic insult (270, 425), one would not expect a
major change in the latter variable to be associated with
ischemic tolerance. This notion was supported by the
elegant studies of Maruoka and co-workers (239, 291), in
which the cerebral glucose metabolic rate (CMRglu) was
measured serially in different regions of freshly prepared
rat brain slices by using [18F]2-fluoro-2-deoxy-D-glucose as
tracer. Compared with controls, 3 days after either
hypoxic or 3-nitropropionic acid preconditioning, CMRglu
in the frontal cortex was similar before and during the
20-min test hypoxia. After reoxygenation, there was a
much better recovery of CMRglu in slices prepared from
preconditioned animals, but this probably reflected increased cellular viability. Similarly, ATP and phosphocreatine levels in the cortex and hippocampus of gerbils were
not changed 24 h after ischemic preconditioning (2-min
bilateral carotid occlusion) or during the subsequent
5-min test ischemia and at 1-day reperfusion (189). However, conflicting data were obtained with immature rats:
brain glycogen was increased 24 h after hypoxic preconditioning, and residual ATP measured at the end of the
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addition, as these events occur early after ischemia onset,
their suppression could contribute significantly to the
reduction of the lesion volume that can be detected within
hours of permanent MCAO (e.g., when measured at 6 h
after MCAO in mice previously subjected to CSD-preconditioning; Godukhin et al., unpublished data). As proposed by Golanov et al. (142), this effect of FN stimulation
may be linked to a reduction of neuronal excitability, a
hypothesis in line with some previous data indicating that
preconditioning (hypoxic, ischemic, or hyperthermic) decreases the susceptibility to seizures evoked by bicuculline, kainic acid, or pentylenetetrazol (101, 320, 345).
However, in two other studies, increased resistance to
kainic acid excitotoxic neuronal damage was not associated with reduced susceptibility to kainic acid-induced
seizures (193, 316).
BRAIN ISCHEMIC TOLERANCE
5. Preservation of mitochondrial membrane potential
and function
Several studies in vitro and in vivo showed that brain
ischemic tolerance is associated with preservation of mitochondrial function. Preconditioning by transient, sublethal exposure to cyanide protected primary cultures of
chick embryonic neurons from neurotoxicity induced
24 h later by a more severe exposure to cyanide, and this
effect was associated with better preservation of the mitochondrial membrane potential (178). These data were
confirmed with cultured hypothalamic neurons when hypoxic preconditioning preceded anoxia (436). When nonsynaptosomal mitochondria prepared from the hippocampus of rats were assessed 24 h after 10 min of global
ischemia, the rate of oxygen consumption and the activities of complexes I–IV were preserved by ischemic preconditioning induced 48 h before the test ischemia (88).
These in vitro data were complemented by two similar
studies in rats. Zhan et al. (453) reported a better preservation of mitochondrial cytochrome c during reperfusion
in preconditioned animals; Zhang et al. (455) reported
confirmatory data with MCAO as test insult. Supporting
data were also obtained in gerbils (273). As the enhanced
stability of mitochondrial membrane potential was assoPhysiol Rev • VOL
ciated with an overexpression of the anti-apoptotic Bcl-2
and Bcl-xL genes in the studies with cultured neurons
(178, 436), it was proposed that the preservation of mitochondria function may be a consequence of Bcl-2 overexpression (see sect. IIE). However, opening of mitochondrial ATP-dependent K⫹ channels (mKATP channels)
emerges as a pertinent, alternative mechanism.
Localized in the inner membranes of mitochondria,
mKATP channels are inhibited by ATP, ADP, long-chain
CoA esters, and 5-hydroxydecanoate (5-HD), and their
ATP inhibition is reversed by GTP, GDP, cromakalim,
diazoxide, and other KATP channel openers. The primary
role of mKATP is thought to be mitochondrial matrix volume regulation, with mKATP opening increasing the matrix volume (or preventing its contraction caused by mild
mitochondrial depolarization) (18), but the physiological
consequences of mKATP opening also include respiratory
stimulation and matrix alkalinization (79). The role of
mKATP channels in cardioprotection is well documented,
with robust evidence that the activation of these channels
acts both as inducer and effector of heart ischemic tolerance (290). Although this issue has not been as intensively
investigated in the CNS, brain mitochondria contain six to
seven times more mKATP than heart mitochondria, brain
and heart mKATP are regulated by the same ligands (18),
and some data suggest that mKATP is also involved in
brain ischemic tolerance. 1) 5-HD, a selective blocker of
mKATP, administered prior to preconditioning with 3nitropropionic acid in rats, blocked the development of
ischemic tolerance to focal cerebral ischemia (165), confirming and clarifying previous results obtained with the
less-selective KATP channel blocker glibenclamide (158).
2) Pretreatment with mKATP channel openers (diazoxide
or BMS-191095) reduced neuronal death produced by
transient focal cerebral ischemia or venous ischemia in
rats (245, 267, 368, 435). In the mouse MCAO model,
diazoxide decreased markedly the cortical lesion and reduced neuronal apoptosis in the peri-infarct region, and
this cerebroprotective effect was abolished by 5-HD
(228). Diazoxide also protected hippocampal and cerebellar neurons from apoptosis induced by staurosporine,
hypoxia, or oxidative stress (168, 228, 409). Note that
although KATP channels are also present at the surface of
cells (including neurons) and some experiments suggested that plasma membrane KATP channels also contribute to cytoprotection, the central role of mKATP is now
widely accepted (290), and delayed ischemic preconditioning of hippocampal neurons was not altered in knockout mice lacking the cellular SUR1-type KATP channels
(260). More information on cell surface KATP channels is
available in section IIID.
Although the cytoprotective mechanisms associated
with increased mitochondrial K⫹ uptake subsequent to
mKATP channel opening in the heart have already received
much attention, the beneficial consequences of increased
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90-min test hypoxia-ischemia was significantly higher
than in controls (48).
Given the rapid increase in brain tissue and extracellular lactate levels, not only during ischemia (121, 232) but
also with peri-infarct depolarizations (164), an improved
ability to use lactate as an energy substrate would be a
potentially important adaptive change of the brain energy
metabolism, especially during reperfusion. Some studies
suggest that the CNS has this capability and that it may be
induced by preconditioning. 1) Neuron-rich slices (i.e.,
incubated in the presence of the glial toxin, fluorocitrate)
prepared from the rat brain left hemisphere, of which the
contralateral MCA was occluded 48 h before slice preparation, were able to utilize lactate as energy substrate, in
contrast to slices of control rats (205). 2) The expression
of monocarboxylate transporter 1 (MCT1, involved in the
uptake and release of lactate, pyruvate and ketone bodies;
312) was increased in cultured primary rat astrocytes
after 1-day hypoxia (423) and under inflammatory conditions (209). However, ischemic preconditioning in adult
gerbils had no effect on lactate levels at 24 h postpreconditioning, during the test ischemia and up to 1 day within
the reperfusion period (189).
Overall, these data do not suggest that an adaptation
of brain energy metabolism, or increased latency for
anoxic depolarization, can significantly account for ischemic tolerance. However, the possibility that the tolerant
brain may have an improved ability to control intracellular Ca2⫹ overload deserves further investigations.
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TIHOMIR PAUL OBRENOVITCH
mitochondrial K⫹ uptake during ischemia/reperfusion remain speculative (for review, see Refs. 12, 108, 131).
These may include energy conservation subsequent to
reduced ATP transport across mitochondrial membranes,
attenuation/prevention of mitochondrial Ca2⫹ overload,
changes in the mitochondrial generation of reactive oxygen species (ROS), and prevention of mitochondrial permeability transition (MPT, a key mechanism of mitochondrial injury shown to occur at reperfusion). Clearly, it is
now timely to investigate how important are these mechanisms to brain ischemic tolerance.
1. Glucose transport
Brain glucose uptake and utilization involve primarily the glucose transporter proteins GLUT1 and GLUT3
(422). A high density of GLUT1 in a highly glycosylated
form is present in cerebral vessels endothelium where it
facilitates the diffusion of glucose across the blood-brain
barrier. In the brain parenchyma, a less glycosylated form
of GLUT1 is present in glia, whereas GLUT3 is essentially
neuronal (148, 422). No study dedicated to the effect of
preconditioning on brain glucose uptake could be found
when this review was prepared, but several lines of evidence suggested that an upregulation of GLUT1 and
GLUT3 may be associated with brain ischemic tolerance.
1) Even though blood-brain glucose transport is not
the rate-limiting step of brain glucose metabolism under
normal conditions, there is evidence that it can adapt to
improve glucose delivery to neurons in situations such as
reduced plasma glucose (hypoglycemia) or excessive
synaptic activity (prolonged/repeated seizures) (223). In
rats, chronic (i.e., 5- or 12- to 14-day duration) insulininduced hypoglycemia produced significant increases in
both GLUT1 mRNA and protein levels together with a
redistribution favoring luminal transporters (212, 373).
Studies with cultured capillary endothelial cells also
showed that glucose deprivation enhanced GLUT1 gene
expression, with maximum effect observed 24 h after
glucose removal (40). There is also convincing in vivo and
in vitro evidence that neuronal GLUT3 is upregulated
when glucose availability is reduced (99, 219, 264, 418);
for example, 3-day starvation in mice increased brain
GLUT3 mRNA by twofold, and 2-day glucose deprivation
increased that of primary neuronal cultures by fourfold
(264). In line with these data, work with primary cultures
of rat neurons showed that 24-h hypoxia rapidly increased
neuronal GLUT1 and GLUT3 mRNA up to 40- and 5-fold,
respectively, with similar changes in GLUT1 mRNA measured in glia (49). Interestingly, the same study showed
that although glucose deprivation alone produced minimal effects on GLUT mRNA levels, hypoxia plus glucose
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B. Transport Systems Across the
Cellular Membrane
deprivation synergized to markedly increase GLUT gene
expression (49). With regard to excessive brain activity, in
adult rats, chronic seizures produced by pentylenetetrazole or kainic acid increased the expression of both
GLUT1 with maximum abundance at 3 days (146). In
contrast, GLUT-1 densities were significantly decreased in
some structures of the visual cortex when rats were subjected to chronic visual deprivation (98). All the aforementioned studies relate to chronic imbalance between
brain glucose supply and demand, but there is also evidence that glucose transport can be very rapidly upregulated. In mice, GLUT1 upregulation was evident in both
hypothalamus and cortex 3 h after mild hypoglycemia
induced by a single insulin injection (241). In adult rats
treated with pentylenetetrazole, acute upregulation of
blood-brain barrier (BBB) glucose transport occurred
within 3 min of an initial seizure (78).
2) Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates the adaptive response to hypoxia in mammalian cells (361, 362). As such, brain HIF-1
was found consistently upregulated early after hypoxic
preconditioning (33, 34, 184, 185, 347), after reversible
cerebral ischemia (181, 311), and in the peri-infarct penumbra (31). More relevant within the context of this
subsection, GLUT1 is one of the HIF-1 target genes, together with erythropoietin (EPO) and vascular endothelial growth factor (VEGF) (362).
3) In line with the early induction of HIF-1 by preconditioning (point 2), differential gene expression analysis identified GLUT1 as an upregulated gene in samples
of preconditioned brain relative to controls (34, 184, 406)
and in the rat MCAO model penumbra (31). Interestingly,
GLUT1 was also upregulated in hypoxic macrophages in
vitro (50), but one can argue that this may be detrimental
to brain cell survival during cerebral ischemia because
macrophages accumulating in ischemic areas could
“steal” an essential fuel away from neurons in vulnerable
areas. Also relevant, especially within the context of LPS
preconditioning, is the study of Cidad et al. (73), showing
that incubation of cultured rat astrocytes with LPS for
24 h increased the level of constitutively expressed
GLUT1 mRNA and triggered GLUT3 mRNA expression
(that was absent in control astrocytes). In the same study,
incubation of astrocytes for 4 h in the absence of glucose,
or under an oxygen-poor atmosphere (3%), also upregulated GLUT3 mRNA.
