|Year : 2015 | Volume
| Issue : 1 | Page : 104-113
Pharmacologic pre- and postconditioning for stroke: Basic mechanisms and translational opportunity
Elga Esposito1, Rakhi Desai1, Xunming Ji2, Eng H Lo1
1 Department of Radiology and Neurology, Harvard Medical School, Massachusetts General Hospital, Massachusetts, USA
2 Department of Neurosurgery, Cerebrovascular Research Institute, Xuan Wu Hospital, Capital Medical University, Beijing, PR China
|Date of Submission||30-Apr-2015|
|Date of Acceptance||27-Jul-2015|
|Date of Web Publication||30-Sep-2015|
Eng H Lo
Massachusetts General Hospital - East Building 149, 13th Street, Charlestown, Massachusetts - 02129
Source of Support: None, Conflict of Interest: None
Beyond reperfusion therapies, there are still no widely effective therapies for ischemic stroke. Although much progress has been made to define the molecular pathways involved, targeted neuroprotective strategies have often failed in clinical trials. An emerging hypothesis suggests that focusing on single targets and mechanisms may not work since ischemic stroke triggers multiple pathways in multiple cell types. In this review, we briefly survey and assess the opportunities that may be afforded by pre- and postconditioning therapies, with particular attention to pharmacologic pre- and postconditioning. Pharmacologic conditioning may be defined as the use of chemical agents either before or shortly after stroke onset to trigger mechanisms of endogenous tolerance that are thought to involve evolutionarily conserved signals that offer broad protection against ischemia. Importantly, many of the pharmacologic agents may also have been previously used in humans, thus providing hope for translating basic mechanisms into clinical applications.
Keywords: Cerebral ischemia, neuroprotection, pharmacologic preconditioning, pharmacologic postconditioning, translation
|How to cite this article:|
Esposito E, Desai R, Ji X, Lo EH. Pharmacologic pre- and postconditioning for stroke: Basic mechanisms and translational opportunity. Brain Circ 2015;1:104-13
| Introduction|| |
The brain is the internal organ with the greatest expenditure of metabolic energy. Neuronal energy metabolism is almost completely dependent on aerobic glycolysis. Thus, when cerebral ischemia occurs, insufficient blood supply causes rapid failure of brain oxygenation and viability. 
Despite considerable efforts to find an appropriate therapy, the only FDA-approved treatment for acute cerebral ischemia is tissue plasminogen activator (rt-PA). When given within the first 4.5 h, rt-PA has demonstrated improvement in long-term outcomes. Though it has proven effective in some patients, the narrow therapeutic window and strict eligibility criteria greatly restrict the percentage of patients that can be treated with rt-PA. 
More than 1,000 different drugs and nonpharmacological therapies have been tested for neuroprotective efficacy in animal models and at least 114 have been administered to acute stroke patients. Even so, no particular treatment has distinguished itself for superior efficacy; this is probably due to the multifaceted nature of the stroke event. For this reason, emerging research aims to define a neuroprotective strategy able to simultaneously target multiple processes altered during and after stroke. ,
In this context, a focus on endogenous protective responses to cerebral ischemia has begun to emerge. Brain cells have evolved an intricate network of signaling pathways that induces self-defense against injury and disease. , These molecular mechanisms underlie the overall concept of tolerance, i.e., an initial nonlethal insult induces protection against a subsequent lethal insult. By focusing on endogenous tolerance mechanisms, one may begin to identify ways to upregulate signaling pathways of multicellular protection following an ischemic insult. Pre- and postconditioning with an ischemic stimulus are both able to produce remarkable neuroprotection in various models of stroke and neuronal injury.  Although these methods may prove useful for proof-of-concept and dissecting molecular mechanisms, they may be difficult to apply in a clinical setting. More recently, it has been suggested that conditioning may also be stimulated with various pharmacologic approaches.  In this review, we will briefly survey the underlying mechanisms of pharmacologic pre- and postconditioning and discuss their translatability in the clinic.
| Innate Tolerance in the Central Nervous System (CNS)|| |
Clinical trials of exogenous drugs administered before or after the stroke onset have constantly failed to demonstrate potential neuroprotective efficacy.  In search of a novel stroke therapy, however, recent research has focused on identifying endogenous neuroprotectants and their associated mechanisms that may be activated after cerebral ischemia.  It has been thought that the molecular mechanisms involved in innate tolerance might be evolutionarily conserved to reduce the damage induced by disruption to cerebral blood supply.  Ischemic preconditioning and ischemic postconditioning, two promising endogenous mechanisms of neuroprotection,  have recently gained attention for the ability to impose their effect on multipathways simultaneously.  These two methods rely on a natural adaptive response that the brain and other organs utilize to protect themselves from a potentially lethal ischemic insult. Interestingly, many of these pathways are highly conserved. This protective response can be induced by a broad range of sublethal triggers ,,, that in turn may also defend against a wide spectrum of insults. Thus, therapies that upregulate these endogenous mechanisms of tolerance may be especially well-suited for stroke where multiple pathways are affected in multiple cell types. ,
| Ischemic Pre and Postconditioning|| |
Ischemic preconditioning is defined as a brief period of sublethal ischemia that is able to protect an organ from a subsequent harmful ischemic event. Several sublethal insults are able to increase the tissue tolerance in the brain, heart, liver, intestine, lung, muscle, kidney, and retina. 
First identified in the heart by Murry et al. in 1986,  preconditioning has rapidly drawn the interest of clinical and basic neuroscientists. Kitagawa described ischemic tolerance in the brain for the first time in 1990 in a gerbil model of global cerebral ischemia.  Since then, many pathways responsible for neuroprotection have been identified and several animal models have been used to confirm feasibility and efficacy in different species.  Moreover, interesting retrospective case-control studies showed a clinical correlation with animal models of preconditioning. Patients with a history of transient ischemic attack (TIA) may have decreased morbidity after stroke. ,,
Ischemic tolerance has been reproduced for in vitro and in vivo models.  In both models, diverse types of endogenous and exogenous stimuli that are not necessarily hypoxic or ischemic in nature can induce neuroprotection. These different stimuli include hypoxia, spreading depression, hyperoxia and oxidative stress, prolonged hypoperfusion, exercise, hyperthermia, or heat shock.  The variety of stimuli responsible for neuroprotection indicates that the respective signaling pathways must converge downstream on the same targets. The chosen stimulus should be easily and readily applied to acute stroke patients. Often, this proves to be a challenging transition from the experimental phenomena to potential clinical relevance.
