Acta Neurochirurgica

, Volume 149, Issue 1, pp 1–10 | Cite as

Ischaemic preconditioning of the brain, mechanisms and applications

  • H.-J. Steiger
  • D. Hänggi


Background. The concept of ischaemic preconditioning was introduced in the late 1980s. The concept emerged that a brief subcritical ischaemic challenge could mobilize intrinsic protective mechanisms that increased tolerance against subsequent critical ischaemia. Tissues with a high sensitivity against ischaemia, i.e. myocardium and central nervous system, present the most promising targets for therapeutic application of ischaemic preconditioning. During the last years the mechanisms of neuronal preconditioning were systematically studied and a number of molecular regulation pathways were discovered to participate in preconditioning. The purpose of the present review is to survey the actual knowledge on cerebral preconditioning, and to define the practical impact for neurosurgery.

Methods. A systematic medline search for the terms preconditioning and postconditioning was filed. Publications related to the nervous system were selected and analysed.

Findings. Preconditioning can be subdivided into early and late mechanisms, depending on whether the effect appears immediately after the nonlethal stress or with a delay of some hours or days. In general early effects can be linked to adaptation of membrane receptors whereas late effects are the result of gene up- or downregulation. Not only subcritical ischaemia can trigger preconditioning but also hypoxia, hyperthermia, isoflurane and other chemical substances. Although a vast amount of knowledge has been accumulated regarding neural preconditioning, it is unknown whether the effects can be potentiated by pharmacological or hypothermic neuroprotection during the critical ischaemia. Furthermore, although the practical importance of these findings is obvious, the resulting protective manipulations have so far not been transferred into clinical neurosurgery. Postconditioning and remote ischaemic preconditioning are additional emerging concepts. Postconditioning with a series of mechanical interruptions of reperfusion can apparently reduce ischaemic damage. Remote ischaemic preconditioning refers to the concept that transient ischaemia for example of a limb can lead to protection of the myocardium and possibly the brain.

Conclusion. Possible cumulative neuroprotection by preconditioning and pharmacological protection during critical ischaemia should be studied systematically. Easy to apply methods of preconditioning, such as the application of volatile anaesthetics or erythropoietin some hours or days prior to planned temporary ischaemia, should be introduced into the practice of operative neurosurgery.

Keywords: Cerebral ischemia; ischemic preconditioning; postconditioning; remote preconditioning. 


