Skip to main content

Advertisement

We’d like to understand how you use our websites in order to improve them. Register your interest.

Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection

Abstract

Ischemic tolerance defines transient resistance to lethal ischemia gained by a prior sublethal noxious stimulus (i.e., preconditioning). This adaptive response is thought to be an evolutionarily conserved defense mechanism, observed in a wide variety of species. Preconditioning confers ischemic tolerance if not in all, in most organ systems, including the heart, kidney, liver, and small intestine. Since the first landmark experimental demonstration of ischemic tolerance in the gerbil brain in early 1990's, basic scientific knowledge on the mechanisms of cerebral ischemic tolerance increased substantially. Various noxious stimuli can precondition the brain, presumably through a common mechanism, genomic reprogramming. Ischemic tolerance occurs in two temporally distinct windows. Early tolerance can be achieved within minutes, but wanes also rapidly, within hours. Delayed tolerance develops in hours and lasts for days. The main mechanism involved in early tolerance is adaptation of membrane receptors, whereas gene activation with subsequent de novo protein synthesis dominates delayed tolerance. Ischemic preconditioning is associated with robust cerebroprotection in animals. In humans, transient ischemic attacks may be the clinical correlate of preconditioning leading to ischemic tolerance. Mimicking the mechanisms of this unique endogenous protection process is therefore a potential strategy for stroke prevention. Perhaps new remedies for stroke are very close, right in our cells.

Review

Surviving a sublethal noxious insult may result in a more powerful state against a following lethal insult, referring to Nietszche; "What doesn't kill you, makes you stronger." This phenomenon named as preconditioning (PC) and tolerance has been shown to exist in many organs, most extensively in the heart. The first in vivo evidence of preconditioning and tolerance in brain was provided in 1960's [1, 2], but almost three decades passed without any interest from researchers on this unique phenomenon, until Kitagawa et al. opened the research era of cerebral ischemic tolerance (IT) [3].

The ability to withstand, respond to, and to cope with ongoing stress is a fundamental property of all living organisms [4]. The fate of the brain tissue after focal cerebral ischemia is determined by the degree and duration of ischemia, and even without preconditioning, resident brain cells naturally respond to brain ischemia by mobilizing a host of defences and counter responses to mitigate cell injury and death [5]. If the subthreshold noxious stimulus is too mild or negligibly mild, it may not induce any response, whereas if it is sufficient enough, it may serve as a PC trigger, or if it is too severe, over the threshold, may permanently injure tissues. The hallmark of PC stimulus is not being injurious. In the scenario of IT, PC stimulus primes the brain for subsequent injurious ischemic injury. Danger signal evoked in the brain by the stressing preconditioning stimulus induces complex endogenous protective mechanisms resulting to a latent protective phenotype. When the lethal ischemic insult is applied onto this latent protective phenotype, a separate set of responses are triggered that constitute ischemia-tolerant phenotype, which strikingly differs from the unprimed or unpreconditioned brain's phenotype (Figure 1). Therefore, the outcome of the brain cells is shifted by PC from death to survival.

Figure 1
figure1

Outcomes in the different settings with middle cerebral artery occlusion (MCAO). In the absence of ischemic preconditioning (IPC), MCAO induces a large infarction (ischemia-sensitive phenotype). IPC results early ischemic tolerance (IT) in minutes; if MCAO is applied during this phase, mainly cortical areas are spared (early ischemia-tolerant phenotype). In hours, the brain regresses to its naïve state. Delayed phase of IT occurs in days, when the latent cerebroprotective phenotype is complete, the brain is again ischemia-tolerant.

During the last years, the mechanisms underlying cerebral IT were intensely studied, and although incomplete, a vast amount of knowledge has been accumulated. The salient features of cerebral IT are presented in Table 1. There are two temporally distinct windows of protection from ischemia afforded by PC. Early protection, i.e., early IT, has been observed in relatively fewer studies than those exposing late IT in the brain. Exploring the functional relevance of these findings has proved difficult, however.

Table 1 Main futures of cerebral ischemic tolerance

In this review article, we first attempted to clarify the IT nomenclature. Various triggers induce cerebral IT; these are mentioned in a separate section discussing the models for IT. This variety among preconditioning triggers indicates that the downstream signaling pathways converge on some common fundamental mechanisms [5], major mechanisms are discussed briefly. A number of tools serve for examination of the efficacy of PC, chief methods are exampled. Lastly, we addressed the challenging issues of IT to encourage further research.

I. Nomenclature

The nomenclature used in the studies addressing the IT phenomenon is not entirely consistent. In this article, in order to keep with consistency while defining the methodology of the IT experiments and to provide ease for reading, the following terms will be used according to the definitions given:

PC

The stimulus or the method applied in an experiment that triggers IT in the brain.

Ischemic preconditioning (IPC)

Method of PC by inducing either global or focal transient cerebral ischemia. When the PC stimulus is different than ischemia, PC will be named according to the nature of the trigger (e.g., hypoxic-PC, anesthetic-PC, chemical-PC). In the literature, sublethal or priming ischemia have been used as alternative terms to IPC. For subsequent ischemic insult given after PC, the term test ischemia is often used [6, 7], among others (final, lethal, reference, or full ischemia). We will prefer to name the subsequent ischemic event as final ischemia.

IT

Briefly, the protection from final ischemia provided by prior PC refers to as IT. Depending on the media used to study the phenomenon of IT, IT may refer to the cell, tissue, or organ's post-ischemic state wherein, due to previous PC exposure, the response to ischemia is different from one observed without previous PC. In this article therefore, PC and IT define two different (but related) entities and are not used interchangeably.

Ischemia-tolerant phenotype (Figure 1)

It is the consequence of both pre- and post-ischemic protective responses induced by PC [5]; in other words, it is the resulting phenotype from both PC and final ischemia.

Latent cerebroprotective phenotype

It determines the status of the cell, tissue, or organ exposed to PC that experiences changes triggered by PC, and it occurs before the application of final ischemia [5]. Hence, the latent cerebroprotective phenotype differs from the ischemia-tolerant phenotype by the lack of exposure to final ischemia (Figure 1).

Cerebroprotection or protection

With the better understanding of the concept of neurovascular unit (i.e., the contribution of glial and vascular endothelial cells and their interactions with neurons in physiological and pathological conditions), researchers' attention shifted from neurons towards cerebrum. Hence, instead of "neuroprotection", we prefer to use "cerebroprotection", which covers not only neurons but all the cerebral cell populations experiencing IT. To interpret IT afforded on single cell type (hippocampal CA1 neurons in global ischemic models or type of cell slice used in vitro study), the protective effect provided by PC will be discussed as "protection".

II. Two phases of IT

Preconditioning induces two phases of IT with different temporal profiles and, to some extent, with different mechanisms of protection: early and delayed IT (Figure 1); the latter plays the major role in the brain. Early IT is a short-lasting protection induced within minutes of exposure to PC and wanes within hours. In this process, rapid changes in activity and posttranslational modifications of existing proteins are involved, whereas delayed IT requires gene induction and de novo protein synthesis, that represent a long-term response through genetic reprogramming [4]. If the final ischemia is induced during the unprotected window, which exists between early and late IT (usually 30 min-1 hour after PC, lasting up to 24 hours), no tolerance occurs (Figure 1).

In the literature, early IT has been termed as the first window of protection [8], rapid IT [5], immediate IT [9], short-term protection [8], classical IT [10], or acute IT [4]. We will prefer to use early IT [10]. Alternative terms for delayed IT are: second window of protection (a term widely used in heart IT studies), classical IT [5], and late IT [11].

III. Models for IT

Study setups for investigating potential phenotypes induced by PC are exampled in Figure 2. A summary of the available rodent models of IT is included in the following link as Additional File 1.

Figure 2
figure2

Exemplary protocol of a series of ischemic tolerance (IT) experiments. Preconditioning ischemia (IPC) lasts 5 min, final ischemia 10 min. Cross indicates the end of the study where the brains are collected for ex vivo evaluations. Set I experiments evaluate early IT: final ischemia is applied 30 min after IPC (upper row), early ischemia-tolerant phenotype is tested by collecting the brains 25 min after PC, and in the control experiment, final ischemia is induced without prior IPC (lower row). In Set II experiments, delayed IT (upper row, final ischemia induction 24 h after the PC) and delayed ischemia-tolerant phenotype (middle row, brains are collected 24 h after PC) are investigated, along with a control experiment (lower row). Set III experiments address long-lasting effects of delayed-IT, with a follow-up lasting several weeks after final ischemia.

Global-Global

Animal models of global cerebral ischemia are designed to mimic cardiac arrest in humans. Global-global IT models include different durations of transient global ischemia as PC and final insult.

Four-vessel occlusion

Rat forebrain ischemia experiments necessitate the occlusion of both posterior and anterior blood circulation of the brain. Four-vessel occlusion was originally described by Pulsinelli et al. [12] as a two-stage procedure wherein first both vertebral arteries are permanently closed and the following day, both carotid arteries are occluded. The model has been modified later by the same authors [13] and others [14]. In rats, delayed IT was provided by 3 [15] and 5 min [16] of four-vessel occlusion to 6 to 20 min of final global ischemia [1517]. Appropriate durations of PC and the interval between PC and final ischemia in this scenario have been studied by monitoring postischemic Hsp72 protein expression as a marker of IT [18]. Neither 3, nor 8 min of IPC induced sufficient synthesis of Hsp72. Once PC was fixed to 4 to 5 min, the minimum 2 days of interval was required between PC and final ischemia.

Two-vessel occlusion and hypotension

This model, originally described by Smith et al. [19] in the rat, includes bilateral carotid artery occlusion and systemic hypotension induced by withdrawal of arterial blood. Compared to four-vessel occlusion, it is less invasive and more reproducible, as the depth of ischemia depends on hypotension, rather than on surgical attenuation of collateral perfusion [20]. PC by 2 to 3 min of two-vessel occlusion induces delayed IT in rats to 5 to 10 min of final global ischemia [2123]. Early IT was also achieved in this model [24].

Two-vessel occlusion in gerbils

The gerbil mostly lacks a functioning circle of Willis [25], a short period of bilateral occlusion of carotid arteries (3-5 min) therefore leads to severe damage in CA1 pyramidal neurons [26, 27]. First introduced by Kitagawa et al. [3], PC by single 2-min bilateral carotid occlusion (or two times), 1 to 7 days before final ischemia in the gerbil brain has been a well-standardized method to study IT [2830]. A disadvantage of the gerbil two-vessel occlusion model is that the severity of forebrain ischemia is highly influenced by the anatomical variations, which are not seldom [31]. Here, we should note that thresholds for severity (i.e., duration of the bilateral carotid occlusion), differentiating the outcome as either PC or final insult, are in a narrow scale. To overcome this issue and ensure a better control over the ischemia severity, Abe and colleagues [7] provided a useful modification of the model. By monitoring depolarizations, they largely eliminated the variability of the ischemia and IT. This approach later was introduced in a rat global-global IT model using four-vessel occlusion [32].

Two-vessel occlusion in mice

This method, borrowed from its equivalent in gerbils, may induce reproducible striatal injury in mice [33]. For a delayed IT paradigm, Wu et al. applied 6 min of two-vessel occlusion as PC and 18 min of bilateral carotid artery occlusion as final ischemia in C57BL/6 mice [34]. As this strain is a common subject of transgenic technology, the model proved useful for investigating the molecular mechanisms of IT in gene-modified mice. In a such scenario, a much longer two-vessel occlusion period (20 min) has induced delayed IT [35].

Focal-Focal

Transient focal-permanent focal

Transient occlusion of the middle cerebral artery (MCA) by intraluminal insertion of a nylon monofilament, which was originally described by Koizumi et al. [36] and modified by others [37], is the most common model to induce focal cerebral ischemia in rats [3841] and also available in mice [4245]. This method was introduced first time in a rat IT experiment, applying 10 min of transient MCA occlusion (tMCAO) as the PC stimulus and permanent MCAO as the final ischemia [46]. Authors evaluated IT phenomenon with several reperfusion periods between IPC and final ischemia and showed that ischemic lesions involving both cortex and basal ganglia could be reduced when final ischemia was applied 1, 2, and 7 days after PC, but not 2, 6, and 12 hours or 14 and 21 days after PC. This model was applied successfully by others to obtain delayed IT [47, 48]. Repeated brief transient ischemia regimen was also proved as a preconditioning paradigm inducing early IT in mice subjected to permanent focal ischemia [49, 50].

Transient focal-transient focal

One [51, 52] or 3 times of 10 min transient focal cerebral ischemia protects from subsequent 120 min of tMCAO in rats [5355]. Shorter durations (2 and 3 min) of tMCAO were severe enough to induce delayed IT, but did not provide early IT to transient ischemia [56, 57]. Transient focal-focal IT paradigm induced IT also in mice and spontaneously hypertensive rats [58, 59]. A recent mouse model of delayed-IT involves 2 periods of 5-min tMCAO as the PC method, against 90-min tMCAO applied in 3 days, but not in 2 or 4 days [6].

Global-Focal

Brief global ischemia can protect from both subsequent transient and permanent focal ischemia [60, 61].

Focal-Global

Brief unilateral occlusion of the MCA induced significant protection from global ischemia in both gerbils [62] and rats [63]. Interestingly, transient (20 min) occlusion of the distal MCA protected only ipsilateral parietal cortex of the rat from global ischemia (10 min) [64].

Cross-Tolerance

Cross-tolerance is tolerance to ischemia provided by miscellaneous noxious stimuli, rather than ischemia. These differ greatly in nature, nevertheless, because of a common reason (most likely by inducing genetic reprogramming), all furnish IT. Examples of cross-tolerance in the scenario of transient focal cerebral ischemia are provided in Table 2.

Table 2 Amount of histological protection afforded by preconditioning in selected studies of focal cerebral ischemia

Hypoxia

Exposure of neonatal rats to 8% oxygen for 3 hours provides cerebroprotection from a combined hypoxia/ischemia model [65] and also from both transient and permanent focal cerebral ischemia [66, 67]. Varying hypoxia durations (1, 3, or 6 hours) result in similar extent of protection, but when the interval between hypoxia and final ischemia exceeds 72 hours, IT abolishes [67].

