Iron and Oxidative Stress in Neonatal Hypoxic-Ischemic Brain Injury Directions for Therapeutic Intervention

  • Charles Palmer


When placental or pulmonary gas exchange is compromised in the fetus or newborn infant it produces hypoxemia, hypercapnia, and metabolic acidosis. Initially during asphyxia, blood flow to the brain increases to maintain cerebral energy metabolism until cardiac depression causes hypotension, bradycardia, and cerebral ischemia (Van-nucci, 1990). Unless prompt and effective resuscitation is achieved, the asphyxiated infant will die. Even when resuscitation is successful, survival may be accompanied by varying degrees of brain injury, the nature of which is related to the duration of the primary insult, the gestational age, and therapeutic interventions initiated during the post-resuscitation period.


Nitric Oxide Nitric Oxide Brain Injury Cerebral Ischemia Middle Cerebral Artery Occlusion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abello, P. A., Fidler, S. A., Bulkley, G. B., and Buchman, T. G., 1994, Antioxidants modulate induction of programmed endothelial cell death (apoptosis) by endotoxin, Arch. Surg. 129:134–141.PubMedGoogle Scholar
  2. Al-Mehdi, A. B., Dodia, C., Jain, M. K., and Fisher, A. B., 1993, A phospholipase A2 inhibitor decreases generation of thiobarbituric acid reactive substance during lung ischemia-reperfusion, Biochim. Biophys. Acta Lipids Lipid Metab. 1167:56–62.Google Scholar
  3. Anderson, D. C., Hughes, B. J., and Smith, C. W., 1981, Abnormal mobility of neonatal polymorphonuclear leukocytes, J. Clin. Invest. 68:863–874.PubMedGoogle Scholar
  4. Anderson, D. C., Rothlein, R., Marlin, S. D., Krater, S. S., and Smith, C. W., 1990, Impaired transendothelial migration by neonatal neutrophils: abnormalities of mac-1 (CD 1 lb/CD 18)-dependent adherence reactions, Blood 76:2613–2621.PubMedGoogle Scholar
  5. Armstead, W. M., Mirro, R., Busija, D. W., and Leffler, C. W., 1988, Postischemic generation of superoxide anion by newborn pig brain, Am. J. Physiol. 255:H401-H403.Google Scholar
  6. Aruoma, O. I., and Halliwell, B., 1987, Superoxide-dependent and ascorbate-dependent formation of hydroxyl radicals from hydrogen peroxide in the presence of iron, Biochem. J. 241:273–278.PubMedGoogle Scholar
  7. Azzopardi, D., Wyatt, J. S., Cady, E. B., Delpy, D. T., Baudin, J., Stewart, A. L., Hope, P. L., Hamilton, P. A., and Reynolds, E. O. R., 1989a, Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy, Pediatr. Res. 25:441–451.Google Scholar
  8. Azzopardi, D., Wyatt, J. S., Hamilton, P. A., Cady, E. B., Delpy, D. T., Hope, P. L., and Reynolds, E. O. R., 1989b, Phosphorus metabolites and intracellular pH in the brains of normal and small for gestational age infants investigated by magnetic resonance spectroscopy, Pediatr. Res. 25:440–444.PubMedGoogle Scholar
  9. Bagenholm, R., Andine, P., and Hagberg, H., 1991, Effects of 21-aminosteroid U74006F on brain damage and edema following perinatal hypoxia-ischemia in the rat, J. Cereb. Blood Flow Metab. 11:S134.Google Scholar
  10. Baiping, L., Xiujuan, T., Hongwei, C., Qiming, X., and Quling, G., 1994, Effect of moderate hypothermia on lipid peroxidation in canine brain tissue after cardiac arrest and resuscitation, Stroke 25:147–151.Google Scholar
  11. Battus, R. T., Baker, K. L., Heiser, A. D., Sawyer, S. D., Dean, R. L., Elliott, P. J., and Straub, J. A., 1994a, Postischemic administration of AK275, a calpain inhibitor, provides substantial protection against focal ischemic brain damage, J. Cereb. Blood Flow Metab. 14:537–544.Google Scholar
  12. Battus, R. T., Hayward, N. J., Elliott, P. J., Sawyer, S. D., Baker, K. L., Dean, R. L., Akiyama, A., Straub, J. A., Harbeson, S. L., Li, Z., and Powers, J., 1994b, Calpain inhibitor AK295 protects neurons from focal brain ischemia: Effects of postocclusion intra-arterial administration, Stroke 25:2265–2270.Google Scholar
  13. Beckman, J. S., 1994, Peroxynitrite versus hydroxyl radical: The role of nitric oxide in superoxide-dependent cerebral injury, Ann. NY Acad. Sci. 738:69–75.PubMedGoogle Scholar
  14. Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A., and Freeman, B. A., 1990, Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide, Proc. Natl. Acad. Sci. USA 87:1620–1624.PubMedGoogle Scholar
  15. Beckman, J. S., Ischiropoulos, H., Chen, J., Zhu, L., and Smith, C. D., 1991, Nitric oxide as a mediator of superoxide-dependent injury, in: Oxidative Damage and Repair: Chemical, Biological and Medical Aspects (K. Davis, ed.), Pergamon Press, Oxford, pp. 251–255.Google Scholar
  16. Beckman, J. S., Chen, J., Ischiropoulos, H., and Crow, J. P., 1994, Oxidative chemistry of peroxynitrite, Methods Enzymol. 233:229–240.PubMedGoogle Scholar
  17. Beilharz, E. J., Williams, C.E., Draguno, M., Sirimanne, E. S., and Gluckman, P. D., 1995, Mechanisms of delayed cell death following hypoxic-ischemic injury in the immature rat: Evidence for apoptosis during selective neuronal loss, Mol. Brain Res. 29:1–14.PubMedGoogle Scholar
  18. Benveniste, H., Drejer, I., Schousboe, A., and Diemer, N. H., 1984, Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia montored by intracerebral microdialysis, J. Neurochem. 43:1369–1374.PubMedGoogle Scholar
  19. Berger, H. M., Mumby, S., and Gutteridge, J. M. C., 1995, Ferrous ions detected in iron-overloaded cord blood plasma from preterm and term babies: Implications for oxidative stress, Free Radic. Res. 22:555–559.PubMedGoogle Scholar
  20. Betz, A. L., 1985, Identification of hypoxanthine transport and xanthine oxidase activity in brain capillaries, J. Neurochem. 44:574–579.PubMedGoogle Scholar
  21. Bielenberg, G. W., and Wagener, G., 1989, Infarct reduction by PAF antagonists after MCA occlusion in the rat, J. Cereb. Blood Flow Metabol 9:(Suppl 1)S274.Google Scholar
  22. Biemond, P., van Eijk, H. G., Swaak, A. J. G., and Koster, J. K, 1984, Iron mobilization from ferritin by superoxide derived from stimulated polymorphonuclear leukocytes. Possible mechanism in inflammatory diseases, J. Clin. Invest. 73:(1984) 1576.PubMedGoogle Scholar
  23. Blissman, G., Menzies, S., Beard, J., Palmer, C., and Connor, J., 1996, The expression of ferritin subunits and iron in oligodendrocytes in neonatal procine brains, Dev. Neurosci. 18:274–281.PubMedGoogle Scholar
  24. Block, F., Kunkel, M., and Sontag, K. H., 1995, Posttreatment with EPC-K1, an inhibitor of lipid peroxidation and of phospholipase A2 activity, reduces functional deficits after global ischemia in rats, Brain Res. Bull. 36:257–260.PubMedGoogle Scholar
  25. Boisvert, D. P., 1991, Effectiveness of postischemic 21-aminosteroid U74006F in preventing reperfusion brain edema, J. Cereb. Blood Flow Metab. 11:S135.Google Scholar
