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Biochemical Basis of Hypoxic-Ischemic Encephalopathy

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Neonatology

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Abstract

Perinatal hypoxia ischemia is the most common cause of neurologic disease during the neonatal period. Hypoxic ischemic encephalopathy (HIE), is associated with a high mortality and morbidity rate, including cerebral palsy, mental retardation, and seizures [1]. The incidence of perinatal asphyxia is about 1.0–1.5% in most centers and is usually related to gestational age and birth weight. It occurs in 9.0% of infants less than 36 weeks’ gestation and in 0.5% of infants more than 36 weeks’ gestation [2, 3]. The etiology of perinatal HIE includes those circumstances that can affect the cerebral blood flow in the fetus and newborn compromising the supply of oxygen to the brain. They may develop antepartum (20%), intrapartum (30%), antepartum and intrapartum (35%), or postpartum (10%) [4].

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References

  1. Volpe J (2001) Neurology of the newborn, 3rd edn. WB Saunders, Philadelphia

    Google Scholar 

  2. Legido A (1994) Perinatal hypoxic-ischemic encephalopathy: current advances in diagnosis and treatment. Int Pediatr 9: 114–136

    Google Scholar 

  3. Hill A, Volpe J (1999) Hypoxic-ischemic cerebral injury in the newborn. In: Swaiman KF, Ashwal S (eds) Pediatric neurology, Principles and practice. Mosby, St. Louis, pp 191–204

    Google Scholar 

  4. Raichle ME (1983) The pathophysiology of brain ischemia. Ann Neurol 13: 2–10

    Article  PubMed  CAS  Google Scholar 

  5. Legido A, Katsetos CD, Mishra OP et al (2001) Perinatal hypoxiaischemia encephalopathy: current and future treatments. Int Pediatr 15: 143–151

    Google Scholar 

  6. Delivoria-Papadopoulos M, Mishra OP (1998) Mechanisms of cerebral injury in perinatal asphyxia and strategies for prevention. J Pediatr 132: S30–S34

    Article  PubMed  CAS  Google Scholar 

  7. Fritz K, Delivoria-Papadopoulos M (2006) Mechanisms of injury to the newborn brain. Clin Perinatol 33: 573–591

    Article  PubMed  Google Scholar 

  8. Linnik MD, Zobirst RH, Hatfield MD (1993) Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Strokes 24: 2002–2008

    Article  CAS  Google Scholar 

  9. Ferrer I, Tortosa A, Macaya A et al (1994) Evidence of nuclear DNA fragmentation following hypoxia-ischemia in the infant rat brain, and transient forebrain ischemia in the adult gerbil. Brain Pathol 4: 115–122

    Article  PubMed  CAS  Google Scholar 

  10. Wylie AH, Kerr JFR, Currie AR (1980) Cell Death, the significance of apoptosis. Int Rev Cytol 68: 251–306

    Article  Google Scholar 

  11. Columbano A (1995) Cell death: current difficulties in discriminating apoptosis and necrosis in the context of pathological processes in vivo. J Cell Biochem 58: 181–190

    Article  PubMed  CAS  Google Scholar 

  12. Rosenbaum DM, Michaelson M, Batter DK et al (1994) Evidence for hypoxia induced programmed cell death of cultured neurons. Ann Neurol 25: 19–33

    Google Scholar 

  13. Dragunow M, Beiharz E, Sirimanne E et al (1994) Immediately early gene protein expression in neurons undergoing delayed death, but not necrosis following hypoxic-ischemic injury to the young rat brain. Brain Res Mol Brain Res 25: 1933

    Article  Google Scholar 

  14. Gillardon F, Lenz C, Waschle KF (1996) Altered expression of Bcl- 2, Bcl-X, Bax and c-Fos colocalizes with DNA fragmentation and ischemic cell damage following middle cerebral artery occlusion in rats. Brain Res Mol Brain Res 40: 254–260

    Article  PubMed  CAS  Google Scholar 

  15. Kitada S, Krajewski S, Miyashita T (1996) Gamma-radiation induces upregulation of Bax protein and apoptosis in radiosensitive cells in vivo. Oncogene 12: 187–192