Hyperbaric oxygen

Hyperbaric oxygen was found protective from subsequent global ischemia in gerbils [68] and from permanent focal ischemia in SV129 mice [69], whereas it did not induce IT to transient focal ischemia in these mice [69]. Rats were protected from transient ischemia by hyperbaric oxygen PC, but they were not protected from permanent ischemia [70]. Repeated hyperbaric oxygen application seems to induce IT to global ischemia in the rat brain for a shorter period than 72 h [71].

Hyperthermia

In rodent experiments, indirect brain temperature can be measured with a probe placed under the temporal muscle and can be maintained at a desired level by heaters allowing feedback adjustments. Chopp et al. first time observed the PC effect of hyperthermia in rats subjected to global ischemia [72]. Hyperthermia was protected as well neonatal rats from hypoxia/ischemia [73].

Hypothermia

The hypothermic-PC has been described in a rat model of focal transient ischemia [74] and later was studied systematically in order to define the optimal depth, duration, and the method of application (global versus focal hypothermia) [75]. The extent of protection was dependent on the depth and duration of the hypothermia, focal cooling being as effective as systemic cooling. Although the deeper the hypothermia, the bigger the IT response was, mild to moderate levels of hypothermia, which are safe in humans [76], were efficient as well. This may encourage clinicians to test hypothermia as a preconditioning strategy, for instance before vascular surgical interventions with high risk of ischemic events.

Spreading depression

Leão's spreading depression is a generalized and stereotyped response of the cerebral cortex to a variety of noxious stimuli and is characterized by a slowly moving, transient, and reversible depression of cortical electrical activity that spreads like ripples in a pond; these waves, from the site of onset, spread usually to the whole cortex of the ipsilateral brain hemisphere with a speed of 2 to 5 mm per minute [77]. Topical application of high concentration of potassium chloride onto the cortex induces spreading depression that repetitively extends from the sites of increased extracellular potassium concentration with a frequency of approximately 7/100 min [78]. This method has been an effective PC trigger in both global [79] and focal ischemia models in rats [8082]. IT induced by spreading depression seems to develop in a delayed manner (in 3-6 days) [83, 84] and was shown to persist up to 15 days [85].

Remote IPC

Limb ischemia by bilateral femoral artery occlusion protects rat from either global ischemia [86] or transient focal ischemia [87]. It can be applied as well repeatedly (5-10 min for 3 times, with 10 minutes intervals in between). This PC approach was successfully tested in humans to induce IT in the heart [88]. Mesenteric artery occlusion for 15 min was protective against bilateral carotid occlusion in mice [89].

3-nitropropionic acid (3-NPA)

This is the most extensively studied chemical PC agent, which inhibits oxidative phosphorylation. Intraperitoneal administration of 3-NPA, 72 hours before transient focal ischemia, is a well-established PC trigger for rats [9093]. Regarding the efficacy of 3-NPA as a PC trigger, some contradictory results came from gerbil models of global ischemia [9496], but these may be related to the doses used [97].

Lipopolysaccharide (LPS)

LPS is a cell-wall component of gram-negative bacteria. A small dose provides IT in the brain. This has been proven in a number of experiments including both transient [98, 99] and permanent [100, 101] focal ischemia models in rats, as well as in a mouse model of transient focal ischemia [102]. With higher doses no PC effect occurs [98].

Anesthetic-PC

Potential protective effects of anesthetics from an ischemic insult have been known for long time [2] and were well-studied in experimental stroke models as a cerebroprotective strategy (for reviews see [103105]). Among anesthetics, isoflurane is the most commonly used volatile anesthetic in IT experiments. Different concentrations (0.5-4%) and varying durations (15 min-3 hours) of isoflurane inhalation have been efficient to induce both early [106, 107] and delayed IT in vivo [108, 109] and in vitro models [110, 111]. Among other anesthetics, xenon [112], halothane [113], and sevoflurane [114] may also induce IT in animal models. Anestetic-PC has been proven a promising PC method for heart in humans [115].

Pharmacological PC

Several clinically available drugs, including estrogen [116], erythromycin [117, 118], and erythropoietin [119, 120], are capable of inducing IT in animal models. Acetylsalicylic acid [121] and kanamycin [122] were effective as PC agents in vitro.

Other models for IT

Repeated electroacupuncture [123, 124], electrical stimulation of cerebellar fastigial nucleus [125], and dietary restriction [126] protected rats from subsequent transient focal ischemia. In global ischemia rat models, repetitive transcranial magnetic stimulation [127], electroconvulsive shock [128], kainite-induced epileptic seizures [129], and sleep deprivation [130] all have served as PC stimuli.

In vitro models

Neuronal cell culture systems provide an ideal microenvironment to study PC, because they lack a vascular compartment and the environment is easily controlled for confounding factors (e.g., see the fascinating work by Gonzalez-Zulueta et al. [131]). In vitro modeling for ischemia consists of oxygen and glucose deprivation (OGD) in the culture medium, and perhaps the most widely used method is the one described by Goldberg and Choi [132, 133]. This model includes the transfer of neocortical cell cultures for several hours to an anaerobic chamber containing a gas mixture of 5% CO2, 10%H2, and 85%N2 (oxygen deprivation), followed by application of a deoxygenated glucose-free medium (glucose deprivation). Organotypic hippocampal slice cultures offer an attractive alternative method, because many aspects of in vivo ischemia, such as delayed death of CA1 neurons and selective vulnerability in response to OGD, can be addressed [134]. Hassen et al. has introduced a new model of IT by isolating hippocampal slices from young rats, to abolish age-dependent resistance to ischemic injury [135]. Also mixed neocortical cultures are available to study IT in vitro [136].

IV. Methods for detecting IT

In most of the IT studies, the ischemia-tolerant phenotype is addressed with assessments performed after the final ischemia; however, to expose the molecular substrates of latent cerebroprotective phenotype, the tissues should be collected after PC (Figure 2). Studies, which used the latter approach, have been recently reviewed [137]. To increase the relevance to the human condition, IT models should include both histological and functional evaluations. However, these imply more challenges for IT researchers [138], because not always a correlation between these two outcome parameters is present [30].

Histological techniques

Determining the extent of injury after focal ischemia is relatively simpler than after global ischemia. For this purpose, traditional histological staining techniques, such as hematoxylin-eosine and 2% solution of 2,3,5-triphenyltetrazolium chloride, are often used. Digital camera-based image analysis systems enable lesion area and volume calculations. Ischemic lesion volume is calculated preferably with the correction of edema effect [38, 39, 139, 140]. In IT experiments, reduction in lesion volume due to PC (lesion size in the näive brain -- lesion size in the preconditioned brain) can be calculated as a percent ratio to the lesion size in the näive brain (Table 2). In global ischemia models, ischemic damage is assessed in hippocampal sections stained with toluidine blue [141], cresyl violet [34, 94], or thionin [142] by counting CA1 neurons, which are highly susceptible to global ischemia and easy to quantify due to their laminar distribution and large size [138]. Protection due to PC can be reported as the percentage of preserved healthy hippocampal CA1 neurons or number of viable CA1 neurons [7, 30, 129]. In vitro models of IT use cellular injury assessments, such as lactate dehydrogenase assay [111, 143].

Functional assessment

Gross measures of sensorimotor abilities are available for rodents [37, 144], and were introduced in IT experiments [46, 47, 97, 107]. However, in these species, gross sensorimotor deficits tend to recover rapidly. That is, more complex tests are needed, especially if outcome is assessed in long-term. A number of somatosensory tests (e.g. limb placing, beam walking, grid walking, rotarod) are available to apply in focal ischemia rat models [145]. In global ischemia models, tests of learning ability, and working and reference memory are particularly useful [138, 146].

Lesion evaluation by magnetic resonance imaging (MRI)

MRI technology allows for temporal and spatial monitoring of ischemic lesion and enables to conduct longitudinal studies [147151]. Besides requiring anesthesia, MRI is risk-free for experimental animals. First MRI-based lesion evaluation in an experimental IT study was reported by Mullins et al. [152]. In a delayed IT model (focal--focal ischemia), rats were imaged 24 and 72 hours after final ischemia. Interestingly, lesion reduction due to PC was greater at 72 hours (70%) compared to that at 24 hours (53%). Authors concluded that 24 hours post-ischemia, which is a common time-point for lesion evaluation in experimental stroke studies [153155], may not be the best time-point for experimental IT studies. Furuya et al., imaged rats serially (at 6 and 24 hours and 4, 7, and 14 days), following a delayed IT paradigm (LPC-PC--focal ischemia) [156]. They evaluated whether decreased lesion size due to PC would increase in long-term. No delayed lesion progression was found.

Means for depicting the mechanisms of IT

Immmunohistochemistry is widely applied in IT research and serves to evaluate tissue alterations by means of antigen-antibody interactions. In situ hybridization and Western blotting techniques are applied to examine the effect of PC on the investigated protein's mRNA expression and abundance [141]. DNA microarray technology, which allows quantification and differential expression of thousands of genes simultaneously, has been used to investigate global changes occurring between ischemia-tolerant and näive brains (see below "genomic reprogramming"). Real-time PCR can be used for confirmation of the selected genes, which found upregulated by microarray analysis [157]; proteomics may provide supplemental insights [158]. Alterations in neurotransmitter receptor density can be evaluated by quantitative in vitro receptor autoradiography [159, 160]. Autoradiographical methods may show changes in the global protein status [29, 161].

Showing attenuation or abolishment of IT by pharmacological inhibition of a molecule before or after PC stimulus proves a robust approach. With this approach, necessary or mandatory components of IT can be explored [162, 163]. Complementary information may come from genetically modified animals by proving abolishment of IT in mutants lacking a functional molecule or protein and showing reestablishment of IT in rescue experiments [164]. Maintenance of IT, despite pharmacological inhibition of a molecule of interest or despite the lack of this molecule in the mutant mouse, may rule out the hypothetic causative role for the investigated molecule in the acquisition of IT [35, 84, 163]. However, it should be noted that, the main effectors of IT can be model- or trigger-specific that, for instance, a specific molecule proven mandatory for hypoxia-induced IT in the rat brain [165] may not necessarily be required in OGD-induced IT in vitro [166].

V. Mechanisms of IT

IT is achieved by the attenuation of broad categories of injury-inducing mechanisms, including excitotoxicity, ion and pH imbalance, oxidative and nitrosative stress, metabolic dysfunction, inflammation, and apoptotic cell death. Additionally, innate survival mechanisms and enhanced endogenous repair mechanisms are involved [5]. Preservation of energy metabolism and mitochondrial functions during the ischemic event is improved [167, 168]. Our knowledge on the underlying mechanisms of cerebral IT is yet patchy. Additionally, different mechanisms may dominate different models. Here, we will review only the major molecular aspects contributing to delayed cerebral IT. The mechanisms of early IT will be discussed separately at the end of this section. Readers seeking for more comprehensive information should consult the recent excellent review of Obrenovitch [169] as well as its antecedents [9, 133, 167].

Hypoxia-inducible factor-1 (HIF-1)

Among several transcription factors sensitive to regulation by hypoxia/ischemia, HIF isoforms have gained the most experimental support [5]. HIF-1 proteins are increased in the brain in the setting of hypoxia resistance [170] and hypoxic PC [67]. Pharmacological activators of HIF-1 (deferoxamine or cobalt chloride) promote PC in hypoxia/ischemia model in neonatal rats [170]. Over the past decade, the signalling pathways involved in HIF-1 activation have been deciphered in detail [171]. Briefly, hypoxia stabilizes alfa subunit of HIF-1, which enters the nucleus in a dimerized form and results in the induction of HIF target genes. Several HIF target genes contribute protection from ischemia [67, 172, 173], and their products involve in wide range of adaptive and pro-survival events, including cellular metabolism, proliferation, vascularization, iron homeostasis, and glucose metabolism [5, 133].

Protein kinase C (PKC)

The role of protein kinase C in mediating stroke injury has been reviewed recently [174]. There are 10 isozymes in the PKC family. Previously, PKC was thought not to have a role in IT phenomenon, because blockage of PKC did not prevent IT [175], and PKC activation did not induce IT [176]. However, accumulating data suggest opposite roles for different PKC isozymes in the brain: γPKC contributes in ischemic cell death in organotypic hippocampal cell cultures, and NMDA triggered IT models require εPKC translocation [177]. Even though non-selective activation of PKC does not induce IT, specific εPKC activation leads to IT [143, 177]. It seems that adenosine-mediated activation of εPKC and subsequent signal transduction pathways through MAPK-K, ERK [178], and cyclooxygenase-2 induction are involved in IT [143].

Anti-excitotoxic mechanisms, NMDA, and calcium

Exogenous application of NMDA or glutamate alone suffice to induce ischemia resistance in cell cultures, and NMDA receptor blockade during preconditioning eliminates IT both in vitro [179] and in vivo [180, 181]. Specific AMPA or kainate receptor blockade do not eliminate or only partially attenuates IT [131, 180]. Contradictory findings exist, however [136, 182]. In gerbils, IPC increased inhibitory γ-amino butyric acid A (GABAA) receptor binding in hippocampus, whereas final ischemia did not [160]. Moreover, microdialysis experiments revealed a temporary increase in GABA release in preconditioned rat hippocampus early after final ischemia, with a decrease in glutamate concentration [21]. Thus, anti-excitotoxic mechanism induced in ischemia-tolerant state in global ischemia models involve a shift between inhibitory and excitatory hippocampal neurotransmission. In vitro, GABAB activation operates as a PC trigger [21], but not GABAA activation [21, 183]. Regarding the role of Ca2+ in IT, it seems not always mandatory [184], but chelation of Ca2+ before and during both OGD- and NMDA-PC prevents IT in vitro [177].