Increasing the capacity of the transport of glucose to
neurons appears to be an efficient way to enhance the
resilience of the brain to ischemia, at least with regard to
glucose transport across the BBB, because procedures
that lead to GLUT1 overexpression, by themselves, were
cerebroprotective. Virus-mediated GLUT1 overexpression
enhanced glucose uptake in hippocampal cultures and in
adult rat hippocampus (160); protected the cultured neurons against exposure to glucose deprivation, glutamate,
BRAIN ISCHEMIC TOLERANCE
2. Excitatory amino acid transporters
Excitatory amino acid transporters (EAATs) in glia
and neurons remove glutamate from the extracellular
space, thereby contributing to terminate glutamate-mediated synaptic signaling and preventing extracellular glutamate to reach neurotoxic levels. Given the variety of
mechanisms that can lead to excitotoxicity (85, 282),
changes in EAATs density could be another adaptive
change contributing to brain ischemic tolerance. However, both EAATs down- and upregulation may be considered potentially neuroprotective, depending on which aspect of ischemia-induced glutamate efflux is considered:
1) an upregulation of EAATs could be beneficial by increasing the efficiency of the removal of extracellular
glutamate, or 2) a reduction of the EAATs density on the
cellular membrane could reduce the amount of glutamate
released by reversed uptake, reported as the most important route for glutamate efflux when ischemia is severe
enough to produced anoxic depolarization (176, 343). In
addition, both in vivo and in vitro studies dedicated to this
issue have provided conflicting data so far.
Physiol Rev • VOL
Ischemic preconditioning produced by 10 min of
MCAO in rats resulted in an upregulation of EAAT2 and
EAAT3, but not of EAAT1 expression (322). In contrast,
CSD preconditioning in the same species downregulated
both the glial transporter isoforms EAAT1 and EAAT2 at
1, 3, and 7 days after preconditioning, with a maximal
decrease at the 3-day time point, i.e., a time frame that
coincides with ischemic tolerance (96). CSD preconditioning also reduced by two-thirds the cortical efflux of
glutamate associated with the subsequent 200 min of focal
ischemia, but one cannot ascertain from such studies
whether this effect was effectively due to a decreased
density of glutamate transporters, and thereby a reduction in glutamate leaking through reversed transport, or a
consequence of reduced ischemic brain damage (96). Still
in vivo, hypoxic preconditioning (i.e., 3-h exposure to 8%
O2) of newborn rats 24 h before their exposure to severe
hypoxia-ischemia protected all the brain regions that
were assessed morphologically (i.e., cortex, striatum, and
hippocampus); in contrast, EAAT1 proteins did not
change in any region 24 h after preconditioning, whereas
EAAT2 levels increased in the cortex by 55% but did not
change in the hippocampus and were decreased by 48% in
the striatum, suggesting that EAAT changes were not
related to ischemic tolerance in this study (74).
When rat cortical cultures (primary neuronal) were
exposed to sublethal oxygen-glucose deprivation (i.e., in
vitro ischemic preconditioning), ischemic tolerance was
associated with upregulation of EAAT2 and EAAT3
(whereas EAAT1 remained unaltered), and glutamate uptake was more efficient in the preconditioned cultures
(338). However, with neuron/astrocyte cocultures, another group of investigators reported that a downregulation of the EAAT2 glutamate was associated with ischemic tolerance induced by ischemic preconditioning
(210, 442).
Overall, these studies do not support the notion that
altered EAATs expression is an essential and/or common
contributor to brain ischemic tolerance.
C. Defense Mechanisms Against Oxidative Stress
A large body of evidence indicates that ROS contribute to the pathogenesis of brain damage produced by
ischemia/reperfusion. ROS may originate from mitochondria in neurons, glia, and endothelial cells (for reviews,
see Refs. 60, 256) or intravascularly from activated leukocytes and platelets (90). During recirculation, excessive
NO formation may also contribute to ischemic brain injury through the formation of reactive nitrogen species
such as peroxynitrite (i.e., reaction product of nitric oxide
with superoxide radicals) (196). There is evidence suggesting that superoxide anion generation during preconditioning induced by transient ischemia is necessary for
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or the mitochondrial toxin 3-nitropropionic acid (161);
and reduced kainic acid-induced neuronal damage in the
rat hippocampus (218). Treatment of ovariectomized female rats with the estrogen 17␤-estradiol, which is known
to upregulate GLUT1 in the BBB (363), reduced the ischemic lesion produced by permanent MCAO (364) and extended the threshold for ischemic damage produced transient MCAO (109). 17␤-Estradiol also protected cultured
rat brain endothelial cells against anoxia and glucose
deprivation (364). Note, however, that estrogen neuroprotection may involve several other mechanisms, besides
GLUT1 upregulation (for review, see Refs. 45, 332).
Against this experimental background, it is relevant to
mention that women appear to be naturally more resistant
to stroke during premenopausal life, and if hormone replacement therapy (HRT) may not be considered because
of adverse effects, hormonal therapy in other forms may
be suitable for neuroprotection in clinical practice (for
review, see Refs. 45, 332). Some antiapoptotic systems
also have the ability to upregulate GLUT1. When human
neuroblastoma cells were exposed to low-glucose medium, treatment with insulin-like growth factor I (IGF-I)
or Bcl-2 upregulated GLUT1, enhanced glucose transport,
and improved neuronal survival (348).
To conclude, an improved capacity of the transport
of glucose from blood to brain cells is likely to be a
feature of brain ischemic tolerance. So far, GLUT1 and
GLUT3 upregulation appears to be the primary changes
for improving the transport of glucose at BBB and neuronal membrane level, respectively. However, it is likely
that other molecules are also implicated, such as the
Na⫹-D-glucose cotransporter (SGLT1) (105).
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TIHOMIR PAUL OBRENOVITCH
1. SODs (Mn-SOD and Cu/Zn-SOD)
With hypoxic preconditioning, three separate studies
using different experimental strategies all suggested that
hypoxic tolerance, when present, was related to increased expression and activities of SODs (133, 143, 292).
In contrast, ischemic preconditioning in rats induced sustained increased levels of SODs when induced by 5 min of
four-vessel occlusion (86), but not when induced by 3-min
MCAO (325). When brain preconditioning was induced in
gerbils by an oxidative stress (287) or in rats by LPS (41),
SOD brain activity increased with ischemic tolerance.
Finally, CSD is a robust stimulus for brain preconditioning, but two separate studies with rats clearly suggested
that CSD-induced ischemic tolerance was not mediated
through the upregulation of SODs (253, 433).
2. Catalase
In rats, when 5 min of four-vessel occlusion was used
to induce brain preconditioning, catalase activity inPhysiol Rev • VOL
creased significantly at all time points considered (5, 24,
and 48 h postpreconditioning) with a peak at the 24 h time
(86), but such a change was not observed with LPSinduced preconditioning (41). In vitro, when primary cultures of rat cortical neurons were subjected to hypoxic
preconditioning, there was no subsequent increase in
catalase activity (14).
3. Glutathione peroxidase
In rats, brain preconditioning induced by 3-min
MCAO significantly reduced the cerebral infarct produced
by 1-h MCAO within the 24- to 72-h postpreconditioning
time window, but ischemic tolerance was not associated
with any changes in the activities of glutathione peroxidase, nor in its neuronal expression (325). In vitro, when
primary cultures of rat cortical neurons were subjected to
hypoxic preconditioning, glutathione peroxidase and glutathione reductase activities were increased by 54 and
73%, respectively (14).
Whenever it is present, Cu/Zn-SOD (SOD1, cytosolic)
and/or Mn-SOD (SOD2, mitochondrial) upregulation presumably contributes to brain tolerance because their
overexpression, by itself, was neuroprotective in various
models.
4. SOD1
Overexpression of this enzyme in transgenic mice
was cerebroprotective during reperfusion following focal
ischemia (125, 208), but not when MCAO was permanent
(61); it reduced neuronal cell loss at 3 days after 8 min of
cardiac arrest in some brain regions (207), which agrees
with findings obtained with SOD1 overexpression in rats
(62). It attenuated the neurotoxicity induced by the systemic administration of the mitochondrial toxin 3-nitropropionic acid (26); it protected cultured astrocytes exposed to oxygen-glucose deprivation for 5 h, and this
beneficial effect was associated with the maintenance of
glutathione at higher levels (428).
5. SOD2
Membrane lipid peroxidation, protein nitration (reflecting damage by peroxynitrite), and neuronal death,
measured 1 day after 1 h of MCAO, were all significantly
reduced in transgenic mice overexpressing human SOD2
(192). In contrast, apoptosis subsequent to transient focal
cerebral ischemia was more pronounced in heterozygous
SOD2 ⫹/⫺ knockout mice as indicated by enhanced accumulation of cytosolic cytochrome c and increased DNA
laddering after ischemia (124).
The latter data (124) and other studies (125, 351, 398)
suggest that the neuroprotective effect of SOD overexpression may be linked, at least partly, to an attenuation
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the subsequent development of ischemic tolerance (see
Ref. 126 for recent in vitro data and Ref. 309 for review).
For example, intravenous administration of human recombinant Cu/Zn-superoxide dismutase (SOD) to rats
prior to ischemic preconditioning suppressed the development of tolerance against a subsequent MCAO insult, as
well as the expression of HSP70 (255). Similarly, there is
good evidence of protective and restorative properties for
nitric oxide (NO), and these include the induction of gene
expression programs that underlie brain preconditioning
(71, 169, 196).
Against this background, it is logical to hypothesize
that ischemic tolerance may involve an enhancement of
defense mechanisms against ROS, and especially an upregulation of antioxidant enzyme activities (i.e., SODs,
catalase, and glutathione peroxidase). Some data support
this concept. In rats previously subjected to focal ischemic preconditioning, there was a significant reduction in
the volume of the cortical lesion produced by a subsequent MCAO, and this ischemic tolerance was associated
with a significant reduction of lipid peroxidation (69). In
cultured neurons subjected to hypoxic preconditioning,
the activity of the antioxidant enzymes glutathione peroxidase, glutathione reductase, and Mn-SOD were significantly increased, and superoxide and hydrogen peroxide
concentrations following a subsequent episode of oxygenglucose deprivation were lower in preconditioned cultures (14). However, according to the numerous studies
dedicated to the key antioxidant enzymes SODs, catalase,
and glutathione peroxidase, brain tolerance is not always
associated with increased activities or upregulation of
these enzymes. Whether or not these antioxidant enzymes
are upregulated appears to depend, at least in part, on the
preconditioning stimulus that was used.
BRAIN ISCHEMIC TOLERANCE
Physiol Rev • VOL
MCAO reduced infarct volume, neurological deficit, and
protein carbonyl content (i.e., a marker of protein oxidation) (153). Overexpression of Trx in PC12 cells prolonged their survival in culture medium lacking nerve
growth factor (NGF) and serum, suggesting that Trx can
delay neuronal apoptosis (170); subsequent studies
showed that Trx was a direct inhibitor of the apoptosis
signal-regulating kinase (ASK) 1 (352). In support of these
data, Trx in the submicromolar range blocked mitochondria-mediated apoptosis in cultured human neuroblastoma cells (10). Finally, overexpression of p32TrxL protected cultured HEK-293 cells against glucose deprivation (180).
To conclude this section, it is likely that an enhancement of the cellular defense mechanisms against oxidative stress contributes to brain tolerance. Upregulation of
the Trx system appears as a common feature, whereas
upregulation of SOD, catalase, and glutathione peroxidase may only occur with some preconditioning stimuli. It
is relevant to mention that Trx upregulation may be induced pharmacologically, as the monoamine oxidase type
B (MAO-B) inhibitor deprenyl upregulated Trx in cultured
neuroblastoma cells, and the associated neuroprotection
was blocked by a Trx-mRNA antisense nucleotide (11).
D. Heat Shock Proteins
Heat shock proteins (HSPs) or stress proteins are
found in all living cells, where they act as molecular
chaperones, carrying out multiple functions that are essential to protein housekeeping. In normal cells, HSPs
assist in the folding of newly synthesized proteins. Briefly,
this is accomplished by HSPs reversibly and cyclically
binding to exposed hydrophobic stretches of nascent
polypeptides exiting ribosomes during translation. HSPs
are also involved in the assembly and maintenance of
multiprotein complexes, intraorganellar protein trafficking, and degradation of misfolded polypeptides (120).
This section is focused primarily on inducible 72-kDa
HSPs (HSP70), as these are well-characterized and the
most studied with regard to cellular stress response and
preconditioning.
1. Increased expression of HSPs with cellular stress,
including brain preconditioning
Increased expression of HSP genes is a universal
feature of the cellular response to insults, and it is now
acknowledged that their chaperone activities contribute
to cytoprotection during periods of stress (114). As proteins denature, HSPs bind to exposed hydrophobic
stretches to stabilize the proteins; they also bind and
attempt to disassemble denatured polypeptides that aggregate nonspecifically.
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of the mitochondrial signaling of apoptosis to which ROS
contribute.