    PubMed  CAS  Google Scholar 

  16. Choi DW (1990) Cerebral hypoxia: some new approaches and unanswered questions. J Neurosci 10: 2493–2501

    PubMed  CAS  Google Scholar 

  17. Rothman SM, Olney JW (1986) Glutanate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol 19: 105–111

    Article  PubMed  CAS  Google Scholar 

  18. Monaghan DT, Bridges RJ, Cotman CW (1989) The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu Rev Pharmacol Toxicol 29: 365–402

    Article  PubMed  CAS  Google Scholar 

  19. Bashir ZI, Alford S, Davies SN et al (1991) Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus. Nature 349: 156–158

    Article  PubMed  CAS  Google Scholar 

  20. Tacconi S, Ratti E, Marien MR et al (1993), Inhibition of (3H)- (+)-MK-801 binding to rat brain sections by CPP and 7-chlorokyneuric acid: an autoradiographic analysis. Br J Pharmacol 108: 668–674

    Google Scholar 

  21. Hoffman DJ, Marro PJ, McGowan JE et al (1994) Protective effect of MgSO4 infusion on NMDA receptor binding characteristics during cerebral cortical hypoxia in newborn piglets. Brain Res 644: 144–149

    Article  PubMed  CAS  Google Scholar 

  22. Johnston MV (1995) Neurotransmitters and vulnerability of the developing brain. Brain Dev 17: 301–306

    Article  PubMed  CAS  Google Scholar 

  23. Aizenman E, Lipton SA, Loring RH (1989) Selective modulation of NMDA responses by reduction and oxidation. Neuron 2: 1257–1263

    Article  PubMed  CAS  Google Scholar 

  24. Lipton S (1999) Redox sensitivity of NMDA receptor. Meth Mol Biol 128: 121–130

    CAS  Google Scholar 

  25. Monaghan DT, Olvenman HJ, Nguyen L et al (1988), Two classes of N-methyl-D-aspartate recognition sites: Differential distribution and differential regulation by glycine. Proc Natl Acad Sci USA 85: 9836–9840

    Google Scholar 

  26. Nowak L, Bregetovski P, Ascher P et al (1984) Magnesium gates glutamate-activated channels in mouse central neurons. Nature 307: 462–465

    Article  PubMed  CAS  Google Scholar 

  27. Mayer ML, Westbrook GL, Guthrie PB (1984) Voltage-dependent block by Mg++ of NMDA responses in spinal cord neurons. Nature 309: 261–263

    Article  PubMed  CAS  Google Scholar 

  28. Collingridge G (1987) Synaptic plasticity. The role of NMDA receptors in learning and memory. Nature 330: 604–605

    Article  PubMed  CAS  Google Scholar 

  29. Tang YP, Shimizu E, Dube GR et al (1999) Genetic enhancement of learning and memory in mice. Nature 401: 63–69

    Article  PubMed  CAS  Google Scholar 

  30. Mishra OP, Delivoria-Papadopoulos M (1992) NMDA receptor modification of the fetal guinea pig brain during hypoxia. Neurochem Res 17: 1211–1216

    Article  PubMed  CAS  Google Scholar 

  31. Hoffman DJ, McGowan JE, Marro PJ et al (1994) Hypoxia-induced modification of the N-methyl-D-aspartate ( NMDA) receptor in the brain of newborn piglets. Neurosci Lett 167: 156–160

    Article  PubMed  CAS  Google Scholar 

  32. Fritz KI, Groenenedaal F, McGowan JE et al (1996) Effects of 3- (2-carboxy-piperzine-4-yl) propyl-1-phosphonic acid ( CPP) on NMDA receptor binding characteristics and brain cell membrane function during cerebral hypoxia in newborn piglets. Brain Res 729: 66–74

    Google Scholar 

  33. Bhat GK, Mahesh VB, Lamar CA et al (1997) Histochemical localization of nitric oxide neurons in the hypothalamus: association with gonadotropin-releasing hormone neurons and co-localization with N-methyl-D-asparate receptors. Neuroendocrinol Lett 62: 187–197

    Article  Google Scholar 

  34. Aoki C, Rhee J, Lubin M et al (1997) NMDA-R1 subunit of the cerebral cortex co-localizes with neuronal nitric oxide synthase at pre and postsynaptic sites and in spines. Brain Res 750: 25–140

    Article  PubMed  CAS  Google Scholar 

  35. Bredt DS, Ferris CD, Snyder SH (1992) Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase, identification of flavin and calmodulin sites. J Biol Chem 267: 10976–10981

