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| REVIEW ARTICLE |
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| Year : 2015 | Volume
: 1
| Issue : 1 | Page : 104-113 |
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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 |
Correspondence Address:
Eng H Lo
Massachusetts General Hospital - East Building 149, 13th Street, Charlestown, Massachusetts - 02129
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2394-8108.166380
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. [1]
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. [2]
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. [3],[4]
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. [5],[6] 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. [7] 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. [8] 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. [3] 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. [9] 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. [10] Ischemic preconditioning and ischemic postconditioning, two promising endogenous mechanisms of neuroprotection, [11] have recently gained attention for the ability to impose their effect on multipathways simultaneously. [7] 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 [12],[13],[14],[15] 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. [16],[17]
| 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. [18]
First identified in the heart by Murry et al. in 1986, [19] 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. [20] 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. [21] 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. [22],[23],[24]
Ischemic tolerance has been reproduced for in vitro and in vivo models. [25] 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. [26] 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. [25] 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. [5]
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. [27] Initially demonstrated to reduce the infarct size after cardiac ischemia both in an experimental setting [25] and a clinical setting, [28] ischemic postconditioning has recently been shown to attenuate neuronal damage in rodent models of spinal cord injury [29] and focal [27] and global [30] 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. [31],[32],[33],[34]
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); [27] 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. [35] 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. [30]
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. [31],[32]
As for ischemic preconditioning, it has been suggested that during postconditioning a different stressor (i.e., hypoxia, [36] isoflurane, [37] norepinephrine, [38] and 3-nitropropionic acid [39] ) 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. [7],[35],[40]
| 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. [41],[42] 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. [30],[36],[43],[44]
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 [45] and macrolide antibiotics [46] 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. [25]
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. [8] In this section, we survey the agents that have been tested and briefly review the mechanisms involved.
Volatile anesthetics
The volatile anesthetics are among the most studied pharmacologic preconditioning stimuli. Preclinical attention has mainly been focused on adult [47] and neonatal rodents. [48] 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. [49],[50],[51] However, other studies show no improvement in histological deficits and behavioral outcomes. [52] 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) [53] and in rat primary mixed neuron-glia cultures subjected to N-methyl-d-aspartate (NMDA) excitotoxocity. [54] 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 [55] and global ischemia [56] but failed in other studies. [57],[58] In vitro experiments have been inconsistent; halothane exposure during NMDA-induced toxicity showed reduction in lactate dehydrogenase release indicating improved survival [59] whereas another study was unable to detect a large effect. [60]
Other gases such as xenon [61] and sevoflurane [62] 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. [63] 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. [64] Selective mitochondrial potassium channel openers (KCOs), such as diazoxide, attenuate blood-results neuroprotective after focal [65] and global [66] cerebral ischemia. Rapid diazoxide preconditioning provided both morphological and functional protection in a canine model of brain injury by hypothermic cardiac arrest. [67] 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. [25] 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. [68] However, the complete pathway from KCO activation to the neuroprotective effects needs to be further investigated.
Erythropoietin
EPO is a glycoprotein hormone produced by the kidney that promotes erythropoiesis, the formation of red blood cells, in the bone marrow. [69] Recent research has investigated the ability of this cytokine to protect brain, kidney, and heart tissues after ischemia/reperfusion damage. [70]
In the brain, it has been shown that EPO is able to induce preconditioning. [71] 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. [72] 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. [72] 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. [73]
Deferoxamine
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. [74] 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. [75]
Iron has also been shown to increase brain injury after ischemic and hemorrhagic stroke. [76],[77] 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. [78] Previous studies have confirmed a strong correlation between regional iron levels in the brain and oxidative damage. [76] Animal models of intracerebral hemorrhage have also demonstrated elevated levels of iron. [79] 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. [80] Additionally, it can reduce brain edema, neurological deficit, and free radical formation. [80],[81] 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. [71] 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. [82]
Erythromycin
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. [83] Erythromycin is both a bacteriostatic and bactericidal; its mechanism depends on the host organism and the drug concentration. [84] 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. [85],[86],[87] Erythromycin can induce tolerance against cerebral ischemia in vivo by reduction of hippocampal and parietal cortex neural loss. [88] 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)]. [46] A single dose of the macrolide antibiotic can induce tolerance against cerebral ischemia in vivo. [88]
Opioids
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. [89] The effects of morphine preconditioning have been shown under in vivo and in vitro conditions. [45],[89] 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. [90] 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. [91]
Lipopolysaccharide
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. [92]
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. [93] Interestingly, there is evidence that this suppression can promote protection against cerebral ischemia without influencing pro-inflammatory cytokine production. [93] 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. [94]
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. [95] Taken together, these data suggest that pre- and postconditioning may also involve mechanisms of rescued cerebral perfusion.
Thrombin
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. [96] Furthermore, other studies have demonstrated that thrombin, via binding its receptor, regulates a number of important activities in cells of the central nervous system. [97]
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. [98] Similarly, in models of ischemia intra-arterial administration of thrombin causes severe neurovascular injury and cell death. [99]
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. [100] In vivo, thrombin preconditioning has also proven effective in reducing infarct volume and behavioral deficit in murine models of cerebral ischemia. [97] In vitro OGD studies have similarly shown decreased cell death. [101] 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). [102]
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. [101]
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. [8]
| 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. [103] Isoflurane postconditioning robustly reduced neurological deficits as well. Moreover, they showed that isoflurane postconditioning protects against ischemic injury after OGD in slice organ cultures. [104] 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. [105] 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. [37]
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. [106] 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. [107] 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). [108]
In addition to isoflurane, sevoflurane can also be used for postconditioning in both in vivo ischemia and in vitro the OGD model. [109],[110] In fact, isoflurane, sevoflurane or desflurane have been shown to inhibit cell death in the SH-SY5Y cells (human-like neurons). [111]
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. [112]
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. [38],[40] Another recent study reports that after global ischemia, kainate application inhibited hippocampal neuronal injury 2 days after ischemia. [113],[114]
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.
Acknowledgments
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
Nil.
Conflicts of interest
There are no conflicts of interest.
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