In addition to the well-known antioxidant enzymes
considered above, the thioredoxin system also contributes to cellular redox balance. Thioredoxins (Trxs) are
small, ubiquitous proteins with two redox-active cysteine
residues that participate in redox reactions through the
reversible oxidation of their active center dithiol to a
disulfide. Oxidized Trxs are reduced to the dithiol form
by the thioredoxin reductase (TrxR) with the use of
electrons from NADPH. Trxs and TrxR constitute the
thioredoxin system (180). Mammalian Trxs include cytosolic thioredoxin-1 (Trx-1), mitochondrial thioredoxin-2
(Trx-2), a larger Trx-like protein p32TrxL, and other family members. The thioredoxin system is present in various
CNS regions and emerges as an important contributor to
the cellular defense against ROS (180). Furthermore, recent studies indicate that specific Trxs are also key regulators of fundamental cellular processes (e.g., gene expression, apoptosis, cell growth) through their interactions with various proteins such as redox-regulated
kinase and transcription factors (303).
In contrast to SODs, catalase, and glutathione peroxidase, Trx upregulation appears to be consistently induced by preconditioning stimuli. Exposure of the rat
retina to transient ischemia or hydrogen peroxide-induced oxidative stress induced mitochondrial Trx (135).
In cultured human neuroblastoma cells, preconditioning
induced by 2-h serum deprivation upregulated Trx and
made the cells more tolerant to oxidative stress (9);
through subsequent studies, the same group showed that
the increased tolerance associated with upregulated Trx
was blocked by Trx mRNA antisense nucleotide and a
TrxR inhibitor (70) and that Trx upregulation may mediate the secondary induction of Mn-SOD and of the antiapoptotic protein Bcl-2 (11). Hypobaric hypoxia-induced
preconditioning increased Trx-2 mRNA expression in the
rat brain (355); the same procedure also markedly
strengthened the increased levels of Trx-1 and Trx-2 produced by a subsequent, severe hypobaric hypoxia (395,
396). It is also pertinent to mention that in rats subjected
to MCAO, both Trx mRNA expression and protein levels
rapidly decreased in the ischemic core (i.e., striatum and
frontoparietal cortex), but increased in perifocal regions
throughout the 4- to 24-h period after MCAO (403).
Trx upregulation may well contribute to brain tolerance, as procedures aiming to increase Trx levels were
neuroprotective both in vivo and in vitro. Overexpression
of Trx in transgenic mice attenuated focal ischemic brain
damage and the associated neurological deficit, and these
beneficial effects correlated with reduced cellular protein
oxidation (402). The same mice were also more resistant
to hippocampal damage produced by administration of
the excitotoxin kainic acid (401). In mice, intravenous
infusion of recombinant human Trx for 2 h after 90 min of
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TIHOMIR PAUL OBRENOVITCH
2. Effect of suppression of HSPs
Early in vitro studies already suggested that HSP70
inactivation impairs adaptive cytoprotection. For example, microinjection of HSP70 antibodies into fibroblasts
(335) and competitive inhibition of HSP70 gene expression in hamster ovary cells (183) markedly increased the
vulnerability of these cells to thermal stress. Nakata et al.
(271) applied the same experimental strategy to brain
preconditioning and showed that the continuous infusion
on the lateral ventricle of gerbils of HSP70 antibody or
Physiol Rev • VOL
quercetin (i.e., an inhibitor of HSP70 expression), started
whether 2 h before or 3 h after the preconditioning
ischemia, prevented the induction of ischemic tolerance
in the CA1 hippocampus.
3. Effect of overexpression of HSPs
Reciprocally, a large body of evidence indicates that
the overexpression of HSP70 and other HSPs is neuroprotective, both in vitro and in vivo (163, 194, 195, 233, 242,
319, 326, 330, 448). Virus-mediated overexpression of
HSP70 improved the survival of striatal neurons when rats
were subjected to 1 h of MCAO, and the survival of
hippocampal neurons after systemic kainic acid administration (448). The same procedure protected hippocampal
neurons in rats subjected to global cerebral ischemia
(195). Neuronal damage produced by 25 min of bilateral
carotid occlusion was reduced in transgenic mice overexpressing HSP70 compared with their wild-type littermates (194). In addition, primary hippocampal cultures
prepared from these transgenic mice were more resistant
to toxic levels of glutamate and oxidative stress. For
example, exposure to 10 ␮M free iron produced a 26%
increase in lactate dehydrogenase release from neurons
cultured from wild-type mice, but a 7% increase in neurons cultured from HSP70 transgenic mice (194). In transgenic mice overexpressing rat HSP70, with HSP70 primarily expressed in neurons under normal conditions, cerebral infraction was markedly reduced after both 6 and
24 h of permanent MCAO (330). Subsequent studies
showed that the same mice had an increased brain tolerance to neonatal hypoxia/ischemia (242). HDJ-2 is a member of the HSP40 family that promotes protein folding
both by binding to unfolded proteins and by regulating the
activity of HSP70. Virus-mediated HDJ-2 overexpression
in cultures of primary mouse astrocytes markedly reduced cell death produced by 24 h of glucose deprivation
or 8 h of oxygen-glucose deprivation (326). Geldanamycin
is a benzoquinone ansamycin that binds HSP90, releases
heat shock factor 1 (HSF1), and stimulates HSP gene
transcription. When injected into the lateral cerebral ventricles of rats prior to 2 h of MCAO, geldanamycin decreased the infarct volumes by 55.7% and the number of
TUNEL-positive cells by 30% in the cerebral cortex. Western blots showed that this protection was associated with
an 8.2- and 2.7-fold increase in HSP70 and HSP25 protein,
respectively (233).
It is clear from all these data that HSP70 overexpression is cerebroprotective when induced prior to ischemia
onset, but one study suggested that it may be also effective when instigated after the insult. When viral vectors
were used to overexpress HSP70 in the striata of rats at
0.5, 2, and 5 h after the onset of 1-h MCAO, significant
neuroprotection was observed at the 0.5 and 2 h time
points, but not at 5 h (163).
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Many in vivo studies have shown that brain preconditioning is also associated with induction of the nonconstitutive HSP70 and other chaperones (66, 84, 138, 149,
171, 202, 278, 279, 372). For example, HSP70 was increased in the hippocampal CA1 region when gerbils were
subjected to 2 min of global ischemia, a brief insult that
markedly enhanced the survival of hippocampal neurons
to a subsequent 5-min ischemia (202). The possibility of a
temporal relationship between HSP70 upregulation and
increased tolerance to ischemia was examined in several
of these studies (66, 84, 278, 279). Chen et al. (66) reported that brief sublethal periods of global ischemia
increased the tolerance to a subsequent permanent focal
ischemia in rats and that HSP70 protein expression increased during times when tolerance was present (2–5
days post-preconditioning). The findings of Liu et al. (230)
and Nishi et al. (278) also suggested a good correlation
between increased HSP70 and ischemic tolerance. However, HSP70 also increased 1 day after preconditioning
when tolerance was not yet present (66), and two other
studies suggested that ischemic tolerance may not correlate well with HSP70 upregulation (84, 279). The latter
data supported the notion that HSP70 (and other chaperones) are not solely responsible for ischemic tolerance
and that they may not be required for cerebroprotection.
This apparent discrepancy between these two sets of
studies may be due to the fact that preconditioning increases HSP70 expression over a relatively long period of
time, starting early after exposure to the initial stressor.
This makes it possible for HSP70 to be also an early
contributor to the signaling cascade(s) that leads to the
development of ischemic tolerance. Indeed, there is evidence that HSP70 can regulate the activation of the nuclear factor KB (NFKB), a well-established “transducer” of
preconditioning (94). In cell lines derived from immune
cells, the double-stranded RNA-dependent protein kinase
(PKR), known to be involved in the activation of NFKB,
was modulated by HSP70 in a way that suggested a prosurvival function of HSP70 through activation of a PKR/
NFKB-dependent protective pathway (115).
A convincing body of evidence indicates that HSP70
is required for adaptative cytoprotection and that high
levels of HSP70 are neuroprotective.
BRAIN ISCHEMIC TOLERANCE
4. Cytoprotective mechanisms of HSPs
FIG. 1. Diagram illustrating the multiple actions of 70-kDa heat
shock protein (HSP70) that may contribute to ischemic tolerance. The
dotted arrows indicate potential interactions between different HSP70
actions. Although protein folding is a key function of HSP70, it may not
be essential to increased tolerance as the overexpression of mutated,
folding-deficient HSP70 was still cerebroprotective (400). *HSP70 effects that did not depend on its protein folding capability (299, 346, 400,
440). Note that HSP70 may also contribute to the initiation of the
inflammatory response (i.e., at an early stage after the induction of
preconditioning) by acting as a “danger signal” for the toll-like receptors
(TLR2/4) (see Fig. 3). MMPs, matrix metalloproteinases; BBB, bloodbrain barrier.
Physiol Rev • VOL
the brain of rats subjected to 2 h of MCAO followed by
24 h of reperfusion and cultured astrocytes from oxygenglucose deprivation (400). These protective actions were
also associated with a better maintenance of mitochondrial physiology (i.e., inhibition of mitochondrial membrane potential change, better maintenance of state IV
respiration, and reduced generation of reactive oxygen
species) in astrocytes subjected to glucose deprivation
(299). Mitochondria play a central role in the induction of
two different types of apoptosis (Fig. 2): “intrinsic”
caspase-dependent apoptosis, through its release of the
proapoptotic factor cytochrome c, and caspase-independent apoptosis, through its release of apoptosis-inducing
factor (AIF) (53). Accordingly, HSP70-induced mitochondrial protection should be expected to promote cell survival after an ischemic insult, and such an anti-apoptotic
action is supported by the demonstration that overexpression of HSP70 reduced the release of cytochrome c in the
cytosol (242) and the nuclear translocation of AIF
(242, 400).
In addition, HSP70 has the capability to antagonize
apoptosis directly. With regard to intrinsic, caspase-dependent apoptosis, HSP70 inhibits events leading up
to mitochondrial membrane permeabilization and cytochrome c release, primarily by inhibiting the translocation
of Bax (a proapoptotic member of the Bcl-2 family) to
mitochondria, apparently through its ability to suppress
JNK activation (382) (Fig. 2). Preconditioning is known to
be associated with an upregulation of the antiapoptotic
oncogene Bcl-2 (see sect. IIE), and HSP70 overexpression
resulted in a marked upregulation of Bcl-2 in both injured
and uninjured neurons (195). However, the latter study
did not ascertain whether this effect was due to a direct
action of HSP70 on Bcl-2 expression. Finally, HSP70 was
reported to bind apoptosis protease activating factor-1
(Apaf-1), thereby preventing the constitution of the apoptosome (i.e., the Apaf-1/cytochrome c/caspase-9 activation
complex) (29, 354) (Fig. 2). However, this action was
subsequently challenged by Steel et al. (384) who proposed that the key action of HSP70 with regard to intrinsic apoptosis is inhibition of cytochrome c release, either
by acting directly on the mitochondria or at some stage
upstream. Clearly, Apaf-1 is not the only target for HSP70
antiapoptotic action, because HSP70 still protected
Apaf-1 ⫺/⫺ cells against apoptotic death (331), and overexpression of mutated HSP70 lacking the ATP-binding
domain, which is required for Apaf-1 binding, still protected astrocytes from ischemic injury (400). With regard
to caspase-independent apoptosis, HSP70 neutralizes the
mitochondrial effector AIF in a reaction that appears to
be independent of the HSP70 ATP-binding domain (331).
Interestingly, distinct HSP70 domains are involved in the
prevention of mitochondrial AIF release and the sequestration of AIF in the cytosol, which supports the notion
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In line with the essential functions of HSPs in cellular
protein management, the protective effects of HDJ-2 or
HSP70 overexpression were associated with a reduction
of the protein aggregation resulting from ischemic injury
(137, 326, 400) (see Fig. 1). However, neither the ability of
HSP70 to fold denatured proteins nor its interactions with
cochaperones or other proteins that bind to the NH2terminal half of HSP70 may be essential to ischemic protection. This was suggested by studies with two mutated
HSP70s, both capable of binding to denatured proteins
and maintaining their solubility, but no longer able to fold
proteins (i.e., folding deficient mutants); the overexpression of either of these two HSP70 mutants still protected
221
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TIHOMIR PAUL OBRENOVITCH
that HSP70 has the potential to suppress apoptotic cell
death through various mechanisms (346).
In contrast to apoptosis, which is a highly coordinated process subject to complex regulation, necrosis is
generally considered to be an unregulated event that occurs whenever cells are damaged beyond their repair
capability. However, emerging evidence suggests that
cells could still die via necrosis following a moderate
stress that did not produce irreparable cellular damages.
Furthermore, signaling pathways such as death receptors,
kinase cascades, and mitochondria participate in both
apoptosis and “programmed” necrosis (324). Within this
context, it is relevant to note that HSP70 overexpression
in cultured astrocytes, whether produced by retroviral
Physiol Rev • VOL
transfection or pharmacological induction, reduced
glucose deprivation-induced necrosis (438, 439). This
antinecrotic effect of HSP70 may well be linked to its
action on intrinsic apoptosis signaling, upstream of mitochondria (Fig. 2), as HSP70 (whether wild-type or folding
deficient mutant) inhibited JNK-related steps of necrotic
pathway induced by transient energy deprivation in H9c2
myogenic cells (128, 440).
