Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cerebral preconditioning and ischaemic tolerance

Nature Reviews Neuroscience volume 7, pages 437–448 (2006)Cite this article

Key Points

  • An increased resistance to ischaemic injury, known as 'ischaemic tolerance', can be realized in the brain if the tissue is exposed previously to a non-damaging stressor, in a process known as 'preconditioning'. Therefore, endogenous pro-survival mechanisms are present in the CNS that can be coaxed from dormancy by the appropriate stimulus.

  • Mechanistically, these 'programmed cell survival' responses may parallel the greater resistance of the neonate brain to oxygen deprivation, of genetically- and physiologically-acclimatized, high altitude natives, and of breath-holding and hibernating animals that withstand prolonged periods of hypoxia/anoxia.

  • Effective preconditioning stimuli are numerous and diverse, suggesting that a downstream convergence of signalling pathways promotes this protective response.

  • Two periods of tolerance can be induced by preconditioning: one appears rapidly (within minutes) as a result of post-translational responses, and the other, classical form of tolerance is delayed (by many hours, or even days), secondary to a dependency on altered gene expression. Both responses are transient, but can be induced repeatedly.

  • Unique sensors (such as receptors), signal transduction pathways and transcription factors transduce the preconditioning stimulus into a multitude of gene expression changes that are ultimately responsible for the ischaemia-tolerant phenotype.

  • Adaptive changes on the part of all resident brain cells, including different glial and vascular cells, contribute to the overall protection induced by preconditioning.

  • Elucidating the molecular basis of these innate protective mechanisms might provide new therapeutic targets for ischaemic stroke, and perhaps for other neurodegenerative diseases.

Abstract

Adaptation is one of physiology's fundamental tenets, operating not only at the level of species, as Darwin proposed, but also at the level of tissues, cells, molecules and, perhaps, genes. During recent years, stroke neurobiologists have advanced a considerable body of evidence supporting the hypothesis that, with experimental coaxing, the mammalian brain can adapt to injurious insults such as cerebral ischaemia to promote cell survival in the face of subsequent injury. Establishing this protective phenotype in response to stress depends on a coordinated response at the genomic, molecular, cellular and tissue levels. Here, I summarize our current understanding of how 'preconditioning' stimuli trigger a cerebroprotective state known as cerebral 'ischaemic tolerance'.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cerebroprotection by preconditioning.

Similar content being viewed by others

References

  1. Dahl, N. A. & Balfour, W. M. Prolonged anoxic survival due to anoxia pre-exposure: brain ATP, lactate, and pyruvate. Am. J. Physiol. 207, 452–456 (1964).

    Article  CAS  PubMed  Google Scholar 

  2. Schurr, A., Reid, K. H., Tseng, M. T., West, C. & Rigor, B. M. Adaptation of adult brain tissue to anoxia and hypoxia in vitro. Brain Res. 374, 244–248 (1986).

    Article  CAS  PubMed  Google Scholar 

  3. Murry, C. E., Jennings, R. B. & Reimer, K. A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74, 1124–1136 (1986).

    Article  CAS  PubMed  Google Scholar 

  4. Chopp, M. et al. Transient hyperthermia protects against subsequent forebrain ischemic cell damage in the rat. Neurology 39, 1396–1398 (1989).

    Article  CAS  PubMed  Google Scholar 

  5. Kitagawa, K. et al. 'Ischemic tolerance' phenomenon detected in various brain regions. Brain Res. 561, 203–211 (1991). The landmark paper documenting the ability of brief bilateral carotid occlusion to protect gerbil hippocampal CA1 pyramidal neurons from more prolonged global ischaemia; the authors coined the term 'ischaemic tolerance' to describe this phenomenon.

    Article  CAS  PubMed  Google Scholar 

  6. Dawson, V. L. & Dawson, T. M. Neuronal ischemic preconditioning. Trends Pharmacol. Sci. 21, 423–424 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Kirino, T. Ischemic tolerance. J. Cereb. Blood Flow Metab. 22, 1283–1296 (2002).

    Article  PubMed  Google Scholar 

  8. Dirnagl, U., Simon, R. P. & Hallenbeck, J. M. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 26, 248–254 (2003). The first review to provide a conceptual integration of this field.

    Article  CAS  PubMed  Google Scholar 

  9. Hagberg, H., Dammann, O., Mallard, C. & Leviton, A. Preconditioning and the developing brain. Semin. Perinatol. 28, 389–395 (2004).

    Article  PubMed  Google Scholar 

  10. Sharp, F. R. et al. Hypoxic preconditioning protects against ischemic brain injury. NeuroRx 1, 26–35 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Sapolsky, R. M. Cellular defenses against excitotoxic insults. J. Neurochem. 76, 1601–1611 (2001). In this paper, the author reviewed the often overlooked protective mechanisms that are activated by ischaemia; although endogenous to the tissue, these mechanisms are largely different from those induced by preconditioning per se.

