|Year : 2015 | Volume
| Issue : 1 | Page : 97-103
Cerebrovascular ischemic protection by pre- and post-conditioning
Jeffrey M Gidday
Department of Neurosurgery; Department of Cell Biology and Physiology; Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA
|Date of Submission||01-Apr-2015|
|Date of Acceptance||27-Jul-2015|
|Date of Web Publication||30-Sep-2015|
Jeffrey M Gidday
Department of Neurosurgery, Washington University School of Medicine, Box 8057, St. Louis, Missouri - 63110
Source of Support: None, Conflict of Interest: None
Stroke and cardiac arrest involve injury to all the brain's resident cells and their respective progenitors, including neurons, all glial subtypes, vascular smooth muscle, vascular endothelium, and pericytes, resulting either in the death of the individual or in a lesion that likely manifests as long-term impairments across a number of cognitive and functional domains. Thousands of studies in experimental animals and results from a few clinical trials in humans have demonstrated that the mechanisms responsible for ischemic brain injury can be blocked or slowed by survival-enhancing epigenetic responses induced by "conditioning" the brain with a stress stimulus paradigm before or even after ictus. The resultant reduction in lesion size and functional deficits are often termed endogenous "neuroprotection," but this in fact involves cytoprotective responses on the part of all the aforementioned resident brain cells and the circulating immune cells as well. The present review will summarize findings demonstrating conditioning-induced protection of the cerebral vasculature, that in turn manifests as reductions in vascularly targeted inflammatory responses; less endothelial injury and improvements in structural integrity of the circulation across all levels of organization; enhanced perfusion with less thrombosis; reductions in vascular dysregulation and reactivity impairments; and, over the longer term, more robust angiogenesis and vascular remodeling. Advancing the mechanistic basis for these innately vasculoprotective phenotypes may provide therapeutic targets for limiting cerebral circulatory injury and dysfunction following stroke and cardiac arrest.
Keywords: Cardiac arrest, endothelium, epigenetics, preconditioning, stroke, tolerance
|How to cite this article:|
Gidday JM. Cerebrovascular ischemic protection by pre- and post-conditioning. Brain Circ 2015;1:97-103
| Introduction|| |
The public health burden of stroke in Western society is significant, ranking fourth in mortality and first in morbidity and related cost of care.  Cerebrovascular function is directly and indirectly affected by stroke and cardiac arrest, and as such is an important contributor to these morbidity/mortality statistics. In brief, as a result of many multifactorial mechanisms, cerebral ischemia leads to an inflammatory response characterized, in part, by: The capture and transmigration of circulating leukocytes into brain parenchyma; ,, a breakdown of the blood-brain barrier (BBB); , cerebral blood flow (CBF) changes that are inadequate for the ongoing metabolic demands of the tissue or are inappropriate for moment-to-moment autoregulatory needs; ,, and direct endothelial cell injury or apoptotic death.  Some of these pathological responses continue well into recovery, including inadequate angiogenesis and vascular remodeling. , Thus, cerebrovascular protection, and secondary neuroprotection, resulting from treatments specifically targeted to these vascular dysfunction and injury mechanisms, could significantly improve outcomes from local and global cerebral ischemia. 
Conditioning-based epigenetics represent a unique therapeutic strategy for impacting multiple injury pathways simultaneously, including the aforementioned vascular-specific ones. Conditioning involves the intentional application of a noninjurious physiologic or pharmacologic stimulus or stimulus train before or after stroke (pre- and postconditioning, respectively) with the intention of triggering cell-specific and tissue-wide adaptive changes in gene expression such that, overall, the brain becomes transiently more resistant to ischemia. ,,,, A strong foundation of experimental conditioning studies is present documenting poststroke protective outcomes across all of the aforementioned vascular dysfunction endpoints. These findings are reviewed below, along with their currently understood mechanistic features. For space considerations, few attempts were made herein to specifically identify the details of the physiologic (hypoxia, brief ischemia of the target or distant tissue, heat shock, exercise, electroacupuncture, etc.) or pharmacologic (anesthetics, 3-nitropropionic acid, prolyl hydroxylase inhibitors, resveratrol, herbals/phytochemicals, etc.) stimulus used when mentioning a given outcome. Of the pharmacologic postconditioning studies cited herein, caveats were not advanced regarding whether a given treatment represents a "true" conditioning approach that triggers an adaptive epigenetic response and/or the agent simply exerts direct protective effects on the vasculature and thus is not conceptually different from a more standard pre- or posttreatment paradigm; in most instances, this important distinction has yet to be experimentally addressed. Finally, the experimental stroke model (global, transient focal, permanent focal, chronic hypoperfusion, in vitro cultures, etc.) used for every study cited herein was not necessarily highlighted, as part of a larger effort to promote brevity within a broad and deep review.
| Endothelial Protection|| |
All cell types in the brain likely respond epigenetically to conditioning stimuli, not just neurons. Thus, the respective phenotypes of endothelial cells, smooth muscle cells, and pericytes become transformed into ones that better resist ischemic injury and death. However, direct evidence for this hypothesis is largely lacking, save for endothelial cells. From studies of cultured cerebrovascular endothelial cells, it has been demonstrated that preconditioning protects against simulated ischemia-induced apoptosis secondary to an Akt-mediated activation of the inhibitor-of-apoptosis protein (IAP) survivin  and cellular inhibitor of apoptosis protein-1 (cIAP1).  Other culture studies have provided evidence for protective signaling pathways involving the vascular endothelial growth factor (VEGF)-A and VEGF receptor-2 (VEGFR2)-mediated phosphorylation of the cyclic AMP response element-binding protein (CREB),  and sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae) (i.e., SIRT1).  Conditioning also protects against glucotoxicity-induced apoptosis in cultured cerebral endothelium,  and correlates with elevated levels of erythropoietin (EPO), endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO), VEGF, and low levels of mitochondrial reactive oxygen species (ROS). The endothelial cell-specific expression of several cytoprotective mediators, e.g., heat shock protein-72 (HSP-72),  and hypoxia-inducible factor-1α (HIF-1α), , documented to increase in conditioned brains or conditioned cultures of cerebral endothelium, may also participate in mediating the enhanced resistance of this specific vascular cell type to ischemic injury.