Some findings suggested that brain tolerance may be induced or mimicked pharmacologically.  Ischemic tolerance can, for example, be induced by many exogenously delivered chemical preconditioning agents (such as inflammatory cytokines, anesthetics, and metabolic inhibitors). The final goal is the possibility in the near future to pharmacologically activate these distal pathways in the human brain. 
The neuroprotective strategy of ischemic postconditioning, also defined as a repetitive series of brief reperfusion/occlusions applied after ischemia, is a relatively novel concept compared to ischemic preconditioning.  Initially demonstrated to reduce the infarct size after cardiac ischemia both in an experimental setting  and a clinical setting,  ischemic postconditioning has recently been shown to attenuate neuronal damage in rodent models of spinal cord injury  and focal  and global  brain ischemia. The neuroprotection induced by early interruption of reperfusion is most likely associated with changes in cerebral blood flow. Subsequent events such as free radical production, blood-brain barrier (BBB) integrity, inflammation, and endothelial function have also been shown to be involved. ,,,
With regard to focal ischemia, two key animal models of ischemic postconditioning have been used. The first was the permanent distal occlusion of the middle cerebral artery followed by a series of occlusions of both common carotid arteries (CCAs);  the second model, performed by Pignataro et al., consists of a harmful transient middle cerebral artery occlusion followed by 10 min of reperfusion and 10 min of reocclusion.  Ischemic postconditioning was also performed in animals subjected to global ischemia induced by occlusion of the CCAs and of the two vertebral arteries, otherwise known as four-vessel occlusion followed by different cycles of noninjurious CCA occlusion. 
Compared to preconditioning, in vitro postconditioning has not been as thoroughly investigated. It has been reproduced in in vitro hippocampal organotypic slice cultures and primary neurons subjected to harmful oxygen glucose deprivation followed by noninjurious cycles of oxygen glucose deprivation and reoxygenation. ,
As for ischemic preconditioning, it has been suggested that during postconditioning a different stressor (i.e., hypoxia,  isoflurane,  norepinephrine,  and 3-nitropropionic acid  ) can induce neuroprotection against ischemia. Several treatments have proven to be a successful in reducing infarct size. In fact, it has been shown that not only brief periods of ischemia/reperfusion but also pharmacological strategies that have been previously used as preconditioning stimuli can be used for postconditioning. ,,
| Ischemic Versus Pharmacologic Induction|| |
Although clinical scenarios of ischemia where preconditioning could have an impact have been defined and there have been several clinical trials for types of preconditioning in other tissues (i.e. heart) the precise occurrence of an ischemic event is not predictable. , Therefore, the demonstration of a post-ischemic neuroprotective approach is more attractive. Rapid ischemic postconditioning applied immediately after the harmful event is able to modify reperfusion-induced adverse events. ,,,
The data supporting the efficacy of ischemic postconditining is interesting; however, the re-occlusion of a cerebral artery in some stroke patients may be a difficult clinical approach to treat cerebral ischemia. For this reason considerable attention has been directed to a more feasible way to induce neuroprotection. Instead of using nonlethal ischemia as the inducer, can we find drugs and chemical agents that can stimulate analogous pathways of ischemic tolerance? If so, then drawing on these agents, many of which have been previously used in humans, may provide promise that can be translated into a clinically feasible therapeutic strategy [Figure 1].
| Pharmacologic Preconditioning|| |
The pharmacologic approach is an appealing stimulus to induce neuroprotection for several reasons. Studying different pharmacological agents with a broad range of action gives us a wider view of all the complex mechanisms following ischemic injury and repair. In addition, many of the agents [i.e., deferoxamine, erythromycin, opioids, and erythropoietin (EPO)] used to induce pharmacologic preconditioning are already used in the clinic. The well-studied profiles of these agents guarantee safety; for example, opioids  and macrolide antibiotics  are already used in the clinic for a different purpose but are lately also used to induce preconditioning. Moreover, drugs can be easily and rapidly administrated and they have the same effects and efficacy as other preconditioning stimuli previously investigated. 
So far, several agents have proven successful in inducing pharmacologic preconditioning. These agents include volatile anesthetics, ATP-sensitive potassium [K(ATP)] channels, erythromycin, EPO, deferoxamine, lipopolysaccharide (LPS), opioids, and thrombin. All of these aim to upregulate the defense mechanisms already present in the brain. Some of them, such as EPO and thrombin, are endogenous compounds while others, such as LPS, are exogenous natural compounds.  In this section, we survey the agents that have been tested and briefly review the mechanisms involved.
The volatile anesthetics are among the most studied pharmacologic preconditioning stimuli. Preclinical attention has mainly been focused on adult  and neonatal rodents.  The fact that they have been extensively used in clinical practice may suggest that they have adequate safety profiles for potential translation as conditioning agents.
Isoflurane is the most investigated preconditioning anesthetic. Although the neuroprotective effect of isoflurane has been proved in several studies, some data suggest that there is no protective effect. Most of the animal stroke models showed that isoflurane, starting at a concentration of 1.2%, ameliorates ischemic damage. ,, However, other studies show no improvement in histological deficits and behavioral outcomes.  A few in vitro studies also showed the neuroprotective effect of isoflurane preconditioning with a decrease in cortical neuronal cell death after oxygen/glucose deprivation (OGD)  and in rat primary mixed neuron-glia cultures subjected to N-methyl-d-aspartate (NMDA) excitotoxocity.  These diverse results may be due to the varying dose of anesthetics and severity of the ischemic or toxic event.
Halothane, another inhaled general anesthetic, has also been investigated as an agent for pharmacologic preconditioning. Similar to isoflurane, halothane has showed its neuroprotection in some animal models of focal  and global ischemia  but failed in other studies. , In vitro experiments have been inconsistent; halothane exposure during NMDA-induced toxicity showed reduction in lactate dehydrogenase release indicating improved survival  whereas another study was unable to detect a large effect. 