  26. Bolann, B. J., and Ulvik, R. J., 1987, Release of iron from ferritin by xanthine oxidase, Biochem. J. 243:55–59.PubMedGoogle Scholar
  27. Boveris, A., and Chance, B., 1973, The mitochondrial generation of hydrogen peroxide, Biochem. J. 134:707–716.PubMedGoogle Scholar
  28. Bralet, J., Schreiber, L., and Bouvier, C., 1992, Effect of acidosis and anoxia on iron derealization from brain homogenates, Biochem. Pharmacol. 43:979–984.PubMedGoogle Scholar
  29. Bromont, C., Marie, C., and Bralet, J., 1989, Increased lipid peroxidation in vulnerable brain regions after transient forebrain ischemia in rats, Stroke 20:918–924.PubMedGoogle Scholar
  30. Briine, B., Dimmeler, S., Molina y Vedia, L., and Lapetina, E. G., 1994, Nitric oxide: A signal for ADP-ribosylation of proteins, Life Sci. 54:61–70.Google Scholar
  31. Busto, R., Dietrich, W. D., Globus, M. T., and Ginsberg, M. D., 1989, Postischemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury, Neurosci. Lett. 101:299–304.PubMedGoogle Scholar
  32. Buttke, T. M., and Sandstrom, P. A., 1994, Oxidative stress as a mediator of apoptosis, Immunol. Today 15:7–10.PubMedGoogle Scholar
  33. Candeias, L. P., Patel, K. B., Stratford, M., and Wardman, P., 1993, Free hydroxyl radicals are formed on reaction between the neutrophil-derived species superoxide anion and hypochlorous acid, FEBS Lett. 333:151–153.PubMedGoogle Scholar
  34. Candeias, L. P., Stratford, M., and Wardman, P., 1994, Formation of hydroxyl radicals on reaction of hypochlorous acid with ferrocyanide, a model iron(II) complex, Free Radic. Res. 20:241–249.PubMedGoogle Scholar
  35. Cao, X., and Phillis, J. W., 1994, Alpha-Phenyl-tert-butyl-nitrone reduces cortical infarct and edema in rats subjected to focal ischemia, Brain Res. 644:267–272.PubMedGoogle Scholar
  36. Chan, P. H., and Fishman, R. A., 1980, Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling, J. Neurochem. 35:1004–1007.PubMedGoogle Scholar
  37. Chan, P. H., Epstein, C. J., Li, Y., Huang, T. T., Carlson, E., Kinouchi, H., Yang, G., Kamii, H., Mikawa, S., Kondo, T., Copin, J. C., Chen, S. F, Chan, T., Gafni, J., Gobbel, G., and Reola, E., 1995, Transgenic mice and knockout mutants in the study of oxidative stress in brain injury, J. Neurotrauma 12:815–824.PubMedGoogle Scholar
  38. Chan, P. H., Schmidley, J. W, Fishman, R. A., and Longar, S. M., 1984, Brain injury, edema and vascular permeability changes induced by oxygen-derived free radicals, Neurology 34:315–320.PubMedGoogle Scholar
  39. Charriaut-Marlangue, C., Margaill, I., Plotkine, M., and Ben-Ari, Y, 1995, Early endonuclease activation following reversible focal ischemia in the rat brain, J. Cereb. Blood Flow Metab. 15:385–388.PubMedGoogle Scholar
  40. Choi, D. W, 1985, Glutamate neurotoxicity in cortical cell culture is calcium dependent, Neurosci. Lett. 58:293–297.PubMedGoogle Scholar
  41. Chopp, M., Chen, H., Dereski, M. O., and Garcia, J. H., 1991, Mild hypothermic intervention after graded ischemic stress in rats, Stroke 22:37–43.PubMedGoogle Scholar
  42. Chopp, M., Zhang, R. L., Chen, H., Li, Y, Jiang, N., and Rusche, J. R., 1994, Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats, Stroke 25:869–875.PubMedGoogle Scholar
  43. Ciuffi, M., Gentilini, G., Franchi-Micheli, S., and Zilletti, L., 1991, Lipid peroxidation induced “in vivo” by iron-carbohydrate complex in the rat brain cortex, Neurochem. Res. 16:43–49.PubMedGoogle Scholar
  44. Coimbra, C., and Weiloch, T., 1994, Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia, Acta Neuropathol. 87:325–331.PubMedGoogle Scholar
  45. Colboume, F., and Corbett, D., 1994, Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil, Brain Res. 654:265–272.Google Scholar
  46. Connor, J. R., Pavlick, G., Karli, D., Menzies, S. L., and Palmer, C., 1995, A histochemical study of iron-positive cells in the developing rat brain, J. Comp. Neurol. 355:111–123.PubMedGoogle Scholar
  47. Davenpeck, K. L., Gauthier, T. W., and Lefer, A. M., 1994, Inhibition of endothelial-derived nitric oxide promotes P-selectin expression and actions in the rat microcirculation, Gastroenterology 107:1050–1058.PubMedGoogle Scholar
  48. Dawson, D. A., 1994, Nitric oxide and focal cerebral ischemia: Multiplicity of actions and diverse outcome, Cerebrovasc. Brain Metab. Rev. 6:299–324.PubMedGoogle Scholar
  49. Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S., and Snyder, S. H., 1991, Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures, Proc. Natl. Acad. Sci. USA 88:6368–6371.PubMedGoogle Scholar
  50. Dawson, V. L., Dawson, T. M., Bartley, D. A., Uhl, G. R., and Snyder, S. H., 1993, Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures, J. Neurosci. 13:2651–2661.PubMedGoogle Scholar
  51. Dawson, V. L., Brahmbhatt, H. P., Mong, J. A., and Dawson, T. M., 1994, Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures, Neuropharmacology 33:1425–1430.PubMedGoogle Scholar
  52. Del Zoppo, G. J., 1994, Microvascular changes during cerebral ischemia and reperfusion, Cerebrovasc. Brain Metab. Rev. 6:47–96.PubMedGoogle Scholar
  53. Dietrich, W. D., Lin, B. W., Globus, M. Y. T., Green, E. J., Ginsberg, M. D., and Busto, R., 1995, Effect of delayed MK-801 (Dizocilpine) treatment with or without immediate postischemic hypothermia on chronic neuronal survival after global forebrain ischemia in rats, J. Cereb. Blood Flow Metab. 15:960–968.PubMedGoogle Scholar
  54. Dirnagl, U., Lindauer, U., Them, A., Schreiber, S., Pfister, H. W., Koedel, U., Reszka, R., Freyer, D., and Villringer, A., 1995, Global cerebral ischemia in the rat: Online monitoring of oxygen free radical production using chemiluminescence in vivo, J. Cereb. Blood Flow Metab. 15:929–940.PubMedGoogle Scholar
  55. Ditelberg, J. S., Sheldon, R. A., Epstein, C. J., and Ferriero, D. M., 1996, Brain injury after perinatal hypoxia-ischemia is exacerbated in copper/zinc superoxide dismutase transgenic mice, Pediatr. Res. 39:204–208.PubMedGoogle Scholar
  56. Drapier, J. C., and Hibbs, J., 1988, Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells, J. Immunol. 140:2829–2838.PubMedGoogle Scholar
  57. Drapier, J. C., Hirling, H., Wietzerbin, J., Kaldy, P., and Kühn, L. C., 1993, Biosynthesis of nitric oxide activates iron regulatory factor in macrophages, EMBO J. 12:3643–3649.PubMedGoogle Scholar
  58. Du, C., Hu, R., Csernansky, C. A., Hsu, C. Y., and Choi, D. W., 1996, Very delayed infarction after mild focal cerebral ischemia: A role for apoptosis? J. Cereb. Blood Flow Metab. 16:195–201.PubMedGoogle Scholar
  59. Dubinsky, J. M., Kristal, B. S., and Elizondo-Fournier, M., 1995, On the probabilistic nature of excitotoxic neuronal death in hippocampal neurons, Neuropharmacology 34:701–711.PubMedGoogle Scholar
  60. Dugan, L. L., Sensi, S. L., Canzoniero, L. M. T., Handran, S. D., Rothman, S. M., Lin, T. S., Goldberg, M. P., and Choi, D. W., 1995, Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate, J. Neurosci. 15:6377–6388.PubMedGoogle Scholar
