NeuroMolecular Medicine

, Volume 8, Issue 4, pp 435–450 | Cite as

Cerebral palsy

Review Article


Cerebral palsy (CP) is a group of disorders of movement and posture resulting from non-progressive disturbances of the fetal or neonatal brain. More than 80% of cases of CP in term infants originate in the prenatal period; in premature infants, both prenatal or postnatal causes contribute. The most prevalent pathological lesion seen in CP is periventricular white matter injury (PWMI) resulting from vulnerability of the immature oligodendrocytes (pre-OLs) before 32 wk of gestation. PWMI is responsible for the spastic diplegia form of CP and a spectrum of cognitive and behavioral disorders. Oxidative stress and excitotoxicity resulting from excessive stimulation of ionotropic glutamate receptors on preOLs are the most prominent molecular mechanisms for PWMI. Asphyxia around the time of birth in term infants accounts for less than 15% of CP in developed countries but the incidence is higher in underdeveloped areas Asphyxia causes a different pattern of brain injury and CP than is seen after preterm injuries. This type of CP is associated with the clinical syndrome of hypoxic-ischemic encephalopathy shortly after the insult, and the cortex, basal ganglia, and brainstem are selectively vulnerable to injury. Experimental models indicate that neurons in the neonatal brain are more likely to die by delayed apoptosis extending over days to weeks than those in the adult brain. Neurons die by glutamate-mediated excitotoxicity involving downstream caspase-dependent and caspase-independent cell death pathways. Recent reports indicate that males and females preferentially utilize different pathways. Clinical trials indicate that mild hypothermia reduces death or disability in term infants following asphyxia and basic research suggests that this approach might be combined with pharmacological strategies in the future.

Index Entries

Apoptosis apoptosis-inducing factor cerebral palsy gender hypoxic-ischemic encephalopathy periventricular leukomalacia white matter 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Accardo J., Kammann H., and Hoon A. H. Jr. (2004) Neuroimaging in cerebral palsy. J. Pediatr. 145, S19-S27.PubMedGoogle Scholar
  2. Back S. A. and Rivkees S. A. (2004) Emerging concepts in periventricular white matter injury. Semin. Perinatol. 28, 405–414.PubMedGoogle Scholar
  3. Back S. A., Luo N. L., Borenstein N. S., Levine J. M., Volpe J. J., and Kinney H. C. (2001) Late oligodendrocyte progenitors conincide with the developmental window of vulnerability for human perinatal white matter injury. J. Neurosci. 21, 1302–1312.PubMedGoogle Scholar
  4. Back S. A., Luo N. L., Mallinson R. A., et al. (2005) Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes. Ann. Neurol. 58, 108–120.PubMedGoogle Scholar
  5. Badawi N., Kurinczuk J. J., and Keogh J. M. (1998) Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ. 317, 1554–1558.PubMedGoogle Scholar
  6. Banker B. Q. and Larroche J. C. (1962) Periventricular leukomalacia of infancy. pp. 386–410.Google Scholar
  7. Bano D., Young K. W., Guerin C. J., et al. (2005) Cleavage of the plasma membrane NA+/Ca+ exchanger in excitotoxicity. Cell. 120, 275–285.PubMedGoogle Scholar
  8. Barkovich A. J., Westmark K., Partridge C., Sola A., and Ferriero D. M. (1995) Perinatal asphyxia: MR findings in the first 10 days. AJNR Am. J. Neuroradiol. 16, 427–438.PubMedGoogle Scholar
  9. Baud O., Li J., Zhang Y., Neve R. L., Volpe J. J., and Rosenberg P. A. (2004) Nitric oxide-induced cell death in developing oligodendrocytes is associated with mitochondrial dysfunction and apoptosis-inducing factor translocation. Eur. J. Neurosci. 20, 1713–1726.PubMedGoogle Scholar