Adenosine and ATP-sensitive K+ (KATP) channels

Adenosine, an ischemia-induced degradation product of ATP, activates A1 receptors, which leads to a cascade of signaling events including KATPchannels. This cascade results in increased resistance to subsequent ischemic damage [185]. The general role of KATP channels, which are named for the inhibitory effect of ATP reducing channel opening probability, is to set membrane potential according to its metabolic state by sensing intracellular nucleotide concentrations [186]. Plasma membrane KATP channels are found widely throughout the brain [186]. The mandatory role of KATP channels for acquisition of IT was demonstrated in a rat delayed IT model (global-global) [187] and in vitro [188]. Interestingly, early IT is also blocked by pharmacological inhibition of KATP channels in vitro [176]. Opening of KATP channels is thought to relate to adenosine A1 receptor activation. Both specific and nonspecific adenosine A1 receptor antagonists attenuate or cancel the IT phenomenon [187, 189, 190]. However, SUR1-containing KATP channels seem not to be involved in IPC [35] and in spreading depression-PC model in rats and inhibition of KATP channels did not block IT [191]. Some authors emphasize a more pronounced role for mitochondrial KATP channel in IT [169, 190].

Nitric oxide (NO)

NO is one of the most extensively studied molecules in IT experiments (for reviews see [192, 193]). Data suggest that generation of NO is crucial for the induction of IT, as a dependence on endothelial NO synthase (eNOS), but not on the neuronal NOS (nNOS) in newborn rats subjected to hypoxic-PC [165]. Whereas, nNOS was required to induce tolerance in vitro [166]. OGD tolerance in cortical cell cultures occurred via the activation of the Ras/extracellular signal-regulated kinase cascade by NO [131]. Atochin's early IT model proved an indispensable role for both eNOS and nNOS [50]. Puisieux et al. used a delayed IT (focal-focal) model in adult rats and showed no effect of NOS blockade on IT, but when the PC stimulus was LPS, IT was abolished by NOS inhibition [194]. Inducible NOS (iNOS) lacking mice experience no IT [164] and iNOS inhibition may nullify delayed IT to permanent focal ischemia, that otherwise follows isoflurane- or halotane-PC [113].

Anti-inflammatory mechanisms

Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) are implicated in IT induction: both cytokines are found increased in ischemic-tolerant state, both act as PC trigger when administered systemically, and their inhibition or lack significantly attenuate or block IT [195198]. Pradillo et. al. explored the involvement of the TNF-α/nuclear factor-κB (NF-κB) signal transduction pathway in IT [48]. This pathway includes at least 131 interactors [199]. Activation of NF-κB is involved in IT in several models [200, 201], likely via the induction of neuroprotective gene products, such as manganese superoxide dismutase and Bcl-2 [9]. Preconditioning with ligands of toll-like receptors 4 and 9 may alter innate inflammatory responses to ischemia by causing an initial activation of inflammatory mediators followed by a burst of inflammation inhibitors [202].

Anti-apoptotic mechanisms

PC blocks enhanced phosphorylation occurring after ischemia [9]. On the other hand, phosphorylation of transcriptional factors can induce long-term changes by regulating the expression of genes. IT is also characterized by reduced apoptosis [5, 142]. Phosphaphatidylinositol 3-kinase/Akt pathway seems to act in two ways: 1) in relation to anti-apoptotic mechanisms and 2) by activating NFkB. In vitro, p21 Ras is required and sufficient to induce IT and Ras/Erk pathway is activated through NMDA receptor and NO production [131]. However, increasing evidences support the existence of a link between Akt activation and anti-apoptosis in IT [157, 203205], perhaps more persistently in penumbral regions in focal IT models [206]. Anti-apoptotic mechanisms induced by PC are several: induction of Bcl-2, reductions in caspase-3 synthesis and p-53 activation, and reductions in mitochondrial cytochrome c [9, 185].

Genomic reprogramming

With the contribution of DNA microarray analysis method to IT research, we gained a better understanding of the preconditioned brain on the genetic level. In 2003, Stenzel-Poore and colleagues published a study, a cornerstone in the field, which introduced the concept of "genomic reprogramming" defining the altered transcriptional response of the ischemia-tolerant brain [207]. Followed by others [208, 209], profiled the genetics of IT induced by IPC in rats were profiled. In the setting of IT, overall transcriptional response to injury was found altered as downregulation, which was strikingly different from that in the naïve brain's postischemic transcriptome. Suppression of gene expression in the ischemia-tolerant state was not simply the lack of response to injurious insult, but rather a reprogramming of the genetic response to ischemia [210]. Most of the genes suppressed are involved in the pathways that regulate metabolism, molecular transport, or cell-cycle control. Genomic transcriptional profile shows a substantial difference also between latent cerebroprotective and ischemia-tolerant states. None but one of the differentially regulated genes compared to healthy hemisphere are in common [208]; however, in both states, overall response is downregulation of genes involved in metabolism and transport/synaptic transmission. Using GeneChip analysis, Dhodda et al. evaluated temporal changes in gene expression after IPC in spontaneously hypertensive rats [158]. At the time-points studied (3, 6, 12, 24, and 72 h after PC), overall 40 transcripts were found up-regulated, among which 30 transcripts were overexpressed at all time-points, and the six HSP70 transcripts showed the highest increase. Other major families of transcripts, which were upregulated during PC, were those that control signal transduction, transcription, ionic homeostasis, and plasticity. Moreover, transcripts that showed upregulation after ischemia in näive brains were not found upregulated in ischemia-tolerant brains [158].

Gene expression response to hypoxic-PC was also studied [173]. As early as 1 hour after hypoxia, but at a greater extent at 6 hours, expression of many genes, which are regulated by HIF-1, were increased. Compared to näive ischemic brains, in the ischemia-tolerant brains preconditioned with hypoxia, several genes were differentially upregulated. Genes with decreased expression in näive ischemic brains were no longer or only to a small degree underexpressed in ischemia-tolerant brains.

Genetic response to hyperbaric oxygen-PC was studied in the rat, in the latent cerebroprotective state (at 6, 12, 24 after PC) [71]. Most of the differential regulations, including overexpression of genes and proteins related to neurotrophin and inflammatory-immune system, occurred around 12 and 24 hours. Genetic reprogramming was described as well for IT induced by erythromycin [118].

Mechanisms of early IT

In vivo models demonstrating early IT in the brain are limited: global-global model in the rat [24], and focal-focal model both in the rat [211], and mouse [49, 50], and anesthetic-PC against focal permanent ischemia in the rat [113].

The molecular mediators of early IT are little known. Changes in membrane channel activity and posttranslational modifications of existing proteins are among the few, which are well-described. Roles for adenosine receptor in vivo [211] and for KATP channel in vitro were also explored [176]. Several immediate-early genes (c-fos, c-jun), growth factors (brain-derived neurotrophic factor, nerve growth factor), and heat shock protein 70 were overexpressed during early latent ischemia-tolerant state [212]. According to Kariko et al. [213], during early tolerance, production of proinflammatory cytokines are suppressed, whereas in delayed tolerance, production of the very same cytokines are induced.

VI. Open Issues and Challenging Features of IT

Several specific questions arise by an overview of past IT experiments. The nature of the PC stimulus and the duration of the interval between PC and final ischemia are among the main parameters that may affect the results. The strain and gender of the experimental animal are additional sources of variability, as we are familiar from stroke experiments. Therefore, findings of an experimental IT study should be interpreted considering the following issues.

Trigger-dependent differences

Experimental data amounted for the last 20 years clearly demonstrated that IT can be afforded in animals by miscellaneous PC triggers. Thus, one can both easily and reasonably make the following assumption: diverse PC are sharing a common or overlapping pathway. As discussed above, a number of effector mechanisms confer ischemia-tolerant phenotype, and recently, genetic reprogramming was proposed as the underlying common process set into motion by these mechanisms [207, 208]. Below, we will have a closer look to studies comparing the mechanistic or molecular features of IT triggered by different PC stimuli.

IPC versus LPS-PC was compared in a transient ischemia rat model and found inducing similar degree of protection (35% reduction in infarct volume) [194]. An interesting finding was that NO synthase inhibition abolished the protective effect of LPS, but not of IPC. IPC induced the expression of heat shock protein 70 in the cerebral cortex, but LPS did not. Recently, ischemia-tolerant phenotypes induced by two well-known preconditioning stimuli -LPS and transient focal ischemia- have been evaluated from the genetic aspect [209]. Authors disclosed that a substantial subset of regulated genes were unique to each PC stimulus. In case of IPC, mainly metabolism and channel/transport-related genes were suppressed; whereas, LPS-PC induced expression of pro-inflammatory molecules and suppressed those genes related to deleterious inflammatory reactions. However, suppression of Toll-like receptor-mediated inflammation is a common mechanism triggered by both PC triggers [213]. Another comparative study of different PC stimuli (IPC and chemical PC with 3-NPA) addressed cytokine mRNA expression after final ischemia [214]. Both PC strategies exerted very similar effects on proinflammatory and cytotoxic cytokine expressions. Later, same authors studied the expression of nerve growth factor separately with IPC and 3-NPA-PC paradigms [215]. Neither trigger showed any effect on nerve growth factor expression, which in another study was found increased by PC with brief global ischemia in both early and delayed IT [212].

Intermodel differences

In focal-global IT paradigm, PC may confer IT in neurons outside the primary area subjected to IPC that is in proximity, but not in the further regions such as contralateral hippocampus [62]. Similar IT paradigm in rats resulted in bilateral protection of hippocampi, however [63]. A functional direct pathway from the entorhinal cortex to both hippocampi was suggested to reflect the changes afforded by IPC to both hemispheres [63]. In the global-global IT paradigm, c-fos expression during the tolerant state was found specific to the cell type [216], which may explain selectivity of IT induction to certain brain areas.

Prass et al. studied the confounding effects of strain and reperfusion on the IT phenomenon [69]. Hyperbaric oxygen was applied as PC stimulus to two common background strains for knockout mice, SV129 and C57BL/6. Final ischemia was either permanent or transient focal ischemia. In SV129 mice, PC induced tolerance to permanent ischemia but not to transient ischemia. In C57BL/6 mice, IT did not occur at all. Consequently, questions to answer with further study are: 1. For what reasons the very same trigger induced IT in a strain but not in another, and 2) Can reperfusion nullify the protection afforded by PC?

Gender

Female rats sustain smaller infarcts after MCAO than males [217] and estrogen is neuroprotective in ovariectomized females and in males subjected to ischemic stroke [218]. Data from heart IT experiments show a clear gender-dependency of the IT phenomenon [219, 220], this issue seems valid also in cerebral IT. Estrogen provided IT in a model of hippocampal organotypic slice culture, which was generated from neonatal female rats [116], and isoflurane induced IT only in male mice and increased the infarction in young female mice [221].

Age

IT phenomenon is preserved in aged animals [222], but may not be as effective as it is in young animals. This aspect was tested with a global-global IT paradigm applied in 4- and 24-month-old rats [223]. The degree of protection due to PC was significantly diminished in aged rats compared to young rats. A retrospective clinical study indicated that IT may not be occurring in the elderly, aged around 75 [224].

Repeated PC

Cumulative injurious effect of repeated cerebral ischemia is a well-known phenomenon. For example, three periods of 5-min forebrain ischemia, induced at 1-hour intervals, result in more extensive brain injury than one single episode of 15-min ischemia in gerbils [225]. However, if PC insults are applied repeatedly, a larger IT response may be gained. This was tested in a mice model of early IT, in which animals underwent either single or 3 episodes of 5-min focal cerebral ischemia, 30 min before permanent ischemia [49]. Only repeated insults conferred IT, the single brief ischemia was insufficient to induce IT. Similarly, a single episode of 2 min OGD is under the threshold to act as a PC stimulus, but four times repeated 2 min of OGD show a cumulative effect and protects from subsequent injurious insult [226]. Hyperbaric oxygen-PC, when applied singly or repeatedly, provide similar degree of protection from transient focal ischemia (63% vs 73% lesion reduction) [227], perhaps this is the maximum affordable protection by hyperbaric oxygen. In a clinical study however, anesthetic-PC with a single application induced no IT in the heart, whereas repeated application did [115]. In the pig heart, PC by repetitive ischemic insults was shown to induce a different set of genetic regulations from those induced with PC with single ischemic episode [228]. A corresponding study in cerebral IT is needed.

"Sublethality" of PC

Although PC is defined as a sublethal stimulus, which per se causes no injury, several studies used relatively severe focal ischemia as the PC trigger and were able to induce IT, despite the injurious nature of the PC itself [63, 64, 190]. As pointed out by Sommer [137], with extended follow-up after the PC insult, some injury or structural changes can be detected. Therefore, it is suggested that PC is postponing these changes [137]. If that holds true, in the long-term, näive ischemic brains and IT experienced brains may have similar outcomes. This issue is discussed next.

IT and long-term effects

Early IT is a short-lasting phenomenon, its protection vanishes around 7 days [24]. In delayed IT models, protection lasts longer and tends to decline after 30-60 days. Ohno et al. applied a global-global IT model to rats [229] and showed that improvement in learning and memory due to IPC was preserved up to 3 weeks. Protective effects of spreading depression-PC and LPS-PC sustained up to 14 days [84, 156]. Ma et al. found a sustained improvement in neurological scores up to 30 days in xenon-preconditioned neonatal mice subjected to global ischemia [112], a similar finding was reported with a focal-focal IT model in rats [51]. In global-global IT models, histological protection is longer preserved in rats (up to 90 days) than in gerbils (up to 60 days) [30, 32, 222, 230]. Optimizing time interval between PC and final ischemia, together with the optimization of the PC stimulus (single or repetitive application) and the severity of final ischemic insult, may result in long-term preservation of protection achieved by PC [32], on which increased neurogenesis after PC [231] may have a potential role.

VII. Clinical Aspects

To date, a body of evidence, which supports the hypothesis that TIAs may confer IT in humans, exists. In a retrospective study, preceding TIA was found to be associated with less-severe stroke on admission and improved outcome on follow-up, compared to stroke patients without preceding TIA [232]. Another retrospective case-control study, found no evidence of PC by TIA in baseline neurological scores, but favorable outcome was associated with the presence of TIA [233]. This study presented "potentially preconditioning" TIA characteristics as: 0-7 day interval between TIA and stroke, 2 or 3 times repeated TIA, and TIA with <20 min duration. Moncayo et al. reported a cohort of 65 patients with acute anterior circulation stroke, among whom those with previous TIAs (lasting less than 20 minutes), had a more favorable outcome than those without [234]. Apparently, duration of TIA should be taken into account while evaluating whether IT exists in humans or not [235]. An MRI study provided the tissue evidence for TIA-induced tolerance to ischemic stroke [236]. Ischemic lesions tended to be smaller on the baseline images and final infarct volumes were smaller in stroke patients with prior TIA than in those without.