Other gases such as xenon  and sevoflurane  have also gained attention for their potential neuroprotective effects. Sevoflurane is the current inhalational anesthetic of choice for human surgery, from infants and children to geriatric patients, and it is also used in veterinary medicine. However, to prove both rapid and delayed preconditioning neuroprotection, further animal studies are warranted. Together with sevoflurane, desflurane is replacing isoflurane and halothane in modern anesthesiology. In global cerebral ischemia (neonatal and adult) rat models, neurological outcome has been improved by using desflurane as an anesthetic.  Although these initial studies are intriguing, they need to be replicated and confirmed before desflurane can be evaluated as a neuroprotector for inducing pre- or postconditioining.
Neuronal K(ATP) channels
K(ATP) channels are widely expressed in many cell types including neurons. Different subtypes of K(ATP) channels exist in various subcellular locations and a multitude of tissues. The initial evidence of K(ATP) channels being involved in preconditioning was found in the heart.  Selective mitochondrial potassium channel openers (KCOs), such as diazoxide, attenuate blood-results neuroprotective after focal  and global  cerebral ischemia. Rapid diazoxide preconditioning provided both morphological and functional protection in a canine model of brain injury by hypothermic cardiac arrest.  In vitro and in vivo studies suggest that KCO-induced tolerance might be due to a reduction in proinflammatory and apoptotic mediators, reactive oxygen species, and BBB breakdown.  Emerging research supports the idea that the activation of mitochondrial KCOs and modulation of mitochondrial function could be the key event through which many pharmacologic preconditioning stimuli play their role for neuroprotection.  However, the complete pathway from KCO activation to the neuroprotective effects needs to be further investigated.
EPO is a glycoprotein hormone produced by the kidney that promotes erythropoiesis, the formation of red blood cells, in the bone marrow.  Recent research has investigated the ability of this cytokine to protect brain, kidney, and heart tissues after ischemia/reperfusion damage. 
In the brain, it has been shown that EPO is able to induce preconditioning.  Furthermore, it seems that EPO might also play a role directly in the neurovascular unit so that the dynamic interactions between endothelial cells, glia, neurons, and matrix are likely involved in the effects mediated by preconditioning. Ruscher et al. demonstrated that astrocytes in vitro release EPO when subjected to an ischemic stress such as OGD.  In turn, this action is able to increase neural resistance to subsequent ischemia. Media transfer from OGD-treated astrocytes to untreated neurons induced protection in neurons against subsequent OGD. This effect was strongly attenuated when treated with antibodies against the EPO receptor. Similar to its role in erythropoiesis where EPO inhibits apoptosis of erythrocytes precursors, EPO is likely to have an antiapoptotic action via phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway that leads to BAD deactivation.  EPO may also have intrinsic advantages for clinical translation; it is relatively safe, it can penetrate the BBB, and it is well tolerated and effective in just few minutes with lasting protection of up to 3 days without continuous dosing. 
Deferoxamine is an iron-chelating agent that binds excess iron in the body. It is then excreted in the urine and feces, resulting in reduction of total body iron levels. Iron is an essential part of hemoglobin, the oxygen-carrying pigment present in red blood cells.  Under physiological conditions iron balance is strictly controlled. Most diets supply an adequate amount of iron and any amount in excess is eliminated. Under abnormal circumstances the normal control fails causing iron accumulation in cells of the kidneys, heart, liver, brain, and other organs; if left untreated, this will ultimately lead to heart failure, liver cirrhosis, or diabetes. 
Iron has also been shown to increase brain injury after ischemic and hemorrhagic stroke. , Iron damage is due to an increase of free radicals responsible for oxidative stress. Alterations in brain iron homeostasis have been linked to acute neuronal injury after cerebral ischemia. When free iron catalyzes the conversion of superoxide and hydrogen peroxide into hydroxyl radicals, oxidative stress occurs, along with subsequent cell death.  Previous studies have confirmed a strong correlation between regional iron levels in the brain and oxidative damage.  Animal models of intracerebral hemorrhage have also demonstrated elevated levels of iron.  Therefore, targeting iron imbalances may be relevant for many brain injuries.
Deferoxamine, administrated subcutaneously, is capable of penetrating the BBB and has a neuroprotective effect by inhibiting the iron-mediated free radical formation.  Additionally, it can reduce brain edema, neurological deficit, and free radical formation. , Deferoxamine preconditioning protects against cerebral ischemia by inducing expressions of hypoxia inducible factor 1 alpha and erythropoietin. Administration of deferoxamine has also been shown to significantly increase the binding of hypoxia-inducible factor-1 (HIF-1) to DNA responsible for cellular oxygen homeostasis and vascularization.  Moreover, preconditioning of mesenchymal stem cells (MSCs) by deferoxamine has been shown to increase homing of MSCs through affecting some chemokine receptors as well as proteases. These emerging findings raise the exciting possibility that preconditioning or postconditioning methods may eventually be applied to amplify the efficacy of cell therapy. 
Erythromycin is a macrolide antibiotic produced by Streptomyces erythreus. By binding the bacterial 50S ribosomal subunits it inhibits peptidyl transferase activity and the translocation of amino acids during proteins synthesis.  Erythromycin is both a bacteriostatic and bactericidal; its mechanism depends on the host organism and the drug concentration.  This broad-spectrum antibiotic acts against a wide variety of bacteria causing several infections, i.e., infections of the upper or lower airways, skin, or soft tissue, eyes or ears, certain sexually transmitted infections, and oral and dental infections. It can also be used to prevent infections in people who are at risk such as patients that have had surgery, trauma, or burns.
Antibiotics are widely used in current clinical practice; they are safe and easy to administrate. This makes erythromycin and other antibiotics potential preconditioning agents. Several in vivo studies have shown a neuroprotective effect by erythromycin preconditioning. ,, Erythromycin can induce tolerance against cerebral ischemia in vivo by reduction of hippocampal and parietal cortex neural loss.  The beneficial effects of erythromycin preconditioning can be attributed to the downregulation of some genes implicated in the ischemic insult [i.e., cytokines, chemokines, and inducible nitric oxide synthase (iNOS)].  A single dose of the macrolide antibiotic can induce tolerance against cerebral ischemia in vivo. 
Opioids are medications that relieve pain by binding the opioid receptors principally found in the nervous system and the gastrointestinal tract. The receptors in these organ systems are also responsible for the related psychoactive side effects.