  61. Elliot, S. J., and Schilling, W. P., 1992, Oxidant stress alters Na+pump and Na+-K+-Cl~ cotransporter activates in vascular endothelial cells, Am. J. Physiol. 263:H96-H102.Google Scholar
  62. Endoh, M., Maiese, K., Pulsinelli, W. A., and Wagner, J. A., 1993, Reactive astrocytes express NADPH diaphorase in vivo after transient ischemia, Neurosci. Lett. 154:125–128.PubMedGoogle Scholar
  63. Evans, P. J., Evans, R., Kovar, I. Z., Holton, A. F., and Halliwell, B., 1992, Bleomycin-detectable iron in the plasma of premature and full-term neonates, FEBS 303:210–212.Google Scholar
  64. Fantone, J. C., and Kinnes, D. A., 1983, Prostaglandin E1 and prostaglandin I2 modulation of superoxide production by human neutrophils, Biophys. Res. Commun. 113:129–137.Google Scholar
  65. Ferrer, I., Tortosa, A., Macaya, A., Sierra, A., Moreno, D., Munell, F., Blanco, R., and Squier, W., 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.PubMedGoogle Scholar
  66. Ferriero, D. M., Arcavi, L. J., Sagar, S. M., Mcintosh, T. K., and Simon, R. P., 1988, Selective sparing of NADPH-diaphorase neurons in neonatal hypoxia-ischemia, Ann. Neurol. 24:670–676.PubMedGoogle Scholar
  67. Ferriero, D. M., Sheldon, R. A., Black, S. M., and Chuai, J., 1995, Selective destruction of nitric oxide synthase neurons with quisqualate reduces damage after hypoxia-ischemia in the neonatal rat, Pediatr. Res. 38:912–918.PubMedGoogle Scholar
  68. Fisher, M., Meadows, M. E., Do, T., Weise, J., Trubetskoy, V., Charette, M., and Finklestein, S. P., 1995, Delayed treatment with intravenous basic fibroblast growth factor reduces infarct size following permanent focal cerebral ischemia in rats, J. Cereb. Blood Flow Metab. 15:953–959.PubMedGoogle Scholar
  69. Forder, J. R., McClanahan, T. B., Gallagher, K. P., Hedlund, B. E., Hallaway, P. E., and Shlafer, M., 1990, Hemodynamic effects of intraatrial administration of deferoxamine or deferoxamine-pentafraction conjugate to conscious dogs, J. Cardiovasc. Pharmacol. 16:742–749.PubMedGoogle Scholar
  70. Galea, E., Reis, D. J., Xu, H., and Feinstein, D. L., 1995, Transient expression of calcium-independent nitric oxide synthase in blood vessels during brain development, FASEB J. 9:1632–1637.PubMedGoogle Scholar
  71. Galet, S., and Schulman, H. M., 1976, The postnatal hypotransferrinemia of early preterm newborn infants, Pediatr. Res. 10:118–120.PubMedGoogle Scholar
  72. Gasic, A. C., McGuire, G., Drater, S., Farhood, A. I., Goldstein, M. A., Smith, C. W., Entman, M. L., and Taylor, A. A., 1991, Hydrogen peroxide pretreatment of perfused canine vessels induces ICAM-1 and CD18-dependent neutrophil adherence, Circulation 84:2154–2166.PubMedGoogle Scholar
  73. Gidday, J. M., Fitzgibbons, J. C., Shah, A. R., Krujalis, M. J., and Park, T. S., 1995, Reduction in cerebral ischemic injury in the newborn rat by potentiation of endogenous adenosine, Pediatr. Res. 38:1–6.Google Scholar
  74. Ginsberg, M. D., Sternau, L. L., Globus, M. T., Dietrich, W. D., and Busto, R., 1992, Therapeutic modulation of brain temperature: Relevance to ischemic brain injury, Cerebrovasc. Brain Metab. Rev. 4:189–225.PubMedGoogle Scholar
  75. Giulian, D., Corpuz, M., Chapman, S., Mansouri, M., and Robertson, C., 1993, Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the central nervous system. J. Neurosci. Res. 36:681–693.PubMedGoogle Scholar
  76. Giulian, D., Li, J., Li, X., George, J., and Rutecki, P. A., 1994, The impact of microglia-derived cytokines upon gliosis in the CNS, Dev. Neurosci. 16:128–136.PubMedGoogle Scholar
  77. Goplerud, J. M., Kim, S., and Delivoria-Papadopoulos, M., 1995, The effect of post-asphyxial reoxygenation with 21% vs. 100% oxygen on Na+,K+-ATPase activity in striatum of newborn piglets, Brain Res. 696:161–164.PubMedGoogle Scholar
  78. Guan, J., Williams, C., Gunning, M., Mallard, C., and Gluckman, P., 1993, The effects of IGF-1 treatment after hypoxic-ischemic brain injury in adult rats, J. Cereb. Blood Flow Metab. 13:609–616.PubMedGoogle Scholar
  79. Gutteridge, J. M. C., 1986, Iron promotors of the Fenton reaction and lipid peroxidation can be released from haemoglobin by peroxides, FEBS Lett. 201:291–295.PubMedGoogle Scholar
  80. Gutteridge, J. M. C., Rowley, D. A., and Halliwell, B., 1982, Superoxide-dependent formation of hydroxyl radicals and lipid peroxidation in the presence of iron salts, Biochem. J. 206:605–609.PubMedGoogle Scholar
  81. Haddad, I. Y, Ischiropoulos, H., Holm, B. A., Beckman, J. S., Baker, J. R., and Matalon, S., 1993, Mechanisms of peroxynitrite-induced injury to pulmonary surfactants, Amer. J. Physiol. 265:L555-L564.Google Scholar
  82. Hagberg, H., Andersson, P., Lacarewicz, J., Jacobson, I., Butcher, S., and Sandberg, M., 1987, Extracellular adenosine, inosine, hypoxanthine, and xanthine in relation to tissue nucleotides and purines in rat striatum during transient ischemia, J. Neurochem. 49:227–231.PubMedGoogle Scholar
  83. Halliwell, B., 1991, Reactive oxygen species in living systems: Source, biochemistry and role in human disease, Am. J. Med. 91(Suppl 3C):14S-22S. Halliwell, B., 1992, Iron and damage to biomolecules, in: Iron and Human Disease (R. B. Lauffer, ed.), CRC Press, Boca Raton, Florida, pp. 210–230.Google Scholar
  84. Halliwell, B., and Gutteridge, J. M. C., 1992, Biologically relevant metal ion-dependent hydroxyl radical generation, FEBS 307:108–112.Google Scholar
  85. Hara, H., Sukamoto, T., and Kogure, K., 1993, Mechanism and pathogenesis of ischemia-induced neuronal damage, Prog. Neurobiol. 40:645–670.PubMedGoogle Scholar
  86. Hattori, H., Morin, A. M., Schwartz, P. H., Fujikawa, D. G., and Wasterlain, C. G., 1989, Post-hypoxic treatment with MK-801 reduces hypoxic-ischemic damage in the neonatal rat, Neurology 39:713–718.PubMedGoogle Scholar
  87. He, Y. Y, Hsu, C. Y, Ezrin, A. M., and Miller, M. S., 1993, Polyethylene glycol-conjugated superoxide dismutase in focal cerebral ischemia-reperfusion, Am. J. Physiol. Heart Circ. Physiol. 265:H252-H256.Google Scholar
  88. Hedlund, B. E., and Hallaway, P. E., 1993, High-dose systemic iron chelation attenuates reperfusion injury, Biochem. Soc. Trans. 21:340–343.PubMedGoogle Scholar
  89. Hill, I. E., MacManus, J. P., Rasquinha, I., and Tuor, U. I., 1995, DNA fragmentation indicative of apoptosis following unilateral cerebral hypoxia-ischemia in the neonatal rat, Brain Res. 676:398–403.PubMedGoogle Scholar
  90. Hocking, D. C., Phillips, P. G., Ferro, T. J., and Johnson, A., 1990, Mechanisms of pulmonary edema induced by tumor necrosis factor-α, Circ. Res. 67:68–77.PubMedGoogle Scholar
