Seminars in Fetal & Neonatal Medicine
Volume 15, Issue 5 , Pages 287-292 , October 2010

Mechanisms of hypothermic neuroprotection

  • Paul P. Drury

      Affiliations

    • Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
  • ,
  • Laura Bennet

      Affiliations

    • Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
  • ,
  • Alistair J. Gunn

      Affiliations

    • Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
    • Starship Children’s Hospital, Grafton, Aukland, New Zealand
    • Corresponding Author InformationCorresponding author. Tel.: +649 3737599; fax: +649 3737499.

References 

  1. Gunn AJ, Gluckman PD. Head cooling for neonatal encephalopathy: the state of the art. Clin Obstet Gynecol. 2007;50:636–651
  2. Hoehn T, Hansmann G, Buhrer C, et al. Therapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units. Resuscitation. 2008;78:7–12
  3. Shah PS. Hypothermia: a systematic review and meta-analysis of clinical trials. Semin Fetal Neonatal Med. 2010;15(5):238–246
  4. Cilio MR, Ferriero DM. Synergistic neuroprotective therapies with hypothermia. Semin Fetal Neonatal Med. 2010;15(5):293–298
  5. Gunn AJ, Gunn TR. The ‘pharmacology’ of neuronal rescue with cerebral hypothermia. Early Hum Dev. 1998;53:19–35
  6. Gunn AJ, Thoresen M. Hypothermic neuroprotection. NeuroRx. 2006;3:154–169
  7. Azzopardi D, Wyatt JS, Cady EB, et al. Prognosis of newborn infants with hypoxic–ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1989;25:445–451
  8. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest. 1997;99:248–256
  9. Lorek A, Takei Y, Cady EB, et al. Delayed (“secondary”) cerebral energy failure after acute hypoxia–ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1994;36:699–706
  10. Bennet L, Roelfsema V, Pathipati P, Quaedackers J, Gunn AJ. Relationship between evolving epileptiform activity and delayed loss of mitochondrial activity after asphyxia measured by near-infrared spectroscopy in preterm fetal sheep. J Physiol. 2006;572:141–154
  11. Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics. 1998;102:1098–1106
  12. Gunn AJ, Bennet L, Gunning MI, Gluckman PD, Gunn TR. Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep. Pediatr Res. 1999;46:274–280
  13. Sirimanne ES, Blumberg RM, Bossano D, et al. The effect of prolonged modification of cerebral temperature on outcome after hypoxic–ischemic brain injury in the infant rat. Pediatr Res. 1996;39:591–597
  14. Thoresen M, Penrice J, Lorek A, et al. Mild hypothermia after severe transient hypoxia–ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res. 1995;37:667–670
  15. Edwards AD, Yue X, Squier MV, et al. Specific inhibition of apoptosis after cerebral hypoxia–ischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun. 1995;217:1193–1199
  16. Tooley JR, Satas S, Porter H, Silver IA, Thoresen M. Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective. Ann Neurol. 2003;53:65–72
  17. Low JA, Lindsay BG, Derrick EJ. Threshold of metabolic acidosis associated with newborn complications. Am J Obstet Gynecol. 1997;177:1391–1394
  18. Colbourne F, Corbett D. Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci. 1995;15:7250–7260
  19. Colbourne F, Li H, Buchan AM. Indefatigable CA1 sector neuroprotection with mild hypothermia induced 6 hours after severe forebrain ischemia in rats. J Cereb Blood Flow Metab. 1999;19:742–749
  20. Colbourne F, Corbett D, Zhao Z, Yang J, Buchan AM. Prolonged but delayed postischemic hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model. J Cereb Blood Flow Metab. 2000;20:1702–1708
  21. Laptook AR, Corbett RJ, Sterett R, Garcia D, Tollefsbol G. Quantitative relationship between brain temperature and energy utilization rate measured in vivo using 31P and 1H magnetic resonance spectroscopy. Pediatr Res. 1995;38:919–925
  22. Erecinska M, Thoresen M, Silver IA. Effects of hypothermia on energy metabolism in Mammalian central nervous system. J Cereb Blood Flow Metab. 2003;23:513–530