There is also evidence that HSP70 may suppress
important effectors of the postischemic inflammatory response, the matrix metalloproteinases (MMPs), proteolytic enzymes that function in the extracellular matrix to
degrade its main components, i.e., collagens, laminin, and
proteoglycans. Ischemic insults elicit a robust inflamma-
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FIG. 2. Multiple effects of HSP70 on apoptosis control. This diagram shows some of the molecular events contributing to two major types of
apoptosis: “intrinsic” caspase-dependent apoptosis (left) and caspase-independent apoptosis (right). On this diagram, the anti-apoptotic actions of
HSP70 identified so far are indicated by HSP70x, with ⫹ or ⫺ indicating a positive or negative action, respectively; each of the actions x is outlined
below. The intrinsic pathway (left) involves apoptosis-inducing mitochondrial proteins, such as cytochrome c, which are released in the cytosol after
permeabilization of the outer mitochondrial membrane. The latter event is controlled by members of the Bcl-2 family (e.g., induced by translocation
of the activated, pro-apoptotic Bax). Once released, cytochrome c associates with pro-caspase-9 and the adaptor protein activating factor-1 (Apaf-1)
to form a complex called the apoptosome. The formation of this complex gives rise to active caspase-9, which stimulates the executive caspases
(i.e., caspases -3, -6, and -7). Caspase-independent apoptosis (right) is mediated by mitochondrial effectors such as the apoptosis-inducing factor
(AIF). The signals that control the release of AIF from mitochondria are still unknown. Once translocated to the nucleus, as AIF does not have
endonuclease activity by itself, its association with endonucleases (e.g., cyclophilin A) is required to achieve DNA degradation. 1Maintenance of
mitochondrial function and membrane potential (299). This effect may be partly a consequence of 2 and 3, especially with regard to mitochondrial
membrane permeabilization, but increasing evidence points also to an effective contribution of mKATP channels (see sect. IIA). 2Suppression of
signals leading to Bax activation (382). 3Upregulation of the anti-apoptotic oncogene Bcl-2 (195). ? it remains uncertain whether or not this effect
results from a direct action of HSP70. 4Neutralization of Apaf-1 (29, 354). ? This notion was subsequently challenged; HSP70 may only act upstream
from mitochondria to suppress cytochrome c release, and thereby intrinsic caspase-dependent apoptosis (382, 384). 5Neutralization of AIF, effector
of caspase-independent apoptosis. [Material on apoptosis was adapted from Krantic et al. (211) and Kim et al. (198).]
BRAIN ISCHEMIC TOLERANCE
E. Control of Cell Death/Survival
Necrosis is generally considered to be the main cause
of cell death in severely ischemic brain regions; in this
case, the death is rapid and the extent of tissue damage
(infarct volume) is closely related to the severity and
duration of the shortage in blood supply (225, 249). In
contrast, at the periphery of the ischemic core with focal
insults, or in selectively vulnerable regions such as the
hippocampus CA1 after a short period of ischemia, neurons may die over a longer period with morphological
signs and biological features indicative of apoptosis (67,
112). In this section, emphasis is placed on the welldocumented notion that an effective suppression of apoptosis is associated with brain tolerance. However, it is important to stress that possible changes in necrosis are not
ruled out 1) because the smaller infarcts observed with
Physiol Rev • VOL
ischemia-tolerant brains imply reduced necrosis, though
this reduction is likely to be a consequence rather than a
cause of increased tolerance; and 2) because more recent
data indicate that the classical necrosis/apoptosis subdivision is an oversimplification of the multiple and more
diverse mechanisms of cell death that are involved in
ischemic brain damage. Indeed, depending on the insult
type and intensity, and on the cells bioenergetic state,
necrosis together with different forms of apoptosis and
other types of programmed cell death may occur and
shape distinct morphological changes (221). In particular,
secondary necrosis may develop as an abortive form of
apoptosis, subsequent to a switch from apoptotic cell
death to necrotic cell death triggered by intracellular ATP
depletion (277).
Classical (i.e., caspase-dependent) apoptosis can be
initiated by two major pathways: the “intrinsic” mitochondrial pathway and the “extrinsic” death receptor pathway,
both converging on a family of caspases (211). In the
“intrinsic” pathway, the release of mitochondrial cytochrome c initiates the activation of the caspase cascade
via the constitution of the apoptosome The (Apaf-1/cytochrome c/caspase-9 complex). Assembly of the apoptosome allows pro-caspase-9 to be autoactivated, and this is
followed by the recruitment and activation of procaspase-3. Cleaved caspase-9 remains bound to the apoptosome, which recruits and activates executioner caspases
such as caspase-3, -6, and -7. Caspase-3 cleaves the inhibitor of caspase-activated deoxyribonuclease (DNase),
thereby activating DNase, resulting in internucleosomal
DNA fragmentation (211). Alternatively, the extrinsic
pathway is driven by activation of plasma membrane
death receptors and activation of caspase-8 (note that the
extrinsic pathway has been omitted from Fig. 2). Both
pathways converge on caspase-3, and cross-talk between
pathways has been described. Mitochondrial, caspaseindependent apoptosis is initiated by the release of AIF
from the intermembrane mitochondrial space to the cytosol, from which it translocates to the nucleus. As AIF by
itself has no endonuclease activity, the resultant DNAdegrading capacity requires the recruitment of downstream nucleases such as cyclophilin A (211).
The central role of mitochondria in intrinsic caspasedependent apoptosis and caspase-independent apoptosis,
and the convincing evidence that mitochondria preservation is associated with ischemic tolerance (see sect. IIA),
already indicates that apoptosis may be suppressed in the
tolerant brain, and this has been demonstrated by numerous studies (54, 316, 405, 464). This notion is further
strengthened by the multiple antiapoptotic actions of
HSP70 (see sect. IID and Fig. 2). To avoid repetition, only
complementary evidence of apoptosis inhibition in the
ischemia-tolerant brain is provided next.
The p53 tumor suppressor gene is as an important
transcription factor that promotes apoptosis following
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tory reaction to which MMPs contribute by promoting
increased vascular permeability, BBB disruption, and inflammatory cell influx (75). Several lines of evidence suggest that MMPs, and especially MMP-9 (gelatinase B),
contribute to the genesis of ischemic lesions. 1) Higher
levels and proteolytic activities of MMP-2 (gelatinase A)
and MMP-9 were demonstrated in ischemic lesions produced by MCAO in rats (317, 340), and in human brain
tissue after ischemic and hemorrhagic stroke (339).
2) The temporal profile and distribution of these changes
suggested that MMP-9 may contribute to secondary tissue
damage and vasogenic edema, whereas MMP-2 may be
involved in tissue repair at a later stage (123, 340).
3) Inhibition of MMP-9, whether induced by antibody
neutralization, drugs, or genetic manipulations, had protective effects in stroke models (15, 134, 147, 337). In
contrast to single, severe ischemic insults, preconditioning stimuli appear to suppress MMPs. 1) Ischemic preconditioning in rats reduced the high expression of MMP-9
that was associated with subsequent MCAO, and this
effect correlated with decreased edema and BBB disruption (454). 2) Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is a specific, endogenous inhibitor for a
group of MMPs, among which MMP-9 is the preferred
target, and ischemic preconditioning induced its expression at a time when ischemic tolerance is increased (431).
Finally, HSP70 upregulation with preconditioning may
contribute to suppress ischemia-induced MMP upregulation, as virus-mediated HSP70 overexpression in cultured
astrocytes suppressed MMP-2 and MMP-9 (220). Unexpectedly, there is evidence suggesting that extracellular HSPs
may be released from cells under stress, to act as potential
danger signals to immune effector cells (see sect. IVA).
From this section, HSP70 clearly emerges as a molecular chaperone with multiple cytoprotective functions
that make it a relevant therapeutic target (380, 460).
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TIHOMIR PAUL OBRENOVITCH
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apoptosis protein (cIAP) to directly inhibit activated
caspase-3 (405).
The protooncogene Akt is a central component of the
phosphatidylinositol 3-kinase (PI 3-kinase) signal transduction pathway. Downstream effector of PI 3-kinase, Akt
promotes cell survival by phosphorylating (i.e., inactivating) several proapoptotic proteins, including caspase-9,
Bad (a Bcl family protein), forkhead transcription factors
(FKHR), and glycogen synthase kinase 3 (GSK3) (390).
Several lines of evidence support the notion that Akt
activation (i.e., maintenance of its phosphorylated form)
is neuroprotective. 1) When apoptosis of primary cultured
hippocampal neurons was induced by hypoxia or NO
treatments, adenovirus-mediated overexpression of activated-Akt suppressed neuronal including (443); and 2)
after 4 h of MCAO in mice, phosphorylated Akt was
decreased in the ischemic core but increased in cortical
peri-infarct region; double staining showed different cellular distributions for phosphorylated Akt and DNA fragmentation, and pretreatment with a PI 3-kinase inhibitor
prevented the increased Akt phosphorylation and promoted DNA fragmentation (281). However, in vivo studies
dedicated to the possibility that Akt activation may contribute to adaptive cytoprotection have provided inconsistent data. On the one hand, data from two studies
support the notion that Akt activation may contribute to
ischemic tolerance. 1) Following sublethal cerebral ischemia in gerbils, Akt phosphorylation was persistently stimulated in the hippocampal CA1 region and, in contrast to
nonpreconditioned animals, Akt phosphorylation showed
no obvious decrease after the subsequent lethal ischemia
(447). In the same study, intracerebroventricular infusion
of the PI 3-kinase inhibitor wortmannin prior to preconditioning blocked both the increase in Akt phosphorylation and the neuroprotective action of preconditioning
(447). 2) Preconditioning, induced by transient focal ischemia in rats, reduced neuronal death produced by subsequent lethal MCAO in the penumbra, and this neuroprotective effect was associated with persistent Akt activation in this region (268). On the other hand, data from two
other studies rather suggested that Akt may play a role in
neuronal survival only after ischemia, as Akt phosphorylation occurred early after the insult and was not sustained (274, 365). Even more conflicting are the data from
a recent study with rat PC12 cells (159). In this cell line,
ischemic tolerance induced by exposure to 6 h of oxygen
and glucose deprivation (OGD) was actually associated
with reduced phosphorylation of Akt and of its targets
GSK-3, FoxO4 (a FKHR family member), and murine double minute 2 (MDM2) protein, and decreasing the availability of phosphorylated Akt, either pharmacologically or
by transfecting PC12 cells with inactive Akt constructs,
reduced cell death produced by OGD and increased the
protective effect of preconditioning (159). Finally, it is
also relevant to mention that reduced Akt phosphoryla-
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neuronal injury (81), and its activation appears to be
reduced in the ischemia-tolerant brain. 1) Both p53 mRNA
and protein levels increased in the rat hippocampus 24 h
after transient, forebrain ischemia, but this change was
markedly diminished when ischemic preconditioning was
induced 48 h prior to the test ischemia (412). 2) The
finding that the mKATP channel agonist diazoxide inhibited the apoptosis of cultured hippocampal CA1 neurons
exposed to hypoxic/anoxic conditions was already mentioned (see sect. IIA). This neuroprotective effect was
associated with a reduced expression of p53 (168).
Several in vivo and in vitro studies carried out in rats,
mice, or gerbils, and using various stimulus for preconditioning and different subsequent test insults, have been
dedicated to changes in the Bcl family proteins (i.e., Bcl-2,
Bcl-xL, and Bax) that play a pivotal role in the control of
cell death. Overall, the data from these studies suggest
strongly that ischemic tolerance is associated with a shift
of Bax/(Bcl-2 Bcl-xL) ratio to suppress apoptosis. Findings supporting this notion include the following: 1) persistent overexpression of the antiapoptotic Bcl-2 and
Bcl-xL genes (44, 190, 246, 248, 349, 366, 369, 434, 436);
2) the proapoptotic Bax gene upregulation that occurred
after the test insult was reduced in the preconditioned
brain of rats (44, 349); Bax expression, however, remained unchanged in a study with mice (434); and
3) cerebroventricular infusion of Bcl-2 antisense oligonucleotide reduced the expression of Bcl-2 and suppressed
ischemic tolerance in the rat brain (369).