Although these findings strongly suggest TIA as the clinical correlate of IPC, other explanations for milder strokes after preceding TIA must be considered. In these patients, a carotid disease with slowly progressing stenosis, which improves collateral circulation may predominate [237]. Another point is that, patients with cardioembolic stoke have lower incidence of TIA than those with atherosclerotic vascular disease, and probably because of larger-sized emboli they sustain larger infarcts and poorer outcome [238].

Several clinical conditions may benefit from strategies using principles of ischemic tolerance, as discussed elegantly by Dirnagl et al. in a recent review article on cerebral IT [239]. Mediators of IT could be used as biochemical markers of IT in stroke patients. Castillo et al. tested this hypothesis by evaluating blood levels of TNF-α and IL-6 in acute stroke patients with or without prior ipsilateral TIA [240]. Better outcome was found in patients with TIA, who showed high plasma concentrations of TNF-α and low concentrations of IL-6. Hence, authors proposed the index of TNF-α/IL-6 as a marker of IT phenomenon in humans.

Conclusions

Experimental IT paradigms investigate the endogenous pathways by which the brain might protect itself from ischemia when geared with an appropriate stimulus. Attempts to elucidate the mechanisms underlying cerebral IT are increasing exponentially, but diversity of models, including PC stimuli, hardens interpretation of the data. In addition, narrow safety margin of PC may prove a limiting factor of the therapeutic utility of PC in clinics. On the other hand, accumulating clinical data suggest that IT might be a clinically relevant phenomenon. Several approaches, including ICP [241], remote-PC by limb ischemia [88], pharmacological-PC with nitroglycerine [242], and anesthetic-PC [115], are tested in clinical trials to protect the heart from cardiovascular interventions with high risk of cardiac ischemic event. Results are promising and give hope that clinical trials of PC to protect brain in situations with a high risk of ischemia can be designed, once PC is proven safe.

Abbreviations

3-NPA:

3-nitropropionic acid

GABA:

γ-amino butyric acid

HIF-1:

hypoxia-inducible factor-1

IL-1:

interleukin-1

IT:

ischemic tolerance

IPC:

ischemic preconditioning

KATP :

ATP-sensitive K+

LPS:

lipopolysaccharide

MCA:

middle cerebral artery

MCAO:

middle cerebral artery occlusion

MRI:

magnetic resonance imaging

NO:

nitric oxide

nNOS:

neuronal NO synthase

iNOS:

inducible NOS

eNOS:

endothelial NOS

NF-KB:

nuclear factor KB

OGD:

oxygen-glucose deprivation

PC:

preconditioning

PKC:

protein kinase C

TIA:

transient ischemic attack

TNF-α:

tumor necrosis factor-α

tMCA:

transient MCAO.

References

  1. 1.

    Dahl NA, Balfour WM: Prolonged anoxic survival due to anoxia pre-exposure: Brain ATP, lactate, and pyruvate. Am J Physiol 1964, 207: 452–456.

  2. 2.

    Wells BA, Keats AS, Cooley DA: Increased tolerance to cerebral ischemia produced by general anesthesia during temporary carotid occlusion. Surgery 1963, 54: 216–223.

  3. 3.

    Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K, Kamada T: 'Ischemic tolerance' phenomenon found in the brain. Brain Res 1990, 528: 21–24. 10.1016/0006-8993(90)90189-I

  4. 4.

    Koerner IP, Alkayed NJ: Ischemic preconditioning. In Acute stroke, bench to bedside. Edited by: Bhardwaj A, Alkayed NJ, Kirsch JR, Traystman RJ. New York: Informa Helthcare; 2006:345–353.

  5. 5.

    Gidday JM: Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 2006, 7: 437–448. 10.1038/nrn1927

  6. 6.

    Zhang J, Yang ZJ, Klaus JA, Koehler RC, Huang J: Delayed tolerance with repetitive transient focal ischemic preconditioning in the mouse. Stroke 2008, 39: 967–974. 10.1161/STROKEAHA.107.497412

  7. 7.

    Abe H, Nowak TS Jr: Induced hippocampal neuron protection in an optimized gerbil ischemia model: insult thresholds for tolerance induction and altered gene expression defined by ischemic depolarization. J Cereb Blood Flow Metab 2004, 24: 84–97. 10.1097/01.WCB.0000098607.42140.4B

  8. 8.

    Perez-Pinzon MA, Basit A, Dave KR, Busto R, Veauvy C, Saul I, Ginsberg MD, Sick TJ: Effect of the first window of ischemic preconditioning on mitochondrial dysfunction following global cerebral ischemia. Mitochondrion 2002, 2: 181–189. 10.1016/S1567-7249(02)00070-3

  9. 9.

    Kirino T: Ischemic tolerance. J Cereb Blood Flow Metab 2002, 22: 1283–1296. 10.1097/00004647-200211000-00001

  10. 10.

    Trendelenburg G, Dirnagl U: Neuroprotective role of astrocytes in cerebral ischemia: focus on ischemic preconditioning. Glia 2005, 50: 307–320. 10.1002/glia.20204

  11. 11.

    Perez-Pinzon MA: Neuroprotective effects of ischemic preconditioning in brain mitochondria following cerebral ischemia. J Bioenerg Biomembr 2004, 36: 323–327. 10.1023/B:JOBB.0000041762.47544.ff

  12. 12.

    Pulsinelli WA, Brierley JB: A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 1979, 10: 267–272.

  13. 13.

    Pulsinelli WA, Duffy TE: Regional energy balance in rat brain after transient forebrain ischemia. J Neurochem 1983, 40: 1500–1503.

  14. 14.

    Schmidt-Kastner R, Paschen W, Ophoff BG, Hossmann KA: A modified four-vessel occlusion model for inducing incomplete forebrain ischemia in rats. Stroke 1989, 20: 938–946.

  15. 15.

    Choi JS, Kim HY, Cha JH, Lee MY: Ischemic preconditioning-induced activation of ERK1/2 in the rat hippocampus. Neurosci Lett 2006, 409: 187–191. 10.1016/j.neulet.2006.09.053

  16. 16.

    Danielisova V, Gottlieb M, Nemethova M, Burda J: The effect of preconditioning on the iron deposition after transient forebrain ischemia in rat brain. Arch Ital Biol 2004, 142: 87–94.

  17. 17.

    Zhang QG, Han D, Xu J, Lv Q, Wang R, Yin XH, Xu TL, Zhang GY: Ischemic preconditioning negatively regulates plenty of SH3s-mixed lineage kinase 3-Rac1 complex and c-Jun N-terminal kinase 3 signaling via activation of Akt. Neuroscience 2006, 143: 431–444. 10.1016/j.neuroscience.2006.07.049

  18. 18.

    Burda J, Hrehorovska M, Bonilla LG, Danielisova V, Cizkova D, Burda R, Nemethova M, Fando JL, Salinas M: Role of protein synthesis in the ischemic tolerance acquisition induced by transient forebrain ischemia in the rat. Neurochem Res 2003, 28: 1213–1219. 10.1023/A:1024232513106

  19. 19.

    Smith ML, Bendek G, Dahlgren N, Rosen I, Wieloch T, Siesjo BK: Models for studying long-term recovery following forebrain ischemia in the rat. 2. A 2-vessel occlusion model. Acta Neurol Scand 1984, 69: 385–401. 10.1111/j.1600-0404.1984.tb07822.x

  20. 20.

    Thaddeus NS: Animal models of global cerebral ischemia. In Acute stroke, bench to bedside. Edited by: Bhardwaj A, Alkayed NJ, Kirsch JR, Traystman RJ. New York: Informa Healthcare; 2006:275–292.

  21. 21.

    Dave KR, Lange-Asschenfeldt C, Raval AP, Prado R, Busto R, Saul I, Perez-Pinzon MA: Ischemic preconditioning ameliorates excitotoxicity by shifting glutamate/gamma-aminobutyric acid release and biosynthesis. J Neurosci Res 2005, 82: 665–673. 10.1002/jnr.20674

  22. 22.

    Hayashi T, Saito A, Okuno S, Ferrand-Drake M, Chan PH: Induction of GRP78 by ischemic preconditioning reduces endoplasmic reticulum stress and prevents delayed neuronal cell death. J Cereb Blood Flow Metab 2003, 23: 949–961. 10.1097/01.WCB.0000077641.41248.EA

  23. 23.

    Liu C, Chen S, Kamme F, Hu BR: Ischemic preconditioning prevents protein aggregation after transient cerebral ischemia. Neuroscience 2005, 134: 69–80. 10.1016/j.neuroscience.2005.03.036

  24. 24.

    Perez-Pinzon MA, Xu GP, Dietrich WD, Rosenthal M, Sick TJ: Rapid preconditioning protects rats against ischemic neuronal damage after 3 but not 7 days of reperfusion following global cerebral ischemia. J Cereb Blood Flow Metab 1997, 17: 175–182. 10.1097/00004647-199702000-00007

  25. 25.

    Tatlisumak T, Li F, Fisher M: Animal models of ischemic stroke. In Acute stroke, bench to bedside. Edited by: Bhardwaj A, Alkayed NJ, Kirsch JR, Traystman RJ. New York: Informa Healthcare; 2006:171–186.

  26. 26.

    Kirino T: Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 1982, 239: 57–69. 10.1016/0006-8993(82)90833-2

  27. 27.

    Kato H, Liu Y, Araki T, Kogure K: Temporal profile of the effects of pretreatment with brief cerebral ischemia on the neuronal damage following secondary ischemic insult in the gerbil: cumulative damage and protective effects. Brain Res 1991, 553: 238–242. 10.1016/0006-8993(91)90831-F

  28. 28.

    Kirino T, Tsujita Y, Tamura A: Induced tolerance to ischemia in gerbil hippocampal neurons. J Cereb Blood Flow Metab 1991, 11: 299–307.

  29. 29.

    Kato H, Kogure K, Nakata N, Araki T, Itoyama Y: Facilitated recovery from postischemic suppression of protein synthesis in the gerbil brain with ischemic tolerance. Brain Res Bull 1995, 36: 205–208. 10.1016/0361-9230(94)00191-3

  30. 30.

    Corbett D, Crooks P: Ischemic preconditioning: a long term survival study using behavioural and histological endpoints. Brain Res 1997, 760: 129–136. 10.1016/S0006-8993(97)00294-1

  31. 31.

    Castro-Pacheco A, Foyo-Niembro E, Perez-Perez V, Garcia-Hernandez J, Grijalva I: [Carotid-basilar artery communication in gerbils (Meriones unguiculatus)]. Rev Neurol 2001, 32: 225–228.

  32. 32.

    Ueda M, Nowak TS Jr: Protective preconditioning by transient global ischemia in the rat: components of delayed injury progression and lasting protection distinguished by comparisons of depolarization thresholds for cell loss at long survival times. J Cereb Blood Flow Metab 2005, 25: 949–958. 10.1038/sj.jcbfm.9600107

  33. 33.

    Terashima T, Namura S, Hoshimaru M, Uemura Y, Kikuchi H, Hashimoto N: Consistent injury in the striatum of C57BL/6 mice after transient bilateral common carotid artery occlusion. Neurosurgery 1998, 43: 900–907. 10.1097/00006123-199810000-00102

  34. 34.

    Wu C, Zhan RZ, Qi S, Fujihara H, Taga K, Shimoji K: A forebrain ischemic preconditioning model established in C57Black/Crj6 mice. J Neurosci Methods 2001, 107: 101–106. 10.1016/S0165-0270(01)00356-9

  35. 35.

    Munoz A, Nakazaki M, Goodman JC, Barrios R, Onetti CG, Bryan J, Aguilar-Bryan L: Ischemic preconditioning in the hippocampus of a knockout mouse lacking SUR1-based K(ATP) channels. Stroke 2003, 34: 164–170. 10.1161/01.STR.0000048215.36747.D1

  36. 36.

    Koizumi J, Yoshida Y, Nakazawa T, Ooneda G: Experimental studies of ischemic brain edema: 1. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn J Stroke 1986, 8: 1–8.

  37. 37.

    Longa EZ, Weinstein PR, Carlson S, Cummins R: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989, 20: 84–91.

  38. 38.

    Takano K, Tatlisumak T, Bergmann AG, Gibson DG, Fisher M: Reproducibility and reliability of middle cerebral artery occlusion using a silicone-coated suture (Koizumi) in rats. J Neurol Sci 1997, 153: 8–11. 10.1016/S0022-510X(97)00184-6

  39. 39.

    Tatlisumak T, Carano RA, Takano K, Opgenorth TJ, Sotak CH, Fisher M: A novel endothelin antagonist, A-12 attenuates ischemic lesion size in rats with temporary middle cerebral artery occlusion: a diffusion and perfusion MRI study. Stroke 7722, 29: 850–857.

  40. 40.

    Durukan A, Tatlisumak T: Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav 2007, 87: 179–197. 10.1016/j.pbb.2007.04.015

  41. 41.

    Durukan A, Strbian D, Tatlisumak T: Rodent models of ischemic stroke: a useful tool for stroke drug development. Curr Pharm Des 2008, 14: 359–370. 10.2174/138161208783497688

  42. 42.

    Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA: Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 1994, 265: 1883–1885. 10.1126/science.7522345

  43. 43.

    Li J, Henman MC, Doyle KM, Strbian D, Kirby BP, Tatlisumak T, Shaw GG: The pre-ischaemic neuroprotective effect of a novel polyamine antagonist, N1-dansyl-spermine in a permanent focal cerebral ischaemia model in mice. Brain Res 2004, 1029: 84–92. 10.1016/j.brainres.2004.09.037

  44. 44.

    Li J, Henman MC, Tatlisumak T, Shaw GG, Doyle KM: The pre-ischaemic neuroprotective effects of N1-dansyl-spermine in a transient focal cerebral ischaemia model in mice. Brain Res 2005, 1055: 180–185. 10.1016/j.brainres.2005.07.023

  45. 45.

    Li J, Henman MC, Atkinson J, Fixon-Owoo S, Tatlisumak T, Shaw GG, Doyle KM: The pre-ischaemic neuroprotective effects of the polyamine analogues BU43b and BU36b in permanent and transient focal cerebral ischaemia models in mice. Brain Res 2006, 1076: 209–215. 10.1016/j.brainres.2005.12.097

  46. 46.