  10. Bax M., Goldstein M., Rosenbaum P., et al. (2005) Proposed definition and classification of cerebral palsy, April 2005. Dev. Med. Child. Neurol. 47, 571–576.PubMedGoogle Scholar
  11. Bergles D. E., Roberts J. D., Somogyi P., and Jahr C. E. (2000) Glutamatergic synapses on oligodendrocyte precursor cells in hippocampus. Nature. 405, 187–191.PubMedGoogle Scholar
  12. Blomgren K., Zhu C., Hallin U., and Hagberg H. (2003) Mitochondria and ischemic reperfusion damage in the adult and in the developing brain. Biochem. Biophys. Res. Commun. 304, 551–559.PubMedGoogle Scholar
  13. Blomgren K., Zhu C., Wang X., et al. (2001) Synergistic activation of caspase-3 by m-calpain after neonatal hypoxia-ischemia: a mechanism of “pathological apoptosis”? J. Biol. Chem. 276, 10,191–10,198.Google Scholar
  14. Chang Y. S., Mu D., Wendland M., et al. (2005) Erythropoietin improves functional and histological outcome in neonatal stroke. Pediatr. Res. 58, 106–111.PubMedGoogle Scholar
  15. Comi A. M., Johnston M. V., and Wilson M. A. (2005) Strain variability, injury distribution, and seizure onset in a mouse model of stroke in the immature brain. Dev. Neurosci. 27, 127–133.PubMedGoogle Scholar
  16. Comi A. M., Weisz C. J., Highet B. H., Johnston M. V., and Wilson M. A. (2004) A new model of stroke and ischemic seizures in the immature brain. Pediatr. Neurol. 31, 254–257.PubMedGoogle Scholar
  17. Costeff H. (2004) Estimated frequency of genetic and nongenetic causes of congenital idiopathic cerebral palsy in west Sweden. Ann. Hum. Genet. 68, 515–520.PubMedGoogle Scholar
  18. Crair M. C. and Malenka R. C. (1995) A critical period for long-term potentiation at thalamocortical synapses. Nature 375, 325–328.PubMedGoogle Scholar
  19. Crothers B. and Paine R. S. (1988) The natural history of cerebral palsy. Mac Keith Press.Google Scholar
  20. Culmsee C., Zhu C., Landshamer S., et al. (2005) Apoptosis-inducing factor triggered by poly (ADP-Ribose) polymerase and bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J. Neurosci. 25, 10,262–10,272.Google Scholar
  21. Dammann O. and Leviton A. (2004a) Biomarker epidemiology of cerebral palsy. Ann. Neurol. 55, 158–161.PubMedGoogle Scholar
  22. Dammann O. and Leviton A. (2004b) Inflammatory brain damage in preterm newborns—dry numbers, wet lab, and causal inferences. Early Hum. Dev. 79, 1–15.PubMedGoogle Scholar
  23. Dammann O., Drescher J., and Veelken N. (2003) Maternal fever at birth and non-verbal intelligence at age 9 years in preterm infants. Dev. Med. Child. Neurol. 45, 148–151.PubMedGoogle Scholar
  24. Dawson V. L. and Dawson T. M. (2004) Deadly conversations: nuclear-mitochondrial cross-talk. J. Bioenerg. Biomembr. 36, 287–294.PubMedGoogle Scholar
  25. De Vries L. S., VnHaastert I. L., Rademaker K. J., Koopman C., and Groenedaal F. (2004) Ultrasound abnormalities preceding cerebral palsy in highrisk preterm infants. J. Pediatr. 144, 815–820.PubMedGoogle Scholar
  26. Derugin N., Wendland M., Muramatsu K., et al. (2000) Evolution of brain injury after transient middle cerebral artery occlusion in neonatal rats. Stroke 31, 1752–1761.PubMedGoogle Scholar
  27. Du L., Zhang X., Han Y. Y., et al. (2003) Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+depletion and cell death induced by oxidative stress. J. Biol. Chem. 278, 18,426–18,433.Google Scholar
  28. Elimian A., Figueroa R., Spitzer A. R., Ogburn P. L., Wiencek V., and Quirk J. G. (2003) Antenatal corticosteroids: are incomplete courses beneficial? Obstet. Gynecol. 102, 352–355.PubMedGoogle Scholar
  29. Ellis M., Manandhar D. S., Manandhar N., Wyatt J., Bolam A. J., and Costello A. M. (2000) Stillbirths and neonatal encephalopathy in Kathmandu, Nepal: an estimate of the contribution of birth asphyxia to perinatal mortality in a low-income urban population. Paediatr. Perinat. Epidemiol. 14, 39–52.PubMedGoogle Scholar