  23. Bart RD, Takaoka S, Pearlstein RD, Dexter F, Warner DS. Interactions between hypothermia and the latency to ischemic depolarization: implications for neuroprotection. Anesthesiology. 1998;88:1266–1273
  24. Nakashima K, Todd MM. Effects of hypothermia, pentobarbital, and isoflurane on postdepolarization amino acid release during complete global cerebral ischemia. Anesthesiology. 1996;85:161–168
  25. Nakashima K, Todd MM. Effects of hypothermia on the rate of excitatory amino acid release after ischemic depolarization. Stroke. 1996;27:913–918
  26. Thoresen M, Satas S, Puka-Sundvall M, et al. Post-hypoxic hypothermia reduces cerebrocortical release of NO and excitotoxins. Neuroreport. 1997;8:3359–3362
  27. Haynes RL, Baud O, Li J, Kinney HC, Volpe JJ, Folkerth DR. Oxidative and nitrative injury in periventricular leukomalacia: a review. Brain Pathol. 2005;15:225–233
  28. Lei B, Tan X, Cai H, Xu Q, Guo Q. Effect of moderate hypothermia on lipid peroxidation in canine brain tissue after cardiac arrest and resuscitation. Stroke. 1994;25:147–152
  29. Kubota M, Nakane M, Narita K, et al. Mild hypothermia reduces the rate of metabolism of arachidonic acid following postischemic reperfusion. Brain Res. 1998;779:297–300
  30. Lei B, Adachi N, Arai T. The effect of hypothermia on H2O2 production during ischemia and reperfusion: a microdialysis study in the gerbil hippocampus. NeurosciLett. 1997;222:91–94
  31. Tan WK, Williams CE, During MJ, et al. Accumulation of cytotoxins during the development of seizures and edema after hypoxic–ischemic injury in late gestation fetal sheep. Pediatr Res. 1996;39:791–797
  32. Bagenholm R, Nilsson UA, Kjellmer I. Formation of free radicals in hypoxic ischemic brain damage in the neonatal rat, assessed by an endogenous spin trap and lipid peroxidation. Brain Res. 1997;773:132–138
  33. Marks KA, Mallard EC, Roberts I, et al. Delayed vasodilation and altered oxygenation after cerebral ischemia in fetal sheep. Pediatr Res. 1996;39:48–54
  34. Karlsson BR, Grogaard B, Gerdin B, Steen PA. The severity of postischemic hypoperfusion increases with duration of cerebral ischemia in rats. Acta Anaesthesiol Scand. 1994;38:248–253
  35. Perlman JM. White matter injury in the preterm infant: an important determination of abnormal neurodevelopment outcome. Early Hum Dev. 1998;53:99–120
  36. Jensen EC, Bennet L, Hunter CJ, Power GG, Gunn AJ. Post-hypoxic hypoperfusion is associated with suppression of cerebral metabolism and increased tissue oxygenation in near-term fetal sheep. J Physiol. 2006;572:131–139
  37. Bennet L, Dean JM, Wassink G, Gunn AJ. Differential effects of hypothermia on early and late epileptiform events after severe hypoxia in preterm fetal sheep. J Neurophysiol. 2007;97:572–578
  38. Canevari L, Console A, Tendi EA, Clark JB, Bates TE. Effect of postischaemic hypothermia on the mitochondrial damage induced by ischaemia and reperfusion in the gerbil. Brain Res. 1999;17:241–245
  39. Huang CH, Chen HW, Tsai MS, et al. Antiapoptotic cardioprotective effect of hypothermia treatment against oxidative stress injuries. Acad Emerg Med. 2009;16:872–880
  40. Blumberg RM, Cady EB, Wigglesworth JS, McKenzie JE, Edwards AD. Relation between delayed impairment of cerebral energy metabolism and infarction following transient focal hypoxia–ischaemia in the developing brain. Exp Brain Res. 1997;113:130–137
  41. Pereira de Vasconcelos A, Ferrandon A, Nehlig A. Local cerebral blood flow during lithium-pilocarpine seizures in the developing and adult rat: role of coupling between blood flow and metabolism in the genesis of neuronal damage. J Cereb Blood Flow Metab. 2002;22:196–205
  42. Ingvar M. Cerebral blood flow and metabolic rate during seizures. Relationship to epileptic brain damage. Ann NY Acad Sci. 1986;462:194–206
  43. Tan WK, Williams CE, Gunn AJ, Mallard CE, Gluckman PD. Suppression of postischemic epileptiform activity with MK-801 improves neural outcome in fetal sheep. Ann Neurol. 1992;32:677–682
  44. Kristian T, Katsura K, Siesjo BK. The influence of moderate hypothermia on cellular calcium uptake in complete ischaemia: implications for the excitotoxic hypothesis. Acta Physiol Scand. 1992;146:531–532
  45. Bruno VM, Goldberg MP, Dugan LL, Giffard RG, Choi DW. Neuroprotective effect of hypothermia in cortical cultures exposed to oxygen-glucose deprivation or excitatory amino acids. J Neurochem. 1994;63:1398–1406
  46. Zeevalk GD, Nicklas WJ. Hypothermia and metabolic stress: narrowing the cellular site of early neuroprotection. J Pharmacol Exp Ther. 1996;279:332–339
  47. Ishimaru MJ, Ikonomidou C, Tenkova TI, et al. Distinguishing excitotoxic from apoptotic neurodegeneration in the developing rat brain. J Comp Neurol. 1999;408:461–476
  48. Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death: the calcium–apoptosis link. Nat Rev Mol Cell Biol. 2003;4:552–565
  49. Johnston MV. Excitotoxicity in perinatal brain injury. Brain Pathol. 2005;15:234–240
  50. Brown GC, Bal-Price A. Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Molec Neurobiol. 2003;27:325–355
  51. Taylor DL, Edwards AD, Mehmet H. Oxidative metabolism, apoptosis and perinatal brain injury. Brain Pathol. 1999;9:93–117
  52. MacGibbon GA, Lawlor PA, Sirimanne ES, et al. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer’s disease hippocampus. Brain Res. 1997;750:223–234
  53. Zhu C, Wang X, Hagberg H, Blomgren K. Correlation between caspase-3 activation and three different markers of DNA damage in neonatal cerebral hypoxia–ischemia. J Neurochem. 2000;75:819–829
  54. Samejima K, Tone S, Kottke TJ, et al. Transition from caspase-dependent to caspase-independent mechanisms at the onset of apoptotic execution. J Cell Biol. 1998;143:225–239
  55. Beilharz EJ, Williams CE, Dragunow M, Sirimanne ES, Gluckman PD. Mechanisms of delayed cell death following hypoxic–ischemic injury in the immature rat: evidence for apoptosis during selective neuronal loss. Brain Res Mol Brain Res. 1995;29:1–14
  56. Edwards AD, Yue X, Cox P, et al. Apoptosis in the brains of infants suffering intrauterine cerebral injury. Pediatr Res. 1997;42:684–689
  57. Scott RJ, Hegyi L. Cell death in perinatal hypoxic–ischaemic brain injury. Neuropathol Appl Neurobiol. 1997;23:307–314
  58. Xu RX, Nakamura T, Nagao S, et al. Specific inhibition of apoptosis after cold-induced brain injury by moderate postinjury hypothermia. Neurosurgery. 1998;43:107–114
  59. Inamasu J, Suga S, Sato S, et al. Postischemic hypothermia attenuates apoptotic cell death in transient focal ischemia in rats. Acta Neurochir Suppl. 2000;76:525–527
  60. Colbourne F, Sutherland GR, Auer RN. Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia. J Neurosci. 1999;19:4200–4210
  61. Hu BR, Liu CL, Ouyang Y, Blomgren K, Siesjo BK. Involvement of caspase-3 in cell death after hypoxia–ischemia declines during brain maturation. J Cereb Blood Flow Metab. 2000;20:1294–1300
  62. Gottron FJ, Ying HS, Choi DW. Caspase inhibition selectively reduces the apoptotic component of oxygen-glucose deprivation-induced cortical neuronal cell death. Mol Cell Neurosci. 1997;9:159–169
  63. Portera-Cailliau C, Price DL, Martin LJ. Excitotoxic neuronal death in the immature brain is an apoptosis–necrosis morphological continuum. J Comp Neurol. 1997;378:70–87
  64. Du C, Hu R, Csernansky CA, Hsu CY, Choi DW. Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis?. J Cereb Blood Flow Metab. 1996;16:195–201
  65. Northington FJ, Zelaya ME, O’Riordan DP, et al. Failure to complete apoptosis following neonatal hypoxia–ischemia manifests as “continuum” phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain. Neuroscience. 2007;149:822–833
  66. Benchoua A, Guegan C, Couriaud C, et al. Specific caspase pathways are activated in the two stages of cerebral infarction. J Neurosci. 2001;21:7127–7134
  67. Roelfsema V, Bennet L, George S, et al. The window of opportunity for cerebral hypothermia and white matter injury after cerebral ischemia in near-term fetal sheep. J Cereb Blood Flow Metab. 2004;24:877–886
  68. Bossenmeyer-Pourie C, Koziel V, Daval JL. Effects of hypothermia on hypoxia-induced apoptosis in cultured neurons from developing rat forebrain: comparison with preconditioning. Pediatr Res. 2000;47:385–391
  69. Hagberg H, Mallard C, Jacobsson B. Role of cytokines in preterm labour and brain injury. BJOG. 2005;112(Suppl. 1):16–18
  70. Graham EM, Sheldon RA, Flock DL, et al. Neonatal mice lacking functional Fas death receptors are resistant to hypoxic–ischemic brain injury. Neurobiol Dis. 2004;17:89–98
  71. Si QS, Nakamura Y, Kataoka K. Hypothermic suppression of microglial activation in culture: inhibition of cell proliferation and production of nitric oxide and superoxide. Neuroscience. 1997;81:223–229
  72. Goss JR, Styren SD, Miller PD, et al. Hypothermia attenuates the normal increase in interleukin 1 beta RNA and nerve growth factor following traumatic brain injury in the rat. J Neurotrauma. 1995;12:159–167
  73. Chatzipanteli K, Alonso OF, Kraydieh S, Dietrich WD. Importance of posttraumatic hypothermia and hyperthermia on the inflammatory response after fluid percussion brain injury: biochemical and immunocytochemical studies. J Cereb Blood Flow Metab. 2000;20:531–542
  74. Brown GC. Nitric oxide inhibition of cytochrome oxidase and mitochondrial respiration: implications for inflammatory, neurodegenerative and ischaemic pathologies. Mol Cell Biochem. 1997;174:189–192
  75. Tatsumi T, Matoba S, Kawahara A, et al. Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes. J Am Coll Cardiol. 2000;35:1338–1346
  76. Samavati L, Lee I, Mathes I, Lottspeich F, Huttemann M. Tumor necrosis factor alpha inhibits oxidative phosphorylation through tyrosine phosphorylation at subunit I of cytochrome c oxidase. J Biol Chem. 2008;283:21134–21144
  77. Druzhyna NM, Musiyenko SI, Wilson GL, LeDoux SP. Cytokines induce nitric oxide-mediated mtDNA damage and apoptosis in oligodendrocytes. Protective role of targeting 8-oxoguanine glycosylase to mitochondria. J Biol Chem. 2005;280:21673–21679
  78. Fraser M, Bennet L, van Zijl PL, Mocatta TJ, Williams CE, Gluckman PD, et al. Extracellular amino acids and peroxidation products in the periventricular white matter during and after cerebral ischemia in preterm fetal sheep. J Neurochem. 2008;105:2214–2223
  79. Nurse S, Corbett D. Neuroprotection after several days of mild, drug-induced hypothermia. J Cereb Blood Flow Metab. 1996;16:474–480
  80. Jensen FE, Wang C, Stafstrom CE, Liu Z, Geary C, Stevens MC. Acute and chronic increases in excitability in rat hippocampal slices after perinatal hypoxia in vivo. J Neurophysiol. 1998;79:73–81
  81. George S, Gunn AJ, Westgate JA, Brabyn C, Guan J, Bennet L. Fetal heart rate variability and brainstem injury after asphyxia in preterm fetal sheep. Am J Physiol Regul Integr Comp Physiol. 2004;287:R925–R933
  82. Dean JM, Gunn AJ, Wassink G, George S, Bennet L. Endogenous alpha(2)-adrenergic receptor-mediated neuroprotection after severe hypoxia in preterm fetal sheep. Neuroscience. 2006;142:615–628
  83. Bennet L, Roelfsema V, George S, Dean JM, Emerald BS, Gunn AJ. The effect of cerebral hypothermia on white and grey matter injury induced by severe hypoxia in preterm fetal sheep. J Physiol. 2007;578:491–506
  84. Bennet L, Booth L, Gunn AJ. Potential biomarkers for hypoxic-ischemic encephalopathy. Semin Fetal Neonatal Med. 2010;15(5):253–260
  85. Dean JM, George SA, Wassink G, Gunn AJ, Bennet L. Suppression of post hypoxic–ischemic EEG transients with dizocilpine is associated with partial striatal protection in the preterm fetal sheep. Neuropharmacology. 2006;50:491–503
  86. Bennet L, Roelfsema V, Dean J, et al. Regulation of cytochrome oxidase redox state during umbilical cord occlusion in preterm fetal sheep. Am J Physiol Regul Integr Comp Physiol. 2007;292:R1569–R1576

PII: S1744-165X(10)00041-7

doi: 10.1016/j.siny.2010.05.005

Seminars in Fetal & Neonatal Medicine
Volume 15, Issue 5 , Pages 287-292 , October 2010