| Reductions In Postischemic Vascular Inflammation|| |
Inflammation represents a classic example of hormesis, or "the dose makes the poison," with respect to conditioning-induced stroke tolerance. More specifically, while the ischemia-tolerant brain is characterized by reductions in a variety of inflammatory metrics (see below), evidence also suggests that low levels of proinflammatory molecules such as lipopolysaccharide can not only trigger tolerance-promoting signaling cascades when given exogenously, ,,,,, but that the elaboration of endogenous proinflammatory cytokines [tumor necrosis factor-alpha (TNFa), interleukin 1-beta (IL-1β), etc.] and chemokines [C-C motif chemokine ligand 2 (CCL2), etc.] by other conditioning stimuli may also play "nontraditional" roles as essential proximal mediators of such cascades, , including CCL2 elaboration in cerebral microvessels. 
A number of distinct features of postischemic vascular inflammation are reduced or abolished in the stroke-tolerant brain. Specifically, preconditioning not only attenuates the numbers of "activated" neutrophils and other leukocyte subtypes induced by ischemia, but also reduces circulating levels of monocytes, T lymphocytes, and granulocytes.  Cerebral endothelial cell expression levels of the message and/or protein levels for the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), required to capture and ultimately promote leukocyte transmigration into the ischemic brain, are reduced by conditioning, in both cerebral endothelial cell cultures  and in vivo.,,,,,, In turn, in preconditioned animals, leukocyte rolling along inflamed endothelium is quantitatively reduced,  as is the extent of overall leukocyte diapedesis into the brain parenchyme. ,,,,,,, More specifically, the infiltration of both innate and adaptive immune cells into the ischemic brain is reduced by conditioning,  with the diapedesis of monocytes, macrophages, neutrophils, and T cells reduced, but not that of B cells, the latter of which may actually contribute to neurovascular protection.  The degree to which ischemia induces activation of microglia is lower in pre- and postconditioned brains. ,,, Finally, in postconditioned animals, the extent of peripheral lymphopenia following stroke is attenuated in postconditioned animals,  as is the extent of monocyte activation. 
Lower levels of proinflammatory cytokine and chemokine elaboration into blood and extracellular spaces following stroke may account for the overall attenuation of these various postischemic inflammation metrics in conditioned animals. ,,, This, in turn, may result from decreases in the overall expression levels of proinflammatory transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB).  Conversely, enhanced expression of survival-enhancing transcription factors such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2)  and HIF-1α may participate in mediating this phenotype. The latter can drive reported increases in cerebral endothelial cell levels of heme oxygenase-1 (HO-1),  EPO,  VEGF,  and other molecules with known anti-inflammatory effects.
| Improvements In Postischemic Bbb Integrity|| |
As with other vascular injury endpoints measured in the postischemic brain, improvements in BBB integrity, manifested as reductions in tracer leakage or tissue water content, represent a widely reported vasculoprotective phenotype in conditioned animals, independent of the variety of physiologic and pharmacologic pre- and postconditioning stimuli used, and the ischemic model. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Similar findings regarding barrier resistance have been reported using in vitro models of the BBB. , The extent of hemorrhagic transformation following focal embolic stroke is also reduced in conditioned animals. 
Mechanistically, reductions in ischemia-induced disruptions in the BBB likely result from molecular changes regulating vascular permeability at a number of levels of vascular organization, including preservation of tight junction protein expression/localization, ,,,,, upregulation of barrier-strengthening integrins on microvessels,  minimization of filamentous actin (F-actin) stress fiber formation,  aquaporin channel modulation, , and reductions in the extent of elaboration of inducible nitric oxide synthase (iNOS)  and matrix metallopeptidase 9 (MMP9). ,,,, In turn, these changes may be driven by conditioning-induced reductions in endothelial NFkB and ROS,  and/or increases in endothelial sphingosine-1-phosphate (S1P) levels, , 70 kilodalton heat shock protein (Hsp-70) expression,  type-1 interferon (IFN),  insulin-like growth factor 1 (IGF-1),  NO production via eNOS, ,,,,,, and/or mitochondrial membrane depolarization. 
