Translational Stroke Research

, Volume 4, Issue 1, pp 3–14 | Cite as

Should the STAIR Criteria Be Modified for Preconditioning Studies?

  • Michael M. WangEmail author
  • Guohua Xi
  • Richard F. Keep
Original Article


Diverse preconditioning (PC) stimuli protect against a wide variety of neuronal insults in animal models, engendering enthusiasm that PC could be used to protect the brain clinically. Candidate clinical applications include cardiac and vascular surgery, after subarachnoid hemorrhage, and prior to conditions in which acute neuronal injury is anticipated. However, disappointments in clinical validation of multiple neuroprotectants suggest potential problems translating animal data into successful human therapies. Thus, despite strong promise of preclinical PC studies, caution should be maintained in translating these findings into clinical applications. The Stroke Therapy Academic Industry Roundtable working group and the National institute of Neurological Diseases and Stroke proposed working guidelines to improve the utility of preclinical studies that form the foundation of therapies for neurological disease. Here, we review the applicability of these consensus criteria to preconditioning studies and discuss additional considerations for PC studies. We propose that special attention should be paid to several areas, including (1) safety and dosage of PC treatments, (2) meticulously matching preclinical modeling to the human condition to be tested, and (3) timing of both the initiation and discontinuation of the PC stimulus relative to injury ictus.


Translational research Preconditioning Ischemic tolerance STAIR Remote ischemic preconditioning 



This work was supported by the National Institutes of Health grants NS054724 (MMW), NS039866 (GX), and NS34709 (RFK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Abe H, Nowak Jr TS. Induced hippocampal neuron protection in an optimized gerbil ischemia model: insult thresholds for tolerance induction and altered gene expression defined by ischemic depolarization. J Cereb Blood Flow Metab. 2004;24(1):84–97.PubMedCrossRefGoogle Scholar
  2. 2.
    Alex J, Laden G, et al. Pretreatment with hyperbaric oxygen and its effect on neuropsychometric dysfunction and systemic inflammatory response after cardiopulmonary bypass: a prospective randomized double-blind trial. J Thorac Cardiovasc Surg. 2005;130(6):1623–30.PubMedCrossRefGoogle Scholar
  3. 3.
    Ara J, Fekete S, et al. Hypoxic-preconditioning induces neuroprotection against hypoxia-ischemia in newborn piglet brain. Neurobiol Dis. 2011;43(2):473–85.PubMedCrossRefGoogle Scholar
  4. 4.
    Bilgin-Freiert A, Dusick JR, et al. Muscle micodialysis to confirm sublethal ischemia in the induction of remote ischemic preconditioning. Trans Stroke Res. 2012;3:266–72.CrossRefGoogle Scholar
  5. 5.
    Blanck TJ, Haile M, et al. Isoflurane pretreatment ameliorates postischemic neurologic dysfunction and preserves hippocampal Ca2+/calmodulin-dependent protein kinase in a canine cardiac arrest model. Anesthesiology. 2000;93(5):1285–93.PubMedCrossRefGoogle Scholar
  6. 6.
    Brambrink AM, Koerner IP, et al. The antibiotic erythromycin induces tolerance against transient global cerebral ischemia in rats (pharmacologic preconditioning). Anesthesiology. 2006;104(6):1208–15.PubMedCrossRefGoogle Scholar
  7. 7.
    Chan MTV, Boet R, et al. Effect of ischemic preconditioning on brain tissue gases and pH during temporary cerebral artery occlusion. Acta Neurochirurgica-Supplement. 2005;95:93–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Chang C-Z, Wu S-C, et al. Atorvastatin preconditioning attenuates the production of endothelin-1 and prevents experimental vasospasm in rats. Acta Neurochirurgica. 2010;152(8):1399–406. discussion 1405–1396.PubMedCrossRefGoogle Scholar
  9. 9.
    Chen J, Graham SH, et al. Stress proteins and tolerance to focal cerebral ischemia. J Cereb Blood Flow Metab. 1996;16(4):566–77.PubMedCrossRefGoogle Scholar
  10. 10.
    Cheng O, Ostrowski RP, et al. Cyclooxygenase-2 mediates hyperbaric oxygen preconditioning in the rat model of transient global cerebral ischemia. Stroke. 2011;42(2):484–90.PubMedCrossRefGoogle Scholar
  11. 11.
    Clarkson AN. Anesthetic-mediated protection/preconditioning during cerebral ischemia. Life Sci. 2007;80(13):1157–75.PubMedCrossRefGoogle Scholar
  12. 12.