    Article  CAS  PubMed  Google Scholar 

  12. Perez-Pinzon, M. A., Xu, G.-P., Dietrich, W. D., Rosenthal, M. & Sick, T. J. Rapid preconditioning protects rats against ischemic neuronal damage after 3 but not 7 days of reperfusion following global cerebral ischemia. J. Cereb. Blood Flow Metab. 17, 175–182 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Stagliano, N. E., Perez-Pinzon, M. A., Moskowitz, M. A. & Huang, P. L. Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice. J. Cereb. Blood Flow Metab. 19, 757–761 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Lu, G. W., Yu, S., Li, R. H., Cui, X. Y. & Gao, C. Y. Hypoxic preconditioning: a novel intrinsic cytoprotective strategy. Mol. Neurobiol. 31, 255–271 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Bernaudin, M., Tang, Y., Reilly, M., Petit, E. & Sharp, F. R. Brain genomic response following hypoxia and re-oxygenation in the neonatal rat. Identification of genes that might contribute to hypoxia-induced ischemic tolerance. J. Biol. Chem. 277, 39728–39738 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Stenzel-Poore, M. P. et al. Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet 362, 1028–1037 (2003). Using microarrays to compare gene expression changes in the rat brain in response to ischaemia with and without prior preconditioning, this study advanced the concept that preconditioning 'reprogrammes' the genomic response to stroke.

    Article  CAS  PubMed  Google Scholar 

  17. Dhodda, V. K., Sailor, K. A., Bowen, K. K. & Vemuganti, R. Putative endogenous mediators of preconditioning-induced ischemic tolerance in rat brain identified by genomic and proteomic analysis. J. Neurochem. 89, 73–89 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Tang, Y. et al. Effect of hypoxic preconditioning on brain genomic response before and following ischemia in the adult mouse: identification of potential neuroprotective candidates for stroke. Neurobiol. Dis. 21, 18–28 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Kato, H., Liu, Y., Araki, T. & Kogure, K. MK-801, but not anisomycin, inhibits the induction of tolerance to ischemia in the gerbil hippocampus. Neurosci. Lett. 139, 118–121 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Ohtsuki, T. et al. Influence of oxidative stress on induced tolerance to ischemia in gerbil hippocampal neurons. Brain Res. 599, 246–252 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Nakata, N., Kato, H. & Kogure, K. Ischemic tolerance and extracellular amino acid concentrations in gerbil hippocampus measured by intracerebral microdialysis. Brain Res. Bull. 35, 247–251 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Ohtsuki, T., Ruetzler, C. A., Tasaki, K. & Hallenbeck, J. M. Interleukin-1 mediates induction of tolerance to global ischemia in gerbil hippocampal CA1 neurons. J. Cereb. Blood Flow Metab. 16, 1137–1142 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Nawashiro, H., Tasaki, K., Ruetzler, C. A. & Hallenbeck, J. M. TNFα pretreatment induces protective effects against focal cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 17, 483–490 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Grabb, M. C. & Choi, D. W. Ischemic tolerance in murine cortical cell culture: critical role for NMDA receptors. J. Neurosci. 19, 1657–1662 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wiegand, F. et al. Respiratory chain inhibition induces tolerance to focal cerebral ischemia. J. Cereb. Blood Flow Metab. 19, 1229–1237 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. McLaughlin, B. et al. Caspase 3 activation is essential for neuroprotection in preconditioning. Proc. Natl Acad. Sci. USA 100, 715–720 (2003). This study demonstrated in vivo that focal ischaemic preconditioning activates caspase 3 over a time frame coincident with tolerance, and that, in vitro , this activation was required for preconditioning-induced neuroprotection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Garnier, P., Ying, W. & Swanson, R. A. Ischemic preconditioning by caspase cleavage of poly(ADP-ribose) polymerase-1. J. Neurosci. 23, 7967–7973 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Puisieux, F. et al. Brain ischemic preconditioning is abolished by antioxidant drugs but does not up-regulate superoxide dismutase and glutathion peroxidase. Brain Res. 1027, 30–37 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Zhang, X. et al. Preconditioning with prolonged oxygen exposure induces ischemic tolerance in the brain via oxygen free radical formation. Can. J. Anaesth. 51, 258–263 (2004).

    Article  PubMed  Google Scholar 

  30. Vlasov, T. D., Korzhevskii, D. E. & Polyakova, E. A. Ischemic preconditioning of the rat brain as a method of endothelial protection from ischemic/repercussion injury. Neurosci. Behav. Physiol. 35, 567–572 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Endres, M. et al. Mechanisms of stroke protection by physical activity. Ann. Neurol. 54, 582–590 (2003).

    Article  PubMed  Google Scholar 

  32. Ding, Y. H. et al. Exercise preconditioning ameliorates inflammatory injury in ischemic rats during reperfusion. Acta Neuropathol. (Berl.) 109, 237–246 (2005).

    Article  CAS  Google Scholar 

  33. Becker, K. J. et al. Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia. Proc. Natl Acad. Sci. USA 94, 10873–10878 (1997). The first report to demonstrate that active immunologic tolerance secondary to preconditioning by intentional presentation of CNS antigens can be neuroprotective in cerebral ischaemia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Frenkel, D. et al. Neuroprotection by IL-10-producing MOG CD4+ T cells following ischemic stroke. J. Neurol. Sci. 233, 125–132 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Chen, Y. et al. Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury. Proc. Natl Acad. Sci. USA 100, 15107–15112 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kariko, K., Weissman, D. & Welsh, F. A. Inhibition of toll-like receptor and cytokine signaling — a unifying theme in ischemic tolerance. J. Cereb. Blood Flow Metab. 24, 1288–1304 (2004). A speculative synthesis that addressed the parallels between ischaemic tolerance and endotoxin tolerance, and the important part that toll-like receptors may play in mediating ischaemic tolerance in response to inflammatory stimuli.