| Augmented Postischemic Perfusion and Vascular Reactivity|| |
Periinfarct CBF is reduced in the early hours following focal stroke, and a period of hypoperfusion follows global ischemia as well; both of these "insults to injury" likely contribute to the ultimate extent of ischemic damage so manifested. While in conditioned animals subjected to transient focal stroke the magnitude of the resultant reactive hyperemia is blunted by postconditioning,  a more general, but not universal,  finding - whether measured as absolute or relative flows - is that levels of postischemic periinfarct CBF, normally depressed in the early hours to days following ischemia, run higher. ,,,,, Moreover, these studies showed that regions of preserved perfusion in tolerant animals were associated with regions of tissue sparing,  that increases in CBF were paralleled by increases in oxygen consumption,  and that the timely reperfusion of the penumbra is critical to conditioning-induced protection in focal stroke.  At longer times of recovery following focal stroke, lower levels of overall CBF may characterize the tolerant brain secondary to a reduced baseline metabolic demand and intact flow-metabolism coupling. ,
During recovery following global ischemia, normally characterized by a state of hypoperfusion, CBF is enhanced in most brain regions studied in animals that were conditioned; ,,, this makes it difficult to unequivocally conclude that enhanced perfusion in selectively vulnerable regions such as the CA1 hippocampal subfield was required for the neuronal protection observed in these regions.  Interestingly, conditioning also attenuates the extent of reactive hyperemia immediately following the period of ischemia. , In a mouse model of vascular cognitive impairment secondary to cerebral hypoperfusion, postischemic CBF levels were higher in animals receiving repetitive remote postconditioning;  moreover, the perfusion improvement was sustained at 1 month, well after discontinuing the postconditioning stimulus.
Of note, preconditioning may actually reduce the extent of CBF reduction during the period of ischemia itself, given findings in newborn  and adult ,, rodents; however, this is not a widespread finding, with others reporting no effect of immediate  or advanced preconditioning ,, on intraischemic CBF. Finally, in mice with subarachnoid hemorrhage (SAH), preconditioning  and postconditioning  reduce the extent of large-artery vasospasm; in humans with SAH, transcranial Doppler measures suggestive of increased blood flow were recorded during periods of remote conditioning. 
Ischemia-induced impairments in vascular reactivity are also abrogated by conditioning. For example, in vivo studies have revealed the prevention of ischemia-impaired dilatory responses of pial arterioles to whisker stimulation, topical acetylcholine, and hypercapnia.  Moreover, in isolated vessel preparations obtained from conditioned adult animals subjected to stroke, , and from neonates subjected to intrauterine asphyxia,  endothelium-dependent dilations to acetylcholine were also restored. In a model of SAH-induced vasospasm, preconditioning with hypoxia  or postconditioning with isoflurane  also prevented impairments in pial arteriolar reactivity to endothelium-dependent dilators. Collectively, these findings indicate that conditioning exerts direct protective effects on both cerebral resistance vessels and larger arteries that allow for appropriate autoregulatory responses.
The mechanisms by which perfusion is generally augmented in the ischemic and postischemic brain of conditioned animals is surely multifactorial, but few studies have directly attempted to elucidate the regulatory steps affected by conditioning; a similar summary applies to understanding how vascular reactivity remains intact in a conditioned brain. A number of lines of evidence support the concept that eNOS-derived NO levels are higher in conditioned animals, perhaps as a result of a reduction in the extent of eNOS uncoupling,  resulting in increases in postischemic tissue perfusion. , Indeed, reductions in eNOS expression and activity levels, as well as NO availability, resulting from SAH were ameliorated by preconditioning,  consistent with the loss of preconditioning-induced protection against SAH-induced vasospasm in eNOS-mull mice.  There is also good causal evidence for the direct involvement of iNOS-derived NO,  or the indirect participation of iNOS-derived NO through its formation of peroxynitrite via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide radical,  in maintaining both CBF and the integrity of endothelium-dependent responsivity. The expression of HIF-1α genes from endothelial cells was demonstrated-by using endothelial cell-specific HIF-1α knockout mice-as critical to the amelioration of vasospasm in the setting of isoflurane postconditioning.  Lower serum levels of the vasoconstrictor endothelin have been measured 24 h following global  and focal  ischemia in mice and rats, respectively, temporally coincident with the higher postischemic CBF recorded in these models. Perfusion improvements may also be forthcoming as a result of reductions in thrombosis. As evidence of this possibility, decreased levels of thrombomodulin and von Willebrand factor in plasma characterize the tolerant brain;  microvascular fibrinogen immunostaining in the cortex of mouse brains subjected to SAH is reduced by postconditioning;  and in humans with large vessel strokes, earlier recanalization is noted following intravenous thrombolysis in a physical exercise cohort relative to sedentary controls.  In fact, remote conditioning in humans with SAH resulted in prolongation of coagulation times. 
| Enhanced Postischemic Angiogenesis and Vascular Remodeling|| |
That the conditioned brain would exhibit an enhanced angiogenic response following stroke is a phenotype expected of the neurovascular plasticity underlying ischemic tolerance. Indeed, angiogenesis genes are upregulated in the neonatal rat brain in response to preconditioning, and the postischemic reduction in capillary density in this model is ameliorated,  or reversed to levels above baseline, , in conditioned animals. In the adult brain, a conditioning-induced increase in capillary density occurs in the penumbra 3 days after focal stroke, , but other studies have found no changes in this angiogenesis metric.  Several different integrins are upregulated in the cerebrovasculature in response to exercise preconditioning, and their expression is preserved following stroke.  Interestingly, postischemic angiogenesis is enhanced following stem cell therapy if the stem cells themselves are conditioned. ,
With respect to the mechanisms underlying this phenotype, in many models of conditioning-induced cerebrovascular protection, increases in VEGF are measured during ischemic recovery, ,,,, which, depending on the temporal pattern of its elaboration, may counteract to some extent conditioning-induced reductions in BBB permeability in exchange for it acting as a mitogen for vasculogenesis. Increases in VEGF are also implicated as mediating the conditioning-induced increase in intraischemic CBF.  Also correlated with an enhanced angiogenesis phenotype are conditioning-associated elevations in the expression of angiopoietin,  insulin-like growth factor 1 (IGF-1),  and angiogenin.  Delayed elevations in MMP9 in conditioned animals may serve to facilitate angiogenesis during the more protracted period of postischemic recovery. 
| Mechanisms and Therapeutic Potential|| |
Predictably, the mechanisms by which conditioning approaches protect the cerebrovasculature across the various aforementioned phenotypes, many of which have already been discussed, are as complex and multifactorial as those responsible for the different manifestations of ischemic vascular injury themselves. Moreover, there are many "levels" to interrogate when considering therapeutic targets: Identifying the proximal players signaling the epigenetic response; elucidating increases and decreases in the expression of the specific genes affected; and characterizing the spatiotemporal features of the new vasculoprotective phenotype. Advances in cerebrovascular proteomics  may help for the latter, but clinically viable therapeutics are more likely to derive from drugs that activate more proximal signaling pathways that are somehow conserved, as reflected by their responsivity to a myriad of conditioning stimuli.