    Codaccioni J-L, Velly LJ, et al. Sevoflurane preconditioning against focal cerebral ischemia: inhibition of apoptosis in the face of transient improvement of neurological outcome. Anesthesiology. 2009;110(6):1271–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Crossley NA, Sena E, et al. Empirical evidence of bias in the design of experimental stroke studies: a metaepidemiologic approach. Stroke. 2008;39(3):929–34.PubMedCrossRefGoogle Scholar
  14. 14.
    Dave KR, Saul I, et al. Remote organ ischemic preconditioning protect brain from ischemic damage following asphyxial cardiac arrest. Neurosci Lett. 2006;404(1–2):170–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Dirnagl U, Becker K, et al. Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol. 2009;8(4):398–412.PubMedCrossRefGoogle Scholar
  16. 16.
    Dowden J, Corbett D. Ischemic preconditioning in 18- to 20-month-old gerbils: long-term survival with functional outcome measures. Stroke. 1999;30(6):1240–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Fairbanks SL, Brambrink AM. Preconditioning and postconditioning for neuroprotection: the most recent evidence. Best Pract Res Clin Anaesthesiol. 2010;24(4):521–34.PubMedCrossRefGoogle Scholar
  18. 18.
    Faries PL, DeRubertis B, et al. Ischemic preconditioning during the use of the PercuSurge occlusion balloon for carotid angioplasty and stenting. Vascular. 2008;16(1):1–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Ferguson Jr TB, Hammill BG, et al. A decade of change—risk profiles and outcomes for isolated coronary artery bypass grafting procedures, 1990–1999: a report from the STS National Database Committee and the Duke Clinical Research Institute. Society of Thoracic Surgeons. Ann Thorac Surg. 2002;73(2):480–9. discussion 489-490.PubMedCrossRefGoogle Scholar
  20. 20.
    Feuerstein GZ, Zaleska MM, et al. Missing steps in the STAIR case: a Translational Medicine perspective on the development of NXY-059 for treatment of acute ischemic stroke. J Cereb Blood Flow Metab. 2008;28(1):217–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Fisher M, et al. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke. 1999;30(12):2752–8.CrossRefGoogle Scholar
  22. 22.
    Fisher M, Feuerstein G, et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40(6):2244–50.PubMedCrossRefGoogle Scholar
  23. 23.
    Fisher M, Vasilevko V, et al. Mixed cerebrovascular disease and the future of stroke prevention. Transl Stroke Res. 2012;3 Suppl 1:39–51.PubMedCrossRefGoogle Scholar
  24. 24.
    Geng X, Ren C, et al. Effect of remote ischemic postconditioning on an intracerebral hemorrhage stroke model in rats. Neurol Res. 2012;34(2):143–8.PubMedGoogle Scholar
  25. 25.
    Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci. 2006;7(6):437–48.PubMedCrossRefGoogle Scholar
  26. 26.
    Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci. 2006;7(6):437–48.PubMedCrossRefGoogle Scholar
  27. 27.
    Gidday JM. Pharmacologic preconditioning: translating the promise. Transl Stroke Res. 2010;1(1):19–30.PubMedCrossRefGoogle Scholar
  28. 28.
    Gigante PR, Appelboom G, et al. Isoflurane preconditioning affords functional neuroprotection in a murine model of intracerebral hemorrhage. Acta Neurochirurgica-Supplement. 2011;111:141–4.PubMedCrossRefGoogle Scholar
  29. 29.
    Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology. 2008;55(3):363–89.PubMedCrossRefGoogle Scholar
  30. 30.
    Gonzalez NR, Liebeskind DS. Letter by Gonzalez and Liebeskind regarding article, “remote ischemic limb preconditioning after subarachnoid hemorrhage: a phase Ib study of safety and feasibility”. Stroke. 2011;42(9):e553.PubMedCrossRefGoogle Scholar
  31. 31.
    Green AR. Pharmacological approaches to acute ischaemic stroke: reperfusion certainly, neuroprotection possibly. Br J Pharmacol. 2008;153 Suppl 1:S325–38.PubMedGoogle Scholar
  32. 32.
    Hahn CD, Manlhiot C, et al. Remote ischemic per-conditioning: a novel therapy for acute stroke? Stroke. 2011;42(10):2960–2.PubMedCrossRefGoogle Scholar
  33. 33.
    Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc Res. 2008;79(3):377–86.PubMedCrossRefGoogle Scholar
  34. 34.