    Article  CAS  PubMed  Google Scholar 

  37. Gonzalez-Zulueta, M. et al. Requirement for nitric oxide activation of p21ras/extracellular regulated kinase in neuronal ischemic preconditioning. Proc. Natl Acad. Sci. USA 97, 436–441 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jones, N. M. & Bergeron, M. Hypoxia-induced ischemic tolerance in neonatal rat brain involves enhanced ERK1/2 signaling. J. Neurochem. 89, 157–167 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Heurteaux, C., Lauritzen, I., Widmann, C. & Lazdunski, M. Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K+ channels in cerebral ischemic preconditioning. Proc. Natl Acad. Sci. USA 92, 4666–4670 (1995). This study provided causal data for the involvement of adenosine and K ATP channels in the induction of ischaemic tolerance; since this early paper, experimental support for these mechanisms has continued to accumulate.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yoshida, M., Nakakimura, K., Cui, Y. J., Matsumoto, M. & Sakabe, T. Adenosine A1 receptor antagonist and mitochondrial ATP-sensitive potassium channel blocker attenuate the tolerance to focal cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 24, 771–779 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Yano, S. et al. Activation of Akt/protein kinase B contributes to induction of ischemic tolerance in the CA1 subfield of gerbil hippocampus. J. Cereb. Blood Flow Metab. 21, 351–360 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Wick, A. et al. Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J. Neurosci. 22, 6401–6407 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hashiguchi, A. 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. 24, 271–279 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Raval, A. P., Dave, K. R., Mochly-Rosen, D., Sick, T. J. & Perez-Pinzon, M. A. εPKC is required for the induction of tolerance by ischemic and NMDA-mediated preconditioning in the organotypic hippocampal slice. J. Neurosci. 23, 384–391 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wingrove, J. A. & O'Farrell, P. H. Nitric oxide contributes to behavioral, cellular, and developmental responses to low oxygen in Drosophila. Cell 98, 105–114 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gidday, J. M. et al. Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. J. Cereb. Blood Flow Metab. 19, 331–340 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Puisieux, F. et al. Differential role of nitric oxide pathway and heat shock protein in preconditioning and lipopolysaccharide-induced brain ischemic tolerance. Eur. J. Pharmacol. 389, 71–78 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Atochin, D. N., Clark, J., Demchenko, I. T., Moskowitz, M. A. & Huang, P. L. Rapid cerebral ischemic preconditioning in mice deficient in endothelial and neuronal nitric oxide synthases. Stroke 34, 1299–1303 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Kawahara, K., Yanoma, J., Tanaka, M., Nakajima, T. & Kosugi, T. Nitric oxide produced during ischemia is toxic but crucial to preconditioning-induced ischemic tolerance of neurons in culture. Neurochem. Res. 29, 797–804 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Kapinya, K. J. et al. Tolerance against ischemic neuronal injury can be induced by volatile anesthetics and is inducible NO synthase dependent. Stroke 33, 1889–1898 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Cho, S. et al. Obligatory role of inducible nitric oxide synthase in ischemic preconditioning. J. Cereb. Blood Flow Metab. 25, 493–501 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Ravati, A., Ahlemeyer, B., Becker, A., Klumpp, S. & Krieglstein, J. Preconditioning-induced neuroprotection is mediated by reactive oxygen species and activation of the transcription factor nuclear factor-κB. J. Neurochem. 78, 909–919 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Plamondon, H., Blondeau, N., Heurteaux, C. & Lazdunski, M. Mutually protective actions of kainic acid epileptic preconditioning and sublethal global ischemia on hippocampal neuronal death: involvement of adenosine A1 receptors and KATP channels. J. Cereb. Blood Flow Metab. 19, 1296–1308 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Nakamura, M., Nakakimura, K., Matsumoto, M. & Sakabe, T. Rapid tolerance to focal cerebral ischemia in rats is attenuated by adenosine A1 receptor antagonist. J. Cereb. Blood Flow Metab. 22, 161–170 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Algeciras-Schimnich, A., Barnhart, B. C. & Peter, M. E. Apoptosis-independent functions of killer caspases. Curr. Opin. Cell Biol. 14, 721–726 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Kapinya, K., Penzel, R., Sommer, C. & Kiessling, M. Temporary changes of the AP-1 transcription factor binding activity in the gerbil hippocampus after transient global ischemia, and ischemic tolerance induction. Brain Res. 872, 282–293 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Hara, T. et al. CREB is required for acquisition of ischemic tolerance in gerbil hippocampal CA1 region. J. Neurochem. 86, 805–814 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Ma, D. et al. Xenon preconditioning reduces brain damage from neonatal asphyxia in rats. J. Cereb. Blood Flow Metab. 26, 199–208 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Meller, R. et al. CREB-mediated Bcl-2 protein expression after ischemic preconditioning. J. Cereb. Blood Flow Metab. 25, 234–246 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Blondeau, N., Widmann, C., Lazdunski, M. & Heurteaux, C. Activation of the nuclear factor-κB is a key event in brain tolerance. J. Neurosci. 21, 4668–4677 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ryu, H. et al. Sp1 and Sp3 are oxidative stress-inducible, antideath transcription factors in cortical neurons. J. Neurosci. 23, 3597–3606 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bergeron, M. et al. Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann. Neurol. 48, 285–296 (2000). Studies in this paper, undertaken in a neonatal rat model of ischaemic tolerance, set a precedent by linking hypoxic preconditioning to HIF 1 expression.