  91. Hope, P. L., Costello, A. M., Cady, E. B., Delpy, D. T., Tofts, P. S., Chu, A., Hamilton, P. A., and Reynolds, E. O. R., 1984, Cerebral energy metabolism studied with phosphorus NMR spectroscopy in normal and birth-asphyxiated infants, Lancet 2:366–370.PubMedGoogle Scholar
  92. Horn, M., and Schlote, W., 1992, Delayed neuronal death and delayed neuronal recovery in the human brain following global ischemia, Acta Neuropathol. 85:79–87.PubMedGoogle Scholar
  93. Hossman, K.-A., 1994, Viability threshold and the penumbra of focal ischemia, Ann. Neurol 36:557–565.Google Scholar
  94. Huang, Z., Huang, P. L., Panahian, N., Dalkara, T., Fishman, M. C., and Moskowitz, M. A., 1994, Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase, Science 265:1883–1885.PubMedGoogle Scholar
  95. Hum, P. D., Koehler, R. C., Blizzard, K. K., and Traystman, R. J., 1995, Deferoxamine reduces early metabolic failure associated with severe cerebral ischemic acidosis in dogs, Stroke 26:688–694.Google Scholar
  96. Iadecola, C., Xu, X., Zhang, F., El-Fakahany, E., and Ross, E., 1995a, Marked induction of calcium-independent nitric oxide synthase activity after focal cerebral ischemia. J. Cereb. Blood Flow Metab. 15:52–59.PubMedGoogle Scholar
  97. Iadecola, C., Zhang, F., Xu, S., Casey, R., and Ross, M. E., 1995b, Inducible nitric oxide synthase gene expression in brain following cerebral ischemia, J. Cereb. Blood Flow Metab. 15:378–384.PubMedGoogle Scholar
  98. Iadecola, C., Zhang, F., and Xu, X., 1995c, Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage, Am. J. Physiol. Regul. Integr. Comp. Physiol. 268:R286-R292.Google Scholar
  99. Inder, T. E., Graham, P., Sanderson, K., and Taylor, B. J., 1994, Lipid peroxidation as a measure of oxygen free radical damage in the very low birthweight infant, Arch. Dis. Child Fetal Neonatal 70:F107-F111.Google Scholar
  100. Ischiropoulos, H., Zhu, L., Chen, J., Tsai, M., Martin, J. C., Smith, C. D., and Beckman, J. S., 1992, Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase, Arch. Biochem. Biophys. 298:431–437.PubMedGoogle Scholar
  101. Ivacko, J. A., Sun, R., and Silverstein, F. S., 1996, Hypoxic-ischemic brain injury induces an acute microglial reaction in perinatal rats, Pediatr. Res. 39:39–47.PubMedGoogle Scholar
  102. Izumi, Y., Benz, A. M., Clifford, D. B., Zorumski, C. F., 1992, Nitric oxide inhibitors attenuate n-methyl-d-aspartate excitotoxicity in rat hippocampus slices, Neurosci. Lett. 135:227–230.PubMedGoogle Scholar
  103. Jiang, N., Moyle, M., Soule, H. R., Rote, W. E., and Chopp, M., 1995, Neutrophil inhibitory factor is neuroprotective after focal ischemia in rats, Ann. Neurol. 38:935–942.PubMedGoogle Scholar
  104. Juckett, M. B., Weber, M., Balla, J., Jacob, H. S., and Vercellotti, G. M., 1996, Nitric oxide donors modulate ferritin and protect endothelium from oxidative injury, Free Radic. Biol Med. 20:63–73.PubMedGoogle Scholar
  105. Karibe, H., Chen, J., Zarow, G. J., Graham, S. H., and Weinstein, P. R., 1994, Delayed induction of mild hypothermia to reduce infarct volume after temporary middle cerebral artery occlusion in rats, J. Neurosurg. 80:112–119.PubMedGoogle Scholar
  106. Kil, H. Y., Zhang, J., and Piantadosi, C. A., 1996, Brain temperature alters hydroxyl radical production during cerebral ischemia perfusion in rats, J. Cereb. Blood Flow Metab. 16:100–106.PubMedGoogle Scholar
  107. Kirsch, J. R., Helfaer, M. A., Haun, S. E., Koehler, R. C., and Traystman, R. J., 1993, Polyethylene glycol-conjugated superoxide dismutase improves recovery of post ischemic hypercapnic cerebral blood flow in pigs, Pediatr. Res. 34:530–537.PubMedGoogle Scholar
  108. Kondo, Y, Ogawa, N., Asanuma, M., Ota, Z., and Mori, A., 1995, Regional differences in late-onset iron deposition, ferritin, transferrin, astrocyte proliferation, and microglial activation after transient forebrain ischemia in rat brain, J. Cereb. Blood Flow Metab. 15:216–226.PubMedGoogle Scholar
  109. Kontos, C. D., Wei, E. P., Williams, J. I., Kontos, H. A., and Povlishock, J. T., 1992, Cytochemical detection of superoxide in cerebral inflammation and ischemia in vivo, Am. J. Physiol. Heart Circ. Physiol. 263:H1234-H1242.Google Scholar
  110. Kuboyama, K., Safar, P., Radovsky, A., Tisherman, S. A., Stezoski, S. W., and Alexander, H., 1993, Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: A prospective, randomized study, Crit. Care Med. 21:1348–1358.PubMedGoogle Scholar
  111. Kuluz, J. W, Gregory, G. A., Han, Y, Dietrich, W. D., and Schleien, C. L., 1993, Fructose-1,6-bisphosphate reduces infarct volume after reversible middle cerebral artery occlusion in rats, Stroke 24:1576–1583.PubMedGoogle Scholar
  112. Lafon-Cazal, M., Culcasi, M., Gaven, F., Pietri, S., and Bockaert, J., 1993a, Nitric oxide, superoxide and peroxynitrite: Putative mediators of NMDA-induced cell death in cerebellar granule cells, Neuropharmacology 32:1259–1266.PubMedGoogle Scholar
  113. Lafon-Cazal, M., Pietri, S., Culacazi, M., and Bockaert, J., 1993b, NMDA-dependent superoxide production and neurotoxicity, Nature 364:535–537.PubMedGoogle Scholar
  114. Lancelot, E., Callebert, J., Revaud, M. L., Boulu, R. G., and Plotkine, M., 1995, Detection of hydroxyl radicals in rat striatum during transient focal cerebral ischemia: Possible implication in tissue damage, Neurosci. Lett. 197:85–88.PubMedGoogle Scholar
  115. Leffler, C. W., Busijia, D. W., Armstead, W. M., Shankin, D. R., Mirro, R., and Thelin, O., 1990, Activated oxygen and arachidonate effects on newborn cerebral arterioles, Am. J. Physiol. 259:H1230-H1238.Google Scholar
  116. Lei, S. Z., Pan, Z.-H., Aggarwal, S. K., Chen, H.-S. V., Hartman, J., Sucher, N. J., and Lipton, S. A., 1992, Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex, Neuron 8:1087–1099.PubMedGoogle Scholar
  117. Li, Y, Kawamura, S., Yasui, N., Shirasawa, M., and Fukasawa, H., 1994, Therapeutic effects of nilvadipine on rat focal cerebral ischemia, Exp. Brain Res. 99:1–6.PubMedGoogle Scholar
  118. Lindsberg, P. J., Yue, T. L., Frerichs, K. U., Hallenbeck, J. M., and Feuerstein, G., 1990, Evidence for platelet-activating factor as a novel mediator in experimental stroke in rabbits, Stroke 21:1452–1457.PubMedGoogle Scholar
  119. Linnik, M. D., Zobrist, R. H., and Hatfield, M. D., 1993, Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats, Stroke 24:2002–2008.PubMedGoogle Scholar
  120. Lipton, S. A., Choi, Y B., Pan, Z. H., Lei, S. Z., Chen, H. S. V., Sucher, N. J., Loscalzo, J., Singel, D. J., and Stamler, J. S., 1993, A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds, Nature 364:626–632.PubMedGoogle Scholar
  121. Liu, T. H., Beckman, J. S., Freeman, B. A., Hogan, E. L., and Hsu, C. Y, 1989, Polyethylene glycol-conjugated superoxide dismutase and catalase reduce ischemic brain injury, Am. J. Physiol. 256:H589–H593.Google Scholar
  122. Lo, W. D., and Betz, A. L., 1986, Oxygen free-radical reduction of brain capillary rubidium uptake, J. Neurochem. 46:394–398.PubMedGoogle Scholar