    He YD, Karabiyikoglu M, et al. Ischemic preconditioning attenuates brain edema after experimental intracerebral hemorrhage. Translational Stroke Res. 2012;3:S180–7.CrossRefGoogle Scholar
  35. 35.
    He Z, Crook JE, et al. Aging blunts ischemic-preconditioning-induced neuroprotection following transient global ischemia in rats. Curr Neurovasc Res. 2005;2(5):365–74.PubMedCrossRefGoogle Scholar
  36. 36.
    Hoole SP, Heck PM, et al. Cardiac remote ischemic preconditioning in coronary stenting (CRISP Stent) study: a prospective, randomized control trial. Circulation. 2009;119(6):820–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Hu S, Dong HL, et al. Effects of remote ischemic preconditioning on biochemical markers and neurologic outcomes in patients undergoing elective cervical decompression surgery: a prospective randomized controlled trial. J Neurosurg Anesthesiol. 2010;22(1):46–52.PubMedCrossRefGoogle Scholar
  38. 38.
    Hua Y, Wu J, et al. Ischemic preconditioning procedure induces behavioral deficits in the absence of brain injury? Neurol Res. 2005;27(3):261–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Jensen HA, Loukogeorgakis S, et al. Remote ischemic preconditioning protects the brain against injury after hypothermic circulatory arrest. Circulation. 2011;123(7):714–21.PubMedCrossRefGoogle Scholar
  40. 40.
    Jensen HA, Loukogeorgakis S, et al. Remote ischemic preconditioning protects the brain against injury after hypothermic circulatory arrest. Circulation. 2011;123(7):714–21.PubMedCrossRefGoogle Scholar
  41. 41.
    Kapinya KJ, Lowl D, et al. Tolerance against ischemic neuronal injury can be induced by volatile anesthetics and is inducible NO synthase dependent. Stroke. 2002;33(7):1889–98.PubMedCrossRefGoogle Scholar
  42. 42.
    Keep RF, Wang MM, et al. Is there a place for preconditioning in the clinic? Trans Stroke Res. 2010;1:4–18.CrossRefGoogle Scholar
  43. 43.
    Kharbanda RK, Nielsen TT, et al. Translation of remote ischaemic preconditioning into clinical practice. Lancet. 2009;374(9700):1557–65.PubMedCrossRefGoogle Scholar
  44. 44.
    Kim SH, Kim EH, et al. Chronic cerebral hypoperfusion protects against acute focal ischemia, improves motor function, and results in vascular remodeling. Curr Neurovasc Res. 2008;5(1):28–36.PubMedCrossRefGoogle Scholar
  45. 45.
    Kirino T, Nakagomi T, et al. Ischemic tolerance. Adv Neurol. 1996;71:505–11.PubMedGoogle Scholar
  46. 46.
    Kitano H, Young JM, et al. Gender-specific response to isoflurane preconditioning in focal cerebral ischemia. J Cereb Blood Flow Metab. 2007;27(7):1377–86.PubMedCrossRefGoogle Scholar
  47. 47.
    Koch S, Katsnelson M, et al. Remote ischemic limb preconditioning after subarachnoid hemorrhage: a phase Ib study of safety and feasibility. Stroke. 2011;42(5):1387–91.PubMedCrossRefGoogle Scholar
  48. 48.
    Koerner IP, Gatting M, et al. Induction of cerebral ischemic tolerance by erythromycin preconditioning reprograms the transcriptional response to ischemia and suppresses inflammation. Anesthesiology. 2007;106(3):538–47.PubMedCrossRefGoogle Scholar
  49. 49.
    Li L, Peng L, et al. Isoflurane preconditioning increases B-cell lymphoma-2 expression and reduces cytochrome c release from the mitochondria in the ischemic penumbra of rat brain. Eur J Pharmacol. 2008;586(1–3):106–13.PubMedCrossRefGoogle Scholar
  50. 50.
    Li L, Zuo Z. Isoflurane preconditioning improves short-term and long-term neurological outcome after focal brain ischemia in adult rats. Neuroscience. 2009;164(2):497–506.PubMedCrossRefGoogle Scholar
  51. 51.
    Li Y, Dong H, et al. Preconditioning with repeated hyperbaric oxygen induces myocardial and cerebral protection in patients undergoing coronary artery bypass graft surgery: a prospective, randomized, controlled clinical trial. J Cardiothorac Vasc Anesth. 2011;25(6):908–16.PubMedCrossRefGoogle Scholar
  52. 52.