    Article  CAS  PubMed  Google Scholar 

  63. Bernaudin, M. et al. Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J. Cereb. Blood Flow Metab. 22, 393–403 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Liu, M. & Alkayed, N. J. Hypoxic preconditioning and tolerance via hypoxia inducible factor (HIF) 1α-linked induction of P450 2C11 epoxygenase in astrocytes. J. Cereb. Blood Flow Metab. 25, 939–948 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Ratan, R. R. et al. Translation of ischemic preconditioning to the patient: prolyl hydroxylase inhibition and hypoxia inducible factor-1 as novel targets for stroke therapy. Stroke 35, 2687–2689 (2004).

    Article  PubMed  Google Scholar 

  66. Wiesener, M. S. et al. Widespread hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J. 17, 271–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Ralph, G. S. et al. Identification of potential stroke targets by lentiviral vector mediated overexpression of HIF-1 α and HIF-2 α in a primary neuronal model of hypoxia. J. Cereb. Blood Flow Metab. 24, 245–258 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Kawahara, N. et al. Genome-wide gene expression analysis for induced ischemic tolerance and delayed neuronal death following transient global ischemia in rats. J. Cereb. Blood Flow Metab. 24, 212–223 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Hong, S. J., Li, H., Becker, K. G., Dawson, V. L. & Dawson, T. M. Identification and analysis of plasticity-induced late-response genes. Proc. Natl Acad. Sci. USA 101, 2145–2150 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Douen, A. G. et al. Preconditioning with cortical spreading depression decreases intraischemic cerebral glutamate levels and down-regulates excitatory amino acid transporters EAAT1 and EAAT2 from rat cerebal cortex plasma membranes. J. Neurochem. 75, 812–818 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Yamaguchi, K., Yamaguchi, F., Miyamoto, O., Hatase, O. & Tokuda, M. The reversible change of GluR2 RNA editing in gerbil hippocampus in course of ischemic tolerance. J. Cereb. Blood Flow Metab. 19, 370–375 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Grabb, M. C., Lobner, D., Turetsky, D. M. & Choi, D. W. Preconditioned resistance to oxygen–glucose deprivation-induced cortical neuronal death: alterations in vesicular GABA and glutamate release. Neuroscience 115, 173–183 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Dave, K. R. et al. Ischemic preconditioning ameliorates excitotoxicity by shifting glutamate/γ-aminobutyric acid release and biosynthesis. J. Neurosci. Res. 82, 665–673 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Vannucci, R. C., Towfighi, J. & Vannucci, S. J. Hypoxic preconditioning and hypoxic-ischemic brain damage in the immature rat: pathologic and metabolic correlates. J. Neurochem. 71, 1215–1220 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Paschen, W. & Mies, G. Effect of induced tolerance on biochemical disturbances in hippocampal slices from the gerbil during and after oxygen/glucose deprivation. Neuroreport 10, 1417–1421 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Brucklacher, R. M., Vannucci, R. C. & Vannucci, S. J. Hypoxic preconditioning increases brain glycogen and delays energy depletion from hypoxia-ischemia in the immature rat. Dev. Neurosci. 24, 411–417 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Nakagomi, T., Kirino, T., Kanemitsu, H., Tsujita, Y. & Tamura, A. Early recovery of protein synthesis following ischemia in hippocampal neurons with induced tolerance in the gerbil. Acta Neuropathol. (Berl.) 86, 10–15 (1993).

    Article  CAS  Google Scholar 

  78. Hayashi, T., Saito, A., Okuno, S., Ferrand-Drake, M. & Chan, P. H. Induction of GRP78 by ischemic preconditioning reduces endoplasmic reticulum stress and prevents delayed neuronal cell death. J. Cereb. Blood Flow Metab. 23, 949–961 (2003).

    Article  PubMed  Google Scholar 

  79. Garcia, L., O'Loghlen, A., Martin, M. E., Burda, J. & Salinas, M. Does phosphorylation of eukaryotic elongation factor eEF2 regulate protein synthesis in ischemic preconditioning? J. Neurosci. Res. 77, 292–298 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Liu, C., Chen, S., Kamme, F. & Hu, B. R. Ischemic preconditioning prevents protein aggregation after transient cerebral ischemia. Neuroscience 134, 69–80 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Sugawara, T., Noshita, N., Lewen, A., Kim, G. W. & Chan, P. H. Neuronal expression of the DNA repair protein Ku 70 after ischemic preconditioning corresponds to tolerance to global cerebral ischemia. Stroke 32, 2388–2393 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Li, W. et al. Ischemic preconditioning in the rat brain enhances the repair of endogenous oxidative DNA damage by activating the base-excision repair pathway. J. Cereb. Blood Flow Metab. 26, 181–198 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Dave, K. R. et al. Ischemic preconditioning preserves mitochondrial function after global cerebral ischemia in rat hippocampus. J. Cereb. Blood Flow Metab. 21, 1401–1410 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Zhang, H. X., Du, G. H. & Zhang, J. T. Ischemic pre-conditioning preserves brain mitochondrial functions during the middle cerebral artery occlusion in rat. Neurol. Res. 25, 471–476 (2003).