Morphine, an agonist for delta-, mu-, and kappa-opioid receptors, has shown significant preconditioning neuroprotective effects in the acute and delayed phases.  The effects of morphine preconditioning have been shown under in vivo and in vitro conditions. , The mechanism of opioid preconditioning probably involves several pathways but they have not yet been fully elucidated. However, the opioid receptors activated in the acute (δ-opioid receptor) and delayed (an μ-opioid receptor) preconditioning may be different.  Recently, it has been shown that neuroprotection induced by opioid preconditioning (i.e., fentanyl) may be due to an improvement in the blood flow to regions affected by ischemia. 
LPSs, also known as lipoglycans and endotoxins, are the major components of the outer membrane of Gram-negative bacteria. They are large molecules consisting of a phospholipid that is responsible for toxic effects and a polysaccharide composed of O-antigen, outer core and inner core joined by a covalent bond. LPS elicit strong immune responses in animals; low doses can lead to dramatic symptoms whereas higher concentrations correlate with higher mortality rate in patients. 
Owing to its potent inflammatory effect, the efficacy of LPS as a preconditioned stimulus was analyzed. LPS-induced preconditioning decreased subsequent brain injury in animal models of ischemia and showed suppression of NFκB activity.  Interestingly, there is evidence that this suppression can promote protection against cerebral ischemia without influencing pro-inflammatory cytokine production.  A potential upstream mediator is thought to be tumor necrosis factor alpha (TNF-α). Though high concentrations of TNF-α worsens outcomes following stroke, more recent data suggest that it can also induce neuroprotection. 
As previously mentioned for opioids, LPS may improve cerebral blood flow to regions affected by stroke. This increase might be due to upregulation of endothelial nitric oxide synthase (NOS) expression.  Taken together, these data suggest that pre- and postconditioning may also involve mechanisms of rescued cerebral perfusion.
Thrombin, a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, is activated from prothrombin at the site of cellular injury to initiate the coagulation cascade. Even though thrombin is predominantly found in the blood of humans and other animals, there is evidence suggesting that thrombin can also be found in extravascular sources including the brain.  Furthermore, other studies have demonstrated that thrombin, via binding its receptor, regulates a number of important activities in cells of the central nervous system. 
Thrombin has been implicated in brain edema formation following intracerebral hemorrhage; direct infusion of a large dose of thrombin into the caudate nucleus causes inflammation, edema formation, reactive gliosis, and scar formation in the brain.  Similarly, in models of ischemia intra-arterial administration of thrombin causes severe neurovascular injury and cell death. 
Despite these deleterious effects, it has been shown that when thrombin is given at low doses before ischemia it is able to induce neuroprotection. Thrombin preconditioning attenuates brain edema when administrated at low doses before intracerebral injection of higher doses, or before intracerebral hemorrhage.  In vivo, thrombin preconditioning has also proven effective in reducing infarct volume and behavioral deficit in murine models of cerebral ischemia.  In vitro OGD studies have similarly shown decreased cell death.  The mechanisms responsible for thrombin neuroprotection may involve activating the protease-activated receptors (PARs) through a wide variety of intracellular pathways (i.e., potentiation of NMDA receptors with neurotoxic hyperexcitability). 
Thrombin preconditioning is also in part dependent on thrombin-receptor activation. These effects may be secondary to downstream activation of p44/42 mitogen-activated protein kinase, possibly playing a role in the synthesis of neuroprotective proteins such as HIF-1. Moreover, thrombin preconditioning efficacy has also been shown to be correlated with the upregulation of heat shock protein 27. 
Taken together, thrombin may be a candidate agent for pharmacologic preconditioining. However, given its complex dose-dependent effects, i.e., deleterious at high concentrations and neuroprotective at low concentrations, any translation of thrombin will required further rigorous investigations. 
| Pharmacologic Postconditioning|| |
A compelling body of preliminary data on the potential mechanisms of ischemic postconditioning argues for clinical trials. This strategy is very promising when applied to patients who have undergone surgery and endovascular therapy associated with blood vessel occlusion and revascularization. However, in many cases the time window before recanalization occurs does not match with the postconditioning neuroprotective time window; other times, the recanalized cerebral artery is not accessible. For cases in which cerebral blood vessels are not available for performing ischemic postconditioning, a pharmacologic stimulus subsequent to the ischemic event results in the best approach to induce neuroprotection (Zhao, 2009 #689). It would be ideal to find anesthetics or drugs that are able to match the actions of ischemic postconditioning. Such agents should be able to mimic the brief ischemia subsequent to the harmful event or activate the same endogenous neuroprotective pathways as a brief ischemic event would. Lately, the protective effects of pharmacological postconditioning have been explored. Already used to induce preconditioning, the anesthetic isoflurane has been shown to protect the brain against ischemia. In 2008 Lee et al. showed isoflurane neuroprotection in in vitro and in vivo models. A rat model, using 2% isoflurane for 60 min from the time of middle cerebral artery (MCA) occlusion, showed a reduction of the ischemic lesion.  Isoflurane postconditioning robustly reduced neurological deficits as well. Moreover, they showed that isoflurane postconditioning protects against ischemic injury after OGD in slice organ cultures.  The protective effects of isoflurane postconditioning, however, were dependent on the duration and concentration of exposure. Recently, more studies have demonstrated the neuroprotective effects of volatile anesthetics as postconditioning treatments with an emphasis on their underlying mechanisms. One study showed how Notch activation participates in isoflurane postconditioning after transient focal brain ischemia in male rats.  Another study subjected neonatal rats to hypoxia/ischemia and then evaluated the possible role of mitochondrial permeability transition pore (mPTP) by inhibiting it with isoflurane postconditioning. 
Isoflurane postconditioning neuroprotection was also analyzed after intracerebral hemorrhage. Using a rat intracerebral hemorrhage model (ICH), our laboratory studied the potential beneficial effect of isoflurane posttreatment.  Two concentrations of isoflurane were tested in a well-established rat model of collagenase-induced ICH. Our data demonstrated that isoflurane postconditioning did not affect edema formation or neurological deficits. In contrast, Khatibi et al.  showed that 1.5% isoflurane posttreatment significantly reduced perihematoma edema, ameliorated apoptotic cell death, and rescued neurologic function in a different model of ICH (infusing autologous blood into the striatum of mice). The disparity in the results could be due to the different species subjected to ICH and/or the different methods used to produce intracerebral hemorrhage.