  123. Lorek, A., Takei, Y, Cady, E. B., Wyatt, J. S., Penrice, J., Edwards, A. D., Peebles, D., Wylezinska, M., Owen-Reece, H., Kirkbridege, V., Cooper, E. E., Aldridge, R. F., Roth, S. C., Brown, G., Delpy, D. T., and Reynolds, E. O. R., 1994, Delayed (“secondary”) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: Continuous 48-hour studies by phophorous magnetic resonance spectroscopy, Pediatr. Res. 36:699–706.PubMedGoogle Scholar
  124. Manzoni, O., Prezeau, L., Marin, P., Deshager, S., Bockaert, J., and Fagni, L., 1992, Nitric oxide-induced blockade of NMDA receptors, Neuron 8:653–662.PubMedGoogle Scholar
  125. Markarian, G. Z., Lee, J. H., Stein, D. J., and Hong, S. C., 1996, Mild hypothermia: Therapeutic window after experimental cerebral ischemia. Neurosurgery 38:542–550.PubMedGoogle Scholar
  126. Marro, P. J., McGowan, J. E., Razdan, B., Mishra, O. P., and Delivoria-Papadopoulos, M., 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.PubMedGoogle Scholar
  127. Matsumoto, T., Pollock, J. S., Nakane, M., and Förstermann, U., 1993, Developmental changes of cytosolic and particulate nitric oxide synthase in rat brain, Dev. Brain Res. 73:199–203.Google Scholar
  128. Matsuo, Y, Onodera, H., Shiga, Y, Nakamura, M., Ninomiya, M., Kihara, T., and Kogure, K., 1994, Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat: Effects of neutrophil depletion, Stroke 25:1469–1475.PubMedGoogle Scholar
  129. Matsuo, Y, Kihara, T., Ikeda, M., Ninomiya, M., Onodera, H., and Kogure, K., 1995, Role of neutrophils in radical production during ischemia and reperfusion of the rat brain: Effect of neutrophil depletion on extracellular ascorbyl radical formation, J. Cereb. Blood Flow Metab. 15:941–947.PubMedGoogle Scholar
  130. McCord, J. M., 1985, Oxygen-derived free radicals in postischemic tissue injury, N. Eng. J. Med. 312:159–163.Google Scholar
  131. McNeill, H., Williams, C., Guan, J., Dragunow, M., Lawlor, P., Sirimanne, E., Nikolics, K., and Gluckman, P., 1994, Neuronal rescue with transforming growth factor-betal after hypoxic-ischemic brain injury, Neuroreport 5:901–904.PubMedGoogle Scholar
  132. McRae, A., Gilland, E., Bona, E., and Hagberg, H., 1995, Microglia activation after neonatal hypoxic-ischemia, Dev. Brain Res. 84:245–252.Google Scholar
  133. Meadows, M. E., Fisher, M., and Minematsu, K., 1994, Delayed treatment with a noncompetitive NMDA antagonist, CNS-1002, reduces infarct size in rats, Cerebrovasc. Dis. 4:26–31.Google Scholar
  134. Mishra, O. P., and Delivoria-Papadopoulos, M. D., 1988, Na+,K+-ATPase in developing fetal guinea pig brain and the effect of maternal hypoxia, Neurochem. Res. 13:765–770.PubMedGoogle Scholar
  135. Moison, R., Palinckx, J., Roest, M., Houdkamp, E., and Berger, H. M., 1993, Induction of lipid peroxidation of pulmonary surfactant by plasma of preterm babies, Lancet 341:79–82.PubMedGoogle Scholar
  136. Moorcraft, J., Bolas, N. M., Ives, N. K., Ouwerkerk, R., Smyth, J., Rajagopalan, B., Hope, P. L., and Radda, G. K., 1991, Global and depth resolved phosphorus magnetic resonance spectroscopy to predict outcome after birth asphyxia, Arch. Dis. Child. 66:1119–1123.PubMedGoogle Scholar
  137. Moos, T., 1995, Developmental profile of non-heme iron distribution in the rat brain during ontogenesis, Dev. Brain Res. 87:203–213.Google Scholar
  138. Mousa, S. A., Ritger, R. C., and Smith, R. D., 1992, Efficacy and safety of deferoxamine conjugated to hydroxyethyl starch, J. Cardiovasc. Pharmacol. 19:425–429.PubMedGoogle Scholar
  139. Murphy, T. H., Schnaar, R. L., and Coyle, J. T., 1990, Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cysteine uptake, FASEB J. 4:1624–1633.PubMedGoogle Scholar
  140. Nathan, C., 1992, Nitric oxide as a secretory product of mammalian cells, FASEB J. 6:3051–3064.PubMedGoogle Scholar
  141. Nelson, C. W., Wei, E. P., Povlishock, J. T., Kontos, H. A., and Moskowitz, M. A., 1992, Oxygen radicals in cerebral ischemia, Am. J. Physiol. Heart Circ. Physiol. 263:H1356-H1362.Google Scholar
  142. Nishida, A., Misaki, Y., Kuruta, H., and Takashima, S., 1994, Developmental expression of copper, zinc-superoxide dismutase in human brain by chemiluminescence, Brain Dev. 16:40–43.PubMedGoogle Scholar
  143. Northington, F. J., Tobin, J. R., Koehler, R. C., and Traystman, R. J., 1995, In vivo production of nitric oxide correlates with NMDA-induced cerebral hyperemia in newborn sheep, Am. J. Physiol. Heart Circ. Physiol. 269:H215-H221.Google Scholar
  144. Nowicki, J. P., Duval, D., Poignet, H., and Scatton, B., 1991, Nitric oxide mediates neuronal death after focal cerebral ischemia in the mouse, Eur. J. Pharmacol. 204:339–340.PubMedGoogle Scholar
  145. Ohno, M., Aotani, H., and Shimada, M., 1995, Glial responses to hypoxic/ischemic encephalopathy in neonatal rat cerebrum, Dev. Brain Res. 84:294–298.Google Scholar
  146. Oka, A., Belliveau, M. J., Rosenberg, P. A., and Volpe, J. J., 1993, Vulnerability of Oligodendroglia to glutamate: Pharmacology, mechanisms, and prevention, J. Neurosci. 13:1441–1453.PubMedGoogle Scholar
  147. Omene, J. A., Longe, A. C., Ihongbe, J. C., Glew, R. H., and Holzman, I. R., 1981, Decreased umbilical cord serum ceruloplasmin concentrations in infants with hyaline membrane disease, J. Ped. 99:136–138.Google Scholar
  148. Ostwald, K., Hagberg, H., Andiné, P., and Karlsson, J. O., 1993, Upregulation of calpain activity in neonatal rat brain after hypoxic-ischemia, Brain Res. 630:289–294.PubMedGoogle Scholar
  149. Palmer, C., 1996, Brain injury in the neonatal rat is reduced by neutrophil depletion induced before but not after a hypoxic ischemic insult, Pediatr. Res. 39:378A.Google Scholar
  150. Palmer, C., and Roberts, R. L., 1991, Reduction of perinatal brain damage with oxypurinol treatment after hypoxic-ischemic injury, Pediatr. Res. 29:362A.Google Scholar
  151. Palmer, C., Brucklacher, R. M., Christensen, M. A., and Vannucci, R. C., 1990, Carbohydrate and energy metabolism during the evolution of hypoxic-ischemic brain damage in the immature rat, J. Cereb. Blood Flow Metab. 10:227–235.PubMedGoogle Scholar
  152. Palmer, C., Pavlick, G., Karley, D., Roberts, R. L., and Connor, J. R., 1993a, The regional localization of iron in the cerebral cortex of the immature rat: relation to hypoxic-ischemic injury, Pediatr. Res. 33: 374A.Google Scholar
  153. Palmer, C., Towfighi, J., Roberts, R. L., and Heitjan, D. F., 1993b, Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats, Pediatr. Res. 33:405–411.PubMedGoogle Scholar
  154. Palmer, C., Horrell, L., and Roberts, R. L., 1994a, Inhibition of nitric oxide synthase after cerebral hypoxia ischemia reduces brain swelling in neonatal rats: a dose response study, Pediatr. Res. 35:385A.Google Scholar