Many studies have focused on NO, primarily that derived from eNOS, ,,,,,,, as a key signaling intermediate between the conditioning stimulus and the resultant change in gene expression. However, in other investigations, evidence has been provided that the NO signal derives from iNOS. , Making causal evidence difficult to obtain with respect to NO's role as a proximal mediator is the fact that NO also acts as an effector of many vasculoprotective phenotypes, in part by countering ischemia-induced reductions in NO bioavailability.  Free radical species may also serve as key signaling intermediates in establishing vasculoprotective phenotypes. ,,
The cerebrovascular endothelium is strategically positioned to serve in a sentry-like capacity to transduce changes in the levels of blood-borne conditioning stimuli to signals that surrounding neurons and glia "understand" as stimuli for adaptive epigenetic change. This is particularly true for remote conditioning paradigms,  but also for systemically based conditioning stimuli such as whole-body hypoxia and lipopolysachharides (LPS), among others. The mechanisms that regulate each step of such an endothelial cell-based paracrine signaling pathway are surely complex, and have yet to be elucidated.
| Conclusions|| |
Conditioning-based treatments for stroke and cardiac arrest exert myriad protective effects at all levels of cerebral macro- and microcirculatory organization that are manifested, in turn, as reductions in cerebrovascular injury and dysfunction. Improvements in neuronal and glial viability may represent secondary benefits that contribute to the overall extent of protection observed in the conditioned brain. A better understanding of the molecular, genetic, and epigenetic bases of the vasculoprotective responses triggered by conditioning stimuli could facilitate the development of therapeutics that robustly impact stroke morbidity and mortality.
Supported by National Institutes of Health (NIH) R01EY018607.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al
.; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive summary: Heart disease and stroke statistics - 2014 update: A report from the American Heart Association. Circulation 2014;129:399-410.
Ahmad M, Dar NJ, Bhat ZS, Hussain A, Shah A, Liu H, et al
. Inflammation in ischemic stroke: Mechanisms, consequences and possible drug targets. C CNS Neurol Disord Drug Targets 2014;13:1378-96.
Hagberg H, Mallard C, Ferriero DM, Vannucci SJ, Levison SW, Vexler ZS, et al
. The role of inflammation in perinatal brain injury. Nat Rev Neurol 2015;11:192-208.
Kawabori M, Yenari MA. Inflammatory responses in brain ischemia. Curr Med Chem 2015;22:1258-77.
Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med 2013;19:1584-96.
Schoknecht K, David Y, Heinemann U. The blood-brain barrier-gatekeeper to neuronal homeostasis: Clinical implications in the setting of stroke. Semin Cell Dev Biol 2014;38:35-42.
Hossmann KA, Traystman RJ. Cerebral blood flow and the ischemic penumbra. Handb Clin Neurol 2009;92:67-92.
Shuaib A, Butcher K, Mohammad AA, Saqqur M, Liebeskind DS. Collateral blood vessels in acute ischaemic stroke: A potential therapeutic target. Lancet Neurol 2011;10:909-21.
Jordan JD, Powers WJ. Cerebral autoregulation and acute ischemic stroke. Am J Hypertens 2012;25:946-50.
Fisher M. Injuries to the vascular endothelium: Vascular wall and endothelial dysfunction. Rev Neurol Dis 2008;5(Suppl 1):S4-11.
Ergul A, Alhusban A, Fagan SC. Angiogenesis: A harmonized target for recovery after stroke. Stroke 2012;43:2270-4.
Liu J, Wang Y, Akamatsu Y, Lee CC, Stetler RA, Lawton MT, et al
. Vascular remodeling after ischemic stroke: Mechanisms and therapeutic potentials. Prog Neurobiol 2014;115:138-56.
Gursoy-Ozdemir Y, Yemisci M, Dalkara T. Microvascular protection is essential for successful neuroprotection in stroke. J Neurochem 2012;123(Suppl 2):2-11.
Mergenthaler P, Dirnagl U. Protective conditioning of the brain: Expressway or roadblock? J Physiol 2011;589:4147-55.
Hess DC, Hoda MN, Bhatia K. Remote limb perconditioning [corrected] and postconditioning: Will it translate into a promising treatment for acute stroke? Stroke 2013;44:1191-7.
Stetler RA, Leak RK, Gan Y, Li P, Zhang F, Hu X, et al
. Preconditioning provides neuroprotection in models of CNS disease: Paradigms and clinical significance. Prog Neurobiol 2014;114:58-83.
Stevens SL, Vartanian KB, Stenzel-Poore MP. Reprogramming the response to stroke by preconditioning. Stroke 2014;45:2527-31.
Gidday JM. Extending injury- and disease-resistant CNS phenotypes by repetitive epigenetics conditioning. Front Neurol 2015;6:42.