Recently, the effect of isoflurane postconditioning has been analyzed after aneurysmal subarachnoid hemorrhage (SAH). Isoflurane postconditioning has shown to significantly reduce cerebral vasospasm, microvessel thrombosis, microvascular dysfunction, and neurological deficits after SAH in mice. The neuroprotection was in part mediated by hypoxia-inducible factor 1-alpha (HIF-1α). 
In addition to isoflurane, sevoflurane can also be used for postconditioning in both in vivo ischemia and in vitro the OGD model. , In fact, isoflurane, sevoflurane or desflurane have been shown to inhibit cell death in the SH-SY5Y cells (human-like neurons). 
Rapid isoflurane postconditioning also reduced cell injury by about 40% in rat organotypic hippocampal slice cultures after OGD. In the same study, the protective effects of postconditioning were induced by low dose of the pharmacological agent, 3,5-dihydroxyphenylglycine (DHPG), a group 1 metabotropic glutamate (mGlu) receptor agonist. DHPG has been shown to be neuroprotective at low doses but it increases neuronal injury at higher concentrations. 
Pharmacological treatments have been proved to induce postconditioning in the rat global ischemia model induced by four-vessel occlusion. Pharmacological postconditioning was conducted by injection of 3-nitropropionic acid (3-NP), norepinephrine or bradykinin. , Another recent study reports that after global ischemia, kainate application inhibited hippocampal neuronal injury 2 days after ischemia. ,
Taken together, the literature strongly suggests that under some conditions, pharmacologic postconditioning may induce endogenous protective signals that overlap with established preconditioning findings. Since the tolerance mechanisms underlying these phenomena may be broad and multifactorial, rigorously investigating these opportunities for clinical feasibility should be warranted.
| Conclusions|| |
Before pharmacologic pre- and postconditioning can be translated clinically, numerous obstacles between the laboratory and the clinic must be overcome. Protective mechanisms need to be further investigated, especially for pharmacologic postconditioning. So far, all of the studies analyzed were conducted in young male rodents. Therefore, pharmacologic pre- and postconditioning must be analyzed in animals of both genders and in aged brains as well. Furthermore, it may be useful to conduct studies in higher vertebrates, beyond rodents, to confirm its ability to protect against stroke. In all these model systems, the causal mechanisms should also be defined. From a clinical perspective, the approach appears attractive for its potential to be translated into an innovative clinical therapy. Before one can take the next step to translate, the mechanisms behind pharmacologic pre- and postconditioning must be defined in long-term studies; presently, the majority of data focuses on the 24 h outcomes. Many endogenous protective pathways have been evolutionarily conserved in order to defend the brain against injury. Finding and validating pharmacologic agents that can induce these endogenous mechanisms may have broad clinical benefit in stroke.
This study was supported in part by grants from the National Institutes of Health (NIH), the Beijing Natural Science Foundation, and the China National Basic Research 973 Program.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ogawa S, Kitao Y, Hori O. Ischemia-induced neuronal cell death and stress response. Antioxid Redox Signal 2007;9:573-87.
Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al
.; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-29.
O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol 2006;59:467-77.
Li S, Ma C, Shao G, Esmail F, Hua Y, Jia L, et al
. Safety and feasibility of remote limb ischemic preconditioning in patients with unilateral middle cerebral artery stenosis and healthy volunteers. Cell Transplant 2014. [Epub ahead of print].
Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 2006;7:437-48.
Zhao H. The protective effect of ischemic postconditioning against ischemic injury: From the heart to the brain. J Neuroimmune Pharmacol 2007;2:313-8.
Pignataro G, Scorziello A, Di Renzo G, Annunziato L. Post-ischemic brain damage: Effect of ischemic preconditioning and postconditioning and identification of potential candidates for stroke therapy. FEBS J 2009;276:46-57.
Guan J, Keep FR, Hua Y, Muraszko MK, Xi G. Pharmacologic preconditioning. In: Gidday JM, Perez-Pinzon MA, Zhang JH, eds. Innate Tolerance in the CNS: Translational Neuroprotection by Pre- and Post-Conditioning. 1 st
ed. New York, NY: Springer; 2013:213-24.
Chen F, Qi Z, Luo Y, Hinchliffe T, Ding G, Xia Y, et al
. Non-pharmaceutical therapies for stroke: Mechanisms and clinical implications. Prog Neurobiol 2014;115:246-69.
Garcia-Bonilla L, Benakis C, Moore J, Iadecola C, Anrather J. Immune mechanisms in cerebral ischemic tolerance. Front Neurosci 2014;8:44.
Zhao H, Joo S, Xie W, Ji X. Using hormetic strategies to improve ischemic preconditioning and postconditioning against stroke. Int J Physiol Pathophysiol Pharmacol 2013;5:61-72.
Pignataro G, Esposito E, Sirabella R, Vinciguerra A, Cuomo O, Di Renzo G, et al
. nNOS and p-ERK involvement in the neuroprotection exerted by remote postconditioning in rats subjected to transient middle cerebral artery occlusion. Neurobiol Dis 54:105-14.
Pignataro G, Boscia F, Esposito E, Sirabella R, Cuomo O, Vinciguerra A, et al
. NCX1 and NCX3: Two new effectors of delayed preconditioning in brain ischemia. Neurobiol Dis 2012;45:616-23.
Esposito E, Mandeville ET, Lo EH. Lower doses of isoflurane treatment has no beneficial effects in a rat model of intracerebral hemorrhage. BMC Neurosci 2013;14:129.
Qi Z, Dong W, Shi W, Wang R, Zhang C, Zhao Y, et al
. Bcl-2 phosphorylation triggers autophagy switch and reduces mitochondrial damage in limb remote ischemic conditioned rats after ischemic stroke. Transl Stroke Res 2015;6:198-206.
Xie R, Wang P, Ji X, Zhao H. Ischemic post-conditioning facilitates brain recovery after stroke by promoting Akt/mTOR activity in nude rats. J Neurochem 2013;127:723-32.
Zhao H, Luo Y, Liu X, Wang R, Yan F, Liu X, et al
. Ischemic post-conditioning partially reverses cell cycle reactivity following ischemia/reperfusion injury: A genome-wide survey. CNS Neurol Disord Drug Targets 2013;12:350-9.