    Article  PubMed  Google Scholar 

  85. Perez-Pinzon, M. A. Neuroprotective effects of ischemic preconditioning in brain mitochondria following cerebral ischemia. J. Bioenerg. Biomembr. 36, 323–327 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Bordet, R. et al. Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance. J. Cereb. Blood Flow Metab. 20, 1190–1196 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Garnier, P. et al. Stress response to hypoxia in gerbil brain: HO-1 and Mn SOD expression and glial activation. Brain Res. 893, 301–309 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Arthur, P. G. et al. The protective effect of hypoxic preconditioning on cortical neuronal cultures is associated with increases in the activity of several antioxidant enzymes. Brain Res. 1017, 146–154 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Glantz, L. et al. Ischemic preconditioning increases antioxidants in the brain and peripheral organs after cerebral ischemia. Exp. Neurol. 192, 117–124 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Pera, J., Zawadzka, M., Kaminska, B. & Szczudlik, A. Influence of chemical and ischemic preconditioning on cytokine expression after focal brain ischemia. J. Neurosci. Res. 78, 132–140 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Brambrink, A. M. et al. Tolerance-inducing dose of 3-nitropropionic acid modulates bcl-2 and bax balance in the rat brain: a potential mechanism of chemical preconditioning. J. Cereb. Blood Flow Metab. 20, 1425–1436 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Xiao, F., Fratkin, J. D., Rhodes, P. G. & Cai, Z. Reduced nitric oxide is involved in prenatal ischemia-induced tolerance to neonatal hypoxic-ischemic brain injury in rats. Neurosci. Lett. 285, 5–8 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Cantagrel, S. et al. Hypoxic preconditioning reduces apoptosis in a rat model of immature brain hypoxia-ischaemia. Neurosci. Lett. 347, 106–110 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Shimizu, S. et al. bcl-2 antisense treatment prevents induction of tolerance to focal ischemia in the rat brain. J. Cereb. Blood Flow Metab. 21, 233–243 (2001). Using BCL2 antisense oligonucleotides, the authors demonstrated that tolerance is dependent on preconditioning-induced expression of BCL2; in doing so, a foundation for the anti-apoptotic basis of ischaemic tolerance was established.

    Article  CAS  PubMed  Google Scholar 

  95. Wu, C. et al. Different expression patterns of Bcl-2, Bcl-xl, and Bax proteins after sublethal forebrain ischemia in C57Black/Crj6 mouse striatum. Stroke 34, 1803–1808 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Zhan, R. Z. et al. Both caspase-dependent and caspase-independent pathways may be involved in hippocampal CA1 neuronal death because of loss of cytochrome c from mitochondria in a rat forebrain ischemia model. J. Cereb. Blood Flow Metab. 21, 529–540 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Tanaka, H. et al. Ischemic preconditioning: neuronal survival in the face of caspase-3 activation. J. Neurosci. 24, 2750–2759 (2004). In this report, post-ischaemic caspase 3 activation was noted in preconditioned neurons destined to survive, implicating the ability of preconditioning to intervene downstream of caspase 3 activation to reduce apoptotic cell death.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Qi, S. et al. Sublethal cerebral ischemia inhibits caspase-3 activation induced by subsequent prolonged ischemia in the C57Black/Crj6 strain mouse. Neurosci. Lett. 315, 133–136 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Tomasevic, G., Shamloo, M., Israeli, D. & Wieloch, T. Activation of p53 and its target genes p21WAF1/Cip1 and PAG608/Wig-1 in ischemic preconditioning. Brain Res. Mol. Brain Res. 70, 304–313 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Mattiasson, G. et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nature Med. 9, 1062–1068 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Tamatani, M. et al. ORP150 protects against hypoxia/ischemia-induced neuronal death. Nature Med. 7, 317–323 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Chang, S. H., Poser, S. & Xia, Z. A novel role for serum response factor in neuronal survival. J. Neurosci. 24, 2277–2285 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ono, T., Sekino-Suzuki, N., Kikkawa, Y., Yonekawa, H. & Kawashima, S. Alivin 1, a novel neuronal activity-dependent gene, inhibits apoptosis and promotes survival of cerebellar granule neurons. J. Neurosci. 23, 5887–5896 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Truettner, J., Busto, R., Zhao, W., Ginsberg, M. D. & Perez-Pinzon, M. A. Effect of ischemic preconditioning on the expression of putative neuroprotective genes in the rat brain. Brain Res. Mol. Brain Res. 103, 106–115 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Yanamoto, H. et al. Spreading depression induces long-lasting brain protection against infarcted lesion development via BDNF gene-dependent mechanism. Brain Res. 1019, 178–188 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Sakaki, T. et al. Brief exposure to hypoxia induces bFGF mRNA and protein and protects rat cortical neurons from prolonged hypoxic stress. Neurosci. Res. 23, 289–296 (1995).