    Limatola V, Ward P, et al. Xenon preconditioning confers neuroprotection regardless of gender in a mouse model of transient middle cerebral artery occlusion. Neuroscience. 2010;165(3):874–81.PubMedCrossRefGoogle Scholar
  53. 53.
    Longhi L, Gesuete R, et al. Long-lasting protection in brain trauma by endotoxin preconditioning. J Cereb Blood Flow Metab. 2011;31(9):1919–29.PubMedCrossRefGoogle Scholar
  54. 54.
    Ludman AJ, Yellon DM, et al. Cardiac preconditioning for ischaemia: lost in translation. Dis Model Mech. 2010;3(1–2):35–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Maas AI, Stocchetti N, et al. Moderate and severe traumatic brain injury in adults. Lancet Neurol. 2008;7(8):728–41.PubMedCrossRefGoogle Scholar
  56. 56.
    Macleod MR, O’Collins T, et al. Systematic review and metaanalysis of the efficacy of FK506 in experimental stroke. J Cereb Blood Flow Metab. 2005;25(6):713–21.PubMedCrossRefGoogle Scholar
  57. 57.
    Macleod MR, van der Worp HB, et al. Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke. 2008;39(10):2824–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Malhotra S, Naggar I, et al. Neurogenic pathway mediated remote preconditioning protects the brain from transient focal ischemic injury. Brain Res. 2011;1386:184–90.PubMedCrossRefGoogle Scholar
  59. 59.
    Matchett GA, Martin RD, et al. Hyperbaric oxygen therapy and cerebral ischemia: neuroprotective mechanisms. Neurol Res. 2009;31(2):114–21.PubMedCrossRefGoogle Scholar
  60. 60.
    Miljkovic-Lolic M, Silbergleit R, et al. Neuroprotective effects of hyperbaric oxygen treatment in experimental focal cerebral ischemia are associated with reduced brain leukocyte myeloperoxidase activity. Brain Res. 2003;971(1):90–4.PubMedCrossRefGoogle Scholar
  61. 61.
    Murry CE, Jennings RB, et al. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–36.PubMedCrossRefGoogle Scholar
  62. 62.
    Nasu I, Yokoo N, et al. The dose-dependent effects of isoflurane on outcome from severe forebrain ischemia in the rat. Anesth Analg. 2006;103(2):413–8.PubMedCrossRefGoogle Scholar
  63. 63.
    O’Collins VE, Macleod MR, et al. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59(3):467–77.PubMedCrossRefGoogle Scholar
  64. 64.
    Obrenovitch TP. Molecular physiology of preconditioning-induced brain tolerance to ischemia. Physiol Rev. 2008;88(1):211–47.PubMedCrossRefGoogle Scholar
  65. 65.
    Ostrowski RP, Colohan ART, et al. Mechanisms of hyperbaric oxygen-induced neuroprotection in a rat model of subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2005;25(5):554–71.PubMedCrossRefGoogle Scholar
  66. 66.
    Ostrowski RP, Tang J, et al. Hyperbaric oxygen suppresses NADPH oxidase in a rat subarachnoid hemorrhage model. Stroke. 2006;37(5):1314–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Payne RS, Akca O, et al. Sevoflurane-induced preconditioning protects against cerebral ischemic neuronal damage in rats. Brain Res. 2005;1034(1–2):147–52.PubMedCrossRefGoogle Scholar
  68. 68.
    Pera J, Zawadzka M, et al. Influence of chemical and ischemic preconditioning on cytokine expression after focal brain ischemia. J Neurosci Res. 2004;78(1):132–40.PubMedCrossRefGoogle Scholar
  69. 69.
    Perez-Pinzon MA, Alonso O, et al. Induction of tolerance against traumatic brain injury by ischemic preconditioning. NeuroReport. 1999;10(14):2951–4.PubMedCrossRefGoogle Scholar
  70. 70.
    Petcu EB, Kocher T, et al. Mild systemic inflammation has a neuroprotective effect after stroke in rats. Curr Neurovasc Res. 2008;5(4):214–23.PubMedCrossRefGoogle Scholar
  71. 71.
    Przyklenk K. Efficacy of cardioprotective ‘conditioning’ strategies in aging and diabetic cohorts: the co-morbidity conundrum. Drugs Aging. 2011;28(5):331–43.PubMedCrossRefGoogle Scholar
  72. 72.