Bhuiyan MI, Kim YJ. Mechanisms and prospects of ischemic tolerance induced by cerebral preconditioning. Int Neurourol J 2010;14:203-12.
Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-36.
Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, et al
. 'Ischemic tolerance' phenomenon found in the brain. Brain Res 1990;528:21-4.
Roux OaM. Brain Hypoxia-Ischemia Research Progress. New York: Nova Biomedical Books; 2008. p. 1-6.
Meng R, Asmaro K, Meng L, Liu Y, Ma C, Xi C, et al
. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology 2012;79:1853-61.
O'Duffy AE, Bordelon YM, McLaughlin B. Killer proteases and little strokes - how the things that do not kill you make you stronger. J Cereb Blood Flow Metab 2007;27:655-68.
Weih M, Kallenberg K, Bergk A, Dirnagl U, Harms L, Wernecke KD, et al
. Attenuated stroke severity after prodromal TIA: A role for ischemic tolerance in the brain? Stroke 1999;30:1851-4.
Gidday JM. Pharmacologic preconditioning: Translating the promise. Transl Stroke Res 2010;1:19-30.
Liebelt B, Papapetrou P, Ali A, Guo M, Ji X, Peng C, et al
. Exercise preconditioning reduces neuronal apoptosis in stroke by up-regulating heat shock protein-70 (heat shock protein-72) and extracellular-signal-regulated-kinase 1/2. Neuroscience 2010;166:1091-100.
Zhao H, Sapolsky RM, Steinberg GK. Interrupting reperfusion as a stroke therapy: Ischemic postconditioning reduces infarct size after focal ischemia in rats. J Cereb Blood Flow Metab 2006;26:1114-21.
Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, et al
. Postconditioning the human heart. Circulation 2005;112:2143-8.
Jiang X, Shi E, Nakajima Y, Sato S. Postconditioning, a series of brief interruptions of early reperfusion, prevents neurologic injury after spinal cord ischemia. Ann Surg 2006;244:148-53.
Wang JY, Shen J, Gao Q, Ye ZG, Yang SY, Liang HW, et al
. Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke 2008;39:983-90.
Zhao H, Ren C, Chen X, Shen J. From rapid to delayed and remote postconditioning: The evolving concept of ischemic postconditioning in brain ischemia. Curr Drug Targets 2012;13:173-87.
Zhao H. The protective effects of ischemic postconditioning against stroke: From rapid to delayed and remote postconditioning. Open Drug Discov J 2011;5:138-47.
Gao X, Zhang H, Takahashi T, Hsieh J, Liao J, Steinberg GK, et al
. The Akt signaling pathway contributes to postconditioning's protection against stroke; the protection is associated with the MAPK and PKC pathways. J Neurochem 2008;105:943-55.
Joo SP, Xie W, Xiong X, Xu B, Zhao H. Ischemic postconditioning protects against focal cerebral ischemia by inhibiting brain inflammation while attenuating peripheral lymphopenia in mice. Neuroscience 2013;243:149-57.
Pignataro G, Meller R, Inoue K, Ordonez AN, Ashley MD, Xiong Z, et al
. In vivo
and in vitro
characterization of a novel neuroprotective strategy for stroke: Ischemic postconditioning. J Cereb Blood Flow Metab 2008;28:232-41.
Leconte C, Tixier E, Freret T, Toutain J, Saulnier R, Boulouard M, et al
. Delayed hypoxic postconditioning protects against cerebral ischemia in the mouse. Stroke 2009;40:3349-55.
Zhao P, Ji G, Xue H, Yu W, Zhao X, Ding M, et al
. Isoflurane postconditioning improved long-term neurological outcome possibly via inhibiting the mitochondrial permeability transition pore in neonatal rats after brain hypoxia-ischemia. Neuroscience 2014;280:193-203.
Danielisová V, Némethová M, Gottlieb M, Burda J. The changes in endogenous antioxidant enzyme activity after postconditioning. Cell Mol Neurobiol 2006;26:1181-91.
Zhu H, Sun S, Li H, Tang E. Involvement of apoptosis in 3-nitropropionic acid-induced ischemic tolerance to transient focal cerebral ischemia in rats. J Huazhong Univ Sci Technolog Med Sci 2004;24:79-82.
Burda J, Danielisová V, Némethová M, Gottlieb M, Matiasová M, Domoráková I, et al
. Delayed postconditionig initiates additive mechanism necessary for survival of selectively vulnerable neurons after transient ischemia in rat brain. Cell Mol Neurobiol 2006;26:1141-51.
Kloner RA, Shook T, Antman EM, Cannon CP, Przyklenk K, Yoo K, et al
. Prospective temporal analysis of the onset of preinfarction angina versus outcome: An ancillary study in TIMI-9b. Circulation 1998;97:1042-5.
Cribier A, Korsatz L, Koning R, Rath P, Gamra H, Stix G, et al
. Improved myocardial ischemic response and enhanced collateral circulation with long repetitive coronary occlusion during angioplasty: A prospective study. J Am Coll Cardiol 1992;20:578-86.
Gao L, Jiang T, Guo J, Liu Y, Cui G, Gu L, et al
. Inhibition of autophagy contributes to ischemic postconditioning-induced neuroprotection against focal cerebral ischemia in rats. PLoS One 2012;7:e46092.
Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X, et al
. Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat. Stroke 2008;39:2362-9.
Lim YJ, Zheng S, Zuo Z. Morphine preconditions purkinje cells against cell death under in vitro
simulated ischemia-reperfusion conditions. Anesthesiology 2004;100:562-8.
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;106:538-47.
Kapinya KJ, Prass K, Dirnagl U. Isoflurane induced prolonged protection against cerebral ischemia in mice: A redox sensitive mechanism? Neuroreport 2002;13:1431-5.
Zhao P, Peng L, Li L, Xu X, Zuo Z. Isoflurane preconditioning improves long-term neurologic outcome after hypoxic-ischemic brain injury in neonatal rats. Anesthesiology 2007;107:963-70.
Sano T, Patel PM, Drummond JC, Cole DJ. A comparison of the cerebral protective effects of etomidate, thiopental, and isoflurane in a model of forebrain ischemia in the rat. Anesth Analg 1993;76:990-7.