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  1. Atochin, DN, Clark, J, Demchenko, IT, Moskowitz, MA, Huang, PL 2003Rapid cerebral ischemic preconditioning in mice deficient in endothelial and neuronal nitric oxide synthasesStroke3412991303PubMedCrossRefGoogle Scholar
  2. Blondeau, N, Widmann, C, Lazdunski, M, Heurteaux, C 2001Activation of the nuclear factor-kappaB is a key event in brain toleranceJ Neurosci2146684677PubMedGoogle Scholar
  3. Chan, JY, Ou, CC, Wang, LL, Chan, SH 2004Heat shock protein 70 confers cardiovascular protection during endotoxemia via inhibition of nuclear factor-kappaB activation and inducible nitric oxide synthase expression in the rostral ventrolateral medullaCirculation11035603566PubMedCrossRefGoogle Scholar
  4. Chan MT, Boet R, Ng SC, Poon WS, Gin T (2005) Effect of ischemic preconditioning on brain tissue gases and pH during temporary cerebral artery occlusion. Acta Neurochir [Suppl 95]: 93–96Google Scholar
  5. Chen, LJ, Su, XW, Qiu, PX, Huang, YJ, Yan, GM 2004Thermal preconditioning protected cerebellar granule neurons of rats by modulating HSP70 expressionActa Pharmacol Sin25458461PubMedGoogle Scholar
  6. Cheung, MM, Kharbanda, RK, Konstantinov, IE, Shimizu, M, Frndova, H, Li, J, Holtby, HM, Cox, PN, Smallhorn, JF, Arsdell, GSV, Redington, AN 2006Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humansJ Am Coll Cardiol4722772282PubMedCrossRefGoogle Scholar
  7. Chiari, PC, Bienengraeber, MW, Pagel, PS, Krolikowski, JG, Kersten, JR, Warltier, DC 2005Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction: evidence for anesthetic-induced postconditioning in rabbitsAnesthesiology102102109PubMedCrossRefGoogle Scholar
  8. Chiueh, CC, Andoh, T, Chock, PB 2005Induction of thioredoxin and mitochondrial survival proteins mediates preconditioning-induced cardioprotection and neuroprotectionAnn NY Acad Sci1042403418PubMedCrossRefGoogle Scholar
  9. Cho, S, Park, EM, Zhou, P, Frys, K, Ross, ME, Iadecola, C 2005Obligatory role of inducible nitric oxide synthase in ischemic preconditioningJ Cereb Blood Flow Metab25493501PubMedCrossRefGoogle Scholar
  10. Xiao, F, Fratkin, JD, Rhodes, PG, Cai, Z 2000Reduced nitric oxide is involved in prenatal ischemia-induced tolerance to neonatal hypoxic-ischemic brain injury in ratsNeurosci Lett28558PubMedCrossRefGoogle Scholar
  11. Gidday, JM, Shah, AR, Maceren, RG, Wang, Q, Pelligrino, DA, Holtzman, DM, Park, TS 1999Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioningJ Cereb Blood Flow Metab19331340PubMedCrossRefGoogle Scholar
  12. Gonzalez-Zulueta, M, Feldman, AB, Klesse, LJ, Kalb, RG, Dillman, JF, Parada, LF, Dawson, TM, Dawson, VL 2000Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioningProc Natl Acad Sci USA97436441PubMedCrossRefGoogle Scholar
  13. Hashiguchi, A, Yano, S, Morioka, M, Hamada, J, Ushio, Y, Takeuchi, Y, Fukunaga, K 2004Up-regulation of endothelial nitric oxide synthase via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampusJ Cereb Blood Flow Metab24271279PubMedCrossRefGoogle Scholar
  14. Heurteaux, C, Lauritzen, I, Widmann, C, Lazdunski, M 1995Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K+ channels in cerebral ischemic preconditioningProc Natl Acad Sci USA9246664670PubMedCrossRefGoogle Scholar
  15. Hiraide, T, Katsura, K, Muramatsu, H, Asano, G, Katayama, Y 2001Adenosine receptor antagonists cancelled the ischemic tolerance phenomenon in gerbilBrain Res9109498PubMedCrossRefGoogle Scholar
  16. Huda, R, Chung, DH, Mathru, M 2005Ischemic preconditioning at a distance: altered gene expression in mouse heart and other organs following brief occlusion of the mesenteric arteryHeart Lung Circ143643PubMedCrossRefGoogle Scholar
  17. Jiang, X, Zhu, D, Okagaki, P 2003N-methyl-D-aspartate and TrkB receptor activation in cerebellar granule cells: an in vitro model of preconditioning to stimulate intrinsic survival pathways in neuronsAnn NY Acad Sci993134145PubMedCrossRefGoogle Scholar
  18. Kapinya, KJ, Prass, K, Dirnagl, U 2002Isoflurane induced prolonged protection against cerebral ischemia in mice: a redox sensitive mechanism?Neuroreport1314311435PubMedCrossRefGoogle Scholar
  19. Kariko, K, Weissmann, D, Welsh, FA 2004Inhibition of toll-like receptor and cytokine signaling – a unifying theme in ischemic toleranceJ Cereb Blood Flow Metab2412881304PubMedCrossRefGoogle Scholar
  20. Katsura, KI, Kurihara, J, Watanabe, M, Takahashi, K, Katayama, Y 2001Ischemic pre-conditioning affects the subcellular distribution of protein kinase C and calcium/calmodulin-dependent protein kinase II in the gerbil hippocampal CA1 neuronsNeurol Res23751754PubMedCrossRefGoogle Scholar
  21. Kawahara, K, Yanoma, J, Tanaka, M, Nakajima, T, Kosugi, T 2004Nitric oxide produced during ischemia is toxic but crucial to preconditioning-induced ischemic tolerance of neurons in cultureNeurochem Res29797804PubMedCrossRefGoogle Scholar
  22. Kurkinen K, Keinanen R, Li W, Koistinaho J (2001) Preconditioning with spreading depression activates specifically protein kinase Cdelta. Neuroreport 269–273Google Scholar
  23. Lange-Asschenfeldt, C, Raval, AP, Dave, KR, Mochly-Rosen, D, Sick, TJ, Perez-Pinzon, MA 2004Epsilon protein kinase C mediated ischemic tolerance requires activation of the extracellular regulated kinase pathway in the organotypic hippocampal sliceJ Cereb Blood Flow Metab24636645PubMedCrossRefGoogle Scholar
  24. Liu, H, Wang, L, Eaton, M, Schaefer, S 2005Sevoflurane preconditioning limits intracellular/mitochondrial Ca2+ in ischemic newborn myocardiumAnesth Analg101349355PubMedCrossRefGoogle Scholar
  25. Liu, Y, Xiong, L, Chen, S, Wang, Q 2006Isoflurane tolerance against focal cerebral ischemia is attenuated by adenosine A1 receptor antagonistsCan J Anaesth53194201PubMedCrossRefGoogle Scholar
  26. Lu, GW, Liu, HY 2001Downregulation of nitric oxide in the brain of mice during their hypoxic preconditioningJ Appl Physiol9111931198PubMedGoogle Scholar
  27. Miyazaki, T, Zipes, DP 1989Protection against autonomic denervation following acute myocardial infarction by preconditioning ischemiaCirc Res64437448PubMedGoogle Scholar
  28. Murry, CE, Jennings, RB, Reimer, KA 1986Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardiumCirculation7411241136PubMedGoogle Scholar
  29. Murry, CE, Richard, VJ, Reimer, KA, Jennings, RB 1990Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episodeCirc Res66913931PubMedGoogle Scholar
  30. Murry, CE, Jennings, RB, Reimer, KA 1991New insights into potential mechanisms of ischemic preconditioningCirculation84442445PubMedGoogle Scholar
  31. Murry, CE, Richard, VJ, Jennings, RB, Reimer, KA 1991Myocardial protection is lost before contractile function recovers from ischemic preconditioningAm J Physiol260H796H804PubMedGoogle Scholar
  32. Nakajima, T, Iwabuchi, S, Miyazaki, H, Okuma, Y, Kuwabara, M, Nomura, Y, Kawahara, K 2004Preconditioning prevents ischemia-induced neuronal death through persistent Akt activation in the penumbra region of the rat brainJ Vet Med Sci66521527PubMedCrossRefGoogle Scholar
  33. Nakamura, M, Nakakimura, K, Matsumoto, M, Sakabe, T 2001Rapid tolerance to focal cerebral ischemia in rats is attenuated by adenosine A1 receptor antagonistJ Cereb Blood Flow Metab22161170Google Scholar
  34. Nozaki, K, Nishimura, M, Hashimoto, N 2001Mitogen-activated protein kinases and cerebral ischemiaMol Neurobiol23119PubMedCrossRefGoogle Scholar
  35. Perez-Pinzon, MA, Xu, GP, Dietrich, WD, Rosenthal, M, Sick, TJ 1997Rapid preconditioning protects rats against ischemic neuronal damage after 3 but not 7 days of reperfusion following global cerebral ischemiaJ Cereb Blood Flow Metab17175182PubMedCrossRefGoogle Scholar
  36. Perez-Pinzon, MA, Alonso, O, Kraydieh, S, Dietrich, WD 1999Induction of tolerance against traumatic brain injury by ischemic preconditioningNeuroreport1029512954PubMedCrossRefGoogle Scholar
  37. Perez-Pinzon, MA, Vitro, TM, Dietrich, WD, Sick, TJ 1999The effect of rapid preconditioning on the microglial, astrocytic and neuronal consequences of global cerebral ischemiaActa Neuropathol (Berl)97495501CrossRefGoogle Scholar
  38. Perez-Pinzon, MA, Basit, A, Dave, KR, Busto, R, Veauvy, C, Saul, I, Ginsberg, MD, Sick, TJ 2002Effect of the first window of ischemic preconditioning on mitochondrial dysfunction following global cerebral ischemiaMitochondrion2181189PubMedCrossRefGoogle Scholar
  39. Perez-Pinzon, MA 2004Neuroprotective effects of ischemic preconditioning in brain mitochondria following cerebral ischemiaJ Bioenerg Biomembr36323327PubMedCrossRefGoogle Scholar
  40. Pugliese, AM, Latini, S, Corradetti, R, Pedata, F 2003Brief, repeated, oxygen-glucose deprivation episodes protect neurotransmission from a longer ischemic episode in the in vitro hippocampus: role of adenosine receptorsBr J Pharmacol140229230CrossRefGoogle Scholar
  41. Ran, R, Xu, H, Lu, A, Bernaudin, M 2005Hypoxia preconditioning in the brainDev Neurosci278792PubMedCrossRefGoogle Scholar
  42. Ravati, A, Ahlemeyer, B, Becker, A, Klumpp, S, Krieglstein, J 2001Preconditioning-induced neuroprotection is mediated by reactive oxygen species and activation of the transcription factor nuclear factor-kappaBJ Neurochem78909919PubMedCrossRefGoogle Scholar
  43. Rosenzweig, HL, Lessov, NS, Henshall, DC, Minami, M, Simon, RP, Stenzel-Poore, MP 2004Endotoxin preconditioning prevents cellular inflammatory response during ischemic neuroprotection in miceStroke3525762581PubMedCrossRefGoogle Scholar
  44. Shamloo, M, Rytter, A, Wieloch, T 1999Activation of the extracellular signal-regulated protein kinase cascade in the hippocampal CA1 region in a rat model of global cerebral ischemic preconditioningNeuroscience938188PubMedCrossRefGoogle Scholar
  45. Shamloo, M, Wieloch, T 1999Rapid decline in protein kinase Cgamma levels in the synaptosomal fraction of rat hippocampus after ischemic preconditioningNeuroreport10931935PubMedCrossRefGoogle Scholar
  46. Sommer, C, Fahrner, A, Kiessling, M 2003Postischemic neuroprotection in the ischemia-tolerant state gerbil hippocampus is associated with increased ligand binding to inhibitory GABA(A) receptorsActa Neuropathol (Berl)105197202Google Scholar
  47. Soriano, FX, Papadia, S, Hofmann, F, Hardingham, NR, Bading, H, Hardingham, GE 2006Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitabilityJ Neurosci2645094518PubMedCrossRefGoogle Scholar
  48. Sorimachi, T, Nowak, TS,Jr 2004Pharmacological manipulations of ATP-dependent potassium channels and adenosine A1 receptors do not impact hippocampal ischemic preconditioning in vivo: evidence in a highly quantitative gerbil modelJ Cereb Blood Flow Metab24556563PubMedCrossRefGoogle Scholar
  49. Stenzel-Poore, MP, Stevens, SL, Xiong, Z, Lessov, NS, Harrington, CA, Mori, M, Meller, R, Rosenzweig, HL, Tobar, E, Shaw, TE, Chu, X, Simon, RP 2003Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant statesLancet36210281037PubMedCrossRefGoogle Scholar
  50. Stenzel-Poore, MP, Stevens, SL, Simon, RP 2004Genomics of preconditioningStroke3526832686PubMedCrossRefGoogle Scholar
  51. Tanaka, M, Fujiwara, H, Yamasaki, K, Yokota, R, Doyama, K, Inada, T, Ohtani, S, Fujiwara, T, Sasayama, S 1998Expression of heat shock protein after ischemic preconditioning in rabbit heartsJpn Circ J62512516PubMedCrossRefGoogle Scholar
  52. Tanaka, S, Itagawa, KK, Ohtsuki, T, Yagita, Y, Takasawa, K, Hori, M, Matsumoto, M 2002Synergistic induction of HSP40 and HSC70 in the mouse hippocampal neurons after cerebral ischemia and ischemic tolerance in gerbil hippocampusJ Neurosci Res673747PubMedCrossRefGoogle Scholar
  53. Wegener, S, Gottschalk, B, Jovanovic, V, Knab, R, Fiebach, JB, Schellinger, PD, Kucinski, T, Jungehulsing, GJ, Brunecker, P, Muller, B, Banasik, A, Amberger, N, Wernecke, KD, Siebler, M, Rother, J, Villringer, A, Weih, M 2004Transient ischemic attacks before ischemic stroke: preconditioning the human brain? A multicenter magnetic resonance imaging studyStroke36616621CrossRefGoogle Scholar
  54. Wick, A, Wick, W, Waltenberger, J, Weller, M, Dichgans, J, Schulz, JB 2002Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and AktJ Neurosci226471Google Scholar
  55. Xiao, L, Zhao, FL, Zhu, XZ 2005Down regulation of cyclooxygenase-2 is involved in delayed neuroprotection by ischemic preconditioning in ratsActa Pharmacol Sin26441446PubMedCrossRefGoogle Scholar
  56. Yamada, T, Kawahara, K, Kosugi, T, Tanaka, M 2006Nitric oxide produced during sublethal ischemia is crucial for the preconditioning-induced down-regulation of glutamate transporter GLT-1 in neuron/astrocyte co-culturesNeurochem Res314956PubMedCrossRefGoogle Scholar
  57. Yanamoto, H, Xue, JH, Miyamoto, S, Nagata, I, Nakano, Y, Murao, K, Kikuchi, H 2004Spreading depression induces long-lasting brain protection against infarcted lesion development via BDNF gene-dependent mechanismBrain Res1019178188PubMedCrossRefGoogle Scholar
  58. Yanamoto, H, Miyamoto, S, Tohnai, N, Nagata, I, Xue, JH, Nakano, Y, Nakajo, Y, Kikuchi, H 2005Induced spreading depression activates persistent neurogenesis in the subventricular zone, generating cells with markers for divided and early committed neurons in the caudate putamen and cortexStroke3615441550PubMedCrossRefGoogle Scholar
  59. Yang, XM, Philipp, S, Downey, JM, Cohen, MV 2005Postconditioning’s protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylyl cyclase activationBasic Res Cardiol1005763PubMedCrossRefGoogle Scholar
  60. Zhang, J, Qian, H, Zhao, P, Hong, SS, Xia, Y 2006Rapid hypoxia preconditioning protects cortical neurons from glutamate toxicity through delta-opioid receptoStroke3710941099PubMedCrossRefGoogle Scholar
  61. Zhang, Y, Wu, YX, Hao, YB, Dun, Y, Yang, SP 2001Role of endogenous opioid peptides in protection of ischemic preconditioning in rat small intestineLife Sci6810131019PubMedCrossRefGoogle Scholar
  62. Zhao H, Sapolsky RM, Steinberg GK (2006) Interrupting reperfusion as a stroke therapy: ischemic postconditioning reduces infarct size after focal ischemia in rats. J Cereb Blood Flow Metab, epub ahead of printGoogle Scholar
  63. Zheng, S, Zuo, Z 2003Isoflurane preconditioning reduces purkinje cell death in an in vitro model of rat cerebellar ischemiaNeuroscience11899106PubMedCrossRefGoogle Scholar
  64. Zheng, S, Zuo, Z 2004Isoflurane preconditioning induces neuroprotection against ischemia via activation of P38 mitogen-activated protein kinasesMol Pharmacol6511721180PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • H.-J. Steiger
    • 1
  • D. Hänggi
    • 1
  1. 1.Department of NeurosurgeryUniversity Hospital, Heinrich-Heine UniversityDüsseldorfGermany

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