    Barone FC, White RF, Spera PA, Ellison J, Currie RW, Wang X, Feuerstein GZ: Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression. Stroke 1998, 29: 1937–1950.

  47. 47.

    Masada T, Hua Y, Xi G, Ennis SR, Keep RF: Attenuation of ischemic brain edema and cerebrovascular injury after ischemic preconditioning in the rat. J Cereb Blood Flow Metab 2001, 21: 22–33. 10.1097/00004647-200101000-00004

  48. 48.

    Pradillo JM, Romera C, Hurtado O, Cardenas A, Moro MA, Leza JC, Davalos A, Castillo J, Lorenzo P, Lizasoain I: TNFR1 upregulation mediates tolerance after brain ischemic preconditioning. J Cereb Blood Flow Metab 2005, 25: 193–203. 10.1038/sj.jcbfm.9600019

  49. 49.

    Stagliano NE, Perez-Pinzon MA, Moskowitz MA, Huang PL: Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 1999, 19: 757–761. 10.1097/00004647-199907000-00005

  50. 50.

    Atochin DN, Clark J, Demchenko IT, Moskowitz MA, Huang PL: Rapid cerebral ischemic preconditioning in mice deficient in endothelial and neuronal nitric oxide synthases. Stroke 2003, 34: 1299–1303. 10.1161/01.STR.0000066870.70976.57

  51. 51.

    Hao Y, Luo Z, Zhou D, Gao L: Cerebral ischemic tolerance induced by focal ischemic preconditioning in rats. Sichuan Da Xue Xue Bao Yi Xue Ban 2003, 34: 455–458.

  52. 52.

    Lee SH, Kim YJ, Lee KM, Ryu S, Yoon BW: Ischemic preconditioning enhances neurogenesis in the subventricular zone. Neuroscience 2007, 146: 1020–1031. 10.1016/j.neuroscience.2007.02.058

  53. 53.

    Alkayed NJ, Goyagi T, Joh HD, Klaus J, Harder DR, Traystman RJ, Hurn PD: Neuroprotection and P450 2C11 upregulation after experimental transient ischemic attack. Stroke 2002, 33: 1677–1684. 10.1161/01.STR.0000016332.37292.59

  54. 54.

    Chen J, Graham SH, Zhu RL, Simon RP: Stress proteins and tolerance to focal cerebral ischemia. J Cereb Blood Flow Metab 1996, 16: 566–577. 10.1097/00004647-199607000-00006

  55. 55.

    Li W, Luo Y, Zhang F, Signore AP, Gobbel GT, Simon RP, Chen J: Ischemic preconditioning in the rat brain enhances the repair of endogenous oxidative DNA damage by activating the base-excision repair pathway. J Cereb Blood Flow Metab 2006, 26: 181–198. 10.1038/sj.jcbfm.9600180

  56. 56.

    Glantz L, Avramovich A, Trembovler V, Gurvitz V, Kohen R, Eidelman LA, Shohami E: Ischemic preconditioning increases antioxidants in the brain and peripheral organs after cerebral ischemia. Exp Neurol 2005, 192: 117–124. 10.1016/j.expneurol.2004.11.012

  57. 57.

    Puisieux F, Deplanque D, Bulckaen H, Maboudou P, Gele P, Lhermitte M, Lebuffe G, Bordet R: Brain ischemic preconditioning is abolished by antioxidant drugs but does not up-regulate superoxide dismutase and glutathion peroxidase. Brain Res 2004, 1027: 30–37. 10.1016/j.brainres.2004.08.067

  58. 58.

    Hoyte LC, Papadakis M, Barber PA, Buchan AM: Improved regional cerebral blood flow is important for the protection seen in a mouse model of late phase ischemic preconditioning. Brain Res 2006, 1121: 231–237. 10.1016/j.brainres.2006.08.107

  59. 59.

    Naylor M, Bowen KK, Sailor KA, Dempsey RJ, Vemuganti R: Preconditioning-induced ischemic tolerance stimulates growth factor expression and neurogenesis in adult rat hippocampus. Neurochem Int 2005, 47: 565–572. 10.1016/j.neuint.2005.07.003

  60. 60.

    Simon RP, Niiro M, Gwinn R: Prior ischemic stress protects against experimental stroke. Neurosci Lett 1993, 163: 135–137. 10.1016/0304-3940(93)90364-Q

  61. 61.

    Matsushima K, Hakim AM: Transient forebrain ischemia protects against subsequent focal cerebral ischemia without changing cerebral perfusion. Stroke 1995, 26: 1047–1052.

  62. 62.

    Miyashita K, Abe H, Nakajima T, Ishikawa A, Nishiura M, Sawada T, Naritomi H: Induction of ischaemic tolerance in gerbil hippocampus by pretreatment with focal ischaemia. Neuroreport 1994, 6: 46–48. 10.1097/00001756-199412300-00013

  63. 63.

    Belayev L, Ginsberg MD, Alonso OF, Singer JT, Zhao W, Busto R: Bilateral ischemic tolerance of rat hippocampus induced by prior unilateral transient focal ischemia: relationship to c-fos mRNA expression. Neuroreport 1996, 8: 55–59. 10.1097/00001756-199612200-00012

  64. 64.

    Glazier SS, O'Rourke DM, Graham DI, Welsh FA: Induction of ischemic tolerance following brief focal ischemia in rat brain. J Cereb Blood Flow Metab 1994, 14: 545–553.

  65. 65.

    Gidday JM, Fitzgibbons JC, Shah AR, Park TS: Neuroprotection from ischemic brain injury by hypoxic preconditioning in the neonatal rat. Neurosci Lett 1994, 168: 221–224. 10.1016/0304-3940(94)90455-3

  66. 66.

    Miller BA, Perez RS, Shah AR, Gonzales ER, Park TS, Gidday JM: Cerebral protection by hypoxic preconditioning in a murine model of focal ischemia-reperfusion. Neuroreport 2001, 12: 1663–1669. 10.1097/00001756-200106130-00030

  67. 67.

    Bernaudin M, Nedelec AS, Divoux D, MacKenzie ET, Petit E, Schumann-Bard P: Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J Cereb Blood Flow Metab 2002, 22: 393–403. 10.1097/00004647-200204000-00003

  68. 68.

    Wada K, Ito M, Miyazawa T, Katoh H, Nawashiro H, Shima K, Chigasaki H: Repeated hyperbaric oxygen induces ischemic tolerance in gerbil hippocampus. Brain Res 1996, 740: 15–20. 10.1016/S0006-8993(96)00831-1

  69. 69.

    Prass K, Wiegand F, Schumann P, Ahrens M, Kapinya K, Harms C, Liao W, Trendelenburg G, Gertz K, Moskowitz MA, Knapp F, Victorov IV, Megow D, Dirnagl U: Hyperbaric oxygenation induced tolerance against focal cerebral ischemia in mice is strain dependent. Brain Res 2000, 871: 146–150. 10.1016/S0006-8993(00)02264-2

  70. 70.

    Xiong L, Zhu Z, Dong H, Hu W, Hou L, Chen S: Hyperbaric oxygen preconditioning induces neuroprotection against ischemia in transient not permanent middle cerebral artery occlusion rat model. Chin Med J (Engl) 2000, 113: 836–839.

  71. 71.

    Hirata T, Cui YJ, Funakoshi T, Mizukami Y, Ishikawa Y, Shibasaki F, Matsumoto M, Sakabe T: The temporal profile of genomic responses and protein synthesis in ischemic tolerance of the rat brain induced by repeated hyperbaric oxygen. Brain Res 2007, 1130: 214–222. 10.1016/j.brainres.2006.10.077

  72. 72.

    Chopp M, Chen H, Ho KL, Dereski MO, Brown E, Hetzel FW, Welch KM: Transient hyperthermia protects against subsequent forebrain ischemic cell damage in the rat. Neurology 1989, 39: 1396–1398.

  73. 73.

    Ikeda T, Xia XY, Xia YX, Ikenoue T: Hyperthermic preconditioning prevents blood-brain barrier disruption produced by hypoxia-ischemia in newborn rat. Brain Res Dev Brain Res 1999, 117: 53–58. 10.1016/S0165-3806(99)00097-8

  74. 74.

    Nishio S, Chen ZF, Yunoki M, Toyoda T, Anzivino M, Lee KS: Hypothermia-induced ischemic tolerance. Ann N Y Acad Sci 1999, 890: 26–41. 10.1111/j.1749-6632.1999.tb07978.x

  75. 75.

    Yunoki M, Nishio S, Ukita N, Anzivino MJ, Lee KS: Characteristics of hypothermic preconditioning influencing the induction of delayed ischemic tolerance. J Neurosurg 2002, 97: 650–657. 10.3171/jns.2002.97.3.0650

  76. 76.

    Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W: Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 1998, 29: 2461–2466.

  77. 77.

    Tatlisumak T, Takano K, Meiler MR, Fisher M: A glycine site antagonist, ZD reduces number of spreading depressions and infarct size in rats with permanent middle cerebral artery occlusion. Stroke 9379, 29: 190–195.

  78. 78.

    Jander S, Schroeter M, Peters O, Witte OW, Stoll G: Cortical spreading depression induces proinflammatory cytokine gene expression in the rat brain. J Cereb Blood Flow Metab 2001, 21: 218–225. 10.1097/00004647-200103000-00005

  79. 79.

    Kawahara N, Ruetzler CA, Klatzo I: Protective effect of spreading depression against neuronal damage following cardiac arrest cerebral ischaemia. Neurol Res 1995, 17: 9–16.

  80. 80.

    Matsushima K, Hogan MJ, Hakim AM: Cortical spreading depression protects against subsequent focal cerebral ischemia in rats. J Cereb Blood Flow Metab 1996, 16: 221–226. 10.1097/00004647-199603000-00006

  81. 81.

    Horiguchi T, Snipes JA, Kis B, Shimizu K, Busija DW: The role of nitric oxide in the development of cortical spreading depression-induced tolerance to transient focal cerebral ischemia in rats. Brain Res 2005, 1039: 84–89. 10.1016/j.brainres.2005.01.047

  82. 82.

    Otori T, Greenberg JH, Welsh FA: Cortical spreading depression causes a long-lasting decrease in cerebral blood flow and induces tolerance to permanent focal ischemia in rat brain. J Cereb Blood Flow Metab 2003, 23: 43–50. 10.1097/00004647-200301000-00005

  83. 83.

    Horiguchi T, Snipes JA, Kis B, Shimizu K, Busija DW: Cyclooxygenase-2 mediates the development of cortical spreading depression-induced tolerance to transient focal cerebral ischemia in rats. Neuroscience 2006, 140: 723–730. 10.1016/j.neuroscience.2006.02.025

  84. 84.

    Yanamoto H, Xue JH, Miyamoto S, Nagata I, Nakano Y, Murao K, Kikuchi H: Spreading depression induces long-lasting brain protection against infarcted lesion development via BDNF gene-dependent mechanism. Brain Res 2004, 1019: 178–188. 10.1016/j.brainres.2004.05.105

  85. 85.

    Yanamoto H, Hashimoto N, Nagata I, Kikuchi H: Infarct tolerance against temporary focal ischemia following spreading depression in rat brain. Brain Res 1998, 784: 239–249. 10.1016/S0006-8993(97)01344-9

  86. 86.

    Sun XC, Li WB, Li QJ, Zhang M, Xian XH, Qi J, Jin RL, Li SQ: Limb ischemic preconditioning induces brain ischemic tolerance via p38 MAPK. Brain Res 2006, 1084: 165–174. 10.1016/j.brainres.2006.02.041

  87. 87.

    Zhao HG, Sun XC, Xian XH, Li WB, Zhang M, Li QJ: The role of nitric oxide in the neuroprotection of limb ischemic preconditioning in rats. Neurochem Res 2007, 32: 1919–1926. 10.1007/s11064-007-9381-2

  88. 88.

    Ali ZA, Callaghan CJ, Lim E, Ali AA, Nouraei SA, Akthar AM, Boyle JR, Varty K, Kharbanda RK, Dutka DP, Gaunt ME: Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation 2007, 116: I98–105. 10.1161/circulationaha.106.679167

  89. 89.

    Rehni AK, Shri R, Singh M: Remote ischaemic preconditioning and prevention of cerebral injury. Indian J Exp Biol 2007, 45: 247–252.

  90. 90.

    Wiegand F, Liao W, Busch C, Castell S, Knapp F, Lindauer U, Megow D, Meisel A, Redetzky A, Ruscher K, Trendelenburg G, Victorov I, Riepe M, Diener HC, Dirnagl U: Respiratory chain inhibition induces tolerance to focal cerebral ischemia. J Cereb Blood Flow Metab 1999, 19: 1229–1237. 10.1097/00004647-199911000-00007

  91. 91.

    Zhu HC, Gao XQ, Xing Y, Sun SG, Li HG, Wang YF: Inhibition of caspase-3 activation and apoptosis is involved in 3-nitropropionic acid-induced ischemic tolerance to transient focal cerebral ischemia in rats. J Mol Neurosci 2004, 24: 299–305. 10.1385/JMN:24:2:299

  92. 92.

    Zhu H, Sun S, Li H, Xu Y: Cerebral ischemic tolerance induced by 3-nitropropionic acid is associated with increased expression of erythropoietin in rats. J Huazhong Univ Sci Technolog Med Sci 2006, 26: 440–443. 10.1007/s11596-006-0416-8

  93. 93.

    Horiguchi T, Kis B, Rajapakse N, Shimizu K, Busija DW: Opening of mitochondrial ATP-sensitive potassium channels is a trigger of 3-nitropropionic acid-induced tolerance to transient focal cerebral ischemia in rats. Stroke 2003, 34: 1015–1020. 10.1161/01.STR.0000063404.27912.5B

  94. 94.

    Garnier P, Bertrand N, Demougeot C, Prigent-Tessier A, Marie C, Beley A: Chemical preconditioning with 3-nitropropionic acid: lack of induction of neuronal tolerance in gerbil hippocampus subjected to transient forebrain ischemia. Brain Res Bull 2002, 58: 33–39. 10.1016/S0361-9230(02)00753-0

  95. 95.