Kwon JY, Bacher A, Deyo DJ, Disterhoft JF, Uchida T, Zornow MH. Effects of pentobarbital and isoflurane on conditioned learning after transient global cerebral ischemia in rabbits. Anesthesiology 2000;92:171-7.
Homi HM, Mixco JM, Sheng H, Grocott HP, Pearlstein RD, Warner DS. Severe hypotension is not essential for isoflurane neuroprotection against forebrain ischemia in mice. Anesthesiology 2003;99:1145-51.
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;27:1108-28.
Popovic R, Liniger R, Bickler PE. Anesthetics and mild hypothermia similarly prevent hippocampal neuron death in an in vitro
model of cerebral ischemia. Anesthesiology 2000;92:1343-9.
Kudo M, Aono M, Lee Y, Massey G, Pearlstein RD, Warner DS. Effects of volatile anesthetics on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cultures. Anesthesiology 2001;95:756-65.
Warner DS, McFarlane C, Todd MM, Ludwig P, McAllister AM. Sevoflurane and halothane reduce focal ischemic brain damage in the rat. Possible influence on thermoregulation. Anesthesiology 1993;79:985-92.
Kurihara J, Tomita H, Ochiai N, Kato H. Protection by halothane of the vagal baroreflex system from transient global cerebral ischemia in dogs. Jpn J Pharmacol 1992;60:63-6.
Ruta TS, Drummond JC, Cole DJ. A comparison of the area of histochemical dysfunction after focal cerebral ischaemia during anaesthesia with isoflurane and halothane in the rat. Can J Anaesth 1991;38:129-35.
Warner DS, Zhou JG, Ramani R, Todd MM. Reversible focal ischemia in the rat: Effects of halothane, isoflurane, and methohexital anesthesia. J Cereb Blood Flow Metab 1991;11:794-802.
Beirne JP, Pearlstein RD, Massey GW, Warner DS. Effect of halothane in cortical cell cultures exposed to N-methyl-D-aspartate. Neurochem Res 1998;23:17-23.
Kudo M, Aono M, Lee Y, Massey G, Pearlstein RD, Warner DS. Absence of direct antioxidant effects from volatile anesthetics in primary mixed neuronal-glial cultures. Anesthesiology 2001;94:212-303.
Ma D, Hossain M, Pettet GK, Luo Y, Lim T, Akimov S, et al
. Xenon preconditioning reduces brain damage from neonatal asphyxia in rats. J Cereb Blood Flow Metab 2006;26:199-208.
Payne RS, Akca O, Roewer N, Schurr A, Kehl F. Sevoflurane-induced preconditioning protects against cerebral ischemic neuronal damage in rats. Brain Res 2005;1034:147-52.
Engelhard K, Werner C, Reeker W, Lu H, Mollenberg O, Mielke L, et al
. Desflurane and isoflurane improve neurological outcome after incomplete cerebral ischaemia in rats. Br J Anaesth 1999;83:415-21.
O'Rourke B. Myocardial K(ATP) channels in preconditioning. Circ Res 2000;87:845-55.
Mayanagi K, Gáspár T, Katakam PV, Busija DW. Systemic administration of diazoxide induces delayed preconditioning against transient focal cerebral ischemia in rats. Brain Res 2007;1168:106-11.
Lenzser G, Kis B, Bari F, Busija DW. Diazoxide preconditioning attenuates global cerebral ischemia-induced blood-brain barrier permeability. Brain Res 2005;1051:72-80.
Shake JG, Peck EA, Marban E, Gott VL, Johnston MV, Troncoso JC, et al
. Pharmacologically induced preconditioning with diazoxide: A novel approach to brain protection. Ann Thorac Surg 2001;72:1849-54.
Dirnagl U, Meisel A. Endogenous neuroprotection: Mitochondria as gateways to cerebral preconditioning? Neuropharmacology 2008;55:334-44.
Jelkmann W. Regulation of erythropoietin production. J Physiol 2011;589:1251-8.
Baker JE. Erythropoietin mimics ischemic preconditioning. Vascular pharmacology 2005;42:233-41.
Prass K, Scharff A, Ruscher K, Löwl D, Muselmann C, Victorov I, et al
. Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin. Stroke 2003;34:1981-6.
Ruscher K, Freyer D, Karsch M, Isaev N, Megow D, Sawitzki B, et al
. Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: Evidence from an in vitro
model. J Neurosci 2002;22:10291-301.
Noguchi CT, Asavaritikrai P, Teng R, Jia Y. Role of erythropoietin in the brain. Crit Rev Oncol Hematol 2007;64:159-71.
Lee JY, Keep RF, He Y, Sagher O, Hua Y, Xi G. Hemoglobin and iron handling in brain after subarachnoid hemorrhage and the effect of deferoxamine on early brain injury. J Cereb Blood Flow Metab 2010;30:1793-803.
Sirlin CB, Reeder SB. Magnetic resonance imaging quantification of liver iron. Magn Reson Imaging Clin N Am 2010;18:359-81, ix.
Palmer C, Roberts RL, Bero C. Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats. Stroke 1994;25:1039-45.
Hua Y, Keep RF, Hoff JT, Xi G. Deferoxamine therapy for intracerebral hemorrhage. Acta Neurochir Suppl 2008;105:3-6.
Selim MH, Ratan RR. The role of iron neurotoxicity in ischemic stroke. Ageing Res Rev 2004;3:345-53.
Hua Y, Nakamura T, Keep RF, Wu J, Schallert T, Hoff JT, et al
. Long-term effects of experimental intracerebral hemorrhage: The role of iron. J Neurosurg 2006;104:305-12.
Nakamura T, Keep RF, Hua Y, Schallert T, Hoff JT, Xi G. Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage. Neurosurg Focus 2003;15:ECP4.
Halliwell B. Protection against tissue damage in vivo
by desferrioxamine: What is its mechanism of action? Free Radic Biol Med 1989;7:645-51.
Najafi R, Sharifi AM. Deferoxamine preconditioning potentiates mesenchymal stem cell homing in vitro
and in streptozotocin-diabetic rats. Expert Opin Biol Ther 2013;13:959-72.
Straughan JL. Another look at erythromycin. S Afr Med J 1978;53:527-30.