  155. Palmer, C., Roberts, R. L., and Bero, C., 1994b, Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats, Stroke 25:1039–1045.PubMedGoogle Scholar
  156. Palmer, C., Roberts, R. L., and Young, P., 1996, The reduction of hypoxic-ischemic brain injury in the 7-day-old rat with PEG-SOD, Pediatr. Res. 39:379A.Google Scholar
  157. Panetta, J. A., and Clemens, J. A., 1994, Novel antioxidant therapy for cerebral ischemia-reperfusion injury, Ann. NY Acad. Sci. 723:239–245.PubMedGoogle Scholar
  158. Panetta, T., Marcheselli, V. L., Braquet, P., Spinnewyn, B., and Bazan, N. G., 1987, Effects of a platelet activating factor antagonist (BN 52021) on free fatty acids, diacylglycerols, polyphosphoinositides and blood flow in the gerbil brain: Inhibition of ischemia-reperfusion induced cerebral injury, Biochem. Biophys. Res. Commun. 149:580–587.PubMedGoogle Scholar
  159. Park, C. K., and Rudolphi, K. A., 1994, Antiischemic effects of propentofylline (HWA 285) against focal cerebral infarction in rats, Neurosci. Lett. 178:235–238.PubMedGoogle Scholar
  160. Parkinson, F. E., Rudolphi, K. A., and Fredholm, B. B., 1994, Propentofylline: a nucleoside transport inhibitor with neuroprotective effects in cerebral ischemia, Gen. Pharmacol. 25:1053–1058.PubMedGoogle Scholar
  161. Patt, A., Horesh, I. R., Berger, E. M., Harken, A. H., and Repine, J. E., 1990, Iron depletion or chelation reduces ischemia/reperfusion-induced edema in gerbil brains, J. Pediatr. Surg. 25:224–228.PubMedGoogle Scholar
  162. Phillis, J. W., 1989, Oxypurinol attenuates ischemia-induced hippocampus damage in the gerbil, Brain Res. Bull. 23:467–470.PubMedGoogle Scholar
  163. Phillis, J. W., and Sen, S., 1993, Oxypurinol attenuates hydroxyl radical production during ischemia/reperfusion injury of the rat cerebral cortex: An ESR study, Brain Res. 628:309–312.PubMedGoogle Scholar
  164. Phillis, J. W., Sen, S., and Cao, X., 1994, Amflutizole, a xanthine oxidase inhibitor, inhibits free radical generation in the ischemic/reperfused rat cerebral cortex, Neurosci. Lett. 169:188–190.PubMedGoogle Scholar
  165. Piantadosi, C. A., and Zhang, J., 1996, Mitochondrial generation of reactive oxygen species after brain ischemia in the rat, Stroke 27:327–331.PubMedGoogle Scholar
  166. Pourcyrous, M., Leffler, C. W., Bada, H. S., Korones, S. B., and Busija, D. W., 1993, Brain superoxide anion generation in asphyxiated piglets and the effect of indomethacin at therapeutic dose, Ped. Res. 34:366–369.Google Scholar
  167. Pulsinelli, W. A., Brierley, J. B., and Plum, F., 1982, Temporal profile of neuronal damage in a model of transient forebrain ischemia, Ann. Neurol. 11:491–498.PubMedGoogle Scholar
  168. Qi, Y., Jamindar, T. M., and Dawson, G., 1995, Hypoxia alters iron homeostasis and induces ferritin synthesis in oligodendrocytes, J. Neurochem. 64:2458–2464.PubMedGoogle Scholar
  169. Radi, R., Beckman, J. S., Bush, K. M., and Freeman, B. A., 1991, Peroxynitrite-induced membrane lipid peroxidation: The cytotoxic potential of superoxide and nitric oxide, Arch. Biochem. Biophys. 288: 481–487.PubMedGoogle Scholar
  170. Ratan, R. R., Murphy, T. H., and Baraban, J. M., 1994, Oxidative stress induces apoptosis in embryonic cortical neurons, J. Neurochem. 62:376–379.PubMedGoogle Scholar
  171. Razdan, B., Marro, P. J., Tammela, O., Goel, R., Mishra, O. P., and Delivoria, P. M., 1993, Selective sensitivity of synaptosomal membrane function to cerebral cortical hypoxia in newborn piglets, Brain Res. 600:308–314.PubMedGoogle Scholar
  172. Reif, D. W., and Simmons, R. D., 1990, Nitric oxide mediates iron release from ferritin, Archiv. Biochem. Biophys. 283:537–541.Google Scholar
  173. Reilly, P. M., Schiller, H. J., and Bulkley, G. B., 1991, Pharmacologic approach to tissue injury mediated by free radicals and other reactive oxygen metabolites, Am. J. Surg. 161:488–503.PubMedGoogle Scholar
  174. Rice, J. E., Vannucci, R. C., and Brierley, J. B., 1981, The influence of immaturity on hypoxic-ischemic brain damage in the rat, Ann. Neurol. 9:131–141.PubMedGoogle Scholar
  175. Rordorf, G., Uemura, Y., and Bonventre, J. V., 1991, Characterization of phospholipase A2 (PLA2) activity in gerbil brain: Enhanced activities of cytosolic, mitochondrial and microsomal forms after ischemia and reperfusion, J. Neurosci. 11:1829–1836.PubMedGoogle Scholar
  176. Rosenberg, A. A., Murdaugh, E., and White, C. W., 1989, The role of oxygen free radicals in postasphyxia cerebral hypoperfusion in newborn lambs, Pediatr. Res. 26:215–219.PubMedGoogle Scholar
  177. Rosenthal, R. E., Chanderbhan, R., Marshall, G., and Fiskum, G., 1992a, Prevention of post-ischemic brain lipid conjugated diene production and neurological injury by hydroxyethyl starch-conjugated deferoxamine, Free Rad. Biol. Med. 12:29–33.PubMedGoogle Scholar
  178. Rosenthal, R. E., Williams, R., Bogaert, Y. E., Getson, P. R., and Fiskum, G., 1992b, Prevention of post-ischemic canine neurological injury through potentiation of brain energy metabolism by acetyl-L-carnitine, Stroke 23:1312–1318.PubMedGoogle Scholar
  179. Roskams, A., and Connor, J. R., 1994, Iron, transferrin, and ferritin in the rat brain during development and aging, J. Neurochem. 63:709–716.PubMedGoogle Scholar
  180. Roth, S. C., Edwards, A. D., Cady, E. B., Delpy, D. T., Wyatt, J. S., Azzopardi, D., Baudin, J., Townsend, J., Stewart, A. L., and Reynolds, E. O., 1992a, Relation between cerebral oxidative metabolism following birth asphyxia, and neurodevelopmental outcome and brain growth at one year [see comments], Develop. Med. Child Neurol. 34:285–295.PubMedGoogle Scholar
  181. Roth, S. C., Edwards, A. D., Cady, E. B., Delpy, D. T., Wyatt, J. S., Azzopardi, D., Baudin, J., Townsend, J., Stewart, A. L., and Reynolds, E. O. R., 1992b, Relation between cerebral oxidative metabolism following birth asphyxia and neurodevelopmental outcome and brain growth at one year, Dev. Med. Child Neurol. 34:285–295.PubMedGoogle Scholar
  182. Rothman, R., 1992, Cellular pool of transient ferric iron, chelatable by deferoxamine and distinct from ferritin, that is involved in oxidation cell injury, Mol. Pharmacol. 42:703–710.PubMedGoogle Scholar
  183. Rothman, S. M., and Olney, J. W., 1986, Glutamate and the pathophysiology of hypoxic-ischemic brain damage, Ann. Neurol. 19:105–111.PubMedGoogle Scholar
  184. Royall, J. A., Kooy, N. W., Ye, Y Z., Kelly, D. R., and Beckman, J. S., 1994, Evidence of peroxynitrite in adult respiratory distress syndrome, Pediatr. Res. 35:57A.Google Scholar
  185. Sadrzadeh, S. M. H., and Eaton, J. W., 1988, Hemoglobin-mediated oxidant damage to the central nervous system requires endogenous ascorbate, J. Clin. Invest. 82:1510–1515.PubMedGoogle Scholar