    Puisieux F, Deplanque D, et al. Differential role of nitric oxide pathway and heat shock protein in preconditioning and lipopolysaccharide-induced brain ischemic tolerance. Eur J Pharmacol. 2000;389(1):71–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Purcell JE, Lenhard SC, et al. Strain-dependent response to cerebral ischemic preconditioning: differences between spontaneously hypertensive and stroke prone spontaneously hypertensive rats. Neurosci Lett. 2003;339(2):151–5.PubMedCrossRefGoogle Scholar
  74. 74.
    Qin Z, Song S, et al. Preconditioning with hyperbaric oxygen attenuates brain edema after experimental intracerebral hemorrhage. Neurosurg Focus. 2007;22(5):E13.PubMedCrossRefGoogle Scholar
  75. 75.
    Rehni AK, Shri R, et al. Remote ischaemic preconditioning and prevention of cerebral injury. Indian J Exp Biol. 2007;45(3):247–52.PubMedGoogle Scholar
  76. 76.
    Ren C, Gao X, et al. Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning. Neuroscience. 2008;151(4):1099–103.PubMedCrossRefGoogle Scholar
  77. 77.
    Sack MN, Murphy E. The role of comorbidities in cardioprotection. J Cardiovasc Pharmacol Ther. 2011;16(3–4):267–72.PubMedCrossRefGoogle Scholar
  78. 78.
    Savitz SI. A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a need for more rigorous testing of neuroprotective agents in animal models of stroke. Exp Neurol. 2007;205(1):20–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Saxena P, Bala A, et al. Does remote ischemic preconditioning prevent delayed hippocampal neuronal death following transient global cerebral ischemia in rats? Perfusion. 2009;24(3):207–11.PubMedCrossRefGoogle Scholar
  80. 80.
    Saxena P, Bala A, et al. Does remote ischemic preconditioning prevent delayed hippocampal neuronal death following transient global cerebral ischemia in rats? Perfusion. 2009;24(3):207–11.PubMedCrossRefGoogle Scholar
  81. 81.
    Schaller BJ. Influence of age on stroke and preconditioning-induced ischemic tolerance in the brain. Exp Neurol. 2007;205(1):9–19.PubMedCrossRefGoogle Scholar
  82. 82.
    Schulz KF, Altman DG, et al. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med. 2010;7(3):e1000251.PubMedCrossRefGoogle Scholar
  83. 83.
    Silver FL, Mackey A, et al. Safety of stenting and endarterectomy by symptomatic status in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). Stroke. 2011;42(3):675–80.PubMedCrossRefGoogle Scholar
  84. 84.
    Steiger HJ, Hanggi D. Ischaemic preconditioning of the brain, mechanisms and applications. Acta Neurochir (Wien). 2007;149(1):1–10.CrossRefGoogle Scholar
  85. 85.
    Stenzel-Poore MP, Stevens SL, et al. Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet. 2003;362(9389):1028–37.PubMedCrossRefGoogle Scholar
  86. 86.
    Sutherland BA, Minnerup J, et al. Neuroprotection for ischaemic stroke: translation from the bench to the bedside. Int J Stroke. 2012;7(5):407–18.PubMedCrossRefGoogle Scholar
  87. 87.
    Tymianski M. Can molecular and cellular neuroprotection be translated into therapies for patients?: yes, but not the way we tried it before. Stroke. 2010;41(10 Suppl):S87–90.PubMedCrossRefGoogle Scholar
  88. 88.
    van der Worp HB, Sena ES, et al. Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis. Brain. 2007;130(Pt 12):3063–74.PubMedCrossRefGoogle Scholar
  89. 89.
    Vellimana AK, Milner E, et al. Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm. Stroke. 2011;42(3):776–82.PubMedCrossRefGoogle Scholar
  90. 90.
    Vergouwen MDI, Participants H, International Multi-Disciplinary Consensus Conference on the Critical Care Management of Subarachnoid. Vasospasm versus delayed cerebral ischemia as an outcome event in clinical trials and observational studies. Neurocritical Care. 2011;15(2):308–11.PubMedCrossRefGoogle Scholar
  91. 91.
    Walsh SR, Nouraei SA, et al. Remote ischemic preconditioning for cerebral and cardiac protection during carotid endarterectomy: results from a pilot randomized clinical trial. Vasc Endovasc Surg. 2010;44(6):434–9.CrossRefGoogle Scholar
  92. 92.
    Wang L, Traystman RJ, et al. Inhalational anesthetics as preconditioning agents in ischemic brain. Curr Opin Pharmacol. 2008;8(1):104–10.PubMedCrossRefGoogle Scholar
  93. 93.
