The term ischemia (Greek iskhein to keep back + haema or hema blood) means a restriction in blood supply to a bodily organ or tissues. Interruption of blood flow to the brain or part(s) of the brain is known as cerebral ischemia or stroke. A stroke is a medical emergency, which can cause permanent neurological damage, complications, and death. More than 2,400 years ago, the father of medicine, Hippocrates, recognized and described stroke as the sudden onset of paralysis. In the past, stroke was referred to as cerebrovascular accident, but the term stroke is now preferred.

Stroke causes 9% of all deaths around the world, is the third most common cause of death after ischemic heart disease and cancer, and may soon become the leading cause of death worldwide. It is the leading cause of adult disability, because 76% of people in the United States and Europe survive their stroke [1].

The central goal of therapy in acute ischemic stroke is to preserve the area of oligemia in the ischemic penumbra. The area of oligemia can be preserved by limiting the severity of ischemic injury (i.e., neuronal protection) or by reducing the duration of ischemia (i.e., restoring blood flow to the compromised area). The ischemic cascade offers many points at which such interventions could be attempted. However, it has become increasingly clear that therapeutic interventions targeting only part of the complex network of mediators that contribute to ischemic brain damage produce only subtle effects on the outcome of stroke in clinical trials [2,3]. A solution to this problem could be derived from an understanding of the mechanisms by which the cell adapts to ischemic stress [4-7].

Ischemic stress induces both harmful and protective responses, and the balance between these two responses determines cellular fate. If the stress is sublethal (i.e., below the threshold of damage), protective mechanisms prevail. When another stress is reapplied at the peak of the stress-controlling period, cells show better tolerance. This phenomenon is known as stress adaptation or preconditioning, in which sublethal stress induces an adaptive response to subsequent lethal stress. In fact, this observation has long been expressed as "Adaptation to perturbations is the basis for homeostasis" (Cannon), "the general adaptation syndrome" (Selye), "The dose makes the poison" (Paracelsus) or "Poisons are stimulants in small doses" (Arndt-Schultz). This cellular response can be observed in a wide variety of species from bacteria to mammalian cells [8]. The terms preconditioning and tolerance were first introduced by Janoff [9] in a study of the shock model. Generally, preconditioning can be defined as "presenting a stressful but non-damaging stimulus to cells to induce an endogenous adaptive response which would help cells to tolerate subsequent severe stresses." A condition of transiently increased resistance to ischemic stress as a result of the activation of endogenous protective mechanisms by preconditioning is known as ischemic tolerance [10]. This novel phenomenon has been described in a variety of organ systems, including the brain, heart, liver, intestine, lung, skeletal muscle, kidney and bladder [11-14]. Although it is generally assumed that the preconditioning phenomenon was first described in the heart in the 1980s [11,15] and not until 1990 in the brain, in fact, Dahl and Balfour [16] first described this phenomenon in 1964 in relation to brain ischemia, 20 years before the classic cardiology experiments were published. Several reports in the late 1980s again drew attention to ischemic tolerance in the brain [17-18]. Since then, this phenomenon has been confirmed in many animal models of global [19] and focal ischemia [20], in in vitro brain slice preparations [21], in cultured primary neurons [22], and in human beings in the form of short episodes of ischemia without infarction, known as a transient ischemic attack (TIA) [23].

Even though short episodes of cerebral ischemia or cerebral hypoxia were initially considered as prototypical preconditioning stimuli, subsequent studies have shown that ischemic tolerance can be induced by exposing animals or cells to diverse types of endogenous and exogenous stimuli that are not necessarily hypoxic or ischemic in nature [5]. These stimuli include spreading depression, hyperoxia, oxidative stress, prolonged hypoperfusion, hypothermia, and hyperthermia. Therefore, one stressor can promote 'cross-tolerance' to another. The diversity of stimuli capable of inducing an ischemia-resistant phenotype in the brain indicates that the signaling pathways activated by these different triggers converge downstream on some common, fundamental mechanisms that ultimately account for the protection. Many exogenously delivered chemical preconditioning agents (e.g., inflammatory cytokines [24], anesthetics [25], and metabolic inhibitors [26]) can also induce ischemic tolerance, which raises the hope that, it will be possible in the future to pharmacologically activate these distal pathways in the human brain. Moreover, physical exercise [27] and skeletal muscle [28] preconditioning- induced neuroprotection against cerebral ischemia promise another attractive strategy, remote preconditioning, to protect organs that are highly susceptible to damage but that are difficult to target, such as the brain. However, the underlying complex molecular mechanisms of ischemic tolerance are still not well known.

Two temporally distinct types of ischemic tolerance are afforded by sublethal pretreatment: early and delayed tolerance, the mechanisms of which may differ. In the early (or rapid) type, the trigger induces tolerance within minutes and is transient; in the delayed type, tolerance takes hours to days to become apparent and lasts for days to weeks. Although both types of ischemic tolerance have been found in the brain and in the heart, the time course of ischemic tolerance in the brain usually follows the delayed pattern; however, in the heart, the tolerance induced by ischemic preconditioning usually follows the rapid pattern, also known as classic preconditioning, which represents a marked difference between the heart and the brain. In general, it is widely accepted that early acquisition of tolerance is independent of protein synthesis, mediated by posttranslational modification, and the effective duration is brief. Conversely, the general agreement is that delayed induction of ischemic tolerance requires new protein synthesis and is sustained for a few days to weeks.