Although most of the anti-apoptotic changes reported so far in the tolerant brain are related to events
that occur upstream of caspase-3 activation (i.e., preceding the execution step of the intrinsic, caspase-dependent
apoptosis; Fig. 2), some data also suggested that preconditioning may promote neuronal survival despite
caspase-3 activation. Preconditioning of rat cortical cultures by a sublethal exposure to cyanide, or in vivo by
10-min MCAO, produced significant caspase-3 cleavage
(i.e., activation) but without subsequent cell death (246).
This study also suggested that some degree of caspase-3
activation was required for the ultimate development of
ischemic tolerance, at least with the models and experimental procedures involved (246). In agreement with
these data, in rats subjected to transient global ischemia
by four-vessel occlusion for both preconditioning and test
insult, the subsequent 10-min ischemia activated
caspase-3 but failed to increase nuclear CAD, induce
p75NTR, and cause DNA fragmentation (i.e., downstream
events toward execution of cell death) (405). Other data
from this study suggested that preconditioning, by preserving mitochondria, may reduce the release of “second mitochondria-derived activator of caspases/direct
IAP-binding protein with low pI” (Smac/DIABLO), and
thereby preserve the capacity of cellular inhibitor-of-
BRAIN ISCHEMIC TOLERANCE
tion was also observed in bats and ground squirrels during
hibernation, another type of adaptation that includes tolerance to pronounced reduction of cerebral perfusion
(51, 103).
F. DNA Repair
Physiol Rev • VOL
chondrial BER activity for ⬃1 h, but a decline to less than
control levels developed over the following 4 –72 h (64);
and 3) in rats subjected to transient global forebrain
ischemia, the immunoreactivity of proliferating cell nuclear antigen (PCNA, required for NER) was largely abolished during reperfusion in the vulnerable CA1 neurons,
prior to their death (411).
A correlation between increased tolerance to MCAO
in rats and marked attenuation of DNA lesions was recently reported, and this may be a consequence of improved DNA repair since ischemic preconditioning induced a marked increase of ␤-polymerase-mediated BER
activity that extended throughout the course of ischemic
tolerance (224). This study agrees with previous findings:
1) ischemic preconditioning in rats induced the expression of the Ku 70 protein, with a time frame overlapping
with ischemic tolerance (397); 2) 1 h of MCAO in rats
markedly induced BER activity in the frontoparietal cortex (i.e., region that survived the insult) for at least 72 h
(214); and 3) a 30-min, preconditioning MCAO in rats
induced mild oxidative mitochondrial DNA (mtDNA)
damage and activated key mitochondrial BER pathway
enzymes for up to 72 h (64). The latter finding may be
especially relevant, first because of the central role of
mitochondria in several aspects of ischemic brain damage, and second because mtDNA is more exposed to
oxidative damage than its nuclear counterpart due to the
effective generation of ROS by mitochondria and mtDNA
lacking the structural features that protect nuclear DNA.
As a consequence, mtDNA damage is more extensive and
persists longer than nuclear DNA damage (441). Altogether, these results suggest strongly that enhanced DNA
repair constitutes an important endogenous mechanism
to protect the brain against ischemia-induced DNA
damage.
G. Self-Repair and Plasticity (Neurogenesis/
Synaptogenesis and Growth Factors)
It is now established that, throughout the life of
mammals, new neurons can be generated from resident
progenitor/stem cells in the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of
the lateral ventricles. The proliferation potential of these
progenitor cells provides the adult brain with a capacity
for plasticity and self-repair through neurogenesis, which
responds to both external stimuli (e.g., environmental
enrichment) and injury (e.g., ischemic and traumatic insults) (for reviews, see Refs. 226, 280). Whether this capacity for self-repair is activated in the tolerant brain was
examined by Naylor et al. (276), using MCAO in rats for
both preconditioning (10-min occlusion) and test insult
(1-h occlusion) applied 3 days later. As in previous studies, progenitor cell proliferation increased after focal
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Lipids and proteins have received the most attention
in the field of oxidative damage and cerebral ischemia,
but oxidatively damaged DNA is particularly detrimental
to cells and, in contrast to altered lipids and proteins that
can be removed and replaced as part of normal turnover,
DNA lesions must be repaired. The pathways for the
removal of DNA lesions can be divided into base excision
repair (BER) and nucleotide excision repair (NER) (106).
Quantitatively, BER is by far the most important route for
the removal of the majority of oxidative lesions. At its
simplest, BER is initiated by a specific enzyme that removes the oxidized base, e.g., 8-oxoguanine glycosylase
(OGG1), leaving an apurinic-apyrimidinic (AP) site, that is
subsequently removed by an AP lyase activity (a separate
enzyme or glycosylase associated). Complementing BER,
NER is directed principally towards bulky lesions, such as
cyclobutane thymine dimers (TT). With both BER and
NER, excision is followed by gap filling and ligation.
Oxidative DNA lesions are a feature of ischemia/
reperfusion injury, independent from DNA fragmentation
detected using TUNEL (83). For example, in gerbils subjected to 5 or 10 min of global ischemia, a marked accumulation of the oxidative DNA damage product 8-hydroxy-2⬘-deoxyguanosine (8-OH-dG) occurred as early as
15 min after recirculation in the hippocampus and persisted for several days (7, 17). Some data also suggested
that oxidatively damaged DNA may contribute to lesion
progression in stroke models. In rats subjected to permanent MCAO, 16 –72 h after ischemia onset, 8-OH-dG levels
and AP sites were selectively increased in the peri-infarct
region, and their colocalization with DNA single-strand
breaks and DNA fragmentation suggested a contribution
to lesion progression (265).
Defective repair of oxidatively damaged DNA can be
a potent initiator of neurodegeneration, and this is most
evident in xeroderma pigmentosum (XP), an autosomal
recessive disease arising from mutations in key genes
associated with NER (106). Few studies have been dedicated to ischemia-induced alterations of DNA repair, but
they concur in suggesting that these changes may play a
role in the development of postischemic neuronal death.
1) In mice subjected to 1-h MCAO, the expression of Ku70
and Ku86 (multifunctional DNA repair proteins that bind
to DNA strand breaks and triggers DNA repair) was decreased in ischemic brain tissue as early as 4 h after
reperfusion and remained reduced until the 24-h time
point (199); 2) MCAO for 100 min in rats increased mito-
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TIHOMIR PAUL OBRENOVITCH
Physiol Rev • VOL
regards to dendritic reorganization, changes preceding
delayed neuronal death produced by transient ischemia in
the rat hippocampal CA1 appear to be associated with
neurodegeneration (238, 344), whereas delayed changes
such as the increase in dendritic density in regions surrounding a cortical ischemic lesion may reflect morphological plasticity and repair (2). As postischemic synaptogenesis in rats could be enhanced by treatments initiated after the insult (e.g., environmental enrichment,
D-amphetamine therapy) (46, 394), the possibility that
preconditioning may promote these processes is another
interesting issue that was addressed recently by Corbett
et al. (77). In their experiments with gerbils, compared
with appropriate controls, dendritic spine densities in
hippocampal CA1 were significantly higher 3 days after
preconditioning alone (i.e., 2 separate episodes of 1.5-min
bilateral carotid occlusion, 24 h apart), and also 10 and 30
days after the 5-min test ischemia when it was preceded
by preconditioning. Clearly, this topic deserves further
attention.
III. SYNAPTIC TRANSMISSION IN THE
TOLERANT BRAIN
A. Balance Between Glutamatergic
and GABAergic Transmission
Excitotoxic glutamate receptor activation or malfunction is widely thought to contribute to ischemic brain
damage, especially to delayed death of vulnerable hippocampal neurons after transient ischemia (for example,
see Refs. 252, 295). GABAergic disinhibition may also
contribute to lesion progression, because neuronal hyperexcitability associated with a sustained downregulation
of GABAA receptors was demonstrated in peri-infarct regions (327, 328, 356), although this response could as well
promote plasticity and recovery from the ischemic injury
(357). From this information, one could expect that the
balance between glutamatergic excitation and GABAergic
inhibition may be shifted in favor of the latter in tolerant
brain, and this notion is supported by several findings
related to GABAergic transmission: 1) Preconditioning
induced by 2.5 min of global ischemia in gerbils resulted
in a significant and sustained increase of [3H]muscimol
binding to GABAA receptors (375). 2) In rats, ischemic
preconditioning increased the activity of glutamate decarboxylase (i.e., the primary enzyme for GABA synthesis)
and resulted in a more pronounced release of GABA
during the subsequent 10-min global ischemia (87); however, such an effect of preconditioning on amino acid
neurotransmitter release during the test ischemia was not
found in a previous study with gerbils (272). 3) In rat
brain cortical slices, preconditioning shifted the release of
glutamate and GABA during the subsequent test hypoxia/
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ischemia alone (by 3.9-fold), but this occurred also after
preconditioning alone (2.7-fold increase), i.e., in the absence of any infarction. Interestingly, in both ischemia
and preconditioned groups, ⬃45% of the progenitor cells
that proliferated in week 1 survived to the end of week 3,
and ⬃21% of those matured into cells expressing a neuronal marker. Similarly, exposure of newborn rats to 5
min of anoxia did not produce any detectable cell death,
but promoted cell proliferation in the subventricular zone
and hippocampal dentate gyrus during the following 3 wk;
these newly generated cells expressed neuronal markers,
migrated to specific sites such as the CA1 layer, and
neurogenesis was associated with improved memory at
40 days (321). In contrast, neurogenesis was not detected when ischemic tolerance in the hippocampus
was induced by 2 min of bilateral carotid occlusion in
gerbils (229).
Studies of growth and neurotrophic factors have provided another line of evidence supporting the notion that
neurogenesis is activated in the tolerant brain. Several
growth factors, including basic fibroblast growth factor
(bFGF), epidermal growth factor (EGF), IGF-I, brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) influence neurogenesis, both in
the intact and ischemic brain (for review, see Ref. 226),
and preconditioning upregulates these factors. 1) bFGF
expression was increased in cultured rat cortical neurons
24 h after hypoxic preconditioning (353), in the rat cortex
and hippocampus at 12 and 24 h after cortical spreading
depression (244), and in the rat retina at 6- and 48-h after
ischemic preconditioning (59). 2) Cerebral mRNA expression of both EGF and IGF-I was increased by preconditioning in the study of Naylor et al. (276) outlined previously. 3) BDNF was also upregulated for several days in
the rat cortex after spreading depression (444) and by
ischemic preconditioning in rats, albeit only at the early
time points of 30 min and 6 h (414). 4) For VEGF, see
section IVB. A number of studies have also demonstrated
that the neurogenesis associated with ischemic brain lesions can be enhanced by supplementing the ischemic
brain with EGF, bFGF, IGF-I, or VEGF (19, 91, 399, 415);
note the negative effect reported with BDNF (215).
However, the key issue of whether or not postischemic neurogenesis is enhanced in the tolerant brain remains unresolved, because preconditioning had neither
an inhibitor nor an additive effect on focal ischemiainduced progenitor cell proliferation in the comprehensive study of Naylor et al. (276).
Synaptogenesis (i.e., axonal sprouting and changes in
dendritic spines) is another potential mechanism for plasticity and self-repair after an ischemic injury to the brain.
In adult rats, poststroke axonal sprouting resulted in a
substantial remapping of the connections of the somatosensory cortex adjacent to the infarct, with a unique
profile of neuronal growth-promoting genes (57, 58). With
BRAIN ISCHEMIC TOLERANCE
Physiol Rev • VOL
tion of preconditioning by 2.5 min global ischemia, i.e., prior
to the window of delayed ischemic tolerance (377).
Overall, it appears that changes in GABAergic transmission, both pre- and postsynaptic, are more likely to
contribute to a shift of the glutamate/GABA balance toward inhibition in the tolerant brain.
B. Role of Adenosine
Adenosine and A1 receptors play a key role in the
induction of brain tolerance (37, 158), but whether adenosine contributes also to the subsequent, delayed adaptive cytoprotection is less clear. In rats, ischemic preconditioning increased A1 receptor immunoreactivity in the
hippocampal CA1 at days 1, 3, and 7 after preconditioning
induction, i.e., within the window of ischemic tolerance
(461), but such a change was not found in mice after
sublethal 3-nitropropionate treatment (427), and whether
this increase of A1 protein level was associated with
functional gain remains to be confirmed. As A1 activation
mainly decreases excitatory synaptic transmission in the
CNS (100), should A1 receptors be upregulated in the tolerant brain, then adenosine either released as neuromodulator or as ATP breakdown product of ATP may contribute
with GABAergic changes to shift the excitatory/inhibitory
balance towards inhibition (see sect. IVA). Within this context, it is relevant to mention that, without any preconditioning, endogenous activation of A1 receptors contributed to
the suppression of synaptic activity occurring at the onset of
global ischemia in both hippocampus CA1 and cortex, indicating that A1 receptor-mediated “shut down” of synaptic
activity with deficient energy supply is already effective in
the naive brain (113, 174).