    Article  CAS  PubMed  Google Scholar 

  107. Wang, X., Deng, J., Boyle, D. W., Zhong, J. & Lee, W. H. Potential role of IGF-I in hypoxia tolerance using a rat hypoxic-ischemic model: activation of hypoxia-inducible factor 1α. Pediatr. Res. 55, 385–394 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Xu, Z. et al. Neuroprotection by neuregulin-1 following focal stroke is associated with the attenuation of ischemia-induced pro-inflammatory and stress gene expression. Neurobiol. Dis. 19, 461–470 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Miao, B., Yin, X. H., Pei, D. S., Zhang, Q. G. & Zhang, G. Y. Neuroprotective effects of preconditioning ischemia on ischemic brain injury through down-regulating activation of JNK1/2 via N-methyl-D-aspartate receptor-mediated Akt1 activation. J. Biol. Chem. 280, 21693–21699 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Ohashi, H. et al. Phosphatidylinositol 3-kinase/Akt regulates angiotensin II-induced inhibition of apoptosis in microvascular endothelial cells by governing survivin expression and suppression of caspase-3 activity. Circ. Res. 94, 785–793 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Storkebaum, E., Lambrechts, D. & Carmeliet, P. VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays 26, 943–954 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Ruscher, K. et al. Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J. Neurosci. 22, 10291–10301 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Chen, J., Graham, S. H., Zhu, R. L. & Simon, R. P. Stress proteins and tolerance to focal cerebral ischemia. J. Cereb. Blood Flow Metab. 16, 566–577 (1996).

    Article  CAS  PubMed  Google Scholar 

  114. Dawson, D. A., Furuya, K., Gotoh, J., Nakao, Y. & Hallenbeck, J. M. 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. 19, 616–623 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Alkayed, N. J. et al. Neuroprotection and P450 2C11 upregulation after experimental transient ischemic attack. Stroke 33, 1677–1684 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Omata, N. et al. Hypoxic tolerance induction in rat brain slices following hypoxic preconditioning due to expression of neuroprotective proteins as revealed by dynamic changes in glucose metabolism. Neurosci. Lett. 329, 205–208 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Zhao, L. & Nowak, T. S. CBF changes associated with focal ischemic preconditioning in the spontaneously hypertensive rat. J. Cereb. Blood Flow Metab. 11 Jan 2006 (doi: 10.1038/sj.jcbfm.9600269).

  118. 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. 103, 715–723 (2005).

    Article  PubMed  Google Scholar 

  119. Nakamura, H. et al. Effect of ischemic preconditioning on cerebral blood flow after subsequent lethal ischemia in gerbils. Life Sci. 78, 1713–1719 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Bastide, M. et al. Delayed cerebrovascular protective effect of lipopolysaccharide in parallel to brain ischemic tolerance. J. Cereb. Blood Flow Metab. 23, 399–405 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Ikeda, T., Xia, X. Y., Xia, Y. X. & Ikenoue, T. Hyperthermic preconditioning prevents blood–brain barrier disruption produced by hypoxia-ischemia in newborn rat. Brain Res. Dev. Brain Res. 117, 53–58 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. Masada, T., Hua, Y., Xi, G., Ennis, S. R. & Keep, R. F. Attenuation of ischemic brain edema and cerebrovascular injury after ischemic preconditioning in the rat. J. Cereb. Blood Flow Metab. 21, 22–33 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Lenzser, G., Kis, B., Bari, F. & Busija, D. W. Diazoxide preconditioning attenuates global cerebral ischemia-induced blood–brain barrier permeability. Brain Res. 1051, 72–80 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Rosenzweig, H. L. et al. Endotoxin preconditioning prevents cellular inflammatory response during ischemic neuroprotection in mice. Stroke 35, 2576–2581 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Andjelkovic, A. V., Stamatovic, S. M. & Keep, R. F. The protective effects of preconditioning on cerebral endothelial cells in vitro. J. Cereb. Blood Flow Metab. 23, 1348–1355 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Konstantinov, I. E. et al. The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol. Genomics 19, 143–150 (2004). Microarray analyses of human blood cells after preconditioning by brief limb ischaemia revealed gene expression changes in circulating leukocytes, with important implications regarding the mechanistic basis of ischaemic tolerance and the need to further expand the 'neurovascular unit' concept.

    Article  CAS  PubMed  Google Scholar 

  127. Pohlman, T. H. & Harlan, J. M. Adaptive responses of the endothelium to stress. J. Surg. Res. 89, 85–119 (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Alavi, A., Hood, J. D., Frausto, R., Stupack, D. G. & Cheresh, D. A. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 301, 94–96 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Trendelenburg, G. & Dirnagl, U. Neuroprotective role of astrocytes in cerebral ischemia: focus on ischemic preconditioning. Glia 50, 307–320 (2005). Recent review that served as the first definitive summary of the emerging field of glial cell preconditioning and the mechanisms by which glial responses contribute to ischaemic tolerance.

    Article  PubMed  Google Scholar 

  130. Romera, C. et al. In vitro ischemic tolerance involves upregulation of glutamate transport partly mediated by the TACE/ADAM17-tumor necrosis factor-α pathway. J. Neurosci. 24, 1350–1357 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Kato, H., Kogure, K., Araki, T. & Itoyama, Y. Astroglial and microglial reactions in the gerbil hippocampus with induced ischemic tolerance. Brain Res. 664, 69–76 (1994).