To induce tolerance by means of ischemic episodes, three factors should be considered: 1) the duration, 2) the time interval, and 3) the number of episodes. First, the preconditioning stimuli must be severe enough to initiate a response, but not so severe as to cause permanent damage. Second, some interval of time must exist between sublethal and lethal stress. Third, the number of short ischemic episodes should be considered for sufficient stimulation of the protective response against a lethal ischemic insult.

Ischemia is an unspecific injury that causes disturbances in a multitude of cellular processes [29]. Therefore, induction of tolerance is most likely the result of several mechanisms and molecular pathways. In general, the process of tolerance induction can be divided into the following elements: sensors of the stress signal, transducers of the stimulus, and effectors of the tolerance [30]. First, the preconditioning stimulus must be recognized by cellular sensors so that the cells can be prepared for upcoming stress. Neurotransmitter and cytokine receptors, ion channels and redox-sensitive enzymes generally work as molecular sensor of stress stimuli. These sensors activate enzymes, such as kinase protein Ras, Raf, mitogen-activated protein kinase (MAPK) kinase (MEK), extracellular regulated kinase (ERK), Akt, and protein kinase C, and signaling molecules, such as nitric oxide (NO), diacylglycerol, inositol triphosphate, Ca²⁺, and ceramide, which transduce the signal and initiate an adaptive response. Finally, effectors of the preconditioning response confer tolerance to cells or tissues through anti-excitotoxicity, anti-apoptosis, anti-inflammation, protection of mitochondria and increased anti-oxidant mechanisms [30-32]. The following is an overview of various components and the potential mechanisms that may responsible for ischemic tolerance.

The preconditioning phenomenon has been successful as an experimental procedure for identifying the mechanisms responsible for brain protection and regeneration. Important examples of strategies to modulate these mechanisms include erythropoietin, activators of mitochondrial K_ATP channels, and volatile anesthetics. The phenomenon of ischemic tolerance has not only been found in cells, organs and animal experimental models; some clinical observational data indicate that this phenomenon may occur naturally in the human brain in the form of short episodes of ischemia without infarction, known as TIA. In a retrospective clinical study, Weih et al. [71]. evaluated 148 stroke patients with and without antecedent TIA and found that TIA before stroke is associated with significantly less severe stroke on admission and improved outcomes on follow-up. Another retrospective study, which included more than 2000 patients, confirmed these results 1 year later [72]. In support of these findings, studies using magnetic resonance imaging and neuroradiological analysis showed that ischemic stroke patients with prodromal TIA have significantly smaller ischemic lesions after stroke than those patients without TIA [73,74]. These observations suggest that endogenous preconditioning triggered by TIA is present in the human brain.

Induction of ischemic tolerance in the brain has been suggested to be a promising clinical strategy for preparing the brain for situations of possible ischemia, such as cardiac or brain surgery and in patients with a high risk of stroke. However, because of ethical and safety concerns associated with ischemic preconditioning, researchers are trying to identify a safer preconditioning stimulus that would be both practical and effective or a biological agent that can mimic preconditioning pharmacologically. Many candidate pharmacological regulators of the stress response and inducers of ischemic tolerance have been proposed [75-79], one of which is erythropoietin. Erythropoietin is approved for the treatment of anemia and seems safe and effective for critically ill patients who are anemic and have experienced trauma [80]. The iron chelator desferrioxamine is clinically approved for various indications, including thalassemia and other iron-overload syndromes. Various inhalational anesthetics used in human beings (e.g., sevoflurane) induce tolerance against brain ischemia and act as brain protectants after ischemia in preclinical experiments [81-83]. These compounds are safe and effective at eliciting early preconditioning in patients undergoing coronary artery bypass graft surgery in randomized controlled trials [84]. These drugs also elicit delayed preconditioning in human beings [85,86].

Another promising approach is remote preconditioning in which preconditioning of one organ or system leads to protection of a different (remote) organ. The prototypical approach for remote preconditioning is the initiation of short ischemic insult(s) to a limb to protect organs such as the heart [87,88] and the brain [89,90]. Remote preconditioning might indicate a crosstalk between the brain and the rest of the body in response to stress through the peripheral nervous system or paracrine signal. Randomized clinical trials have already shown the efficacy of this strategy for the heart [91,92]. Remote preconditioning is a particularly attractive strategy for protecting organs that are highly susceptible to damage but that are difficult to target, such as the brain.

Although many researchers are actively characterizing the signaling mechanisms of ischemic preconditioning in the nervous system, our knowledge of cerebral ischemic tolerance is still in its infancy and insufficient to be able to translate the laboratory results into application. Many issues need to be resolved to avoid disappointing results from the clinical application of ischemic preconditioning, e.g., whether the tolerant state can be maintained long term and provide chronic neuroprotection. Thus far, it appears that ischemic tolerance persists for approximately 1 week in the brain. Are there side effects from the long-term expression of ischemic preconditioning-induced genes? The threshold for tolerance induction and for cell injury needs to be determined. Pharmacological substances used for tolerance induction need to be safe.

In conclusion, the past two decades have provided interesting insights into the mechanisms and potential applications of ischemic tolerance in the brain. Current knowledge suggests that the preconditioning strategy and related interventions, such as remote preconditioning and pharmacological preconditioning, can protect neurons and improve neuronal survival after critical ischemia, and, thus, have promise for practical application in cases of vascular neurosurgery and endo-vascular therapy and possibly in the management of brain trauma. As knowledge in this field advances, the unresolved issues concerning the preconditioning cascade will likely be resolved and will lead to pharmacological strategies for protecting the brain from ischemic injury, traumatic brain injury, and other neurodegenerative disorders.