Piccolomini R, Catamo G, Di Bonaventura G. Bacteriostatic and bactericidal in vitro
activities of clarithromycin and erythromycin against periodontopathic actinobacillus actinomycetemcomitans. Antimicrob Agents Chemother 1998;42:3000-1.
Lu WC, Li GY, Xie H, Qiu B, Yang RM, Guo ZZ. Erythromycin pretreatment induces tolerance against focal cerebral ischemia through up-regulation of nNOS but not down-regulation of HIF-1α in rats. Neurol Sci 2014;35:687-93.
Yin L, Ye S, Chen Z, Zeng Y. Rapamycin preconditioning attenuates transient focal cerebral ischemia/reperfusion injury in mice. Int J Neurosci 2012;122:748-56.
Sakata H, Niizuma K, Yoshioka H, Kim GS, Jung JE, Katsu M, et al
. Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats. J Neurosci 2012;32:3462-73.
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;104:1208-15.
Lehmann KA. Opioids: Overview on action, interaction and toxicity. Support Care Cancer 1997;5:439-44.
Zhao P, Huang Y, Zuo Z. Opioid preconditioning induces opioid receptor-dependent delayed neuroprotection against ischemia in rats. J Neuropathol Exp Neurol 2006;65:945-52.
Chi OZ, Hunter C, Liu X, Chokshi SK, Weiss HR. Effects of fentanyl pretreatment on regional cerebral blood flow in focal cerebral ischemia in rats. Pharmacology 2010;85:153-7.
Davies B, Cohen J. Endotoxin removal devices for the treatment of sepsis and septic shock. Lancet Infect Dis 2011;11:65-71.
Vartanian KB, Stevens SL, Marsh BJ, Williams-Karnesky R, Lessov NS, Stenzel-Poore MP. Lps preconditioning redirects tlr signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury. J Neuroinflammation 2011;8:140.
Tuttolomondo A, Di Raimondo D, di Sciacca R, Pinto A, Licata G. Inflammatory cytokines in acute ischemic stroke. Curr Pharm Des 2008;14:3574-89.
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;103:715-23.
Riek-Burchardt M, Striggow F, Henrich-Noack P, Reiser G, Reymann KG. Increase of prothrombin-mRNA after global cerebral ischemia in rats, with constant expression of protease nexin-1 and protease-activated receptors. Neurosci Lett 2002;329:181-4.
Masada T, Xi G, Hua Y, Keep RF. The effects of thrombin preconditioning on focal cerebral ischemia in rats. Brain Res 2000;867:173-9.
Lee KR, Colon GP, Betz AL, Keep RF, Kim S, Hoff JT. Edema from intracerebral hemorrhage: The role of thrombin. J Neurosurg 1996;84:91-6.
Chen B, Cheng Q, Yang K, Lyden PD. Thrombin mediates severe neurovascular injury during ischemia. Stroke 2010;41:2348-52.
Xi G, Hua Y, Keep RF, Hoff JT. Induction of colligin may attenuate brain edema following intracerebral hemorrhage. Acta Neurochir Suppl 2000;76:501-5.
Hu H, Yamashita S, Hua Y, Keep RF, Liu W, Xi G. Thrombin-induced neuronal protection: Role of the mitogen activated protein kinase/ribosomal protein S6 kinase pathway. Brain Res 2010;1361:93-101.
Hamill CE, Mannaioni G, Lyuboslavsky P, Sastre AA, Traynelis SF. Protease-activated receptor 1-dependent neuronal damage involves NMDA receptor function. Exp Neurol 2009;217:136-46.
Lee JJ, Li L, Jung HH, Zuo Z. Postconditioning with isoflurane reduced ischemia-induced brain injury in rats. Anesthesiology 2008;108:1055-62.
McMurtrey RJ, Zuo Z. Isoflurane preconditioning and postconditioning in rat hippocampal neurons. Brain Res 2010;1358:184-90.
Yin J, Li H, Feng C, Zuo Z. Inhibition of brain ischemia-caused notch activation in microglia may contribute to isoflurane postconditioning-induced neuroprotection in male rats. CNS Neurol Disord Drug Targets 2014;13:718-32.
Esposito E, Mandeville ET, Lo EH. Lower doses of isoflurane treatment has no beneficial effects in a rat model of intracerebral hemorrhage. BMC Neurosci 2013;14:129.
Khatibi NH, Ma Q, Rolland W, Ostrowski R, Fathali N, Martin R, et al
. Isoflurane posttreatment reduces brain injury after an intracerebral hemorrhagic stroke in mice. Anesth Analg 2011;113:343-8.
Milner E, Johnson AW, Nelson JW, Harries MD, Gidday JM, Han BH, et al
. Hif-1α mediates isoflurane-induced vascular protection in subarachnoid hemorrhage. Ann Clin Transl Neurol 2015;2:325-37.
Adamczyk S, Robin E, Simerabet M, Kipnis E, Tavernier B, Vallet B, et al
. Sevoflurane pre- and post-conditioning protect the brain via the mitochondrial K ATP channel. Br J Anaesth 2010;104:191-200.
Wang JK, Yu LN, Zhang FJ, Yang MJ, Yu J, Yan M, et al
. Postconditioning with sevoflurane protects against focal cerebral ischemia and reperfusion injury via PI3K/AKT pathway. Brain Res 2010;1357:142-51.
Lin D, Li G, Zuo Z. Volatile anesthetic post-treatment induces protection via inhibition of glycogen synthase kinase 3β in human neuron-like cells. Neuroscience 2011;179:73-9.
Scartabelli T, Gerace E, Landucci E, Moroni F, Pellegrini-Giampietro DE. Neuroprotection by group I mGlu receptors in a rat hippocampal slice model of cerebral ischemia is associated with the PI3K-AKT signaling pathway: A novel postconditioning strategy? Neuropharmacology 2008;55:509-16.
Nagy D, Kocsis K, Fuzik J, Marosi M, Kis Z, Teichberg VI, et al
. Kainate postconditioning restores LTP in ischemic hippocampal CA1: Onset-dependent second pathophysiological stress. Neuropharmacology 2011;61:1026-32.
Zhao H, Ren C, Chen X, Shen J. From rapid to delayed and remote postconditioning: The evolving concept of ischemic postconditioning in brain ischemia. Curr Drug Targets 2012;13:173-87.