    Article  CAS  PubMed  Google Scholar 

  132. Liu, J., Bartels, M., Lu, A. & Sharp, F. R. Microglia/macrophages proliferate in striatum and neocortex but not in hippocampus after brief global ischemia that produces ischemic tolerance in gerbil brain. J. Cereb. Blood Flow Metab. 21, 361–373 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Ginis, I. et al. TNF-α-induced tolerance to ischemic injury involves differential control of NF-κB transactivation: the role of NF-κB association with p300 adaptor. J. Cereb. Blood Flow Metab. 22, 142–152 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Hochachka, P. W., Buck, L. T., Doll, C. J. & Land, S. C. Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc. Natl Acad. Sci. USA 93, 9493–9498 (1996). A seminal paper that conceptually integrated many previous findings in the comparative physiology of hypoxia- and anoxia-adapted species.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Bickler, P. E. Clinical perspectives: neuroprotection lessons from hypoxia-tolerant organisms. J. Exp. Biol. 207, 3243–3249 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Frerichs, K. U., Kennedy, C., Sokoloff, L. & Hallenbeck, J. M. Local cerebral blood flow during hibernation, a model of natural tolerance to 'cerebral ischemia'. J. Cereb. Blood Flow Metab. 14, 193–205 (1994).

    Article  CAS  PubMed  Google Scholar 

  137. Azzam, N. A., Hallenbeck, J. M. & Kachar, B. Membrane changes during hibernation. Nature 407, 317–318 (2000).

    Article  CAS  PubMed  Google Scholar 

  138. Hochachka, P. W. et al. The brain at high altitude: hypometabolism as a defense against chronic hypoxia? J. Cereb. Blood Flow Metab. 14, 671–679 (1994).

    Article  CAS  PubMed  Google Scholar 

  139. Corbett, D. & Crooks, P. Ischemic preconditioning: a long term survival study using behavioural and histological endpoints. Brain Res. 760, 129–136 (1997).

    Article  CAS  PubMed  Google Scholar 

  140. Ueda, M. & Nowak, T. S. Jr. Protective preconditioning by transient global ischemia in the rat: components of delayed injury progression and lasting protection distinguished by comparisons of depolarization thresholds for cell loss at long survival times. J. Cereb. Blood Flow Metab. 25, 949–958 (2005).

    Article  PubMed  Google Scholar 

  141. Gustavsson, M., Anderson, M. F., Mallard, C. & Hagberg, H. Hypoxic preconditioning confers long-term reduction of brain injury and improvement of neurological ability in immature rats. Pediatr. Res. 57, 305–309 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. Dooley, P. & Corbett, D. Competing processes of cell death and recovery of function following ischemic preconditioning. Brain Res. 794, 119–126 (1998).

    Article  CAS  PubMed  Google Scholar 

  143. Hua, Y. et al. Ischemic preconditioning procedure induces behavioral deficits in the absence of brain injury? Neurol. Res. 27, 261–267 (2005).

    Article  PubMed  Google Scholar 

  144. Vinten-Johansen, J. et al. Postconditioning — a new link in nature's armor against myocardial ischemia–reperfusion injury. Basic Res. Cardiol. 100, 295–310 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Yellon, D. M. & Hausenloy, D. J. Realizing the clinical potential of ischemic preconditioning and postconditioning. Nature Clin. Pract. Cardiovasc. Med. 2, 568–575 (2005). An updated review on preconditioning against myocardial ischaemia that included perspectives on, and potential clinical implications of, the recent documentation of postconditioning for reducing ischaemic injury in this tissue.

    Article  Google Scholar 

  146. Davis, A. E., Campbell, S. J., Wilainam, P. & Anthony, D. C. Post-conditioning with lipopolysaccharide reduces the inflammatory infiltrate to the injured brain and spinal cord: a potential neuroprotective treatment. Eur. J. Neurosci. 22, 2441–2450 (2005).

    Article  PubMed  Google Scholar 

  147. Semenza, G. L. & Wang, G. L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell Biol. 12, 5447–5454 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Sakanaka, M. et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl Acad. Sci. USA 95, 4635–4640 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Brines, M. L. et al. Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc. Natl Acad. Sci. USA 97, 10526–10531 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Siren, A. L. et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc. Natl Acad. Sci. USA 98, 4044–4049 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Prass, K. et al. Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin. Stroke 34, 1981–1986 (2003). Intracerebroventricular administration of a soluble erythropoietin receptor in adult mice allowed this group to demonstrate for the first time that the protection afforded by (hypoxic) preconditioning was erythropoietin-dependent.

    Article  CAS  PubMed  Google Scholar 

  152. Prass, K. et al. Desferrioxamine induces delayed tolerance against cerebral ischemia in vivo and in vitro. J. Cereb. Blood Flow Metab. 22, 520–525 (2002).

    Article  CAS  PubMed  Google Scholar 

  153. Bernaudin, M. et al. A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 19, 643–651 (1999).

    Article  CAS  PubMed  Google Scholar 

  154. Sun, Y., Zhou, C., Polk, P., Nanda, A. & Zhang, J. H. Mechanisms of erythropoietin-induced brain protection in neonatal hypoxia-ischemia rat model. J. Cereb. Blood Flow Metab. 24, 259–270 (2004).

    Article  CAS  PubMed  Google Scholar 

  155. Liu, J., Narasimhan, P., Yu, F. & Chan, P. H. Neuroprotection by hypoxic preconditioning involves oxidative stress-mediated expression of hypoxia-inducible factor and erythropoietin. Stroke 36, 1264–1269 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Maiese, K., Li, F. & Chong, Z. Z. Erythropoietin in the brain: can the promise to protect be fulfilled? Trends Pharmacol. Sci. 25, 577–583 (2004).