Zhang Y, Park TS, Gidday JM. Hypoxic preconditioning protects human brain endothelium from ischemic apoptosis by Akt-dependent survivin activation. Am J Physiol Heart Circ Physiol 2007;292:H2573-81.
Lin WY, Chang YC, Ho CJ, Huang CC. Ischemic preconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatal brain. Stroke 2013;44:162-9.
Lee HT, Chang YC, Tu YF, Huang CC. VEGF-A/VEGFR-2 signaling leading to cAMP response element-binding protein phosphorylation is a shared pathway underlying the protective effect of preconditioning on neurons and endothelial cells. J Neurosci 2009;29:4356-68.
Clark D, Tuor UI, Thompson R, Institoris A, Kulynych A, Zhang X, et al
. Protection against recurrent stroke with resveratrol: Endothelial protection. PLoS One 2012;7:e47792.
Correia SC, Santos RX, Cardoso SM, Santos MS, Oliveira CR, Moreira PI. Cyanide preconditioning protects brain endothelial and NT2 neuron-like cells against glucotoxicity: Role of mitochondrial reactive oxygen species and HIF-1α. Neurobiol Dis 2012;45:206-18.
Ikeda T, Xia XY, Xia YX, Ikenoue T. Hyperthermic preconditioning prevents blood-brain barrier disruption produced by hypoxia-ischemia in newborn rat. Brain Res Dev Brain Res 1999;117:53-8.
Milner E, Johnson AW, Nelson JW, Harrier 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.
Puisieux F, Deplanque D, Pu Q, Souil E, Bastide M, Bordet R. Differential role of nitric oxide pathway and heat shock protein in preconditioning and lipopolysaccharide-induced brain ischemic tolerance. Eur J Pharmacol 2000;389:71-8.
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.
Kunz A, Park L, Abe T, Gallo EF, Anrather J, Zhou P, et al
. Neurovascular protection by ischemic tolerance: Role of nitric oxide and reactive oxygen species. J Neurosci 2007;27:7083-93.
Stevens SL, Ciesielski TM, Marsh BJ, Yang T, Homen DS, Boule JL, et al
. Toll-like receptor 9: A new target of ischemic preconditioning in the brain. J Cereb Blood Flow Metab 2008;28:1040-7.
Marsh B, Stevens SL, Packard AE, Gopalan B, Hunter B, Leung PY, et al
. Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: A critical role for IRF3. J Neurosci 2009;29:9839-49.
Lin HY, Wu CL, Huang CC. The Akt-endothelial nitric oxide synthase pathway in lipopolysaccharide preconditioning-induced hypoxic-ischemic tolerance in the neonatal rat brain. Stroke 2010;41:1543-51.
Ding YH, Young CN, Luan X, Li J, Rafols JA, Clark JC, et al
. Exercise preconditioning ameliorates inflammatory injury in ischemic rats during reperfusion. Acta Neuropathol (Berl) 2005;109:237-46.
Bowen KK, Naylor M, Vemuganti R. Prevention of inflammation is a mechanism of preconditioning-induced neuroprotection against focal cerebral ischemia. Neurochem Int 2006;49:127-35.
Stowe AM, Wacker BK, Cravens PD, Perfater JL, Li MK, Hu R, et al
. CCL2 upregulation triggers hypoxic preconditioning-induced protection from stroke. J Neuroinflammation 2012;9:33.
An P, Xue YX. Effects of preconditioning on tight junction and cell adhesion of cerebral endothelial cells. Brain Res 2009;1272:81-8.
Ouk T, Laprais M, Bastide M, Mostafa K, Gautier S, Bordet R. Withdrawal of fenofibrate treatment partially abrogates preventive neuroprotection in stroke via loss of vascular protection. Vascul Pharmacol 2009;51:323-30.
Curry A, Guo M, Patel R, Liebelt B, Sprague S, Lai Q, et al
. Exercise pre-conditioning reduces brain inflammation in stroke via tumor necrosis factor-alpha, extracellular signal-regulated kinase 1/2 and matrix metalloproteinase-9 activity. Neurol Res 2010;32:756-62.
Stowe AM, Altay T, Freie AB, Gidday JM. Repetitive hypoxia extends endogenous neurovascular protection for stroke. Ann Neurol 2011;69:975-85.
Yu Q, Chu M, Wang H, Lu S, Gao H, Li P, et al
. Sevoflurane preconditioning protects blood-brain-barrier against brain ischemia. Front Biosci (Elite Ed) 2011;3:978-88.
Miao M, Zhang X, Bai M, Wang L. Persimmon leaf flavonoid promotes brain ischemic tolerance. Neural Regen Res 2013;8:2625-32.
Khan MB, Hoda MN, Vaibhav K, Giri S, Wang P, Waller JL, et al
. Remote ischemic postconditioning: Harnessing endogenous protection in a murine model of vascular cognitive impairment. Transl Stroke Res 2015;6:69-77.
Wang Q, Kalogeris TJ, Wang M, Jones AW, Korthuis RJ. Antecedent ethanol attenuates cerebral ischemia/reperfusion-induced leukocyte-endothelial adhesive interactions and delayed neuronal death: Role of large conductance, Ca2+-activated K+ channels. Microcirculation 2010;17:427-38.
Monson NL, Ortega SB, Ireland SJ, Meeuwissen AJ, Chen D, Plautz EJ, et al
. Repetitive hypoxic preconditioning induces an immunosuppressed B cell phenotype during endogenous protection from stroke. J Neuroinflammation 2014;11:22.