  30. Folkerth R. D. (2005) Neuropathologic substrate of cerebral palsy. J. Child. Neurol. 20, 940–949.PubMedGoogle Scholar
  31. Folkerth R. D., Keefe R. J., Haynes R. L., Trachtenberg F. L., Volpe J. J., and Kinney H. C. (2004a) Interferon-gamma expression in periventricular leukomalacia in the human brain. Brain Pathol. 14, 265–274.PubMedCrossRefGoogle Scholar
  32. Folkerth R. D., Haynes R. L., Borenstein N. S., et al. (2004b) Developmental lag in superoxide dismutases relative to other antioxidant enzymes in premyelinated human telencephalic white matter. J. Neuropathol. Exp. Neurol. 63, 990–999.PubMedGoogle Scholar
  33. Follett P. L., Rosenberg P. A., Volpe J. J., and Jensen F. E. (2000) NBQX attenuates excitotoxic injury in developing white matter. J. Neurosci. 20, 9235–9241.PubMedGoogle Scholar
  34. Follett P. L., Deng W., Dai W., et al. (2004) Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate. J. Neurosci. 24, 4412–4420.PubMedGoogle Scholar
  35. Gilland E., Puka-Sundvall M., Hillered L., and Hagberg H. (1998) Mitochondrial function and energy metabolism after hypoxia-ischemia in the immature rat brain: involvement of NMDA-receptors. J. Cereb. Blood Flow Metab. 18, 297–304.PubMedGoogle Scholar
  36. Gluckman P. D., Wyatt J. S., Azzopardi D., et al. (2005) Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 365, 663–670.PubMedGoogle Scholar
  37. Golomb M. R. (2003) The contribution of prothrombotic disorders to peri- and neonatal ischemic stroke. Semin. Thromb. Hemost. 29, 415–424.PubMedGoogle Scholar
  38. Golomb M. R., Dick P. T., MacGregor D. L., Curtis R., Sofronas M., and deVeber G. A. (2004) Neonatal arterial ischemic stroke and cerebral sinovenous thrombosis are more commonly diagnosed in boys. J. Child. Neurol. 19, 493–497.PubMedGoogle Scholar
  39. Guan J., Bennet T. L., George S., et al. (2000) Selective neuroprotective effects with insulin-like growth factor-1 in phenotypic striatal neurons following ischemic brain injury in fetal sheep. Neuroscience 95, 831–839.PubMedGoogle Scholar
  40. Hagberg H. (2004) Mitochondrial impairment in the developing brain after hypoxia-ischemia. J. Bioenerg. Biomembr. 36, 369–373.PubMedGoogle Scholar
  41. Hagberg H., Peebles D. and Mallard C. (2002) Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults. Ment. Retard. Dev. Disabil. Res. Rev. 8, 30–38.PubMedGoogle Scholar
  42. Hagberg H., Lehmann A., Sandberg M., Nystrom B., Jacobson I., and Hamberger A. (1985) Ischemia-induced shift of inhibitory and excitatory amino acids from intra- to extracellular compartments. J. Cereb. Blood Flow Metab. 5, 413–419.PubMedGoogle Scholar
  43. Hagberg H., Thornberg E., Blennow M., et al. (1993) Excitatory amino acids in the cerebrospinal fluid of asphyxiated infants: relationship to hypoxic-ischemic encephalopathy. Acta Paediatr. 82, 925–929.PubMedGoogle Scholar
  44. Hagberg H., Wilson M. A., Matsushita H., et al. (2004) PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury. J. Neurochem. 90, 1068–1075.PubMedGoogle Scholar
  45. Hamrick S. E., Miller S. P., Leonard C., et al. (2002) Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants: the role of cystic periventricular leukomalacia. J. Pediatr. 145, 593–599.Google Scholar
  46. Han B. H. and Holtzman D. M. (2000) BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J. Neurosci. 20, 5775–5781.PubMedGoogle Scholar
  47. Han B. H., D'Costa A., Back S. A., et al. (2000) BDNF blocks caspase-3 activation in neonatal hypoxia-ischemia. Neurobiol. Dis. 7, 38–53.PubMedGoogle Scholar
  48. Hansen H. H., Briem T., Dzietko M., et al. (2004) Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain. Neurobiol. Dis. 16, 440–453.PubMedGoogle Scholar
  49. Harum K. H., Hoon A. H. Jr., Kato G. J., Casella J. F., Breiter S. N., and Johnston M. V. (1999) Homozygous factor-V mutation as a genetic cause of perinatal thrombosis and cerebral palsy. Dev. Med. Child. Neurol. 41, 777–780.PubMedGoogle Scholar
  50. Haynes R. L., Baud O., Li J., Kinney H. C., Volpe J. J., and Folkerth D. R. (2005) Oxidative and nitrative injury in periventricular leukomalacia: a review. Brain Pathol. 15, 225–233.PubMedCrossRefGoogle Scholar
  51. Haynes R. L., Folkerth R. D., Keefe R. J., et al. (2003) Nitrosative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia. J. Neuropathol. Exp. Neurol. 62, 441–450.PubMedGoogle Scholar
  52. Hoon A. H. Jr. (1995) Neuroimaging in the high-risk infant: relationship to outcome. J. Perinatol. 15, 389–394.PubMedGoogle Scholar
  53. Hoon A. H. Jr. (2005) Neuroimaging in cerebral palsy: patterns of brain dysgenesis and injury. J. Child. Neurol. 20, 936–939.PubMedGoogle Scholar
  54. Hoon A. H. Jr., Belsito K. M., and Nagae-Poetscher L. M. (2003) Neuroimaging in spasticity and movement disorders. J. Child. Neurol. 18(Suppl.), S25-S39.PubMedGoogle Scholar
  55. Hoon A. H. Jr., Lawrie W. T. Jr., Melhem E. R., et al. (2002) Diffusion tensor imaging of periventricular leukomalacia shows affected sensory cortex white matter pathways. Neurology 59, 752–756.PubMedGoogle Scholar
  56. Hoon A. H. Jr., Reinhardt E. M., Kelley R. I., et al. (1997) Brain magnetic resonance imaging in suspected extrapyramidal cerebral palsy: observations in distinguishing genetic-metabolic from acquired causes. J. Pediatr. 131, 240–245.PubMedGoogle Scholar
  57. Hu B. R., Liu C. L., Ouvang Y., Blomgren A. M., and Siesjo B. K. (2000) Involvement of caspase 3 in cell death after hypoxia-ischemia declines during brain maturation. J. Cereb. Blood Flow Metab. 20, 1294–1300.PubMedGoogle Scholar
  58. Husson I., Rangon C. M., Lelievre V., et al. (2005) BDNF-induced white matter neuroprotection and stage-dependent neuronal survival following a neonatal excitotoxic challenge. Cereb. Cortex 15, 250–261.PubMedGoogle Scholar
  59. Inder T. E., Anderson N. J., Spencer C., Wells S., and Volpe J. J. (2003) White matter injury in the premature infant: comparison between serial cranial ultrasonographic and MR findings at term. Am. J. Neuroradiol. 24, 805–809.PubMedGoogle Scholar
  60. Inder T. E., Warfield S. K., Wang H., Huppi P. S., and Volpe J. J. (2005) Abnormal cerebral structure is present at term in premature infants. Pediatrics, 115, 286–294.PubMedGoogle Scholar
  61. Ishida A., Trescher W. H., Lange M. S., and Johnston M. V. (2001a) Prolonged suppression of brain nitric oxide synthase activity by 7-nitroindazole protects against cerebral hypoxic-ischemic injury in neonatal rat. Brain Dev. 23, 349–354.PubMedGoogle Scholar
  62. Ishida A., Ishiwa S., Trescher W. H., et al. (2001b) Delayed increase in neuronal nitric oxide synthase immunoreactivity in thalamus and other brain regions after hypoxic-ischemic injury in neonatal rats. Exp. Neurol. 168, 323–333.PubMedGoogle Scholar
  63. Jarvis S., Glinianaia S. V., Arnaud C., et al. (2005) Case gender and severity in cerebral palsy varies with intrauterine growth. Arch. Dis. Child. 90, 474–479.PubMedGoogle Scholar
  64. Jensen F. E. (2002) The role of glutamate receptor maturation in perinatal seizures and brain injury. Int. J. Dev. Neurosci. 20, 339–347.PubMedGoogle Scholar
  65. Jensen F. E. (2005) Role of glutamate receptors in periventricular leukomalacia. J. Child. Neurol. 20, 950–959.PubMedGoogle Scholar
  66. Johnston B. M., Mallard E. C., Williams C. E., and Gluckman P. D. (1996) Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxicischemic injury in fetal lambs. J. Clin. Invest. 97, 300–308.PubMedCrossRefGoogle Scholar
  67. Johnston M. V. (2005) Excitotoxicity in perinatal brain injury. Brain Pathol. 15, 234–240.PubMedCrossRefGoogle Scholar
  68. Johnston M. V. and Hoon A. H. Jr. (2000) Possible mechanisms in infants for selective basal ganglia damage from asphyxia kernicterus, or mitochondrial encephalopathies. J. Child. Neurol. 15, 588–591.PubMedGoogle Scholar