    Article  CAS  PubMed  Google Scholar 

  157. Marti, H. H. Erythropoietin and the hypoxic brain. J. Exp. Biol. 207, 3233–3242 (2004).

    Article  CAS  PubMed  Google Scholar 

  158. Tsai, P. T. et al. A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. J. Neurosci. 26, 1269–1274, 2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ehrenreich, H. et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol. Med. 8, 495–505 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Erbayraktar, S. et al. Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc. Natl Acad. Sci. USA 100, 6741–6746 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Leist, M. et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305, 239–242 (2004).

    Article  CAS  PubMed  Google Scholar 

  162. Singer, D. Neonatal tolerance to hypoxia: a comparative–physiological approach. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 123, 221–234 (1999).

    Article  CAS  PubMed  Google Scholar 

  163. Wada, T., Kondoh, T. & Tamaki, N. Ischemic 'cross' tolerance in hypoxic ischemia of immature rat brain. Brain Res. 847, 299–307 (1999).

    Article  CAS  PubMed  Google Scholar 

  164. Jones, N. M. & Bergeron, M. Hypoxic preconditioning induces changes in HIF-1 target genes in neonatal rat brain. J. Cereb. Blood Flow Metab. 21, 1105–1114 (2001).

    Article  CAS  PubMed  Google Scholar 

  165. Moncayo, J., de Freitas, G. R., Bogousslavsky, J., Altieri, M. & van Melle, G. Do transient ischemic attacks have a neuroprotective effect? Neurology 54, 2089–2094 (2000).

    Article  CAS  PubMed  Google Scholar 

  166. Sitzer, M. et al. Transient ischaemic attack preceding anterior circulation infarction is independently associated with favourable outcome. J. Neurol. Neurosurg. Psychiatry 75, 659–660 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Wegener, S. et al. Transient ischemic attacks before ischemic stroke: preconditioning the human brain? A multicenter magnetic resonance imaging study. Stroke 35, 616–621 (2004).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Due to space limitations, the author regrets being unable to cite many outstanding publications in this field. Thanks to Y. M. Rangel for critical reading and useful feedback. The author was supported by grants from the National Heart, Lung and Blood Institute, vand the National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Author information

Authors and Affiliations

  1. Departments of Neurosurgery, Cell Biology and Physiology, and Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Jeffrey M. Gidday

Authors
  1. Jeffrey M. Gidday
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Supplementary information

Related links

Related links

FURTHER INFORMATION

Author's homepage

Glossary

Ischaemic tolerance

A condition of transiently increased resistance to ischaemic injury as a result of the activation of endogenous adaptive mechanisms by preconditioning.

Preconditioning

Presenting a stressful but non-damaging stimulus to cells, tissues or organisms to promote a transient adaptive response so that injury resulting from subsequent exposure to a harmful stimulus is reduced.

Anoxia

Complete lack of oxygen; in contrast to hypoxia, or low oxygen.

Ischaemia

The condition of reduced or blocked blood flow to a tissue, which, as a result of reduced oxygen and nutrient delivery, can lead to tissue injury.

Stroke

A cerebrovascular injury in which blood supply to part of the brain is suddenly interrupted by vessel occlusion (ischaemic stroke) or by vessel wall rupture (haemorrhagic stroke); brain damage and death can rapidly ensue.

Cerebral plasticity

The ability of the brain to reorganize or change both structurally and functionally in response to a challenge, stressor or new experience; this change can be short- or long-lasting, or permanent.

Oxidative and nitrosative stress

A potentially helpful or harmful condition that is due to the actions of molecular compounds with reactive oxygen or reactive nitrogen groups, respectively.

Reactive oxygen species

Highly reactive compounds containing oxygen with an unpaired electron; at low concentrations they subserve signalling functions, but at higher concentrations they can damage cellular macromolecules.

Inflammatory cytokines

Members of a group of intercellular signalling molecules, produced by stimulated immune cells and other cells, that trigger and/or amplify inflammatory responses.

Caspases

A family of aspartate-specific cysteine proteases most well known for their involvement in promoting apoptotic cell death, although they may also exhibit apoptosis-independent signalling functions.

Spreading depression

A decrease in neuronal activity evoked by local stimulation of brain tissue leading to a wave of depolarization that spreads slowly across the entire tissue.

Autocrine and paracrine

A form of localized signalling in which a cell secretes a given substance that then acts on the same cell, or neighbouring target cells to achieve a biological effect.

Normoxia

Normal (sea level) oxygen levels.

Proteasome pathway

A mechanism whereby proteins are degraded by other proteins; these other proteins often exist as a complex of various proteases.

Decoy receptors

Soluble or cell-surface-binding proteins that bind the ligand with high affinity and specificity, but do not induce a biological response; used in immunological regulation.

Neurovascular unit

A practical construct consisting of brain endothelium, astrocytes and microglia, neurons, and the extracellular matrix, and the dynamic interactions that occur between them in health and disease.

Epoxy eicosatrienoic acids

Epoxides of arachidonic acid generated by cytochrome P450 epoxygenases that have various regulatory actions.

Arousal

The intentional act of periodic brief awakening characteristic of hibernating animals, characterized by distinct physiological changes and states of activity, depending on species.

Translational research

The process of taking results from the laboratory and translating them into therapies for clinical use.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gidday, J. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 7, 437–448 (2006). https://doi.org/10.1038/nrn1927

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1927

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing