Preconditioning and Neuroprotection in the Immature Brain

  • Nicole M. JonesEmail author
  • Adam A. Galle
Part of the Springer Series in Translational Stroke Research book series (SSTSR)


Preconditioning of the newborn brain can cause resistance to injury, and some of the mechanisms involved are similar to those described for the development of tolerance to injury in mature brain; however, there are also some mechanisms which appear to be distinct. Over the years, there have been a number of different types of preconditioning stimuli that have shown to protect against injury in the immature brain, and these include hyperthermia, anaesthetics, hypoxia and lipopolysaccharide exposure. Whilst these preconditioning paradigms have proven useful in animal models, the neuroprotective efficacy of preconditioning has not yet been examined in human infants. Delineating some of the common endogenous pathways involved in preconditioning of the immature brain could lead to major advances in the treatment of brain injuries occurring in newborns as well as adults.


Vascular Endothelial Growth Factor Ischemic Precondition Hypoxic Precondition Preconditioned Animal Isoflurane Precondition 
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  1. Alkan T et al (2008) Effects of hypoxic preconditioning in antioxidant enzyme activities in hypoxic-ischemic brain damage in immature rats. Turk Neurosurg 18(2):165–171PubMedGoogle Scholar
  2. Althaus J et al (2006) Expression of the gene encoding the pro-apoptotic BNIP3 protein and stimulation of hypoxia-inducible factor-1a (HIF-1a) following focal cerebral ischemia in rats. Neurochem Int 2006(48):687–695CrossRefGoogle Scholar
  3. Bergeron M et al (2000a) Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann Neurol 48(3):285–296PubMedCrossRefGoogle Scholar
  4. Bergeron M et al (2000b) Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann Neurol 48:285–296PubMedCrossRefGoogle Scholar
  5. Bernaudin M et al (2002a) 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(42):39728–39738PubMedCrossRefGoogle Scholar
  6. Bernaudin M et al (2002b) Brain genomic responses following hypoxia and re-oxygenation in neonatal rat. J Biol Chem 277(42):39728–39738PubMedCrossRefGoogle Scholar
  7. Brucklacher RM, Vannucci RC, Vannucci SJ (2002) Hypoxic preconditioning increases brain glycogen and delays energy depletion from hypoxia-ischemia in the immature rat. Dev Neurosci 24(5):411–417PubMedCrossRefGoogle Scholar
  8. Chavez JC et al (2006) The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes. J Neurosci 26(37):9471–9481PubMedCrossRefGoogle Scholar
  9. Cheung MMH et al (2006) Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery. J Am Coll Cardiol 47(11):2277–2282PubMedCrossRefGoogle Scholar
  10. Cimarosti H et al (2005) Hypoxic preconditioning in neonatal rat brain involves regulation of excitatory amino acid transporter 2 and estrogen receptor alpha. Neurosci Lett 385:52–57PubMedCrossRefGoogle Scholar
  11. Dawson DA et al (1999) Cerebrovascular hemodynamics and ischemic tolerance[colon] 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(6):616–623PubMedCrossRefGoogle Scholar
  12. Eklind S et al (2005) Lipopolysaccharide induces both a primary and a secondary phase of sensitization in the developing rat brain. Pediatr Res 58(1):112–116PubMedCrossRefGoogle Scholar
  13. Feng Y, Rhodes PG, Bhatt AJ (2010) Hypoxic preconditioning provides neuroprotection and increases vascular endothelial growth factor A, preserves the phosphorylation of Akt-Ser-473 and diminishes the increase in caspase-3 activity in neonatal rat hypoxic-ischemic model. Brain Res 1325:1–9PubMedCrossRefGoogle Scholar
  14. Gidday JM (2006) Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 7(6):437–448PubMedCrossRefGoogle Scholar
  15. Gidday JM et al (1994) Neuroprotection from ischemic brain injury by hypoxic preconditioning in the neonatal rat. Neurosci Lett 168:221–224PubMedCrossRefGoogle Scholar
  16. Gidday J et al (1999) Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. J Cereb Blood Flow Metab 19:331–340PubMedCrossRefGoogle Scholar
  17. Gustavsson M et al (2005) Hypoxic preconditioning confers long-term reduction of brain injury and improvement of neurological ability in immature rats. Pediatr Res 57(2):305–309PubMedCrossRefGoogle Scholar
  18. Gustavsson M et al (2007a) Vascular response to hypoxic preconditioning in the immature brain. J Cereb Blood Flow Metab 27(5):928–938PubMedGoogle Scholar
  19. Gustavsson M et al (2007b) Global gene expression in the developing rat brain after hypoxic preconditioning: involvement of apoptotic mechanisms? Pediatr Res 61(4):444–450PubMedCrossRefGoogle Scholar
  20. Hagberg H et al (2004) Preconditioning and the developing brain. Semin Perinatol 28(6):389–395PubMedCrossRefGoogle Scholar
  21. Halterman MW, Federoff HJ (1999) HIF-1a and p53 promote hypoxia-induced delayed neuronal death in models of CNS ischemia. Exp Neurol 159:65–72PubMedCrossRefGoogle Scholar
  22. Helton R et al (2005) Brain-specific knock-out of hypoxia-inducible factor-1a reduces rather than increases hypoxic-ischemic damage. J Neurosci 25(16):4099–4107PubMedCrossRefGoogle Scholar
  23. Hickey E et al (2011) Lipopolysaccharide-induced preconditioning against ischemic injury is accociated with changes in Toll-like receptor 4 expression in the rat developing brain. Pediatr Res 70(1):10–14PubMedCrossRefGoogle Scholar
  24. Ikeda T et al (2006) Endotoxin-induced hypoxic-ischemic tolerance is mediated by up-regulation of corticosterone in neonatal rat. Pediatr Res 59(1):56–60PubMedCrossRefGoogle Scholar
  25. Jones NM, Bergeron M (2001) Hypoxic preconditioning induces changes in HIF-1 target genes in neonatal rat brain. J Cereb Blood Flow Metab 21:1105–1114PubMedCrossRefGoogle Scholar
  26. Jones NM, Bergeron M (2004) Hypoxia-induced tolerance in neonatal rat brain involves enhanced ERK1/2 signalling. J Neurochem 89:157–167PubMedCrossRefGoogle Scholar
  27. Jones NM et al (2006) Hypoxic preconditioning produces differential expression of hypoxia-inducible factor-1a (HIF-1a) and its regulatory enzyme HIF prolyl hydroxylase 2 in neonatal rat brain. Neurosci Lett 404:72–77PubMedCrossRefGoogle Scholar
  28. Jones NM et al (2008) Long term functional and protective actions of preconditioning with hypoxia, cobalt chloride and desferrioxamine against hypoxic-ischemic injury in neonatal rats. Pediatr Res 63(6):620–624PubMedCrossRefGoogle Scholar
  29. Kawahara N et al (2004) 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(2):212–223PubMedCrossRefGoogle Scholar
  30. Kitagawa K et al (1991) ‘Ischemic tolerance’ phenomenon detected in various brain regions. Brain Res 561(2):203–211PubMedCrossRefGoogle Scholar
  31. Kunz A et al (2007) Neurovascular protection by ischemic tolerance: role of nitric oxide and reactive oxygen species. J Neurosci 27(27):7083–7093PubMedCrossRefGoogle Scholar
  32. Laudenbach V et al (2007) Neonatal hypoxic preconditioning involves vascular endothelial growth factor. Neurobiol Dis 26:243–252PubMedCrossRefGoogle Scholar
  33. Lee H-T et al (2004) cAMP response element-binding protein activation in ligation preconditioning in neonatal brain. Ann Neurol 56:611–623PubMedCrossRefGoogle Scholar
  34. Lin JHC et al (2008) A central role of connexin 43 in hypoxic preconditioning. J Neurosci 28(3):681–695PubMedCrossRefGoogle Scholar
  35. Lin WY et al (2009) CREB activation in the rapid, intermediate, and delayed ischemic preconditioning against hypoxic-ischemia in neonatal rat. J Neurochem 108(4):847–859PubMedCrossRefGoogle Scholar
  36. Lin H-Y, Wu C-L, Huang C-C (2010) The Akt-Endothelial nitric oxide synthase pathway in lipopolysaccharide preconditioning-induced hypoxic-ischemic tolerance in the neonatal rat brain. Stroke 41:1543–1551PubMedCrossRefGoogle Scholar
  37. Lu G-W et al (2005) Hypoxic preconditioning. Mol Neurobiol 31(1):255–271PubMedCrossRefGoogle Scholar
  38. Luo Y et al (2008) Xenon and sevoflurane protect against brain injury in a neonatal asphyxia model. Anesthesiology 109:782–789PubMedCrossRefGoogle Scholar
  39. McAuliffe J, Miles L, Vorhees C (2006) Adult neurological function following neonatal hypoxia-ischemia in a mouse model of the term neonate: water maze performance is dependent upon separable cognitive and motor components. Brain Res 1118(1):208–221PubMedCrossRefGoogle Scholar
  40. Meller R et al (2006) Rapid degradation of Bim by the ubiquitin-proteasome pathway mediates short-term ischemic tolerance in cultured neurons. J Biol Chem 281(11):7429–7436PubMedCrossRefGoogle Scholar
  41. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74(5):1124–1136PubMedCrossRefGoogle Scholar
  42. Obrenovitch TP (2008) Molecular physiology of preconditioning-induced brain tolerance to ischemia. Physiol Rev 88(1):211–247PubMedCrossRefGoogle Scholar
  43. Perez-Pinzon MA et al (1997) 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(2):175–182PubMedCrossRefGoogle Scholar
  44. Sapolsky RM (2001) Cellular defenses against excitotoxic insults. J Neurochem 76(6):1601–1611PubMedCrossRefGoogle Scholar
  45. Sasaoka N et al (2009) Isoflurane exerts a short-term but not a long-term preconditioning effect in neonatal rats exposed to a hypoxic-ischaemic neuronal injury. Acta Anaesthesiol Scand 53(1):46–54PubMedCrossRefGoogle Scholar
  46. Sharp FR et al (2004) Hypoxic preconditioning protects against ischemic brain injury. NeuroRx 1(1):26–35PubMedCrossRefGoogle Scholar
  47. Sheldon RA et al (2007) Hypoxic preconditioning reverses protection after neonatal hypoxia-ischemia in glutathione peroxidase transgenic murine brain. Pediatr Res 61(6):666–670PubMedCrossRefGoogle Scholar
  48. Shpargel KB et al (2008) Preconditioning paradigms and pathways in the brain. Cleve Clin J Med 75(Suppl 2):S77PubMedCrossRefGoogle Scholar
  49. Stagliano NE et al (1999) Focal Ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 19(7):757–761PubMedCrossRefGoogle Scholar
  50. Stenzel-Poore MP et al (2003) Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet 362(9389):1028–1037PubMedCrossRefGoogle Scholar
  51. Stenzel-Poore MP et al (2007) Preconditioning reprograms the response to ischemic injury and primes the emergence of unique endogenous neuroprotective phenotypes: a speculative synthesis. Stroke 38(2):680–685PubMedCrossRefGoogle Scholar
  52. Tang Y et al (2006) 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(1):18–28PubMedCrossRefGoogle Scholar
  53. Trendelenburg G, Dirnagl U (2005) Neuroprotective role of astrocytes in cerebral ischemia: focus on ischemic preconditioning. Glia 50(4):307–320PubMedCrossRefGoogle Scholar
  54. Vangeison G et al (2008) The good, the bad, and the cell type-specific roles of hypoxia inducible factor-1α in neurons and astrocytes. J Neurosci 28(8):1988–1993PubMedCrossRefGoogle Scholar
  55. Vannucci R (1998) Hypoxic preconditioning and hypoxic-ischemic brain damage in the immature rat: pathologic and metabolic correlates. J Neurochem 71:1215–1220PubMedCrossRefGoogle Scholar
  56. Vannucci RC, Towfighi J, Vannucci SJ (1998) Hypoxic preconditioning and hypoxic-ischemic brain damage in the immature rat: pathologic and metabolic correlates. J Neurochem 71(3):1215–1220PubMedCrossRefGoogle Scholar
  57. Wada T, Kondoh T, Tamaki N (1999) Ischemic “cross” tolerance in hypoxia ischemia of immature rat brain. Brain Res 847:299–307PubMedCrossRefGoogle Scholar
  58. Wang YP et al (2002) Lipopolysaccharide triggers late preconditioning against myocardial infarction via inducible nitric oxide synthase. Cardiovasc Res 56(1):33–42PubMedCrossRefGoogle Scholar
  59. Weih M et al (1999) Attenuated stroke severity after prodromal TIA: a role for ischemic tolerance in the brain? Stroke 30(9):1851–1854PubMedCrossRefGoogle Scholar
  60. Yin W et al (2007) Preconditioning suppresses inflammation in neonatal hypoxic ischemia via Akt activation. Stroke 38:1017–1024PubMedCrossRefGoogle Scholar
  61. Zhao P et al (2007) Isofluorane preconditioning improves long-term neurologic outcome after hypoxic-ischemic brain injury in neonatal rats. Anesthesiology 107:963–970PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of New South WalesSydneyAustralia

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