  69. Johnston M. V., Nakajima W., and Hagberg H. (2002) Mechanisms of hypoxic neurodegeneration in the developing brain. Neuroscientist. 8, 212–220.PubMedGoogle Scholar
  70. Johnston M. V., Ferriero D. M., Vannucci S. J., and Hagberg H. (2005) Models of cerebral palsy: which ones are best? J. Child. Neurol. 20, 984–987.PubMedGoogle Scholar
  71. Johnston M. V., Trescher W. H., Ishida A., and Nakajima W. (2000) Novel treatments after experimental brain injury. Semin. Neonatol. 5 75–86.PubMedGoogle Scholar
  72. Johnston M. V., Trescher W. H., Ishida A., and Nakajima W. (2001) Neurobiology of hypoxic-ischemic injury in the developing brain. Pediatr. Res. 49, 735–741.PubMedGoogle Scholar
  73. Karadottir R., Cavelier P., Bergersen L. H., and Attwell D. (2005) NMDA receptors are expressed in oligo-dendrocytes and activated in ischaemia. Nature 438, 1162–1166.PubMedGoogle Scholar
  74. Kent A., Lomas F., Hurrion E., and Dahlstrom J. E. (2005) Antenatal steroids may reduce adverse neurological outcome following chorioamnionitis: neurodevelopmental outcome and chorioamnionitis in premature infants. J. Paediatr. Child. Health 41, 186–190.PubMedGoogle Scholar
  75. Kuban K. C. K. and Leviton A. (1996) Cerebral palsy. N. Engl. J. Med. 330, 188–195.Google Scholar
  76. LaFranchi S. H., Haddow J. E., and Hollowell J. G. (2005) Is thyroid inadequacy during gestation a risk factor for adverse pregnancy and developmental outcomes? Thyroid. 15, 60–71.PubMedGoogle Scholar
  77. Lee H. T., Chang Y. C., Wang L. Y., Wang S. T., Huang C. C., and Ho C. J. (2004) cAMP response element-binding protein activation in ligation preconditioning in neonatal brain. Ann. Neurol. 56, 611–623.PubMedGoogle Scholar
  78. Li H., Pin S., Zeng Z., Wang M. M., Andreasson K. A., and McCullough L. D. (2005) Sex differences in cell death. Ann. Neurol. 58, 317–321.PubMedGoogle Scholar
  79. Li J. H. and Zhang J. (2001) PARP inhibitors. I Drugs 4, 804–812.PubMedGoogle Scholar
  80. Liu Y., Barks J. D., Xu G., and Silverstein F. S. (2004) Topiramate extends the therapeutic window for hypothermia-mediated neuroprotection after stroke in neonatal rats. Stroke 35, 1460–1465.PubMedGoogle Scholar
  81. Ma D., Hossain M., Chow A., et al. (2005) Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann. Neurol. 58, 182–193.PubMedGoogle Scholar
  82. Magistretti P. J., Pellerin L., Rothman D. L., and Shulman R. G. (1999) Energy on demand. Science 283, 496–497.PubMedGoogle Scholar
  83. Mallard C., Welin A. K., Peebles D., Hagberg H., and Kjellmer I. (2003) White matter injury following systemic endotoxemia or asphyxia in the fetal sheep. Neurochem. Res. 28, 215–223.PubMedGoogle Scholar
  84. Marlow N. (2004) Neurocognitive outcome after very preterm birth. Arch. Dis. Child. Fetal Neonatal Ed. 89, F224-F228.PubMedGoogle Scholar
  85. Martin L. J., Al-Abdulla N. A., Brambrink A. M., et al. (1998) Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: a perspective on the contributions of a poptosis and necrosis. Brain Res. Bull. 46, 281–309.PubMedGoogle Scholar
  86. Matsushita H., Johnston M. V., Lange M. S. and Wilson M. A. (2003) Protective effect of erythropoietin in neonatal hypoxic ischemia in mice. Neuroreport. 14, 1757–1761.PubMedGoogle Scholar
  87. McCullough L. D., Zeng Z., Blizzard K. K., Debchoudhury I., and Hurn P. D. (2005) Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J. Cereb. Blood Flow Metab. 25, 502–512.PubMedGoogle Scholar
  88. McDonald J. W. and Johnston M. V. (1990) Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res. Brain Res. Rev. 15, 41–70.PubMedGoogle Scholar
  89. McDonald J. W., Silverstein F. S., and Johnston M. V. (1987) MK-801 protects the neonatal brain from hypoxic-ischemic damage. Eur. J. Pharmacol. 140, 359–361.PubMedGoogle Scholar