    PubMed  CAS  Google Scholar 

  36. Dawson TM, Steiner JP, Dawson VL et al (1993) Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity. Proc Natl Aca Sci 90: 9808–9812

    Article  CAS  Google Scholar 

  37. Gow AJ, Duran D, Malcom S et al (1996) Effect of peroxynitriteinduced protein modification on tyrosine phosphorylation and degradation. FEBS Lett 385: 63–66

    Article  PubMed  CAS  Google Scholar 

  38. Kiedrowski I, Costa E, Wroblewski JT (1992) Glutamate receptor agonist stimulate nitric oxide synthase in primary cultures of cerebellar granule cells. J Neuroch 58: 335–341

    Article  CAS  Google Scholar 

  39. Aoki C, Fenstemaker S, Lubin M et al (1993) Nitric oxide synthase in the visual cortex of monocular monkeys as revealed by light and electron microscopic immunocytochemistry. Brain Res 620: 97–113

    Article  PubMed  CAS  Google Scholar 

  40. Christopherson KS, Hillier BJ, Lim WAS et al (1999) PSD-95 assembles a ternary complext with the N-Methyl-D-Aspartic acid receptor and bivalent neuronal NO synthase PDX domain. J Boi Chem 274: 27467–27473

    Article  CAS  Google Scholar 

  41. Zanelli SA (1999) NMDA receptor-mediated calcium influx in cerebral cortical synaptosomes of the hypoxic guinea pig fetus. Neurochem Res 24: 434–446

    Article  Google Scholar 

  42. Dawson DA (1994) Nitric oxide and focal cerebral ischemia: multiplicity of actions and diverse outcome. Cerebrovasc Brain Metab 64: 299–324

    Google Scholar 

  43. Dawson TM (1994) Gases as biological messengers: nitric oxide and carbon monoxide in the brain. J Neurosci 14: 5147–5159

    PubMed  CAS  Google Scholar 

  44. Huang Z (1994) Effects of cerebral ischemia in mice deficient neuronal nitric oxide. Science 265: 1883–1885

    Article  PubMed  CAS  Google Scholar 

  45. Beckman JS (1991) The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Dev Physiol 15: 53–59

    PubMed  CAS  Google Scholar 

  46. Cazevielle C (1993), Superoxide and nitric oxide cooperation in hypoxia/reoxgenation-induced neuron injury. Free Radic Biol Med 14: 359–395

    Article  Google Scholar 

  47. Faraci FM (1991) Role of endothelium-derived relaxing factor in cerebral circulation: large arteries vs. microcirculation. Am J Physiol 261: H1038–H1042

    PubMed  CAS  Google Scholar 

  48. Beckman JS (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87: 1620–1624

    Article  PubMed  CAS  Google Scholar 

  49. Dawson VL (1991) Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 88: 6368–6371

    Article  PubMed  CAS  Google Scholar 

  50. Delivoria-Papadopoulos M, Mishra OP (1998) Mechanisms of cerebral injury in perinatal asphyxia and strategies for prevention. J Pediatr 132: S30–S34

    Article  PubMed  CAS  Google Scholar 

  51. Hamada Y (1994) Inhibitors of nitric oxide synthesis reduce hypoxicischemic brain damage in the neonatal rat. Pediatr Res 35: 10–14

    Article  PubMed  CAS  Google Scholar 

  52. Nowicki JP (1991) Nitric oxide mediates neuronal death after focal cerebral ischemia in the mouse. Eur J Pharmacol 204: 339–340

    Article  PubMed  CAS  Google Scholar 

  53. Numagami Y (1997) Lipid free radical generation and brain cell membrane alteration following nitric oxide synthase inhibition during cerebral hypoxia in the newborn piglet. J Neurochem 69: 1542–1547

    Article  PubMed  CAS  Google Scholar 

  54. Baum RM (1984) Superoxide theory of oxygen toxicity is center of heated debate. Chem Eng News 9: 20–28

    Article  Google Scholar 

  55. Sawyer DT (1981) How super is superoxide? Acc Chem Res 14: 393–400

    Article  CAS  Google Scholar 

  56. Mishra OP, Delivoria-Papadopoulos M (1999) Cellular mechanisms of hypoxic injury in the developing brain. Brain Res Bull 48: 233–238