  186. Sadrzadeh, S. M. H., and Eaton, J. W., 1992, Hemoglobin-induced oxidant damage to the central nervous system, in: Free Radical Mechanisms of Tissue Injury (M. T. Moslen and C. V. Smith, eds.), CRC Press, Boca Raton, Florida, pp. 23–32.Google Scholar
  187. Sadrzadeh, S. M. H., Graf, E., Panter, S. S., Hallaway, P. E., and Eaton, J. W., 1984, Hemoglobin: A biological fenton reagent, J. Biol. Chem. 259:14354.PubMedGoogle Scholar
  188. Sadrzadeh, S. M. H., Anderson, D. K., Panter, S. S., Hallaway, P. E., and Eaton, J. W., 1987, Hemoglobin potentiates central nervous system damage, J. Clin. Invest. 79:662–664.PubMedGoogle Scholar
  189. Schiff, S. J., and Somjen, G. G., 1985, Hyperexcitability following moderate hypoxia in hippocampal tissue slices, Brain Res. 337:337–340.PubMedGoogle Scholar
  190. Schleien, C. L., Koehler, R. C., Shaffner, D. H., and Traystman, R. J., 1990, Blood-brain barrier integrity during cardiopulmonary resuscitation in dogs, Stroke 21:1185–1191.PubMedGoogle Scholar
  191. Schmid-Schonbein, G. W., and Lee, J., 1995, Leukocytes in capillary flow, Int. J. Microcirc. Clin. Exp. 15:255–264.PubMedGoogle Scholar
  192. Schraufstatter, I. U., Hyslop, P. A., Hinshaw, D. B., Spragg, R. G., Sklaar, L. A., and Cochrane, C. G., 1986, Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly (ADP-ribose) polymerase, Proc. Natl. Acad. Sci. USA 83:4908–4912.PubMedGoogle Scholar
  193. Siesjo, B., and Bengtsson, F., 1989, Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: A unifying hypothesis, J. Cereb. Blood Flow Metab. 9:127–140.PubMedGoogle Scholar
  194. Siesjo, B. K., 1988, Mechanisms of Ischemic Brain Damage, Cht. Care. Med. 16:954–963.Google Scholar
  195. Siesjo, B. K., 1992, Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment (review), J. Neurosurg. 77:337–354.PubMedGoogle Scholar
  196. Siesjo, B. K., Agardh, C.-D., and Bengtsson, F., 1989, Free radicals and brain damage, Cerebrovasc. Brain Metab. Rev. 1:165–211.PubMedGoogle Scholar
  197. Sirimanne, E. S., Blumberg, R. M., Bossano, D., Gunning, M., Edwards, A. D., Gluckman, P. D., and Williams, C. E., 1996, The effect of prolonged modification of cerebral temperature on outcome after hypoxic-ischemic brain injury in the infant rat, Pediatr. Res. 39:591–597.PubMedGoogle Scholar
  198. Smith, C. V., Hansen, T. N., Martin, N. E., McMicken, H. W., and Elliott, S. J., 1993, Oxidant stress responses in premature infants during exposure to hyperoxia, Pediatr. Res. 34:360–365.PubMedGoogle Scholar
  199. Smith, S. E., and Meldrum, B. S., 1996, Cerebroprotective effect of lamotrigine after focal ischemia in rats, Stroke, 26:117–121.Google Scholar
  200. Spinnewyn, B., Blavet, N., Clostre, F., Bazan, N., and Braquet, P., 1987, Involvement of platelet-activating factor (PAF) in cerebral post-ischemic phase in mongolian gerbils, Prostaglandins 34:337–349.PubMedGoogle Scholar
  201. Stein, D. T., and Vannucci, R. C., 1988, Calcium accumulation during the evolution of hypoxic-ischemic brain damage in the immature rat, J. Cereb. Blood Flow Metab. 8:834–842.PubMedGoogle Scholar
  202. Steinberg, G. K., Kunis, D., DeLaPaz, R., and Poljak, A., 1993, Neuroprotection following focal cerebral ischemia with the NMDA antagonist dextromethorphan, has a favourable dose response profile, Neurol. Res. 15:174–180.PubMedGoogle Scholar
  203. Subbarao, K. V., and Richardson, J. S., 1990, Iron-dependent peroxidation of rat brain: a regional study, J. Neurosci. Res. 26:224–232.PubMedGoogle Scholar
  204. Sullivan, J. L., 1992, Iron Metabolism and Oxygen Radical Injury in Premature Infants, CRC Press, Boca Raton, Florida.Google Scholar
  205. Sweeney, M. I., Yager, J. Y., Walz, W., and Juurlink, B. H. J., 1995, Cellular mechanisms involved in brain ischemia, Can. J. Physiol. Pharmacol. 73:1525–1535.PubMedGoogle Scholar
  206. Takashima, S., Juruta, H., Mito, T., Houdou, S., Konomi, H., Yao, R., and Onodera, K., 1990, Immunohistochemistry of superoxide dismutase-1 in developing human brain, Brain Dev. 12:211–213.PubMedGoogle Scholar
  207. Tan, S., Yokoyama, Y, Dickens, E., Cash, T. G., Freeman, B. A., and Parks, D. A., 1993, Xanthine oxidase activity in the circulation of rats following hemorrhagic shock, Free Radic. Biol. Med. 15:407–414.PubMedGoogle Scholar
  208. Tan, S., Gelman, S., Wheat, J. K., and Parks, D. A., 1995, Circulating xanthine oxidase in human ischemia reperfusion, South. Med. J. 88:479–482.PubMedGoogle Scholar
  209. Tan, W., Williams, C. E., Mallard, C. E., and Gluckman, P. D., 1994, Monosialoganglioside GM1 treatment after a hypoxic-ischemic episode reduces the vulnerability of the fetal sheep brain to subsequent injuries, Am. J. Obstet. Gynecol. 170:663–670.PubMedGoogle Scholar
  210. Thiringer, K., Hrbek, A., Karlsson, K., Rosen, K. G., and Kjellmer, I., 1987, Postasphyxiai cerebral survival in newborn sheep after treatment with oxygen free radical scavengers and a calcium antagonist, Ped. Res. 22:62–66.Google Scholar
  211. Thoresen, M., Penrice, J., Lorek, A., Cady, E. B., Wylezinska, M., Kirkbride, B., Cooper, C. E., Brown, G. C, Edwards, A. D., Wyatt, J. S., and Reynolds, E. O. R., 1995, Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet, Pediatr. Res. 37:667–670.PubMedGoogle Scholar
  212. Tomic, D., Zobundzija, M., and Meâugorac, M., 1994, Postnatal development of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) positive neurons in rat prefrontal cortex, Neurosci. Lett. 170:217–220.PubMedGoogle Scholar
  213. Towfighi, J., Zee, N., Yager, J., Housman, C., and Vannucci, R. C., 1995, Temporal evolution of neuropathologic changes in an immature rat model of cerebral hypoxia: A light microscopic study, Acta Neuropathol.(Berl.) 90:375–386.Google Scholar
  214. Traystman, R. J., Kirsch, J. R., and Koehler, R. C., 1991, Oxygen radical mechanisms of brain injury following ischemia and reperfusion, J. Appl. Physiol. 71:1185–1195.PubMedGoogle Scholar
  215. Tsukahara, T., Yonekawa, Y, Tanaka, K., Ohara, O., Watanabe, S., Kimura, T., Nishijima, T., and Taniguchi, T., 1994, The role of brain-derived neurotrophic factor in transient forebrain ischemia in the rat brain, Neurosurgery 34:323–331.PubMedGoogle Scholar
  216. Turrens, J. F., and Boveris, A., 1980, Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria, Biochem. J. 191:421–427.PubMedGoogle Scholar
  217. Umemura, A., Mabe, H., and Nagai, H., 1992, A phospholipase C inhibitor ameliorates postischemic neuronal damage in rats, Stroke 23:1163–1166.PubMedGoogle Scholar
  218. Umemura, K., Wada, K., Uematsu, T., Mizuno, A., and Nakashima, M., 1994, Effect of 21-aminosteroid lipid peroxidation inhibitor, U74006F, in the rat middle cerebral artery occlusion model, Eur. J. Pharmacol. 251:69–74.PubMedGoogle Scholar
  219. Valentino, K., Newcomb, R., Gadbois, T., Singh, T., Bowersox, S., Bitner, S., Justice, A., Yamashiro, D., Hoffman, B. B., Ciaranello, R., Miljanich, G., and Ramachandran, J., 1993, A selective N-type calcium channel antagonist protects against neuronal loss after global cerebral ischemia, Proc. Natl. Acad. Sci. USA 90:7894–7897.PubMedGoogle Scholar