C. Nicotinic-Cholinergic Transmission
In addition to epidemiological and clinical studies
suggesting that chronic exposure to nicotine may be cytoprotective, several lines of evidence indicate that activation of nicotinic acetylcholine receptors (nAChR) can
provide neuroprotection both in cell culture systems and
animal models (for review, see Ref. 293). 1) Nicotine
protected primary cortical cultures from hypoxia-induced
apoptosis and glutamate excitotoxicity, and these effects
were mediated by both ␣7- and ␤2-containing nAChR
subtypes (157, 388). 2) The selective partial ␣7-agonist
3-(2,4-dimethoxybenzylidene)-anabaseine dihydrochloride
(GTS-21) protected hippocampal CA1 neurons against delayed cell death produced by transient global brain ischemia in gerbils (275); the acetylcholinesterase inhibitor
donepezil reduced the infarct volume produced by MCAO
in rats, and this effect was prevented by the nAChR
antagonist mecamylamine (122).
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hypoglycemia in favor of inhibition (182). 4) Twenty-four
hours after preconditioning by exposure to high-potassium medium, cultured cortical neurons exhibited an enhanced depolarization-induced presynaptic release of
GABA that contrasted with a modest decrease in glutamate release (144).
With regard to scavenging of extracellular glutamate
in the tolerant brain, the data reviewed in section IIB do
not support the notion that altered EAAT expression is an
essential feature of ischemic tolerance. However, an upregulation of glutamine synthase was found after preconditioning with 3-nitropropionic acid, and as this enzyme
converts glutamate to glutamine in astrocytes, this change
was interpreted as a potential contributor to increased
extracellular glutamate scavenging (166).
As transient, severe global cerebral ischemia selectively reduced the expression of GluR2 in CA1 hippocampal neurons, thereby promoting Ca2⫹ permeability of
AMPA receptors and postischemic cell death (295, 306),
several studies have examined whether changes in GluR2
expression are associated with ischemic tolerance. One
day after ischemic preconditioning in rats, the expression
of the AMPA receptor subunit GluR2 protein was actually
increased in the CA1 region (206), but complementary
experiments pointed to a selective upregulation of GluR2/
GluR2 flop in tolerant animals, and the latter change
proposed as potential mechanism for enhanced AMPA
receptor desensitization leading to ischemic tolerance (6).
However, similar findings were not found in the gerbil
hippocampus CA1 after ischemic preconditioning (376,
404), in the mouse cortex after preconditioning induced
with spreading depression (63), nor in rat hippocampal
neuronal cultures exposed to sublethal OGD (450).
There is convincing evidence that NMDA receptor
activation is critical to the induction of ischemic tolerance
in neurons (179, 379), but whether some NMDA receptor
changes contribute to adaptive cytoprotection remains
unclear. Two separate studies do not suggest that ischemic tolerance is associated with changes in the expression of NMDA receptor subunits (i.e., NR1, NR2A, and
NR2B) (3, 63). However, changes in NMDA receptor function may occur. In hippocampal slices prepared from
gerbils 2–3 days after ischemic preconditioning, anoxiainduced long-term potentiation (anoxia-LTP, known to be
NMDA receptor mediated) was inhibited (191). One day
after sublethal exposure of cultured cortical neurons to
cyanide, whole cell recordings of NMDA-induced currents
revealed a significant increase in voltage-dependent extracellular Mg2⫹ block that could decrease the overall
current flowing through the channel, but the block reverted to control levels within 48 h (3).
Finally, with regard to metabotropic glutamate receptors (mGluR), only mGluR1b and mGluR5 protein levels
were transiently downregulated in the preconditioned hippocampal CA1 of gerbils, but this occurred 8 h after induc-
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TIHOMIR PAUL OBRENOVITCH
D. Other Changes in Ion Channels, Exocytotic
Mechanisms, and Receptors
The previous sections (i.e., sect. III, A–C) discuss
possible, inherent cerebroprotective strategies that de-
pend on changes in synaptic transmission. These were
selected, essentially, on the grounds of data availability.
Given the complexity of synaptic transmission (exocytosis mechanisms, receptors, synaptic modulation, synaptic
plasticity, etc.), it is clear that numerous studies are still
required to provide a clear picture of the changes in
synaptic machinery that are associated with, and contribute to, ischemic tolerance. Next, and again on the grounds
of data availability, attention is given to KATP channels
and cannabinoid receptors.
Beside the possible contribution of mKATP channels
to ischemic tolerance (see sect. IIA), that of cell surface
membrane KATP channels deserves to be mentioned here
because these ATP-operated channels appear as important effectors for the coupling between energy availability
and neuronal excitability. There is supporting evidence
that KATP channels play a protective role against energy
deficiency, already in the naive brain (for review, see Ref.
21); for example, cell surface KATP channels mediated the
hyperpolarization that precedes anoxic depolarization in
hippocampal slices (257). A number of early studies also
suggested that surface KATP channels are essential for the
induction of preconditioning and subsequent ischemic
tolerance (37, 158, 308, 334). However, more recent data,
interpreted with an improved knowledge of mKATP channels and KATP channel drug selectivity (i.e., effects on
mitochondrial versus surface KATP channels; Ref. 132)
have led to the question of the role of surface KATP
channels in ischemic tolerance. For example, a study with
FIG. 3. Inflammatory responses during preconditioning and ischemic tolerance. This diagram illustrates the concept that preconditioning
produces a mild inflammatory response subsequent to Toll-like receptor (TLR) activation, which results in the production of several negativefeedback inhibitors of inflammation, ultimately leading to reduced inflammatory responsiveness in the tolerant brain (see text and Ref. 188 for
details). TLRs are transmembrane receptors, present in microglia and astrocytes, acting as pathogen sensors. However, some TLRs respond also to
molecules released by injured tissue, and to HSP70. ? The corresponding box displays the emerging hypothesis that an upregulation of ␣7 nicotinic
acetylcholine receptors (␣7AChR) might also mediate immunosuppressive effects (see sect. IIIC).
Physiol Rev • VOL
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With regard to preconditioning, 1 day after repeated
CSD in mice, robust ischemic tolerance was associated
with a very marked and selective increase in ␣7-nAChR
protein levels (63). Although it remains to be verified that
an ␣7-nAChR functional gain resulted from the increased
␣7-subtype protein level, this discovery is worth discussing. The upregulation of ␣7-nAChR in the tolerant brain
could be neuroprotective through direct activation of processes at neuronal level, because prolonged exposure of
cultured neurons to nicotine was neuroprotective, and
this treatment upregulated ␣7-nAChR (186), and ␣7nAChR overexpression in PC12 cells, by itself (i.e., without nicotine), reduced the effects of hypoxia on cell cycle
(G1 arrest) and DNA fragmentation (420). In addition, in
the brain parenchyma, preconditioning-induced ␣7nAChR upregulation could contribute to reduce the brain
inflammatory responsiveness that underlies ischemic tolerance (Fig. 3). Indeed, the existence of a brain cholinergic anti-inflammatory pathway mediated by ␣7-nAChR
is now well substantiated: macrophages, microvascular
endothelial cells, and microglia express ␣7-nAChR on
their surface, and the activation of these receptors resulted in immunosuppressive effects (350, 370, 451).
BRAIN ISCHEMIC TOLERANCE
IV. FEATURES OF BRAIN TOLERANCE AT
TISSUE LEVEL
A. Inflammatory Mechanisms
Focal cerebral ischemia elicits a strong inflammatory
response through the activation of proinflammatory cytokines such as tumor necrosis factor (TNF)-␣, interleukin
(IL)-1␤, and IL-6 (35), involving both the brain’s endogenous inflammatory cells (i.e., microglia and astrocytes)
and peripheral leukocytes (151, 217, 358, 459). It is generally considered that postischemic inflammation contributes to infarct progression and worsens neurologic deficit, but it remains unclear whether the detrimental effects
of inflammation (e.g., altered microcirculation, increased
vascular permeability, adherence and extravasation of
leukocytes into brain parenchyma) actually outweigh its
neuroprotective and beneficial processes such as rapid
debris removal and tissue repair (for review, see Ref.
391). Indeed, studying the contribution of cytokines to
neurodegeneration is very challenging because the mechanisms involved are complex, with cytokines acting at
very low concentrations on numerous cell types within
Physiol Rev • VOL
and outside the brain, and mediating interdependent pathways that may be pro- or anti-inflammatory (52, 465; for
review, see Ref. 5). Nevertheless, blocking the leukocyte
adhesion to endothelial cells and their infiltration in brain
tissue reduced the volume of infarct after transient MCAO
(167, 424, 445, 449; for earlier studies, see Ref. 391), and
the studies outlined next suggested that preconditioninginduced delayed tolerance was associated with a reduced
inflammatory response to the subsequent ischemia. LPS
preconditioning reduced ischemic brain injury in a mouse
model of stroke, and this protective effect was associated
with suppressed neutrophil infiltration and microglial/
macrophage activation in the ischemic hemisphere, and
reduced monocyte activation in peripheral blood (342).
Preconditioning, induced 3 days before 90-min MCAO by
either brief MCAO or injection of the mitochondrial toxin
3-nitropropionic acid, reduced the infarct volume as well
as the postischemic expression of IL-1␤ and IL-6 (307).
Ischemic preconditioning 3 days before 1-h MCAO in rats
reduced the postischemic increased expression of several
inflammatory genes, prevented the infiltration of neutrophils and macrophages in the ischemic lesion, and decreased the infarct volume produced by a subsequent 1-h
MCAO (43). These studies clearly demonstrated that the
reduction of ischemic lesion was associated with suppressed inflammatory response, but whether the latter
contributed effectively to, or was a consequence of, reduced ischemic damage was difficult to ascertain in vivo.
Within this context, the study of Zahler et al. (452) is
especially pertinent; when cultured endothelial cells were
preconditioned by a transient oxidative stress, their inflammatory responses to TNF-␣ [i.e., expression of the
adhesion molecules intercellular adhesion molecule-1
(ICAM-1) and E-selectin, and release of the pro-inflammatory cytokines IL-6 and IL-8] were markedly suppressed.
Such actions of preconditioning at the endothelial interface may account for the antiadhesive/extravasation effects of preconditioning, and its protection of the microvasculature and BBB (see sect. IVC).
The potential mechanisms leading to, and underlying,
the reduced inflammatory responsiveness that is associated with ischemic tolerance were reviewed by Karikó
et al. (188). Through their analysis, these investigators
argued that preconditioning produces a mild inflammatory response subsequent to Toll-like receptor (TLR) activation, which ultimately results in the production of
several negative-feedback inhibitors of inflammation (Fig.
3). For the purpose of this review, this theory is outlined
and discussed herein in simplified terms, with emphasis
placed on selected and recent data.
Paradoxically, at first brain preconditioning elicits
inflammation through activation of the proinflammatory
transcription factor nuclear factor ␬B (NF␬B) and induction of proinflammatory cytokines such as TNF-␣, IL-1␤,
IL-6, and IL-8 (188), i.e., apparently through the same
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mice lacking the neuronal/␤-cell-type (Kir6.x/SUR1) KATP
channels suggested that these channels are not obligatory
for brain preconditioning (260). Further studies with improved pharmacological tools and transgenic mice are
required to resolve this issue.
The recent demonstration that, in the hippocampus
of gerbils, ischemic preconditioning decreased the binding density of cannabinoid CB1 receptors at 1, 2, and 4
days postpreconditioning deserves a mention (360), because CB1 receptor antagonists reduced the size of infarct
and improved neurological function in the MCAO rat
model (263). However, whether cannabinoids are neuroprotective or worsen neuronal damage after ischemia is
still debated. For example, the CB1 agonist WIN 55212-2
was cerebroprotective in brain ischemia models (266),
and the endogenous cannabinoid 2-arachidonoyl glycerol
(2-AG) reduced brain damage in mice subjected to closed
head injury (301).
To conclude this section, the ischemia-tolerant brain
appears to be characterized by a shift of the neuronal
excitatory/inhibitory balance toward inhibition. This potentially neuroprotective change does not appear to be
effective during the test insult, because delayed latency of
anoxic/ischemic depolarization is neither a common nor a
remarkable feature of the ischemia-tolerant brain (see
sect. IIA); this would be expected if, during a severe
ischemic insult, synaptic transmission is already “shutdown” early and efficiently in the naive brain. Rather,
enhanced neuronal inhibition may protect the tolerant
brain against postischemic hyperexcitability.