    Article  PubMed  CAS  Google Scholar 

  57. Radi R (1991) Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys 288: 481–487

    Article  PubMed  CAS  Google Scholar 

  58. Delivoria-Papadopoulos M, Akhter W, Mishra OP (2003) Hypoxiainduced Ca2+-influx in cerebral cortical neuronal nuclei of newborn piglets. Neurosci Lett 342: 119–123

    Article  PubMed  CAS  Google Scholar 

  59. Ghosh A, Greenberg ME (1995) Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science 268: 239–247

    Article  PubMed  CAS  Google Scholar 

  60. Hardingham GE, Bading H (1998) Nuclear calcium: a key regulator of gene expression. Biometals 11: 345–358

    Article  PubMed  CAS  Google Scholar 

  61. Chawla S, Bading H (2001) CREB/CBP and SRE-interacting transcriptional regulators are fast on-off switches: duration of calcium transients specifies the magnitude of transcriptional responses. J Neurochem 79: 849–858

    Article  PubMed  CAS  Google Scholar 

  62. Fields RD, Esthete F, Stevens B et al (1997) Action potential-dependent regulation of gene expression: temporal specificity in Ca2+, cAMP-responsive element binding proteins, and mitogen-activated protein kinase signaling. J Neurosci 17: 7252–7266

    PubMed  CAS  Google Scholar 

  63. Lerea L, McNamara JO (1993) Ionotropic glutamate receptor subtypes activate c-fos transcription by distinct calcium-requiring intracellular signaling pathways. Neuron 10: 31–41

    Article  PubMed  CAS  Google Scholar 

  64. Hardingham GE, Chawla S, Cruzalegui FH, Bading H (1999) Control of recruitment and transcription-activating function of CBP determines gene regulation by NMDA receptors and L-type calcium channels. Neuron 22: 789–798

    Article  PubMed  CAS  Google Scholar 

  65. Dolmetsch RE, Pajvani U, Fife et al (2001) Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 294: 333–339

    Article  PubMed  CAS  Google Scholar 

  66. Dolmetsch RE, Lewis RS, Goodnow CC (1997) Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386: 855–858

    Article  PubMed  CAS  Google Scholar 

  67. Mishra OP, Delivoria-Papadopoulos M (2000) Hypoxia-induced generation of nitric oxide free radicals in cerebral cortex of newborn guinea pigs. Neurochem Res 25: 1559–1565

    Article  PubMed  CAS  Google Scholar 

  68. Vannucci RC (1990) Experimental biology of cerebral hypoxia-ischemia: relation to perinatal brain damage. Pediatr Res 27:317–326

    Article  PubMed  CAS  Google Scholar 

  69. Mishra OP, Delivoria-Papadopoulos M (2002) Nitric oxide-mediated Ca++-influx in neuronal nuclei and cortical synaptosomes of normoxic and hypoxic newborn piglets. Neurosci Lett 318: 93–97

    Google Scholar 

  70. Mishra OP, Delivoria-Papadopoulos M (2001) Effect of graded hypoxia on high-affinity Ca2+-ATPase activity in cortical neuronal nuclei of newborn piglets. Neurochem Res 26: 1335–1341

    Article  PubMed  CAS  Google Scholar 

  71. Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74: 609–619

    Google Scholar 

  72. Chen J, Zhu RL, Nakayama M et al (1996) Expression of the apoptosis- effector gene, Bax, is up-regulated in vulnerable hippocampal CA1 neurons following global ischemia. J Neurochem 67: 64–71

    Article  PubMed  CAS  Google Scholar 

  73. Reed JC (1996) Mechanisms of Bcl-2 family protein function and dysfunction in health and disease. Behring Inst Mitt 97: 72–100

    PubMed  CAS  Google Scholar 

  74. Ravishankar S, Ashraf QM, Mishra OP et al (2001) Expression of Bax and Bcl-2 proteins during hypoxia in cerebral cortical neuronal nuclei of newborn piglets: effect of administration of magnesium sulfate. Brain Res 901: 23–29

    Article  PubMed  CAS  Google Scholar 

  75. Zanelli SA, Ashraf QM, Mishra OP (2002) Nitration is a mechanism of regulation of the NMDA receptor function during hypoxia. Neurosci 112: 869–877

    Article  CAS  Google Scholar 

  76. Delivoria-Papadopoulos M, Ashraf QM, Ara J, Mishra OP (2008) Nuclear mechanisms of hypoxic cerebral injury in the newborn: the role of caspases. Semin Perinatol 32: 334–343

    Article  PubMed  Google Scholar 

  77. Mishra OP, Fritz KI, Delivoria-Papadopoulos M (2001) NMDA receptor and neonatal hypoxic brain injury. Ment Retard Dev Disabil Res Rev 7: 249–253

    Article  PubMed  CAS  Google Scholar 

  78. Mishra OP, Delivoria-Papadopoulos M (2010) Mechanism of tyrosine phosphorylation of procaspase-9 and Apaf-1 in cytosolic fractions of the cerebral cortex of newborn piglets during hypoxia. Neurosci Lett 480: 35–39

    Article  PubMed  CAS  Google Scholar 

  79. Ashraf QM, Mishra OP, Delivoria-Papadopoulos M (2007) Mechanisms of expression of apoptotic protease activating factor-1 (Apaf-1) in nuclear, mitochondrial and cytosolic fractions of the cerebral cortex of newborn piglets. Neurosci Lett 415: 253–258

    Article  PubMed  CAS  Google Scholar 

  80. Mishra OP, Delivoria-Papadopoulos M (2006) Effect of neuronal nitric oxide synthase inhibition on caspase-9 activity during hypoxia in the cerebral cortex of newborn piglets. Neurosci Lett 401: 81–85

    Article  PubMed  CAS  Google Scholar 

  81. Chiang MC, Ashraf QM, Mishra OP, Delivoria-Papadopoulos M (2008) Mechanism of DNA fragmentation during hypoxia in the cerebral cortex of newborn piglets. Neurochem Res 33: 1232–1237

    Article  PubMed  CAS  Google Scholar 

  82. Chiang MC, Ashraf QM, Ara J et al (2007) Mechanism of caspase- 3 activation during hypoxia in the cerebral cortex of newborn piglets. Neurosci Lett 421: 67–71

    Article  PubMed  CAS  Google Scholar 

  83. Ishida R, Akiyoshi H, Takahashi T (1974) Isolation and purification of calcium and magnesium dependent endonuclease from rat liver nuclei. Biochem Biophys Res Commun 56: 703–710

    Article  PubMed  CAS  Google Scholar 

  84. Hameed A, Olsen KJ, Lee MK et al (1989) Cytolysis by Ca-permeable transmembrane channels: pore formation causes extensive DNA degradation and cell lysis. J Exp Med 169: 765–777

    Article  PubMed  CAS  Google Scholar 

  85. Tominaga T, Kagure S, Narisawa K et al (1993), Endonuclease activation following focal ischemic injury in the rat brain. Brain Res 608: 21–26

    Article  PubMed  CAS  Google Scholar 

  86. Waseem W, Ashraf QM, Zanelli SA et al (2001) Effect of graded hypoxia on cerebral cortical genomic DNA fragmentation in newborn piglet. Biol Neonate 79: 187–193

    Article  Google Scholar 

  87. Levene MI, Evans DJ, Mason S et al (1999) An international network for evaluation neuroprotective therapy after severe birth asphyxia. Sem Perinatol 23: 226–233

    Article  CAS  Google Scholar 

  88. Nelson KB, Grether JK (1995) Can magnesium sulphate reduce the risk of cerebral palsy in very low birth weight infants? Pediatrics 95: 263–269

    PubMed  CAS  Google Scholar 

  89. The Eclampsia Trial Collaborative Group (1995) Which anticonvulsant for eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 345: 1455–1463

    Google Scholar 

  90. Mittendorf R, Covert R, Boman J et al (1997) Is tocolytic magnesium sulphate associated with increased total pediatric mortality? Lancet 350: 1517–1519

    Article  PubMed  CAS  Google Scholar 

  91. Benichou J, Zupan V, Fernandez H et al (1997) Tocolytic magnesium sulphate and pediatric mortality. Lancet 351: 290–291

    Article  Google Scholar 

  92. Rouse D, Hirtz DG, Thom E et al (2008) A randomized controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl. J Med 359: 895–905

    Google Scholar 

  93. Moriette G, Barrat J, Truffert P et al (2008) Effect of magnesium sulphate on mortality and neurologic morbidity of the very preterm newborn (of less than 33 weeks) with two-year neurological outcome: results of the prospective PREMAG trial. Gynecol Obstet Fertil 36: 278–288