    Sugino T, Nozaki K, Takagi Y, Hashimoto N: 3-Nitropropionic acid induces ischemic tolerance in gerbil hippocampus in vivo. Neurosci Lett 1999, 259: 9–12. 10.1016/S0304-3940(98)00875-1

  96. 96.

    Kato K, Shimazaki K, Kamiya T, Amemiya S, Inaba T, Oguro K, Katayama Y: Differential effects of sublethal ischemia and chemical preconditioning with 3-nitropropionic acid on protein expression in gerbil hippocampus. Life Sci 2005, 77: 2867–2878. 10.1016/j.lfs.2005.01.037

  97. 97.

    Hoshi A, Nakahara T, Ogata M, Yamamoto T: The critical threshold of 3-nitropropionic acid-induced ischemic tolerance in the rat. Brain Res 2005, 1050: 33–39. 10.1016/j.brainres.2005.05.028

  98. 98.

    Bordet R, Deplanque D, Maboudou P, Puisieux F, Pu Q, Robin E, Martin A, Bastide M, Leys D, Lhermitte M, Dupuis B: Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance. J Cereb Blood Flow Metab 2000, 20: 1190–1196. 10.1097/00004647-200008000-00004

  99. 99.

    Bastide M, Gele P, Petrault O, Pu Q, Caliez A, Robin E, Deplanque D, Duriez P, Bordet R: Delayed cerebrovascular protective effect of lipopolysaccharide in parallel to brain ischemic tolerance. J Cereb Blood Flow Metab 2003, 23: 399–405. 10.1097/00004647-200304000-00003

  100. 100.

    Dawson DA, Furuya K, Gotoh J, Nakao Y, Hallenbeck JM: Cerebrovascular hemodynamics and ischemic tolerance: lipopolysaccharide-induced resistance to focal cerebral ischemia is not due to changes in severity of the initial ischemic insult, but is associated with preservation of microvascular perfusion. J Cereb Blood Flow Metab 1999, 19: 616–623. 10.1097/00004647-199906000-00004

  101. 101.

    Tasaki K, Ruetzler CA, Ohtsuki T, Martin D, Nawashiro H, Hallenbeck JM: Lipopolysaccharide pre-treatment induces resistance against subsequent focal cerebral ischemic damage in spontaneously hypertensive rats. Brain Res 1997, 748: 267–270. 10.1016/S0006-8993(96)01383-2

  102. 102.

    Rosenzweig HL, Lessov NS, Henshall DC, Minami M, Simon RP, Stenzel-Poore MP: Endotoxin preconditioning prevents cellular inflammatory response during ischemic neuroprotection in mice. Stroke 2004, 35: 2576–2581. 10.1161/01.STR.0000143450.04438.ae

  103. 103.

    Wang L, Traystman RJ, Murphy SJ: Inhalational anesthetics as preconditioning agents in ischemic brain. Curr Opin Pharmacol 2008, 8: 104–110. 10.1016/j.coph.2007.09.005

  104. 104.

    Kitano H, Kirsch JR, Hurn PD, Murphy SJ: Inhalational anesthetics as neuroprotectants or chemical preconditioning agents in ischemic brain. J Cereb Blood Flow Metab 2007, 27: 1108–1128. 10.1038/sj.jcbfm.9600410

  105. 105.

    Clarkson AN: Anesthetic-mediated protection/preconditioning during cerebral ischemia. Life Sci 2007, 80: 1157–1175. 10.1016/j.lfs.2006.12.022

  106. 106.

    Blanck TJ, Haile M, Xu F, Zhang J, Heerdt P, Veselis RA, Beckman J, Kang R, Adamo A, Hemmings H: Isoflurane pretreatment ameliorates postischemic neurologic dysfunction and preserves hippocampal Ca2+/calmodulin-dependent protein kinase in a canine cardiac arrest model. Anesthesiology 2000, 93: 1285–1293. 10.1097/00000542-200011000-00023

  107. 107.

    Liu Y, Xiong L, Chen S, Wang Q: Isoflurane tolerance against focal cerebral ischemia is attenuated by adenosine A1 receptor antagonists. Can J Anaesth 2006, 53: 194–201. 10.1007/BF03021827

  108. 108.

    Zheng S, Zuo Z: Isoflurane preconditioning induces neuroprotection against ischemia via activation of P38 mitogen-activated protein kinases. Mol Pharmacol 2004, 65: 1172–1180. 10.1124/mol.65.5.1172

  109. 109.

    McAuliffe JJ, Joseph B, Vorhees CV: Isoflurane-delayed preconditioning reduces immediate mortality and improves striatal function in adult mice after neonatal hypoxia-ischemia. Anesth Analg 2007, 104: 1066–1077. 10.1213/01.ane.0000260321.62377.74

  110. 110.

    Zheng S, Zuo Z: Isoflurane preconditioning reduces purkinje cell death in an in vitro model of rat cerebellar ischemia. Neuroscience 2003, 118: 99–106. 10.1016/S0306-4522(02)00767-4

  111. 111.

    Kaneko T, Yokoyama K, Makita K: Late preconditioning with isoflurane in cultured rat cortical neurones. Br J Anaesth 2005, 95: 662–668. 10.1093/bja/aei228

  112. 112.

    Ma D, Hossain M, Pettet GK, Luo Y, Lim T, Akimov S, Sanders RD, Franks NP, Maze M: Xenon preconditioning reduces brain damage from neonatal asphyxia in rats. J Cereb Blood Flow Metab 2006, 26: 199–208. 10.1038/sj.jcbfm.9600184

  113. 113.

    Kapinya KJ, Lowl D, Futterer C, Maurer M, Waschke KF, Isaev NK, Dirnagl U: Tolerance against ischemic neuronal injury can be induced by volatile anesthetics and is inducible NO synthase dependent. Stroke 2002, 33: 1889–1898. 10.1161/01.STR.0000020092.41820.58

  114. 114.

    Payne RS, Akca O, Roewer N, Schurr A, Kehl F: Sevoflurane-induced preconditioning protects against cerebral ischemic neuronal damage in rats. Brain Res 2005, 1034: 147–152. 10.1016/j.brainres.2004.12.006

  115. 115.

    Frassdorf J, Borowski A, Ebel D, Feindt P, Hermes M, Meemann T, Weber R, Mullenheim J, Weber NC, Preckel B, Schlack W: Impact of preconditioning protocol on anesthetic-induced cardioprotection in patients having coronary artery bypass surgery. J Thorac Cardiovasc Surg 2009, 137: 1436–1442. 10.1016/j.jtcvs.2008.04.034

  116. 116.

    Raval AP, Bramlett H, Perez-Pinzon MA: Estrogen preconditioning protects the hippocampal CA1 against ischemia. Neuroscience 2006, 141: 1721–1730. 10.1016/j.neuroscience.2006.05.016

  117. 117.

    Brambrink AM, Koerner IP, Diehl K, Strobel G, Noppens R, Kempski O: The antibiotic erythromycin induces tolerance against transient global cerebral ischemia in rats (pharmacologic preconditioning). Anesthesiology 2006, 104: 1208–1215. 10.1097/00000542-200606000-00016

  118. 118.

    Koerner IP, Gatting M, Noppens R, Kempski O, Brambrink AM: Induction of cerebral ischemic tolerance by erythromycin preconditioning reprograms the transcriptional response to ischemia and suppresses inflammation. Anesthesiology 2007, 106: 538–547. 10.1097/00000542-200703000-00019

  119. 119.

    Ruscher K, Freyer D, Karsch M, Isaev N, Megow D, Sawitzki B, Priller J, Dirnagl U, Meisel A: Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci 2002, 22: 10291–10301.

  120. 120.

    Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, Petit E: A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 1999, 19: 643–651. 10.1097/00004647-199906000-00007

  121. 121.

    Riepe MW, Kasischke K, Raupach A: Acetylsalicylic acid increases tolerance against hypoxic and chemical hypoxia. Stroke 1997, 28: 2006–2011.

  122. 122.

    Huber R, Kasischke K, Ludolph AC, Riepe MW: Increase of cellular hypoxic tolerance by erythromycin and other antibiotics. Neuroreport 1999, 10: 1543–1546. 10.1097/00001756-199905140-00027

  123. 123.

    Xiong L, Lu Z, Hou L, Zheng H, Zhu Z, Wang Q, Chen S: Pretreatment with repeated electroacupuncture attenuates transient focal cerebral ischemic injury in rats. Chin Med J (Engl) 2003, 116: 108–111.

  124. 124.

    Xiong LZ, Yang J, Wang Q, Lu ZH: Involvement of delta-and mu-opioid receptors in the delayed cerebral ischemic tolerance induced by repeated electroacupuncture preconditioning in rats. Chin Med J (Engl) 2007, 120: 394–399.

  125. 125.

    Reis DJ, Kobylarz K, Yamamoto S, Golanov EV: Brief electrical stimulation of cerebellar fastigial nucleus conditions long-lasting salvage from focal cerebral ischemia: conditioned central neurogenic neuroprotection. Brain Res 1998, 780: 161–165. 10.1016/S0006-8993(97)01017-2

  126. 126.

    Yu ZF, Mattson MP: Dietary restriction and 2-deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: evidence for a preconditioning mechanism. J Neurosci Res 1999, 57: 830–839. 10.1002/(SICI)1097-4547(19990915)57:6<830::AID-JNR8>3.0.CO;2-2

  127. 127.

    Ogiue-Ikeda M, Kawato S, Ueno S: Acquisition of ischemic tolerance by repetitive transcranial magnetic stimulation in the rat hippocampus. Brain Res 2005, 1037: 7–11. 10.1016/j.brainres.2004.10.063

  128. 128.

    Mishima Y, Harada H, Sugiyama K, Miyagawa Y, Uehara N, Kano T: Induction of neuronal tolerance by electroconvulsive shock in rats subjected to forebrain ischemia. Kurume Med J 2005, 52: 153–160. 10.2739/kurumemedj.52.153

  129. 129.

    Plamondon H, Blondeau N, Heurteaux C, Lazdunski M: Mutually protective actions of kainic acid epileptic preconditioning and sublethal global ischemia on hippocampal neuronal death: involvement of adenosine A1 receptors and K(ATP) channels. J Cereb Blood Flow Metab 1999, 19: 1296–1308. 10.1097/00004647-199912000-00002

  130. 130.

    Hsu JC, Lee YS, Chang CN, Ling EA, Lan CT: Sleep deprivation prior to transient global cerebral ischemia attenuates glial reaction in the rat hippocampal formation. Brain Res 2003, 984: 170–181. 10.1016/S0006-8993(03)03128-7

  131. 131.

    Gonzalez-Zulueta M, Feldman AB, Klesse LJ, Kalb RG, Dillman JF, Parada LF, Dawson TM, Dawson VL: Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning. Proc Natl Acad Sci USA 2000, 97: 436–441. 10.1073/pnas.97.1.436

  132. 132.

    Goldberg MP, Choi DW: Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury. J Neurosci 1993, 13: 3510–3524.

  133. 133.

    Kapinya KJ: Ischemic tolerance in the brain. Acta Physiol Hung 2005, 92: 67–92. 10.1556/APhysiol.92.2005.1.9

  134. 134.

    Valentim LM, Rodnight R, Geyer AB, Horn AP, Tavares A, Cimarosti H, Netto CA, Salbego CG: Changes in heat shock protein 27 phosphorylation and immunocontent in response to preconditioning to oxygen and glucose deprivation in organotypic hippocampal cultures. Neuroscience 2003, 118: 379–386. 10.1016/S0306-4522(02)00919-3

  135. 135.

    Hassen GW, Tian D, Ding D, Bergold PJ: A new model of ischemic preconditioning using young adult hippocampal slice cultures. Brain Res Brain Res Protoc 2004, 13: 135–143. 10.1016/j.brainresprot.2004.03.004

  136. 136.

    Grabb MC, Choi DW: Ischemic tolerance in murine cortical cell culture: critical role for NMDA receptors. J Neurosci 1999, 19: 1657–1662.

  137. 137.

    Sommer C: Ischemic preconditioning: postischemic structural changes in the brain. J Neuropathol Exp Neurol 2008, 67: 85–92. 10.1097/nen.0b013e3181630ba6

  138. 138.

    Corbett D, Nurse S: The problem of assessing effective neuroprotection in experimental cerebral ischemia. Prog Neurobiol 1998, 54: 531–548. 10.1016/S0301-0082(97)00078-6

  139. 139.

    Tatlisumak T, Takano K, Carano RA, Fisher M: Effect of basic fibroblast growth factor on experimental focal ischemia studied by diffusion-weighted and perfusion imaging. Stroke 1996, 27: 2292–2297.

  140. 140.

    Takano K, Carano RA, Tatlisumak T, Meiler M, Sotak CH, Kleinert HD, Fisher M: Efficacy of intra-arterial and intravenous prourokinase in an embolic stroke model evaluated by diffusion-perfusion magnetic resonance imaging. Neurology 1998, 50: 870–875.

  141. 141.

    Tanaka H, Calderone A, Jover T, Grooms SY, Yokota H, Zukin RS, Bennett MV: Ischemic preconditioning acts upstream of GluR2 down-regulation to afford neuroprotection in the hippocampal CA1. Proc Natl Acad Sci USA 2002, 99: 2362–2367.

  142. 142.

    Ostrowski RP, Graupner G, Titova E, Zhang J, Chiu J, Dach N, Corleone D, Tang J, Zhang JH: The hyperbaric oxygen preconditioning-induced brain protection is mediated by a reduction of early apoptosis after transient global cerebral ischemia. Neurobiol Dis 2007, 29: 1–13. 10.1016/j.nbd.2007.07.020

  143. 143.

    Kim E, Raval AP, Defazio RA, Perez-Pinzon MA: Ischemic preconditioning via epsilon protein kinase C activation requires cyclooxygenase-2 activation in vitro. Neuroscience 2007, 145: 931–941. 10.1016/j.neuroscience.2006.12.063

  144. 144.

    Menzies SA, Hoff JT, Betz AL: Middle cerebral artery occlusion in rats: a neurological and pathological evaluation of a reproducible model. Neurosurgery 1992, 31: 100–106. 10.1097/00006123-199207000-00014

  145. 145.