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TIHOMIR PAUL OBRENOVITCH
Physiol Rev • VOL
tions: 1) inhibition of the synthesis of a variety of proinflammatory cytokines, including TNF-␣, IL-1␤, and IL-8; 2)
suppression of cytokine receptor expression; 3) inhibition
of cytokine receptor activation; and 4) mediator of cellmediated immunomodulation. IL-10 is synthesized in the
CNS, and IL-10 receptors have been demonstrated on
microglia, astrocytes, and oligodendrocytes (392). Although there may be no report yet on an effective role of
IL-10 in brain ischemic tolerance, several lines of evidence support this possibility. Endotoxin preconditioning
enhanced IL-10 renal expression in rats, and this change
correlated with ischemic tolerance (140). In the liver of
wild-type mice, hypertonic preconditioning increased
IL-10 expression and prevented ischemia/reperfusion injury; ischemic tolerance was suppressed in IL-10 knockout mice (296). In cultured microglia and astrocytes, the
expression of IL-10 mRNA as well as the production of
IL-10 protein was enhanced by innate activation with LPS
(52, 254). Finally, procedures that increased IL-10 were
cerebroprotective in two separate studies: 1) intracerebroventricular or systemic administration of IL-10 decreased the infarct size produced in rats by MCAO (381),
and 2) when viral vectors encoding human IL-10 were
injected in the lateral ventricle of rats, 60 or 90 min after
focal ischemia, the infarct volume was smaller and the
inflammatory response reduced. The same procedure also
protected hippocampal neurons against global ischemia, a
beneficial effect that was associated with attenuated IL1␤, but increased TNF-␣ (294).
IL-1ra is an endogenous protein acting as a highly
selective, competitive antagonist of the IL-1 receptor type
I (IL-1R1), the receptor through which IL-1␤ exerts its
proinflammatory actions (13, 175). IL-1ra mRNA is constitutively expressed in the brain, and three IL-1ra protein
isoforms (secreted IL-1ra and intracellular IL-1ra type 1
and 2) were upregulated in response to LPS treatment
(300). Ischemic tolerance induced by 10 min of MCAO in
rats was associated with increased IL-1ra mRNA and protein expression (23), and several studies suggest that
increased IL-1ra contributed effectively to ischemic tolerance. Intracerebroventricular or peripheral injection of
IL-1ra reduced ischemic brain damage in rodents (130,
231, 393), and IL-1ra was still effective when it was administered as late as 3 h after 60-min MCAO (259). Furthermore, endogenous IL-1ra was demonstrated to be
neuroprotective by itself, as IL-1ra knockout mice exhibited infarcts produced by transient MCAO that were 3.6fold larger than in wild-type animals (315). Reciprocally,
IL-1ra overexpression, whether induced by adenoviral
gene transfer or drug associated, protected rats against
cerebral ischemia (36, 302) and attenuated the ischemic
inflammatory response in the mouse brain (445).
True decoy receptors are defined as cell surface ligand-binding proteins with high affinity and specificity,
but which neither induce downstream signaling nor
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mechanisms as those initiated by a severe ischemic insult,
albeit with a response of lesser intensity. This initial,
proinflammatory step is required for the development of
ischemic tolerance: 1) inhibition of NF␬B, by pretreatment with either the NF␬B inhibitor diethyldithiocarbamate or a NF␬B oligonucleotide decoy, abolished the
neuroprotective effects of different preconditioning methods against ischemia and kainate neurotoxicity (38); 2)
treatment with a recombinant human IL-1 receptor antagonist (IL-1ra) blocked the development of ischemic tolerance induced in gerbils by 2 min of global ischemia (289);
and 3) BB-1101, an inhibitor of MMPs, and TNF-␣ convertase (TACE) blocked the release of TNF-␣ caused by
ischemic preconditioning and inhibited the development
of ischemic tolerance (56).
The initial trigger of the inflammatory response induced by preconditioning is an interesting issue. TLRs are
transmembrane receptors that recognize pathogen-associated molecular patterns (PAMPs) (80), thereby acting as
pathogen sensors. However, some TLRs respond also to
molecules released by injured tissue (30, 304), and a
variety of TLRs are expressed in the brain, especially in
microglia and astrocytes (177, 197). With a severe ischemic insult, it is clear that a variety of molecules derived
from dead cells or damaged blood vessels may act as
endogenous TLR ligands and initiate a strong inflammatory response. TLR activation is also to be expected with
LPS-induced preconditioning, as LPS is a TLR ligand
(251). However, the origin of TLR activation is less obvious with preconditioning stimuli that are reputed not to
induce any cellular injury (e.g., cortical spreading depression). In the latter cases, TLR activation may be due to
HSP70, since it was identified as an endogenous stimulus
for inflammatory responses mediated by TLR2 and TLR4
(16, 336, 421), and upregulated HSP expression is a consistent feature of preconditioning (see sect. IID). As TLRs
are sensors for extracellular ligands, this would imply a
potential role for HSP70 at extracellular level, although
some data suggest that there may not be a direct ligand/
receptor interaction between HSP70 and TLR2/4 (410).
With regard to the subsequent, reduced inflammatory
responsiveness that contributes to ischemic tolerance,
several negative regulators of inflammation appear to be
involved (Fig. 3; for review, see Ref. 188). By acting at the
extracellular level, anti-inflammatory cytokines (e.g., IL10), cytokine receptor antagonists (e.g., IL-1ra), and decoy receptors (e.g., IL-1RII) may limit the progression of
inflammation away from the damaged brain regions,
whereas intracellular inhibitors (e.g., TTP and SOCS-3)
may reduce the intensity of the inflammatory response.
Although this concept of multifactorial, negative regulation of inflammation with ischemic tolerance is novel, it is
already supported by convincing data.
IL-10 has been identified as an anti-inflammatory cytokine that can limit inflammation through various ac-
BRAIN ISCHEMIC TOLERANCE
Physiol Rev • VOL
where the administered antigen is located. In simpler
terms, this process (termed bystander suppression) leads
to a relatively organ-specific immunosuppression. In several studies, CNS antigens were used to test whether this
type of immunologic tolerance (i.e., induction of antigenspecific mucosal tolerance for suppression of cell-mediated autoimmune responses) could protect against a subsequent ischemic insult. Rats fed five times over 2 wk with
1 mg bovine myelin basic protein (MBP) had smaller
infarcts after transient MCAO (induced 2 days following
the last antigen feeding); this immunologic tolerance and
its neuroprotective effects were associated with an increased expression of TGF-␤, and were transferred to
naive animals that received splenocytes from MBP-tolerized donors (27, 28). In mice, nasal tolerance to myelin
oligodendrocyte glycoprotein (MOG; applied 3 times every other day) decreased by 70% the size of infarct (MCAO
was induced 2 days after the last nasal administration)
and reduced also the neurological deficit; this protective
effect, which was associated with a marked increase in
the anti-inflammatory cytokine IL-10 (but not of TGF-␤),
was absent in IL-10 knockout mice (116, 117). Similar
results were obtained with nasal tolerance to E-selectin, a cytokine-inducible adhesion molecule restricted
to blood vessel endothelium activated by inflammatory
stimuli (68).
It is pertinent to note that whether these “tolerization
strategies” act primarily at brain tissue level or on the
adaptive immune system is an important, unanswered
question. Clearly, the interactions between CNS and immune system are finely balanced (466), and if brain injuries are capable of inducing immunodepression (247),
neuroprotection may be achievable via the adaptive immune system. Other peripheral systems (e.g., cardiovascular, autonomic nervous system) may also contribute to
ischemic tolerance. One example is coagulation. 1) In
mice, 3 days after preconditioning by 15 min of focal
ischemia, the vasodilator and platelet aggregation inhibitor cyclooxygenase-1 was upregulated, and bleeding
times were about 5 times longer than in controls (387).
2) Hypocoagulation is a feature of hibernation, thought to
reduce the risk of thrombus formation associated with the
very low blood flow levels that are associated with this
condition (97).
B. Cerebrovascular Adaptation (Vascular
Remodeling and Reactivity)
1. Vascular remodeling: an inherent capability of the
cerebrovascular system
Vascular remodeling could contribute to reduce the
severity of the subsequent test ischemia (e.g., by improving collateral blood supply in stroke models), thereby
complementing the possible adaptation of energy metab-
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present ligand to a signaling receptor. Soluble “decoy
receptors” (e.g., released by cell-surface shedding) also
exist (236, 237). The IL-1 type II receptor (transmembrane
IL-1RII or soluble sIL-1RII) was the first pure decoy to be
identified, with others subsequently discovered for members of the TNF-R and IL-1R families. IL1-RII mRNA expression was detected in cultured astrocytes and increased by LPS treatment (314), but there is apparently no
report directly related to the potential role of IL1-RII in
brain ischemic tolerance. Nevertheless, some data support this possibility. When IL-1␤ was microinjected into
the brain of rats to generate an inflammatory response
without neuronal death, this procedure induced an increase of de novo IL-1␤ synthesis with a concomitant
increase of IL-1RI (i.e., the IL-1␤ signaling receptor), but
there was also a much greater increase of IL-1RII (i.e.,
IL-1␤ decoy receptor) with immunostaining, indicating
that IL-1RII was expressed on brain endothelial cells and
on infiltrating neutrophils (95). In two studies with rodents subjected to MCAO, the low basal level of IL-1RII
mRNA in the cortex was markedly elevated after ischemia
(413, 430).
Among the numerous intracellular and transmembrane inhibitor proteins involved in negative regulation of
TLR-mediated immune responses (188, 227), only the potential role of SOCS-3 (suppressor of cytokine signaling-3,
a negative regulator of cytokine signaling, especially of
IL-6; Ref. 4) and tristetraprolin (TTP, a component of a
negative-feedback loop that interferes with TNF-␣ production by destabilizing its mRNA; Ref. 55) were investigated so far. Application of hypertonic salt solutions to
the cerebral cortex of rats, a procedure that increases
ischemic tolerance, produced a sustained increase in the
levels of SOCS-3 and TTP mRNA (261). Previous data also
support the notion that these cytosolic inhibitors of inflammation may contribute to ischemic tolerance. Transient MCAO produced an upregulation of the SOCS-3 gene
in the rat cerebral cortex, and antisense knockdown of
ischemia-induced SOCS-3 increased the infarct volume,
suggesting a neuroprotective role for SOCS-3 (329). A
marked and sustained upregulation of SOCS-3 was also
observed in cortices of rats subjected to permanent
MCAO (25). With regard to TTP, the expression of its gene
was upregulated in the canine myocardium 16 h after
ischemic preconditioning (467).
To conclude this section, preconditioning appears to
induce, secondarily, the expression of several endogenous inhibitors of inflammation that reduced the brain
inflammatory responsiveness, a condition that may be an
important feature of ischemic tolerance. Interestingly, a
similar state can be produced by mucosal vaccination
with pertinent antigens. Mucosal (nasal or oral) antigen
administration, when appropriately dosed and scheduled,
preferentially induces regulatory T cells that secrete the
anti-inflammatory IL-10 and TGF-␤ at the anatomic site
231
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TIHOMIR PAUL OBRENOVITCH
olism and brain cell membrane ionic homeostasis (see
sect. IIA). There is convincing evidence that the cerebrovascular system has such an adaptive capability through
arteriogenesis (formation of collaterals from existing arteries; Ref. 156) and angiogenesis (capillary proliferation;
Ref. 145). When both carotid arteries are ligated in rats to
produce a chronic hypoperfusion, cerebral blood flow
(CBF) drops sharply right after the occlusion, but then
increases gradually during the following weeks (110, 298),
and recent studies confirmed that both arteriogenesis and
angiogenesis may contribute to this adaptive process
(72, 286).
VEGF is a key regulator of angiogenesis (111, 389),
another target of HIF-1 besides GLUT1 (see sect. IIB)
(362), and brain VEGF was upregulated early after
hypoxic preconditioning (exposure to 8% O2) in both
neonatal and adult rats (34, 406). The induction of VEGF
gene expression was also demonstrated after MCA occlusion in rats and mice, both in the infarct and peri-infarct
regions (155, 318, 429), but contradictory data were also
reported (222). These data suggest that angiogenesis may
be initiated at an early stage after preconditioning, at least
with some stimuli, but the ultimate contribution of VEGF
upregulation to ischemic tolerance through angiogenesis
is difficult to assess: 1) because it is well established that
VEGF-induced angiogenesis is associated with a marked
increase in vascular permeability (82, 102), which implies
that VEGF upregulation may exacerbate ischemia-induced BBB disruption and edema (457); and 2) because
VEGF is also an important signaling molecule in the CNS
capable of suppressing apoptosis and stimulating neurogenesis (145).
3. Residual CBF during the test ischemia:
is it improved by ischemic tolerance?
Several studies examined how chronic hypoperfusion or preconditioning altered residual CBF during a
subsequent test ischemia, but the results are conflicting.