Tu XK, Yang WZ, Chen JP, Chen Y, Chen Q, Chen PP, et al
. Repetitive ischemic preconditioning attenuates inflammatory reaction and brain damage after focal cerebral ischemia in rats: Involvement of PI3K/Akt and ERK1/2 signaling pathway. J Mol Neurosci 2015;55:912-22.
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.
Rosenzweig HL, Lessov NS, Henshall DC, Minami M, Simon RP, Stenzel-Poore MP. Endotoxin preconditioning prevents cellular inflammatory response during ischemic neuroprotection in mice. Stroke 2004;35:2576-81.
Li XQ, Cao XZ, Wang J, Fang B, Tan WF, Ma H. Sevoflurane preconditioning ameliorates neuronal deficits by inhibiting microglial MMP-9 expression after spinal cord ischemia/reperfusion in rats. Mol Brain 2014;7:69.
Alfieri A, Srivastava S, Siow RC, Cash D, Modo M, Duchen MR, et al
. Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurological deficits in stroke. Free Radic Biol Med 2013;65:1012-22.
Dai Y, Li W, Zhong M, Chen J, Liu Y, Cheng Q, et al
. Preconditioning and post-treatment with cobalt chloride in rat model of perinatal hypoxic-ischemic encephalopathy. Brain Dev 2014;36:228-40.
Al Ahmad A, Gassmann M, Ogunshola OO. Maintaining blood-brain barrier integrity: Pericytes perform better than astrocytes during prolonged oxygen deprivation. J Cell Physiol 2009;218:612-22.
Masada T, Hua Y, Xi G, Ennis SR, Keep RF. Attenuation of ischemic brain edema and cerebrovascular injury after ischemic preconditioning in the rat. J Cereb Blood Flow Metab 2001;21:22-33.
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.
Ping A, Chun ZX, Xue XY. Bradykinin preconditioning induces protective effects against focal cerebral ischemia in rats. Brain Res 2005;1059:105-12.
Vlasov TD, Korzhevskii DE, Polyakova EA. Ischemic preconditioning of the rat brain as a method of endothelial protection from ischemic/repercussion injury. Neurosci Behav Physiol 2005;35:567-72.
Ding YH, Li J, Yao WX, Rafols JA, Clark JC, Ding Y. Exercise preconditioning upregulates cerebral integrins and enhances cerebrovascular integrity in ischemic rats. Acta Neuropathol 2006;112:74-84.
Zhang FY, Chen XC, Ren HM, Bao WM. Effects of ischemic preconditioning on blood-brain barrier permeability and MMP-9 expression of ischemic brain. Neurol Res 2006;28:21-4.
Bigdeli MR, Hajizadeh S, Froozandeh M, Rasulian B, Heidarianpour A, Khoshbaten A. Prolonged and intermittent normobaric hyperoxia induce different degrees of ischemic tolerance in rat brain tissue. Brain Res 2007;1152:228-33.
Bigdeli MR, Khoshbaten A. In vivo
preconditioning with normobaric hyperoxia induces ischemic tolerance partly by triggering tumor necrosis factor-alpha converting enzyme/tumor necrosis factor-alpha/nuclear factor-kappaB. Neuroscience 2008;153:671-8.
Hua F, Ma J, Ha T, Kelley J, Williams DL, Kao RL, et al
. Preconditioning with a TLR2 specific ligand increases resistance to cerebral ischemia/reperfusion injury. J Neuroimmunol 2008;199:75-82.
Kalpana S, Dhananjay S, Anju B, Lilly G, Sai Ram M. Cobalt chloride attenuates hypobaric hypoxia induced vascular leakage in rat brain: Molecular mechanisms of action of cobalt chloride. Toxicol Appl Pharmacol 2008;231:354-63.
Methy D, Bertrand N, Prigent-Tessier A, Mossiat C, Stanimirovic D, Beley A, et al
. Beneficial effect of dipyridyl, a liposoluble iron chelator against focal cerebral ischemia: In vivo
and in vitro
evidence of protection of cerebral endothelial cells. Brain Res 2008;1193:136-42.
Peng Z, Ren P, Kang Z, Du J, Lian Q, Liu Y, et al
. Up-regulated HIF-1alpha is involved in the hypoxic tolerance induced by hyperbaric oxygen preconditioning. Brain Res 2008;1212:71-8.
Ren C, Gao X, Steinberg GK, Zhao H. Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning. Neuroscience 2008;151:1099-103.
Dong W, Gao D, Lin H, Zhang X, Li N, Li F. New insights into mechanism for the effect of resveratrol preconditioning against cerebral ischemic stroke: Possible role of matrix metalloprotease-9. Medical hypotheses 2008;70:52-5.
Wacker BK, Park TS, Gidday JM. Hypoxic preconditioning-induced cerebral ischemic tolerance: Role of microvascular sphingosine kinase 2. Stroke 2009;40:3342-8.
Gesuete R, Orsini F, Zanier ER, Albani D, Deli MA, Bazzoni G, et al
. Glial cells drive preconditioning-induced blood-brain barrier protection. Stroke 2011;42:1445-53.
Hoshi A, Yamamoto T, Shimizu K, Sugiura Y, Ugawa Y. Chemical preconditioning-induced reactive astrocytosis contributes to the reduction of post-ischemic edema through aquaporin-4 downregulation. Exp Neurol 2011;227:89-95.
Ren C, Gao M, Dornbos D 3 rd
, Ding Y, Zeng X, Luo Y, et al
. Remote ischemic post-conditioning reduced brain damage in experimental ischemia/reperfusion injury. Neurol Res 2011;33:514-9.
Bigdeli MR, Asheghabadi M, Khalili A. Time course of neuroprotection induced by normobaric hyperoxia in focal cerebral ischemia. Neurol Res 2012;34:439-46.
Soejima Y, Ostrowski RP, Manaenko A, Fujii M, Tang J, Zhang JH. Hyperbaric oxygen preconditioning attenuates hyperglycemia enhanced hemorrhagic transformation after transient MCAO in rats. Med Gas Res 2012;2:9.
Wacker BK, Freie AB, Perfater JL, Gidday JM. Junctional protein regulation by sphingosine kinase 2 contributes to blood-brain barrier protection in hypoxic preconditioning-induced ischemic tolerance. J Cereb Blood Flow Metab 2012;32:1014-23.
Wei D, Ren C, Chen X, Zhao H. The chronic protective effects of limb remote preconditioning and the underlying mechanisms involved in inflammatory factors in rat stroke. PLoS One 2012;7:e30892.
Rezazadeh H, Hoseini Kahnuee M, Roohbakhsh A, Shamsizadeh A, Rahmani MR, Bidaki R, et al
. Neuroprotective consequences of postconditioning on embolic model of cerebral ischemia in rat. Iran J Basic Med Sci 2013;16:144-9.
Yang F, Zhang X, Sun Y, Wang B, Zhou C, Luo Y, et al
. Ischemic postconditioning decreases cerebral edema and brain blood barrier disruption caused by relief of carotid stenosis in a rat model of cerebral hypoperfusion. PLoS One 2013;8:e57869.
Han D, Zhang S, Fan B, Wen LL, Sun M, Zhang H, et al
. Ischemic postconditioning protects the neurovascular unit after focal cerebral ischemia/reperfusion injury. J Mol Neurosci 2014;53:50-8.
Hoda MN, Bhatia K, Hafez SS, Johnson MH, Siddiqui S, Ergul A, et al
. Remote ischemic perconditioning is effective after embolic stroke in ovariectomized female mice. Transl Stroke Res 2014;5:484-90.
Liu Q, Zhou S, Wang Y, Qi F, Song Y, Long S. A feasible strategy for focal cerebral ischemia-reperfusion injury: Remote ischemic postconditioning. Neural Regen Res 2014;9:1460-3.
Zhang Q, Bian H, Li Y, Guo L, Tang Y, Zhu H. Preconditioning with the traditional Chinese medicine Huang-Lian-Jie-Du-Tang initiates HIF-1α -dependent neuroprotection against cerebral ischemia in rats. J Ethnopharmacol 2014;154:443-52.
Geng Y, Li E, Mu Q, Zhang Y, Wei X, Li H, et al
. Hydrogen sulfide inhalation decreases early blood-brain barrier permeability and brain edema induced by cardiac arrest and resuscitation. J Cereb Blood Flow Metab 2015;35:494-500.
Shin JA, Kim YA, Jeong SI, Lee KE, Kim HS, Park EM. Extracellular signal-regulated kinase1/2-dependent changes in tight junctions after ischemic preconditioning contributes to tolerance induction after ischemic stroke. Brain Struct Funct 2015;220:13-26.
Gesuete R, Packard AE, Vartanian KB, Conrad VK, Stevens SL, Bahjat FR, et al
. Poly-ICLC preconditioning protects the blood-brain barrier against ischemic injury in vitro
through type I interferon signaling. J Neurochem 2012;123(Suppl 2):75-85.
Chen RL, Ogunshola OO, Yeoh KK, Jani A, Papadakis M, Nagel S, et al
. HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice. J Neurochem 2014. [Epub ahead of print].
Hirt L, Ternon B, Price M, Mastour N, Brunet JF, Badaut J. Protective role of early aquaporin 4 induction against postischemic edema formation. J Cereb Blood Flow Metab 2009;29:423-33.
Dong H, Fan YH, Zhang W, Wang Q, Yang QZ, Xiong LZ. Repeated electroacupuncture preconditioning attenuates matrix metalloproteinase-9 expression and activity after focal cerebral ischemia in rats. Neurol Res 2009;31:853-8.
Wacker BK, Perfater JL, Gidday JM. Hypoxic preconditioning induces stroke tolerance in mice via a cascading HIF, sphingosine kinase, and CCL2 signaling pathway. J Neurochem 2012;123:954-62.
Gidday JM, Shah AR, Maceren RG, Wang Q, Pelligrino DA, Holtzman DM, et al
. Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. J Cereb Blood Flow Metab 1999;19:331-40.
Hashiguchi A, Yano S, Morioka M, Hamada J, Ushio Y, Takeuchi Y, et al
. Up-regulation of endothelial nitric oxide synthase via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampus. J Cereb Blood Flow Metab 2004;24:271-9.
Vellimana AK, Milner E, Azad TD, Harries MD, Zhou ML, Gidday JM, et al
. Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm. Stroke 2011;42:776-82.
Chen J, Graham SH, Zhu RL, Simon RP. Stress proteins and tolerance to focal cerebral ischemia. J Cereb Blood Flow Metab 1996;16:566-77.
Dawson DA, Furuya K, Gotoh J, Nakao Y, Hallenbeck JM. Cerebrovascular hemodynamics and ischemic tolerance: Lipopolysaccharide-induced resistance to focal cerebral ischemia is not due to changes in severity of the initial ischemic insult, but is associated with preservation of microvascular perfusion. J Cereb Blood Flow Metab 1999;19:616-23.
Zhao L, Nowak TS Jr. CBF changes associated with focal ischemic preconditioning in the spontaneously hypertensive rat. J Cereb Blood Flow Metab 2006;26:1128-40.
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.