    Hunter AJ, Hatcher J, Virley D, Nelson P, Irving E, Hadingham SJ, Parsons AA: Functional assessments in mice and rats after focal stroke. Neuropharmacology 2000, 39: 806–816. 10.1016/S0028-3908(99)00262-2

  146. 146.

    Nunn J, Hodges H: Cognitive deficits induced by global cerebral ischaemia: relationship to brain damage and reversal by transplants. Behav Brain Res 1994, 65: 1–31. 10.1016/0166-4328(94)90069-8

  147. 147.

    Tatlisumak T, Li F: Use of diffusion- and perfusion-weighted magnetic resonance imaging in drug development for ischemic stroke. Curr Drug Targets CNS Neurol Disord 2003, 2: 131–141. 10.2174/1568007033482968

  148. 148.

    Tatlisumak T, Strbian D, Abo Ramadan U, Li F: The role of diffusion- and perfusion-weighted magnetic resonance imaging in drug development for ischemic stroke: from laboratory to clinics. Curr Vasc Pharmacol 2004, 2: 343–355. 10.2174/1570161043385493

  149. 149.

    Durukan A, Tatlisumak T: Magnetic resonance imaging in drug development for ischemic stroke: a translational approach. In Drug Design Research Perspectives. Edited by: Kaplan SP. NY: Nova Science Pub Inc; 2007:171–211.

  150. 150.

    Strbian D, Durukan A, Pitkonen M, Marinkovic I, Tatlisumak E, Pedrono E, Abo-Ramadan U, Tatlisumak T: The blood-brain barrier is continuously open for several weeks following transient focal cerebral ischemia. Neuroscience 2008, 153: 175–181. 10.1016/j.neuroscience.2008.02.012

  151. 151.

    Durukan A, Marinkovic I, Strbian D, Pitkonen M, Pedrono E, Soinne L, Abo-Ramadan U, Tatlisumak T: Post-ischemic blood-brain barrier leakage in rats: one-week follow-up by MRI. Brain Res 2009, 1280: 158–165. 10.1016/j.brainres.2009.05.025

  152. 152.

    Mullins PG, Reid DG, Hockings PD, Hadingham SJ, Campbell CA, Chalk JB, Doddrell DM: Ischaemic preconditioning in the rat brain: a longitudinal magnetic resonance imaging (MRI) study. NMR Biomed 2001, 14: 204–209. 10.1002/nbm.703

  153. 153.

    Tatlisumak T, Carano RA, Takano K, Meiler MR, Li F, Sotak CH, Arndts D, Pschorn U, Fisher M: Broad-spectrum cation channel inhibition by LOE 908 MS reduces infarct volume in vivo and postmortem in focal cerebral ischemia in the rat. J Neurol Sci 2000, 178: 107–113. 10.1016/S0022-510X(00)00380-4

  154. 154.

    Carano RA, Li F, Irie K, Helmer KG, Silva MD, Fisher M, Sotak CH: Multispectral analysis of the temporal evolution of cerebral ischemia in the rat brain. J Magn Reson Imaging 2000, 12: 842–858. 10.1002/1522-2586(200012)12:6<842::AID-JMRI7>3.0.CO;2-5

  155. 155.

    Li F, Carano RA, Irie K, Tatlisumak T, Silva MD, Pschorni U, Sotak CH, Fisher M: Neuroprotective effects of a novel broad-spectrum cation channel blocker, LOE 908 MS, on experimental focal ischemia: a multispectral study. J Magn Reson Imaging 1999, 10: 138–145. 10.1002/(SICI)1522-2586(199908)10:2<138::AID-JMRI5>3.0.CO;2-G

  156. 156.

    Furuya K, Zhu L, Kawahara N, Abe O, Kirino T: Differences in infarct evolution between lipopolysaccharide-induced tolerant and nontolerant conditions to focal cerebral ischemia. J Neurosurg 2005, 103: 715–723. 10.3171/jns.2005.103.4.0715

  157. 157.

    Gustavsson M, Wilson MA, Mallard C, Rousset C, Johnston MV, Hagberg H: Global gene expression in the developing rat brain after hypoxic preconditioning: involvement of apoptotic mechanisms? Pediatr Res 2007, 61: 444–450. 10.1203/pdr.0b013e3180332be4

  158. 158.

    Dhodda VK, Sailor KA, Bowen KK, Vemuganti R: Putative endogenous mediators of preconditioning-induced ischemic tolerance in rat brain identified by genomic and proteomic analysis. J Neurochem 2004, 89: 73–89. 10.1111/j.1471-4159.2004.02316.x

  159. 159.

    Kato H, Araki T, Kogure K: Preserved neurotransmitter receptor binding following ischemia in preconditioned gerbil brain. Brain Res Bull 1992, 29: 395–400. 10.1016/0361-9230(92)90074-8

  160. 160.

    Sommer C, Fahrner A, Kiessling M: [3H]muscimol binding to gamma-aminobutyric acid(A) receptors is upregulated in CA1 neurons of the gerbil hippocampus in the ischemia-tolerant state. Stroke 2002, 33: 1698–1705. 10.1161/01.STR.0000016404.14407.77

  161. 161.

    Nakagomi T, Kirino T, Kanemitsu H, Tsujita Y, Tamura A: Early recovery of protein synthesis following ischemia in hippocampal neurons with induced tolerance in the gerbil. Acta Neuropathol 1993, 86: 10–15. 10.1007/BF00454892

  162. 162.

    Nishimura M, Sugino T, Nozaki K, Takagi Y, Hattori I, Hayashi J, Hashimoto N, Moriguchi T, Nishida E: Activation of p38 kinase in the gerbil hippocampus showing ischemic tolerance. J Cereb Blood Flow Metab 2003, 23: 1052–1059. 10.1097/01.WCB.0000084251.20114.65

  163. 163.

    Cho S, Park EM, Zhou P, Frys K, Ross ME, Iadecola C: Obligatory role of inducible nitric oxide synthase in ischemic preconditioning. J Cereb Blood Flow Metab 2005, 25: 493–501. 10.1038/sj.jcbfm.9600058

  164. 164.

    Kunz A, Park L, Abe T, Gallo EF, Anrather J, Zhou P, Iadecola C: Neurovascular protection by ischemic tolerance: role of nitric oxide and reactive oxygen species. J Neurosci 2007, 27: 7083–7093. 10.1523/JNEUROSCI.1645-07.2007

  165. 165.

    Gidday JM, Shah AR, Maceren RG, Wang Q, Pelligrino DA, Holtzman DM, Park TS: Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. J Cereb Blood Flow Metab 1999, 19: 331–340. 10.1097/00004647-199903000-00011

  166. 166.

    Centeno JM, Orti M, Salom JB, Sick TJ, Perez-Pinzon MA: Nitric oxide is involved in anoxic preconditioning neuroprotection in rat hippocampal slices. Brain Res 1999, 836: 62–69. 10.1016/S0006-8993(99)01610-8

  167. 167.

    Dirnagl U, Simon RP, Hallenbeck JM: Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 2003, 26: 248–254. 10.1016/S0166-2236(03)00071-7

  168. 168.

    Dirnagl U, Meisel A: Endogenous neuroprotection: mitochondria as gateways to cerebral preconditioning? Neuropharmacology 2008, 55: 334–344. 10.1016/j.neuropharm.2008.02.017

  169. 169.

    Obrenovitch TP: Molecular physiology of preconditioning-induced brain tolerance to ischemia. Physiol Rev 2008, 88: 211–247. 10.1152/physrev.00039.2006

  170. 170.

    Bergeron M, Gidday JM, Yu AY, Semenza GL, Ferriero DM, Sharp FR: Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann Neurol 2000, 48: 285–296. 10.1002/1531-8249(200009)48:3<285::AID-ANA2>3.0.CO;2-8

  171. 171.

    Ratan RR, Siddiq A, Aminova L, Lange PS, Langley B, Ayoub I, Gensert J, Chavez J: Translation of ischemic preconditioning to the patient: prolyl hydroxylase inhibition and hypoxia inducible factor-1 as novel targets for stroke therapy. Stroke 2004, 35: 2687–2689. 10.1161/01.STR.0000143216.85349.9e

  172. 172.

    Sharp FR, Ran R, Lu A, Tang Y, Strauss KI, Glass T, Ardizzone T, Bernaudin M: Hypoxic preconditioning protects against ischemic brain injury. NeuroRx 2004, 1: 26–35. 10.1602/neurorx.1.1.26

  173. 173.

    Tang Y, Pacary E, Freret T, Divoux D, Petit E, Schumann-Bard P, Bernaudin M: Effect of hypoxic preconditioning on brain genomic response before and following ischemia in the adult mouse: identification of potential neuroprotective candidates for stroke. Neurobiol Dis 2006, 21: 18–28. 10.1016/j.nbd.2005.06.002

  174. 174.

    Bright R, Mochly-Rosen D: The role of protein kinase C in cerebral ischemic and reperfusion injury. Stroke 2005, 36: 2781–2790. 10.1161/01.STR.0000189996.71237.f7

  175. 175.

    Tauskela JS, chakravarthy BR, Murray CL, Wang Y, Comas T, Hogan M, Hakim A, Morley P: Evidence from cultured rat cortical neurons of differences in the mechanism of ischemic preconditioning of brain and heart. Brain Res 1999, 827: 143–151. 10.1016/S0006-8993(99)01322-0

  176. 176.

    Perez-Pinzon MA, Born JG: Rapid preconditioning neuroprotection following anoxia in hippocampal slices: role of the K+ ATP channel and protein kinase C. Neuroscience 1999, 89: 453–459. 10.1016/S0306-4522(98)00560-0

  177. 177.

    Raval AP, Dave KR, Mochly-Rosen D, Sick TJ, Perez-Pinzon MA: Epsilon PKC is required for the induction of tolerance by ischemic and NMDA-mediated preconditioning in the organotypic hippocampal slice. J Neurosci 2003, 23: 384–391.

  178. 178.

    Lange-Asschenfeldt C, Raval AP, Dave KR, Mochly-Rosen D, Sick TJ, Perez-Pinzon MA: Epsilon protein kinase C mediated ischemic tolerance requires activation of the extracellular regulated kinase pathway in the organotypic hippocampal slice. J Cereb Blood Flow Metab 2004, 24: 636–645. 10.1097/01.WCB.0000121235.42748.BF

  179. 179.

    Tauskela JS, Comas T, Hewitt K, Monette R, Paris J, Hogan M, Morley P: Cross-tolerance to otherwise lethal N-methyl-D-aspartate and oxygen-glucose deprivation in preconditioned cortical cultures. Neuroscience 2001, 107: 571–584. 10.1016/S0306-4522(01)00381-5

  180. 180.

    Bond A, Lodge D, Hicks CA, Ward MA, O'Neill MJ: NMDA receptor antagonism, but not AMPA receptor antagonism attenuates induced ischaemic tolerance in the gerbil hippocampus. Eur J Pharmacol 1999, 380: 91–99. 10.1016/S0014-2999(99)00523-3

  181. 181.

    Wang RM, Yang F, Zhang YX: Preconditioning-induced activation of ERK5 is dependent on moderate Ca2+ influx via NMDA receptors and contributes to ischemic tolerance in the hippocampal CA1 region of rats. Life Sci 2006, 79: 1839–1846. 10.1016/j.lfs.2006.06.041

  182. 182.

    Duszczyk M, Gadamski R, Ziembowicz A, Danysz W, Lazarewicz JW: NMDA receptor antagonism does not inhibit induction of ischemic tolerance in gerbil brain in vivo. Neurotox Res 2005, 7: 283–292. 10.1007/BF03033886

  183. 183.

    Lange-Asschenfeldt C, Raval AP, Perez-Pinzon MA: Ischemic tolerance induction in organotypic hippocampal slices: role for the GABA(A) receptor? Neurosci Lett 2005, 384: 87–92. 10.1016/j.neulet.2005.04.053

  184. 184.

    Tauskela JS, Morley P: On the role of Ca2+ in cerebral ischemic preconditioning. Cell Calcium 2004, 36: 313–322. 10.1016/j.ceca.2004.02.008

  185. 185.

    Pong K: Ischaemic preconditioning: therapeutic implications for stroke? Expert Opin Ther Targets 2004, 8: 125–139. 10.1517/14728222.8.2.125

  186. 186.

    Rodrigo GC, Standen NB: ATP-sensitive potassium channels. Curr Pharm Des 2005, 11: 1915–1940. 10.2174/1381612054021015

  187. 187.

    Heurteaux C, Lauritzen I, Widmann C, Lazdunski M: Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K+ channels in cerebral ischemic preconditioning. Proc Natl Acad Sci USA 1995, 92: 4666–4670. 10.1073/pnas.92.10.4666

  188. 188.

    Reshef A, Sperling O, Zoref-Shani E: Opening of K(ATP) channels is mandatory for acquisition of ischemic tolerance by adenosine. Neuroreport 2000, 11: 463–465. 10.1097/00001756-200002280-00007

  189. 189.

    Hiraide T, Katsura K, Muramatsu H, Asano G, Katayama Y: Adenosine receptor antagonists cancelled the ischemic tolerance phenomenon in gerbil. Brain Res 2001, 910: 94–98. 10.1016/S0006-8993(01)02647-6

  190. 190.

    Yoshida M, Nakakimura K, Cui YJ, Matsumoto M, Sakabe T: Adenosine A(1) receptor antagonist and mitochondrial ATP-sensitive potassium channel blocker attenuate the tolerance to focal cerebral ischemia in rats. J Cereb Blood Flow Metab 2004, 24: 771–779. 10.1097/01.WCB.0000122742.72175.1B

  191. 191.

    Horiguchi T, Kis B, Rajapakse N, Shimizu K, Busija DW: Cortical spreading depression (CSD)-induced tolerance to transient focal cerebral ischemia in halothane anesthetized rats is affected by anesthetic level but not ATP-sensitive potassium channels. Brain Res 2005, 1062: 127–133. 10.1016/j.brainres.2005.09.010

  192. 192.

    Nandagopal K, Dawson TM, Dawson VL: Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance. J Pharmacol Exp Ther 2001, 297: 474–478.

  193. 193.