  220. van Bel, F., Dorrepaal, C. A., Benders, M. J. N. L., Houdkamp, E., van de Bor, M., and Berger, H. M., 1994, Neurologie abnormalities in the first 24 h following birth asphyxia are associated with increasing plasma levels of free iron and TBA-reactive species, Pediatr. Res. 35:388A.Google Scholar
  221. Vannucci, R. C., 1990, Experimental biology of cerebral hypoxia-ischemia: Relation to perinatal brain damage, Pediatr. Res. 27:317–326.PubMedGoogle Scholar
  222. Vannucci, R. C., 1993, Experimental models of perinatal hypoxic-ischemic brain damage, APIMS Suppl. 101:89–95.Google Scholar
  223. Vannucci, R. C., Christensen, M. A., and Yager, J. Y, 1993, Nature, time-course, and extent of cerebral edema in perinatal hypoxic-ischemic brain damage, Pediatr. Neurol. 9:29–34.PubMedGoogle Scholar
  224. Vannucci, R. C., Yager, J. Y., and Vannucci, S. J., 1994, Cerebral glucose and energy utilization during the evolution of hypoxic-ischemic brain damage in the immature rat, J. Cereb. Blood Flow Metab. 14:279–288.PubMedGoogle Scholar
  225. Volpe, J. J., 1987, Intracranial hemorrhage: Periventricular-intraventricular hemorrhage of the premature infant, in: Neurology of the Newborn (W. B. S. Staff, ed.), W. B. Saunders, Philadelphia, pp. 311–361.Google Scholar
  226. Volterra, A., Trotti, D., Tromba, C., and Racagni, G., 1993, Additive inhibition of glutamate uptake by arachidonic acid and oxygen free radicals via two distinct mechanisms, Neurosci. Abstr. 19:1350.Google Scholar
  227. Walker, P. R., Weaver, V. M., Lach, B., LeBlanc, J., and Sikorska, M., 1994, Endonuclease activities associated with high molecular weight and internucleosomal DNA fragmentation in apoptosis, Exp. Cell Res. 213:100–106.PubMedGoogle Scholar
  228. Wallis, R. A., Panisson, K. L., Henry, D., and Wasterlain, C. G., 1993, Neuroprotection against nitric oxide injury with inhibitors of ADP-ribosylation, Neuroreport 5:245–248.PubMedGoogle Scholar
  229. Watanabe, T., Yuki, S., Egawa, M., and Nishi, H., 1994, Protective effects of MCI-186 on cerebral ischemia: Possible involvement of free radical scavenging and antioxidant actions, J. Pharmacol Exp. Then 268:1597–1604.Google Scholar
  230. Watkins, M. T., Haudenschild, C. C., Al-Badawi, H., Velazquez, F. R., and Larson, D. M., 1995, Immediate responses of endothelial cells to hypoxia and reoxygenation: An in vitro model of cellular dysfunction, Am. J. Physiol. Heart Circ. Physiol. 268:H749-H758.Google Scholar
  231. Watkins, M. T., Al-Badawi, H., Cardenas, R., Dubois, E., and Larson, D. M., 1996, Endogenous reactive oxygen metabolites mediate sublethal endothelial cell dysfunction during reoxygenation, J. Vase. Surg. 23:95–103.Google Scholar
  232. Wei, E. P., Ellison, M. D., Kontos, H. A., and Povlishock, J. T., 1986, 02 radicals in arachidonate-induced increased blood-brain barrier permeability to proteins, Am. J. Physiol. 251:H693-H699.Google Scholar
  233. Weiss, G., Goossen, B., Doppler, W., Fuchs, D., Pantopoulos, K., Werner-Felmayer, G., Wächter, H., and Hentze, M. W., 1993, Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway, EMBO J. 12:3651–3657.PubMedGoogle Scholar
  234. Weiss, S. J., 1989, Tissue destruction by neutrophils, N. Engl. J. Med. 320:365–376.PubMedGoogle Scholar
  235. White, B. C., Daya, A., DeGracia, D. J., O’Neil, B. J., Skjaerlund, J. M., Trumble, S., Krause, G. S., and Rafols, J. A., 1993, Fluorescent histochemical localization of lipid peroxidation during brain reperfusion following cardiac arrest, Acta Neuropathol. 86:1–9.PubMedGoogle Scholar
  236. Whiteman, M., Tritschler, H., and Halliwell, B., 1996, Protection against peroxynitrite-dependent tyrosine nitration and arantiproteinase inactivation by oxidized and reduced lipoic acid, FEBS Lett. 379 :14–16. Wyatt, J. S., 1993, Near-infrared spectroscopy in asphyxiai brain injury (review), Clinics in Perinatology 20:369–378.Google Scholar
  237. Yamakawa, T., Yamaguchi, S., Niimi, H., and Sugiyama, I., 1987, White blood cell plugging and blood flow maldistribution in the capillary network of cat cerebral cortex in acute hemorrhagic hypotension: An intravital microscopic study, Circ. Shock. 22:323–332.PubMedGoogle Scholar
  238. Yasuda, H., and Nakajima, A., 1993, Brain protection against ischemic injury by nizofenone, Cerebrovasc. Brain Metab. Rev. 5:264–276.PubMedGoogle Scholar
  239. Yoshida, T., Limmroth, V., Irikura, K., and Moskowitz, M. A., 1994, The NOS inhibitor, 7-nitroindazole, decreases focal infarct volume but not the response to topical acetylcholine in pial vessels, J. Cereb. Blood Flow Metab. 14:924–929.PubMedGoogle Scholar
  240. Yoshida, T., Tanaka, M., Sotomatsu, A., and Hirai, S., 1995, Activated microglia cause superoxide-mediated release of iron from ferritin, Neurosci. Lett. 190:21–24.PubMedGoogle Scholar
  241. Zaleska, M. M., and Floyd, R. A., 1995, Regional lipid peroxidation in rat brain in vitro: Possible role of endogenous iron, Neurochem. Res. 10:397–410.Google Scholar
  242. Zhang, J., and Piantadosi, C. A., 1994, Prolonged production of hydroxyl radical in rat hippocampus after brain ischemia-reperfusion is decreased by 21-aminosteroids, Neurosci. Lett. 177:127–130.PubMedGoogle Scholar
  243. Zhang, J., Dawson, V. L., Dawson, T. M., and Snyder, S. H., 1994, Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity, Science 263:687–689.PubMedGoogle Scholar
  244. Zhang, R. L., Chopp, M., Chen, H., and Garcia, J. H., 1994a, Temporal profile of ischemic tissue damage, neutrophil response, and vascular plugging following permanent and transient (2H) middle cerebral artery occlusion in the rat, J. Neurol. Sci. 125:3–10.PubMedGoogle Scholar
  245. Zhang, R. L., Chopp, M., Li, Y, Zalonga, C., Jiang, M., Jones, M., Miyasaka, M., and Ward, P., 1994b, Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat, Neurology 44:1747–1751.PubMedGoogle Scholar
  246. Zhang, Z. G., Chopp, M., Tang, W. X., Jiang, N., and Zhang, R. L., 1995, Postischemic treatment (2–4 h) with anti-CD11b and anti-CD 18 monoclonal antibodies are neuroprotective after transient (2 h) focal cerebral ischemia in the rat, Brain Res. 698:79–85.PubMedGoogle Scholar
  247. Zhao, Q., Pahlmark, K., Smith, M. L., and Siesjö, B. K., 1994, Delayed treatment with the spin trap a-phenyl-N-tert-butyl nitrone (PBN) reduces infarct size following transient middle cerebral artery occlusion in rats, Acta Physiol. Scand. 152:349–350.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Charles Palmer
    • 1
  1. 1.Division of Newborn Medicine, Department of Pediatrics, M. S. Hershey Medical CenterPennsylvania State University College of MedicineHersheyUSA

Personalised recommendations