    Wang Q, Li X, et al. Activation of epsilon protein kinase C-mediated anti-apoptosis is involved in rapid tolerance induced by electroacupuncture pretreatment through cannabinoid receptor type 1. Stroke. 2011;42(2):389–96.PubMedCrossRefGoogle Scholar
  94. 94.
    Wang Q, Peng Y, et al. Pretreatment with electroacupuncture induces rapid tolerance to focal cerebral ischemia through regulation of endocannabinoid system. Stroke. 2009;40(6):2157–64.PubMedCrossRefGoogle Scholar
  95. 95.
    Wang Q, Wang F, et al. Electroacupuncture pretreatment attenuates cerebral ischemic injury through alpha7 nicotinic acetylcholine receptor-mediated inhibition of high-mobility group box 1 release in rats. J Neuroinflammation. 2012;9:24.PubMedCrossRefGoogle Scholar
  96. 96.
    Wang Q, Xiong L, et al. Rapid tolerance to focal cerebral ischemia in rats is induced by preconditioning with electroacupuncture: window of protection and the role of adenosine. Neurosci Lett. 2005;381(1–2):158–62.PubMedCrossRefGoogle Scholar
  97. 97.
    Wegener S, Gottschalk B, et al. Transient ischemic attacks before ischemic stroke: preconditioning the human brain? A multicenter magnetic resonance imaging study. Stroke. 2004;35(3):616–21.PubMedCrossRefGoogle Scholar
  98. 98.
    Wei DT, Ren CC, et al. The chronic protective effects of limb remote preconditioning and the underlying mechanisms involved in inflammatory factors in rat stroke. PLoS One. 2012;7(2).Google Scholar
  99. 99.
    Xi G, Hua Y, et al. Induction of colligin may attenuate brain edema following intracerebral hemorrhage. Acta Neurochirurgica-Supplement. 2000;76:501–5.PubMedGoogle Scholar
  100. 100.
    Xiong L, Lu Z, et al. Pretreatment with repeated electroacupuncture attenuates transient focal cerebral ischemic injury in rats. Chin Med J. 2003;116(1):108–11.PubMedGoogle Scholar
  101. 101.
    Xu T, Gong Z, et al. Remote ischemic preconditioning protects neurocognitive function of rats following cerebral hypoperfusion. Medical Science Monitor. 2011;17(11):BR299–304.PubMedCrossRefGoogle Scholar
  102. 102.
    Yamashita S, Hirata T, et al. Repeated preconditioning with hyperbaric oxygen induces neuroprotection against forebrain ischemia via suppression of p38 mitogen activated protein kinase. Brain Res. 2009;1301:171–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Yeh C-H, Wang Y-C, et al. Ischemic preconditioning or heat shock pretreatment ameliorates neuronal apoptosis following hypothermic circulatory arrest. J Thorac Cardiovasc Surg. 2004;128(2):203–10.PubMedCrossRefGoogle Scholar
  104. 104.
    Yu Q, Chu M, et al. Sevoflurane preconditioning protects blood–brain-barrier against brain ischemia. Front Biosci. 2011;3:978–88.Google Scholar
  105. 105.
    Yung LM, Wei Y, et al. Sphingosine kinase 2 mediates cerebral preconditioning and protects the mouse brain against ischemic injury. Stroke. 2012;43(1):199–204.PubMedCrossRefGoogle Scholar
  106. 106.
    Zhang H-P, Yuan L-B, et al. Isoflurane preconditioning induces neuroprotection by attenuating ubiquitin-conjugated protein aggregation in a mouse model of transient global cerebral ischemia. Anesth Analg. 2010;111(2):506–14.PubMedCrossRefGoogle Scholar
  107. 107.
    Zheng S, Zuo Z. Isoflurane preconditioning induces neuroprotection against ischemia via activation of P38 mitogen-activated protein kinases. Mol Pharmacol. 2004;65(5):1172–80.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2012

Authors and Affiliations

  • Michael M. Wang
    • 1
    • 2
    • 4
    Email author
  • Guohua Xi
    • 3
  • Richard F. Keep
    • 2
    • 3
  1. 1.Department of NeurologyUniversity of MichiganAnn ArborUSA
  2. 2.Department of Molecular and Integrative PhysiologyUniversity of MichiganAnn ArborUSA
  3. 3.Department of NeurosurgeryUniversity of MichiganAnn ArborUSA
  4. 4.Neurology ServiceVA Ann Arbor Healthcare SystemAnn ArborUSA

Personalised recommendations