    Huang PL: Nitric oxide and cerebral ischemic preconditioning. Cell Calcium 2004, 36: 323–329. 10.1016/j.ceca.2004.02.007

  194. 194.

    Puisieux F, Deplanque D, Pu Q, Souil E, Bastide M, Bordet R: Differential role of nitric oxide pathway and heat shock protein in preconditioning and lipopolysaccharide-induced brain ischemic tolerance. Eur J Pharmacol 2000, 389: 71–78. 10.1016/S0014-2999(99)00893-6

  195. 195.

    Zimmermann C, Ginis I, Furuya K, Klimanis D, Ruetzler C, Spatz M, Hallenbeck JM: Lipopolysaccharide-induced ischemic tolerance is associated with increased levels of ceramide in brain and in plasma. Brain Res 2001, 895: 59–65. 10.1016/S0006-8993(01)02028-5

  196. 196.

    Lastres-Becker I, Cartmell T, Molina-Holgado F: Endotoxin preconditioning protects neurones from in vitro ischemia: role of endogenous IL-1beta and TNF-alpha. J Neuroimmunol 2006, 173: 108–116. 10.1016/j.jneuroim.2005.12.006

  197. 197.

    Ohtsuki T, Ruetzler CA, Tasaki K, Hallenbeck JM: Interleukin-1 mediates induction of tolerance to global ischemia in gerbil hippocampal CA1 neurons. J Cereb Blood Flow Metab 1996, 16: 1137–1142. 10.1097/00004647-199611000-00007

  198. 198.

    Cardenas A, Moro MA, Leza JC, O'Shea E, Davalos A, Castillo J, Lorenzo P, Lizasoain I: Upregulation of TACE/ADAM17 after ischemic preconditioning is involved in brain tolerance. J Cereb Blood Flow Metab 2002, 22: 1297–1302. 10.1097/00004647-200211000-00002

  199. 199.

    Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G: A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol 2004, 6: 97–105. 10.1038/ncb1086

  200. 200.

    Blondeau N, Widmann C, Lazdunski M, Heurteaux C: Activation of the nuclear factor-kappaB is a key event in brain tolerance. J Neurosci 2001, 21: 4668–4677.

  201. 201.

    Digicaylioglu M, Lipton SA: Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 2001, 412: 641–647. 10.1038/35088074

  202. 202.

    Marsh BJ, Williams-Karnesky RL, Stenzel-Poore MP: Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience 2009, 158: 1007–1020. 10.1016/j.neuroscience.2008.07.067

  203. 203.

    Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME: Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 1999, 286: 1358–1362. 10.1126/science.286.5443.1358

  204. 204.

    Miao B, Yin XH, Pei DS, Zhang QG, Zhang GY: Neuroprotective effects of preconditioning ischemia on ischemic brain injury through down-regulating activation of JNK1/2 via N-methyl-D-aspartate receptor-mediated Akt1 activation. J Biol Chem 2005, 280: 21693–21699. 10.1074/jbc.M500003200

  205. 205.

    Zhang Y, Park TS, Gidday JM: Hypoxic preconditioning protects human brain endothelium from ischemic apoptosis by Akt-dependent survivin activation. Am J Physiol Heart Circ Physiol 2007, 292: H2573–2581. 10.1152/ajpheart.01098.2006

  206. 206.

    Nakajima T, Iwabuchi S, Miyazaki H, Okuma Y, Kuwabara M, Nomura Y, Kawahara K: Preconditioning prevents ischemia-induced neuronal death through persistent Akt activation in the penumbra region of the rat brain. J Vet Med Sci 2004, 66: 521–527. 10.1292/jvms.66.521

  207. 207.

    Stenzel-Poore MP, Stevens SL, Xiong Z, Lessov NS, Harrington CA, Mori M, Meller R, Rosenzweig HL, Tobar E, Shaw TE, Chu X, Simon RP: Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet 2003, 362: 1028–1037. 10.1016/S0140-6736(03)14412-1

  208. 208.

    Stenzel-Poore MP, Stevens SL, Simon RP: Genomics of preconditioning. Stroke 2004, 35: 2683–2686. 10.1161/01.STR.0000143735.89281.bb

  209. 209.

    Stenzel-Poore MP, Stevens SL, King JS, Simon RP: Preconditioning reprograms the response to ischemic injury and primes the emergence of unique endogenous neuroprotective phenotypes: a speculative synthesis. Stroke 2007, 38: 680–685. 10.1161/01.STR.0000251444.56487.4c

  210. 210.

    Stevens SL, Stenzel-Poore MP: Toll-like receptors and tolerance to ischaemic injury in the brain. Biochem Soc Trans 2006, 34: 1352–1355. 10.1042/BST0340492

  211. 211.

    Nakamura M, Nakakimura K, Matsumoto M, Sakabe T: Rapid tolerance to focal cerebral ischemia in rats is attenuated by adenosine A1 receptor antagonist. J Cereb Blood Flow Metab 2002, 22: 161–170. 10.1097/00004647-200202000-00004

  212. 212.

    Truettner J, Busto R, Zhao W, Ginsberg MD, Perez-Pinzon MA: Effect of ischemic preconditioning on the expression of putative neuroprotective genes in the rat brain. Brain Res Mol Brain Res 2002, 103: 106–115. 10.1016/S0169-328X(02)00191-2

  213. 213.

    Kariko K, Weissman D, Welsh FA: Inhibition of toll-like receptor and cytokine signaling--a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab 2004, 24: 1288–1304. 10.1097/01.WCB.0000145666.68576.71

  214. 214.

    Pera J, Zawadzka M, Kaminska B, Szczudlik A: Influence of chemical and ischemic preconditioning on cytokine expression after focal brain ischemia. J Neurosci Res 2004, 78: 132–140. 10.1002/jnr.20232

  215. 215.

    Pera J, Zawadzka M, Kaminska B, Szczudlik A: Neurotrophic factor expression after focal brain ischemia preceded by different preconditioning strategies. Cerebrovasc Dis 2005, 19: 247–252. 10.1159/000084088

  216. 216.

    Nyitrai G, Puskas L, Antal K, Takacs V, Sass M, Juhasz G, Kardos J, Palkovits M: Preconditioning-specific reduction of c-fos expression in hippocampal granule and pyramidal but not other forebrain neurons of ischemic brain: a quantitative immunohistochemical study. Neurosci Lett 2005, 381: 344–349. 10.1016/j.neulet.2005.02.045

  217. 217.

    Alkayed NJ, Harukuni I, Kimes AS, London ED, Traystman RJ, Hurn PD: Gender-linked brain injury in experimental stroke. Stroke 1998, 29: 159–165.

  218. 218.

    Gibson CL, Gray LJ, Murphy SP, Bath PM: Estrogens and experimental ischemic stroke: a systematic review. J Cereb Blood Flow Metab 2006, 26: 1103–1113.

  219. 219.

    Song X, Li G, Vaage J, Valen G: Effects of sex, gonadectomy, and oestrogen substitution on ischaemic preconditioning and ischaemia-reperfusion injury in mice. Acta Physiol Scand 2003, 177: 459–466. 10.1046/j.1365-201X.2003.01068.x

  220. 220.

    Wang C, Chiari PC, Weihrauch D, Krolikowski JG, Warltier DC, Kersten JR, Pratt PF Jr, Pagel PS: Gender-specificity of delayed preconditioning by isoflurane in rabbits: potential role of endothelial nitric oxide synthase. Anesth Analg 2006, 103: 274–280. 10.1213/01.ANE.0000230389.76351.0C

  221. 221.

    Kitano H, Young JM, Cheng J, Wang L, Hurn PD, Murphy SJ: Gender-specific response to isoflurane preconditioning in focal cerebral ischemia. J Cereb Blood Flow Metab 2007, 27: 1377–1386. 10.1038/sj.jcbfm.9600444

  222. 222.

    Dowden J, Corbett D: Ischemic preconditioning in 18- to 20-month-old gerbils: long-term survival with functional outcome measures. Stroke 1999, 30: 1240–1246.

  223. 223.

    He Z, Crook JE, Meschia JF, Brott TG, Dickson DW, McKinney M: Aging blunts ischemic-preconditioning-induced neuroprotection following transient global ischemia in rats. Curr Neurovasc Res 2005, 2: 365–374. 10.2174/156720205774962674

  224. 224.

    Della Morte D, Abete P, Gallucci F, Scaglione A, D'Ambrosio D, Gargiulo G, De Rosa G, Dave KR, Lin HW, Cacciatore F, Mazzella F, Uomo G, Rundek T, Perez-Pinzon MA, Rengo F: Transient ischemic attack before nonlacunar ischemic stroke in the elderly. J Stroke Cerebrovasc Dis 2008, 17: 257–262. 10.1016/j.jstrokecerebrovasdis.2008.03.004

  225. 225.

    Tomida S, Nowak TS Jr, Vass K, Lohr JM, Klatzo I: Experimental model for repetitive ischemic attacks in the gerbil: the cumulative effect of repeated ischemic insults. J Cereb Blood Flow Metab 1987, 7: 773–782.

  226. 226.

    Pugliese AM, Latini S, Corradetti R, Pedata F: Brief, repeated, oxygen-glucose deprivation episodes protect neurotransmission from a longer ischemic episode in the in vitro hippocampus: role of adenosine receptors. Br J Pharmacol 2003, 140: 305–314. 10.1038/sj.bjp.0705442

  227. 227.

    Bigdeli MR, Hajizadeh S, Froozandeh M, Rasulian B, Heidarianpour A, Khoshbaten A: Prolonged and intermittent normobaric hyperoxia induce different degrees of ischemic tolerance in rat brain tissue. Brain Res 2007, 1152: 228–233. 10.1016/j.brainres.2007.03.068

  228. 228.

    Shen YT, Depre C, Yan L, Park JY, Tian B, Jain K, Chen L, Zhang Y, Kudej RK, Zhao X, Sadoshima J, Vatner DE, Vatner SF: Repetitive ischemia by coronary stenosis induces a novel window of ischemic preconditioning. Circulation 2008, 118: 1961–1969. 10.1161/CIRCULATIONAHA.108.788240

  229. 229.

    Ohno M, Watanabe S: Ischemic tolerance to memory impairment associated with hippocampal neuronal damage after transient cerebral ischemia in rats. Brain Res Bull 1996, 40: 229–236. 10.1016/0361-9230(96)00050-0

  230. 230.

    Shamloo M, Wieloch T: Changes in protein tyrosine phosphorylation in the rat brain after cerebral ischemia in a model of ischemic tolerance. J Cereb Blood Flow Metab 1999, 19: 173–183. 10.1097/00004647-199902000-00009

  231. 231.

    Sommer C: Neuronal plasticity after ischemic preconditioning and TIA-like preconditioning ischemic periods. Acta Neuropathol 2009, 117: 511–523. 10.1007/s00401-008-0473-0

  232. 232.

    Weih M, Kallenberg K, Bergk A, Dirnagl U, Harms L, Wernecke KD, Einhaupl KM: Attenuated stroke severity after prodromal TIA: a role for ischemic tolerance in the brain? Stroke 1999, 30: 1851–1854.

  233. 233.

    Schaller B: Ischemic preconditioning as induction of ischemic tolerance after transient ischemic attacks in human brain: its clinical relevance. Neurosci Lett 2005, 377: 206–211. 10.1016/j.neulet.2004.12.004

  234. 234.

    Moncayo J, de Freitas GR, Bogousslavsky J, Altieri M, van Melle G: Do transient ischemic attacks have a neuroprotective effect? Neurology 2000, 54: 2089–2094.

  235. 235.

    Johnston SC: Ischemic preconditioning from transient ischemic attacks? Data from the Northern California TIA Study. Stroke 2004, 35: 2680–2682. 10.1161/01.STR.0000143322.20491.0f

  236. 236.

    Wegener S, Gottschalk B, Jovanovic V, Knab R, Fiebach JB, Schellinger PD, Kucinski T, Jungehulsing GJ, Brunecker P, Muller B, Banasik A, Amberger N, Wernecke KD, Siebler M, Röther J, Villringer A, Weih M, MRI in Acute Stroke Study Group of the German Competence Network Stroke: Transient ischemic attacks before ischemic stroke: preconditioning the human brain? A multicenter magnetic resonance imaging study. Stroke 2004, 35: 616–621. 10.1161/01.STR.0000115767.17923.6A

  237. 237.

    Steiger HJ, Hanggi D: Ischaemic preconditioning of the brain, mechanisms and applications. Acta Neurochir (Wien) 2007, 149: 1–10. 10.1007/s00701-006-1057-1

  238. 238.

    Caplan LR: Do transient ischemic attacks have a neuroprotective effect? Neurology 2000, 55: 1596.

  239. 239.

    Dirnagl U, Becker K, Meisel A: Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol 2009, 8: 398–412. 10.1016/S1474-4422(09)70054-7

  240. 240.

    Castillo J, Moro MA, Blanco M, Leira R, Serena J, Lizasoain I, Davalos A: The release of tumor necrosis factor-alpha is associated with ischemic tolerance in human stroke. Ann Neurol 2003, 54: 811–819. 10.1002/ana.10765

  241. 241.

    Laskey WK, Beach D: Frequency and clinical significance of ischemic preconditioning during percutaneous coronary intervention. J Am Coll Cardiol 2003, 42: 998–1003. 10.1016/S0735-1097(03)00909-4

  242. 242.

    Jneid H, Leessar M, Bolli R: Cardiac preconditioning during percutaneous coronary interventions. Cardiovasc Drugs Ther 2005, 19: 211–217. 10.1007/s10557-005-2466-8

Download references

Acknowledgements

This work was supported in part by the Helsinki University Central Hospital and the Finnish Academy of Sciences.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Aysan Durukan.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

Both AD and TT made the conception and design of the manuscript and analysis and interpretation of the data, drafted and revised the manuscript, and have given approval of its final version.

Electronic supplementary material

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Durukan, A., Tatlisumak, T. Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection. Exp & Trans Stroke Med 2, 2 (2010). https://doi.org/10.1186/2040-7378-2-2

Download citation

Keywords

  • KATP Channel
  • Global Ischemia
  • Focal Ischemia
  • Ischemic Tolerance
  • Transient Focal Ischemia