    Article  Google Scholar 

  94. Doyle LW, Crowther CA, Middleton P et al (2009) Magnesium bias sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 1:CD004661

    Google Scholar 

  95. Palmer C, Vanucci RC, Towfighi J (1990) Reduction of perinatal hypoxic-ischemic brain damage with allopurinol. Res Pediatr 27: 332–336

    Article  CAS  Google Scholar 

  96. Williams GD, Palmer C, Heitjan DF et al (1992) Allopurinol preserves cerebral energy metabolism during perinatal hypoxic-ischemia: a 31P NMR study in anaesthetized immature rats. Neurosci Lett 144: 104–106

    Article  Google Scholar 

  97. Palmer C, Roberts RL (1991) Reduction of perinatal brain damage with oxypurinol treatment after hypoxic-ischemic injury. Pediatr Res 29: 362–368

    Article  Google Scholar 

  98. Marro PJ, McGowan JE, Razdan B et al (1994) Effect of allopurinol on uric acid levels and brain cell membrane Na+, K+-ATPase activity during hypoxia in newborn piglets. Brain Res 650: 9–15

    Google Scholar 

  99. Maro PJ, Hoffman D, Schneiderman R et al (1998) Effect of allopurinol on NMDA receptor modification following recurrent asphyxia in newborn piglets. Brain Res 787: 71–77

    Article  Google Scholar 

  100. Russell GA, Cooke RW (1995) Randomized controlled trial of allopurinol prophylaxis in very preterm infants. Arch Dis Child Fetal Neonatal Ed 73: F27–F31

    Article  PubMed  CAS  Google Scholar 

  101. Van Bel F, Shadid M, Moison RM et al (1998) Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics 101: 185–193

    Article  PubMed  Google Scholar 

  102. Clancy RR, McGaurn SA, Goin JE et al (2001) Allopurinol neurocardiac protection trial in infants undergoing heart surgery using deep hypothermic circulatory arrest. Pediatrics 108: 61–70

    Article  PubMed  CAS  Google Scholar 

  103. Bender MJ, Bos AF, Rademaker CM et al (2006) Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia. Arch Dis Child Fetal Neonatal Ed 91: F163–F165

    Article  Google Scholar 

  104. Chaudhari T, McGuire W (2008) Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischemic encephalopathy. Cochrane Database Syst Rev 2:CD006817

    Google Scholar 

  105. Lee J, Kim MS, Park C et al (2004) Morphine prevents glutamateinduced death of primary rat neonatal astrocytes through modulation of intracellular redox. Immunopharmacol Immunotoxicol 26: 17–28

    Article  PubMed  CAS  Google Scholar 

  106. Yamakura T, Sakimura K, Shimoji K (1999) Direct inhibition of the N-methyl-D-aspartate receptor channel by high concentration of opioids. Anesthesiology 91: 1053–1063

    Article  PubMed  CAS  Google Scholar 

  107. Zhang J, Gibney GT, Zhao P (2002) Neuroprotective role of deltaopioid receptors in cortical neurons. Am J Physiol 282: C1225–C1234

    CAS  Google Scholar 

  108. Zhang J, Haddad GG, Xia Y (2000) Delta-, but not mu- and kappa, opioid receptor activation protects neocortical neurons from glutamate- induced excitotoxic injury. Brain Res 885: 143–153

    Article  PubMed  CAS  Google Scholar 

  109. Lim YJ, Zheng S, Zuo Z (2004) Morphine preconditions Purkinje cells against cell death under in vitro simulated ischemia- reperfusion conditions. Anesthesiology 100: 562–568

    Article  PubMed  CAS  Google Scholar 

  110. Mayfield KP, D’Alecy LG (1992) Role of endogenous opioid peptides in the acute adaptation to hypoxia. Brain Res 582: 226–231

    Article  PubMed  CAS  Google Scholar 

  111. Mayfield KP, D’Alecy LG (1994) Delta-1 opioid agonist acutely increases hypoxic tolerance. J Pharmacol Exp Ther 268: 683–688

    PubMed  CAS  Google Scholar 

  112. Chein S, Oeltgen PR, Diana JN et al (1994) Extension of tissue survival time in multiorgan block preparation with a delta DADLE (D-Ala2, D-leu5)-enkephalin). J Thorac Cardiovasc Surg 107: 964–967

    Google Scholar 

  113. Angeles DM, Wycliffe N, Michelson D et al (2005) Use of opioids in asphyxiated term neonates: effects of neuroimaging and clinical outcome. Pediatr Res 57: 873–878

    Article  PubMed  CAS  Google Scholar 

  114. Angeles DM, Ashwal S, Wycliffe ND et al (2007) Relationship between opioid therapy, tissue damaging procedures, and brain metabolites as measured by proton MRS in asphyxiated term neonatales. Pediatr Res 60: 614–621

    Google Scholar 

  115. Gunn AJ, Gunn TR (1998) The ‘pharmacology’ of neuronal rescue with cerebral hypothermia. Early Hum Dev 53: 19–35

    Article  PubMed  CAS  Google Scholar 

  116. Wagner CL, Eicher DJ, Katikkaneni LD et al (1999) The use of hypothermia: a role in the treatment of neonatal asphyxia? Pediatr Neurol 21: 429–443

    Article  PubMed  CAS  Google Scholar 

  117. Coimbria C, Wielock T (1994) Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia. Acta Neuropathol (Berlin) 87: 325–331

    Article  Google Scholar 

  118. Trescher WH, Ishiwa S, Johnston MV (1997) Brief post-HI hypothermia markedly delays neonatal brain injury. Brain Dev 19: 326–328

    Article  PubMed  CAS  Google Scholar 

  119. Thorensen M, Penrice J, Lorek A (1995) Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 37: 667–670

    Article  Google Scholar 

  120. Miller JA (1971) New approaches to preventing brain damage during asphyxia. Am J Obstet Gynecol 110: 125–132

    Google Scholar 

  121. Gunn AJ, Bennet L, Gunning MI et al (1999) Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep. Pediatr Res 46: 274–280

    Article  PubMed  CAS  Google Scholar 

  122. Gunn AJ, Gluckman PD, Gunn TR (1998) Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 102: 885–892

    Article  PubMed  CAS  Google Scholar 

  123. Battin MR, Dezoete JA, Gunn TR et al (2001) Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. Pediatrics 107: 480–484

    Article  PubMed  CAS  Google Scholar 

  124. Battin MR, Penrice J, Gunn TR, Gunn AJ (2003) Treatment of term infants with head cooling and systematic hypothermia (35.0 degrees and 34.5 degrees C) after perinatal asphyxia. Pediatrics 111: 244–251

    Article  PubMed  Google Scholar 

  125. Gluckman PD, Wyatt JS, Azzopardi D et al (2005) Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicenter randomized trial. Lancet 365: 663–670

    PubMed  Google Scholar 

  126. Azzopardi D, Robertson NJ, Cowan FM et al (2000) Pilot study of treatment with whole body hypothermia for neonatal encephalopathy. Pediatrics 106: 684–694

    Article  PubMed  CAS  Google Scholar 

  127. Shankaran S, Laptook A, Wright LL et al (2002) Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for randomized, controlled pilot study in term infants. Pediatrics 110: 377–385

    Article  PubMed  Google Scholar 

  128. Debillon T, Daoud P, Durand P et al (2003) Whole-body cooling after perinatal asphyxia: a study in term neonates. Dev Med Child Neurol 45: 17–23

    Article  PubMed  Google Scholar 

  129. Eicher DJ, Wagner CL, Katikaneni LP et al (2005) Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr Neurol 32: 18–24

    Article  PubMed  Google Scholar 

  130. Shankaran S, Laptook AR, Ehrenkranz RA et al (2005) Wholebody hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 353: 1574–1584

    Article  PubMed  CAS  Google Scholar 

  131. Parikh NA, Lasky RE, Garza CN et al (2009) Volumetric and anatomical MRI hypoxic-ischemic encephalopathy: relationship to hypothermia therapy and neurosensory impairments. J Perinatol 29: 143–149

    Article  PubMed  CAS  Google Scholar 

  132. Zanelli SA, Naylor M, Dobbins N et al (2008) Implementation of a “hypothermia for HIE” program: 2-year experience in a single NICU. J Perinatol 28: 171–175

    Article  PubMed  CAS  Google Scholar 

  133. Kapetanakis A, Azzopardi D, Wyatt J et al (2008) Therapeutic hypothermia for neonatal encephalopathy: a UK survey of opinion, practice and neuron-investigation at the end of 2007. Acta Paediatr 98: 631–635

    Article  PubMed  Google Scholar 

  134. Tan S, Parks DA (1999) Preserving brain function during neonatal asphyxia. Clin Perinatol 26: 733–747

    PubMed  CAS  Google Scholar 

  135. Gunn AJ, Battin M, Gluckman PD et al (2005) Therapeutic hypothermia: from lab to NICU. J Perinat Med 33: 340–346

    Article  PubMed  Google Scholar 

  136. Sahni R, Sanocka UM (2008) Hypothermia for hypoxic-ischemic encephalopathy. Clin Perinatol 35: 717–734

    Article  PubMed  Google Scholar 

  137. Wagner BP, Nedelcu J, Martin E (2002) Delayed postischemic hypothermia improves long-term behavioral outcome after cerebral hypoxia-ischemia in neonatal rats. Pediatr Res 51: 182–193

    Article  Google Scholar 

  138. Hoeger H, Engidawork E, Stolzlechner D et al (2006) Long-term effect of moderate and profound hypothermia on morphology, neurological, cognitive and behavioural functions in a rat model of perinatal asphyxia. Amino Acids 31: 385–396

    Article  PubMed  CAS  Google Scholar 

  139. Talati AJ, Yang W, Yolton K et al (2005) Combination of early perinatal factors to identify near-term and term neonates for neuroprotection. J Perinatol 25: 245–250

    Article  PubMed  Google Scholar 

  140. Van Bel F, Groenendaal F (2008) Long-term pharmalogic neuroprotection after birth asphyxia: where do we stand? Neonatology 94: 203–210

    Article  PubMed  Google Scholar 

  141. Higgins RD, Rahu TN, Perlman J et al (2006) Hypothermia and perinatal asphyxia: executive summary of the National Institute of Child Health and Human Development workshop. J Pediatr 148: 170–175

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, Drexel University College of Medicine, St. Christopher’s Hospital for Children, Philadelphia, USA

    Maria Delivoria-Papadopoulos

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  1. Maria Delivoria-Papadopoulos
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  2. Endla Anday
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Editors and Affiliations

  1. Department of Pediatrics, Obstetrics and Reproductive Medicine, Division of Neonatology, University of Siena General Hospital S. Maria alle Scotte Azienda Ospedaliera Universitaria Senese, Siena, Italy

    Giuseppe Buonocore (Professor of Pediatrics and Neonatology, Head of School of Pediatrics) (Professor of Pediatrics and Neonatology, Head of School of Pediatrics)

  2. University of Siena, Siena, Italy

    Rodolfo Bracci (Formerly Professor of Pediatrics and Head of Department of Pediatrics, Obstetrics and Reproductive Medicine) (Formerly Professor of Pediatrics and Head of Department of Pediatrics, Obstetrics and Reproductive Medicine)

  3. University of Liverpool, UK

    Michael Weindling (Professor of Perinatal Medicine, Director of Postgraduate Research, Head of School of Paediatrics Mersey Deanery) (Professor of Perinatal Medicine, Director of Postgraduate Research, Head of School of Paediatrics Mersey Deanery)

  4. Department of Women’s and Children’s Health, Institute of Translational Medicine, Liverpool, UK

    Michael Weindling (Professor of Perinatal Medicine, Director of Postgraduate Research, Head of School of Paediatrics Mersey Deanery) (Professor of Perinatal Medicine, Director of Postgraduate Research, Head of School of Paediatrics Mersey Deanery)

  5. Liverpool Women’s Hospital, Liverpool, UK

    Michael Weindling (Professor of Perinatal Medicine, Director of Postgraduate Research, Head of School of Paediatrics Mersey Deanery) (Professor of Perinatal Medicine, Director of Postgraduate Research, Head of School of Paediatrics Mersey Deanery)

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Delivoria-Papadopoulos, M., Anday, E. (2012). Biochemical Basis of Hypoxic-Ischemic Encephalopathy. In: Buonocore, G., Bracci, R., Weindling, M. (eds) Neonatology. Springer, Milano. https://doi.org/10.1007/978-88-470-1405-3_135

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  • DOI: https://doi.org/10.1007/978-88-470-1405-3_135

  • Publisher Name: Springer, Milano

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  • Online ISBN: 978-88-470-1405-3

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