In mice, Kitagawa et al. (204) showed that 14 days of
chronic mild reduction of cerebral perfusion pressure,
produced by unilateral carotid artery ligation, were necessary for efficient collateral development (i.e., preservation of cortical perfusion after MCA occlusion). Such a
delay is well beyond the time window of ischemic tolerance induced by brain preconditioning (generally 1–7
days). However, in an earlier study carried out with rats
and using forebrain ischemia as subsequent test insult,
both residual CBF and ATP levels in the parietal cortex
were improved significantly at 3 and 7 days after unilateral carotid artery ligation (47).
In the study of Matsushima and Hakim (243) with
rats, a 2- or 3-h test MCAO was preceded 4 days earlier by
Physiol Rev • VOL
4. Does preservation of the vascular reactivity after
the test ischemia contribute to ischemic tolerance?
More important for ischemic tolerance may be the
preservation of vascular control/reactivity as the pathophysiology of ischemic damage progresses, especially the
endothelium-dependent arterial relaxation to acetylcholine that is selectively impaired by ischemia-reperfusion
(76, 341) and hypoxia-reoxygenation in vitro (383). In
support of this notion, cerebral endothelial cells could be
preconditioned in vitro (8), HSP70 expression in endothelial cells was associated with hypoxic-ischemic tolerance
induced by hyperthermic preconditioning in immature
rats (172), and the vascular endothelium was protected in
ischemia-tolerant regions (see also sect. IVC). Ischemic
preconditioning in rats improved CBF during the reperfusion that followed the subsequent 30-min forebrain ischemia, and this functional effect was associated with reduced endothelial desquamation and brain edema (426).
An upregulation of endothelial NOS (eNOS) may also
contribute to improved recirculation in tolerant brain regions, since increased expression of eNOS mRNA was
associated with ischemic tolerance induced by ischemic
or LPS preconditioning (127, 152, 127). The protective
effect of preconditioning (at least when it is induced by
LPS) on cerebrovascular reactivity may also include an
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2. Induction of VEGF by preconditioning
30-min MCAO, 5-min global ischemia, or sham surgery.
CBF was improved significantly in the frontoparietal cortex during the test MCAO when rats were subjected to the
prior focal ischemia, but this change was not associated
with a reduction in infarct volume. In contrast, the infarct
volume was significantly reduced when MCAO was preceded by global ischemia, but without any change in
residual CBF. Similar, negative data (i.e., effective ischemic tolerance without change in CBF during the subsequent test MCAO) were reported by Chen et al. (66).
In contrast to the studies outlined in section II, data
obtained with CSD preconditioning in rats and ischemic
preconditioning in gerbils suggested that ischemic tolerance was associated with improved tissue perfusion during the subsequent test ischemia (269, 297).
With LPS preconditioning in rats, Dawson et al. (89)
reported that local CBF was not significantly different
(relative to saline control) at 15 min after permanent
MCAO, but that microvascular perfusion was later improved in LPS-treated rats, i.e., at 4 and 24 h after MCAO.
More recently, the same procedure was found to improve
CBF in the peri-infarct area during the test MCAO (127).
Overall, the relatively long delay necessary for effective cerebrovascular remodeling appears difficult to reconcile with the window of ischemic tolerance (i.e., 1–7
days post-preconditioning), and residual CBF does not
appear to be consistently improved in tolerant regions
early during the test ischemia.
BRAIN ISCHEMIC TOLERANCE
action on vascular smooth muscles, because this treatment prior to ischemia-reperfusion prevented both the
impairment of endothelium-dependent relaxation to acetylcholine and the reduction in potassium inward rectifier
(Kir) density measured in dissociated smooth muscle
cells dissected from the occluded MCA (24).
C. BBB Integrity
Physiol Rev • VOL
cytes to vascular bed, but also trigger signaling cascades
that promote BBB leakage and leukocyte infiltration
(416). Increased expression of ICAM-1 by endothelial
cells was demonstrated during ischemia/reperfusion, both
in vivo and when simulated in vitro (119, 456). Oxidative
stress preconditioning of cultured endothelial cells reduced their inflammatory response and completely
blocked increased ICAM-1 levels induced by TNF-␣ (452);
supporting data were obtained with hypoxic preconditioning, which also inhibited the neutrophil adhesion to
the endothelial cells induced by hypoxia/reoxygenation (463).
V. CONCLUDING REMARKS
As preconditioning implies pretreatment, and the severity of an ischemic insult depends on the balance between energy demand and supply, ischemic tolerance
could include adaptive mechanisms to reduce energy demand (e.g., through changes in voltage- and/or ligandoperated ion channels) or improve residual energy supply
(e.g., collateral blood supply). However, on the basis of
the information assembled in sections IIA (energy metabolism and cellular ionic homeostasis) and IVB (cerebrovascular adaptation), this type of adaptation may not
contribute significantly to preconditioning-induced ischemic tolerance. When a cerebral artery is occluded in the
tolerant brain, the severity of the resultant insult appears
to be the same as in the naive brain, but the resulting
neuronal damage is substantially less. Overall, the data
available so far suggest that the adaptive changes in the
tolerant brain may be directed primarily against postischemic and delayed deleterious processes that contribute to
ischemic damage. However, adaptive changes that are
beneficial during the subsequent lethal ischemia cannot
be ruled out, and the possibility that the tolerant brain
may have an improved ability to control intracellular Ca2⫹
overload deserves further studies (see data on cytosolic
Ca2⫹ homeostasis in sect. IIA).
Interrelated, multifactorial processes are responsible
for ischemic tolerance (Fig. 4). This is a key feature of
adaptive cytoprotection that appears throughout this
analysis. Does it imply that several cytoprotective processes must be activated for effective protection against
ischemic damage, or is there some degree of redundancy
among these endogenous processes? On the one hand, in
several studies, the reproduction of only one feature identified in the tolerant brain (e.g., through genetic manipulation) induced a significant cerebroprotection. On the
other hand, the former notion agrees with the fact that
ischemic brain damage involves multiple, parallel, and
sequential pathophysiological events. Indeed, it is now
recognized that the suppression of a single deleterious
cascade may not be sufficient for effective protection
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The BBB is anatomically defined by the tight junctions between adjacent endothelial cells lining the lumen
of cerebral microvessels, but the BBB function also involves astrocytes, pericytes, neurons, and the extracellular matrix. The latter constitutes the basement membrane
underlying the vasculature, and its disruption is strongly
associated with increased BBB permeability in pathological states (154). BBB breakdown with associated vasogenic edema is an important and early feature of ischemic
brain damage and appears as a precursor and good predictor of poor outcome (216). Several studies have shown
that ischemic tolerance includes a better preservation of
the BBB and reduced edema formation during the test
ischemia. With preconditioning induced by 15-min MCAO
and 3 days before the test ischemia in rats, both BBB
disruption and edema measured 24 h after permanent
MCAO were attenuated in perilesion regions, but not in
the ischemic core (240). The latter data were confirmed
by the more recent study of Zhang et al. (454). When
immature rats were subjected to 2 h of hypoxia-ischemia,
IgG extravasation indicating BBB disruption was closely
associated with early neuronal damage, and both were
significantly attenuated by hyperthermic preconditioning
(173). Here again, it is difficult to determine whether the
preservation of BBB integrity contributes to, or is a consequence of, reduced ischemic damage. From mechanistic point of view, it is clear that a reduction of the brain
inflammatory responsiveness (see sect. IVA) is likely to
help maintain BBB integrity. However, preservation of
BBB integrity may be a primary and important feature of
ischemic tolerance, given that it is the interface between
damaged/vulnerable tissue and circulating inflammatory
cells during recirculation. This notion is supported by at
least two separate lines of evidence.
MMPs, especially MMP-9, are known to degrade the
neurovascular matrix during reperfusion, thereby contributing to BBB breakdown (339, 446, 458). Both BBB disruption and MMP-9 expression were reduced when
MCAO was preceded by ischemic preconditioning in rats
(454), a protective effect to which HSP70 may contribute
as HSP overexpression suppresses MMP-9. As already
mentioned, inhibition of MMP-9 has protective effects in
stroke models (see sect. IID for further information and
references on HSP70 and MMPs).
The adhesion molecules expressed by endothelial
cells (e.g., ICAM-1) mediate the firm adhesion of leuko-
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TIHOMIR PAUL OBRENOVITCH
against ischemic damage, and a number of investigators are
now working on combination therapies (213, 359, 378).
Combination therapy is inherently difficult for drug
development because of possible drug-drug interaction
and adverse effect superimposition, and this is where an
improved knowledge of the molecular physiology of ischemic tolerance is likely to help. Several innovative neuroprotective strategies with combination therapeutic potential are already emerging from this field of study.
Physiol Rev • VOL
An obvious approach is to activate one of the sensors
that is initially activated by preconditioning, such as HIF-1
(323, 371), as this will induce the transcription of several
target genes (GLU-1, VEGF, and EPO in the case of HIF-1)
and ultimately contribute to several neuroprotective components of ischemic tolerance. However, this strategy
may have a potential drawback: overstimulation of the
targeted preconditioning sensor may mimic the effect of a
damaging stressor, thereby initiating cell death rather
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FIG. 4. Current understanding of the cellular features of brain ischemic tolerance and
of their consequences on selected determinants of the pathogenesis of ischemic damage
(italic captions in red). The solid green arrows
point to pertinent molecular targets for neuroprotection; these are justified briefly in section
V. ⴝ, No marked changes reported so far; (⬃),
variable, inconsistent data (e.g., with different
animal models and preconditioning stimuli);
(ⴙ), upregulation; (⫺), downregulation; ?,
requires confirmation/further investigations.
cIAP, cellular inhibitor of apoptosis protein.
BRAIN ISCHEMIC TOLERANCE
Physiol Rev • VOL
ACKNOWLEDGMENTS
I am grateful to Drs. Marcus S. Cooke and Mark D. Evans
(Dept. of Cancer Studies and Molecular Medicine, Univ. of
Leicester) for their insightful input on DNA repair.
Address for reprint requests and other correspondence:
T. P. Obrenovitch, Prof. of Neuroscience, Div. of Pharmacology,
School of Life Sciences, Univ. of Bradford, Bradford BD7 1DP,
UK (e-mail: [email protected]).
GRANTS
Our work in this field was supported by European Commision Contract no. QLG3-CT-2000-00934, Biotechnology and
Biological Sciences Research Council Grant 16/C20070, and
Medical Research Council Grant G0501827.
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than tolerance. Indeed, as pointed out by Dirnagl et al.
(94), preconditioning/ischemic tolerance is part of a continuum spectrum of responses to noxious stimuli, and
although the tissue response (i.e., tolerance or cell death)
depends on the stimulus intensity, there are no clear
boundaries between tolerance, apoptosis, and necrosis. In
other words, pharmacological activation of preconditioning sensors may lead to tolerance only when drugs are
administered within a narrow range of concentrations.
An alternative is to interfere with a transducer (i.e.,
downstream from the preconditioning sensors), and this
is the case of EPO (93), which is attracting much interest
as a potential neuroprotector (94, 104), partly because it is
already approved for the treatment of various conditions
in humans.
Combinatorial neuroprotective strategies may be
also achieved at effector level, i.e., with molecular targets
underlying ischemic tolerance. The most obvious target of
this type is HSP70 because its upregulation results in
multiple, beneficial actions (Fig. 1) (380, 460). Although
mKATP channels are not involved in multiple, endogenous
neuroprotective processes (Fig. 4), it is also a pertinent
target because its opening results in the preservation of
mitochondria membrane potential and function, which
then leads to multiple benefits (e.g., attenuation of mitochondrial Ca2⫹ overload, reduced mitochondrial ROS
generation, reduced release of proapoptotic factors). It is
important and timely to investigate further the role of
mKATP channels in brain ischemic tolerance. Finally, the
thioredoxin (Trx) system deserves a mention because, in
addition to its contribution to cellular defense against
ROS, it is emerging as a key regulator of fundamental
cellular processes (see sect. IIC), and the antidepressant
deprenyl upregulated Trx in vitro (11).
Although mimicking the reduced inflammatory responsiveness of the tolerant brain cannot be assimilated
to a combination therapy, this strategy is worth pursuing
because this adaptive response is robust and consistently
induced by a variety of preconditioning stimuli. Among
others, and rightly so, the mucosal vaccination strategy
for neuroprotection (see sect. IVA) is triggering much
interest because of its potential, direct applicability to
clinical practice.
With regard to clinical relevance, the earliest clinical
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with ischemic insults, especially those that can be anticipated (i.e., essentially surgery related). For example, coronary artery bypass surgery has become a common, lifesaving procedure, but potential adverse effects do include
neurological damage and cognitive impairment (310).
Patients with a history of TIA constitute another large
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