Chi OZ, Hunter C, Liu X, Weiss HR. The effects of isoflurane pretreatment on cerebral blood flow, capillary permeability, and oxygen consumption in focal cerebral ischemia in rats. Anesth Analg 2010;110:1412-8.
Bracko O, Di Pietro V, Lazzarino G, Amorini AM, Tavazzi B, Artmann J, et al
. 3-Nitropropionic acid-induced ischemia tolerance in the rat brain is mediated by reduced metabolic activity and cerebral blood flow. J Cereb Blood Flow Metab 2014;34:1522-30.
Gonzalez NR, Hamilton R, Bilgin-Freiert A, Dusick J, Vespa P, Hu X, et al
. Cerebral hemodynamic and metabolic effects of remote ischemic preconditioning in patients with subarachnoid hemorrhage. Acta Neurochir Suppl 2013;115:193-8.
Nakamura H, Katsumata T, Nishiyama Y, Otori T, Katsura K, Katayama Y. Effect of ischemic preconditioning on cerebral blood flow after subsequent lethal ischemia in gerbils. Life Sci 2006;78:1713-9.
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.
Della-Morte D, Raval AP, Dave KR, Lin HW, Perez-Pinzon MA. Post-ischemic activation of protein kinase C ε protects the hippocampus from cerebral ischemic injury via alterations in cerebral blood flow. Neurosci Lett 2011;487:158-62.
Liu K, Yan M, Zheng X, Yang Y. The dynamic detection of NO during the ischemic postconditioning against global cerebral ischemia/reperfusion injury. Nitric Oxide 2014;38:17-25.
Gustavsson M, Mallard C, Vannucci SJ, Wilson MA, Johnston MV, Hagberg H. Vascular response to hypoxic preconditioning in the immature brain. J Cereb Blood Flow Metab 2007;27:928-38.
Hoyte LC, Papadakis M, Barber PA, Buchan AM. Improved regional cerebral blood flow is important for the protection seen in a mouse model of late phase ischemic preconditioning. Brain Res 2006;1121:231-7.
Fan YY, Hu WW, Dai HB, Zhang JX, Zhang LY, He P, et al
. Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice. J Cereb Blood Flow Metab 2011;31:305-14.
103 Atochin DN, Clark J, Demchenko IT, Moskowitz MA, Huang PL. Rapid cerebral ischemic preconditioning in mice deficient in endothelial and neuronal nitric oxide synthases. Stroke 2003;34:1299-303.
Alkayed NJ, Goyagi T, Joh HD, Klaus J, Harder DR, Traystman RJ, et al
. Neuroprotection and P450 2C11 upregulation after experimental transient ischemic attack. Stroke 2002;33:1677-84.
Takeda K, Aguila HL, Parikh NS, Li X, Lamothe K, Duan LJ, et al
. Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood 2008;111:3229-35.
Strackx E, Zoer B, Van den Hove D, Steinbusch H, Steinbusch H, Blanco C, et al
. Brain apoptosis and carotid artery reactivity in fetal asphyctic preconditioning. Front Biosci (Schol Ed) 2010;2:781-90.
Chen G, Yang J, Lu G, Guo J, Dou Y. Limb remote ischemic post-conditioning reduces brain reperfusion injury by reversing eNOS uncoupling. Indian J Exp Biol 2014;52:597-605.
Ricciardi AC, López-Cancio E, Pérez de la Ossa N, Sobrino T, Hernández-Pérez M, Gomis M, et al
. Prestroke physical activity is associated with good functional outcome and arterial recanalization after stroke due to a large vessel occlusion. Cerebrovasc Dis 2014;37:304-11.
Mayor F, Bilgin-Freiert A, Connolly M, Katsnelson M, Dusick JR, Vespa P, et al
. Effects of remote ischemic preconditioning on the coagulation profile of patients with aneurysmal subarachnoid hemorrhage: A case-control study. Neurosurgery 2013;73:808-15.
López-Aguilera F, Plateo-Pignatari MG, Biaggio V, Ayala C, Seltzer AM. Hypoxic preconditioning induces an AT2-R/VEGFR-2(Flk-1) interaction in the neonatal brain microvasculature for neuroprotection. Neuroscience 2012;216:1-9.
Li S, Zhang Y, Shao G, Yang M, Niu J, Lv G, et al
. Hypoxic preconditioning stimulates angiogenesis in ischemic penumbra after acute cerebral infarction. Neural Regen Res 2013;8:2895-903.
Duan S, Shao G, Yu L, Ren C. Angiogenesis contributes to the neuroprotection induced by hyperbaric oxygen preconditioning against focal cerebral ischemia in rats. Int J Neurosci 2014. [Epub ahead of print].
Sakata H, Narasimhan P, Niizuma K, Maier CM, Wakai T, Chan PH. Interleukin 6-preconditioned neural stem cells reduce ischaemic injury in stroke mice. Brain 2012;135:3298-310.
Wei L, Fraser JL, Lu ZY, Hu X, Yu SP. Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis 2012;46:635-45.
Badhwar A, Stanimirovic DB, Hamel E, Haqqani AS. The proteome of mouse cerebral arteries. J Cereb Blood Flow Metab 2014;34:1033-46.
Faraci FM. Vascular protection. Stroke 2003;34:327-9.
Busija DW, Katakam PV. Mitochondrial mechanisms in cerebral vascular control: Shared signaling pathways with preconditioning. J Vasc Res 2014;51:175-89.
Dezfulian C, Garrett M, Gonzalez NR. Clinical application of preconditioning and postconditioning to achieve neuroprotection. Transl Stroke Res 2013;4:19-24.
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