  90. McDonald J. W., Silverstein F. S., and Johnston, M. V. (1988) Neurotoxicity of N-methyl-d-aspartate is markedly enhanced in developing rat central nervous system. Brain Res. 459, 200–203.PubMedGoogle Scholar
  91. McQuillen P. S., Sheldon R. A., Shatz C. J., and Ferriero D. M. (2003) Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia. J. Neurosci. 23, 3308–3315.PubMedGoogle Scholar
  92. Melhem E. R., Hoon A. H. Jr., Ferrucci J. T. Jr., et al. (2000) Periventricular leukomalacia: relationship between lateral ventricular volume on brain MR images and severity of cognitive and motor impairment. Radiology 214 199–204.PubMedGoogle Scholar
  93. Ment L. R., Oh W., Ehrenkranz R. A., Philip A. G., Duncan C. C., and Makuch R. W. (1995) Antenatal steroids, delivery mode, and intraventricular hemorrhage in preterm infants. Am. J. Obstet. Gynecol. 172, 795–800.PubMedGoogle Scholar
  94. Ment L. R., Vohr B. R., Makuch R. W., et al. (2004) Prevention of intraventricular hemorrhage by indomethacin in male preterm infants. J. Pediatr. 145, 832–834.PubMedGoogle Scholar
  95. Micu I., Jiang Q., Coderre E., et al. (2006) NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439, 988–992.PubMedGoogle Scholar
  96. Mikkola K., Ritari N., Tommiska V., et al. (2006) Neuro-developmental outcome at 5 years of age of a national cohort of extremely low birth weight infants who were born in 1996–1997. Pediatrics. 116, 1391–1400.Google Scholar
  97. Mishra O. P. and Delivoria-Papadopoulos M. (2002) Nitric oxide-mediated Ca2+-influx in neuronal nuclei and cortical synaptosomes of normoxic and hypoxic newborn piglets. Neurosci. Lett. 318, 93–97.PubMedGoogle Scholar
  98. Monyer H., Brunashev N., and Laurie D. J. (1993) Development and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron. 12, 529–540.Google Scholar
  99. Nakajima W., Ishida A., Lange M.S., et al. (2000) A poptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat. J. Neurosci. 20, 7994–8004.PubMedGoogle Scholar
  100. Nelson K. B. and Ellenberg J. H. (1986) Antecedents of cerebral palsy. Multivariate analysis of risk. N. Engl. J. Med. 315, 81–86.PubMedCrossRefGoogle Scholar
  101. Nelson K. B. and Lynch J. K. (2006) Stroke in newborn infants. Lancet Neurol. 3, 150–158.Google Scholar
  102. Nelson K. B., Grether J. K., Dambrosia J. M., et al. (2003) Neontal cytokines and cerebral palsy in very preterm infants. Pediatr. Res. 53, 600–607.PubMedGoogle Scholar
  103. Northington F. J., Ferriero D. M., Flock D. L., and Martin L. J. (2001) Delayed neurodegeneration in neonatal rat thalamus after hypoxia-ischemia is a poptosis. J. Neurosci. 21, 1931–1938.PubMedGoogle Scholar
  104. Oka A., Belliveau M. J., Rosenberg P. A., and Volpe J. J. (1993) Vulnerability of oligodendroglial to glutamate: pharmacology, mechanisms, and prevention. J. Neurosci. 13, 1441–1453.PubMedGoogle Scholar
  105. Osler W. (1987) The cerebral palsies of children. Mac Keith Press. London.Google Scholar
  106. Papile L. A., Munsick-Bruno G., and Schaefer A. (1983) Relationship of cerebral intraventricular hemorrhage and early childhood neurologic handicaps. J. Pediatr. 103, 273–277.PubMedGoogle Scholar
  107. Pasternak J. F. and Gorey M. T. (1998) The syndrome of acute near-total intrauterine asphyxia in the term infant. Pediatr. Neurol. 18, 391–398.PubMedGoogle Scholar
  108. Perlman J. M. (1998) White matter injury in the preterm infant: an important determination of abnormal neurodevelopment outcome. Early Hum. Dev. 53, 99–120.PubMedGoogle Scholar
  109. Plesnila N. (2004) Role of mitochondrial proteins for neuronal cell death after focal cerebral ischemia. Acta Neurochir. (Suppl. 89), 15–19.Google Scholar
  110. Plesnila N., Zhu C., Culmsee C., Groger M., Moskowitz M. A., and Blomgren K. (2004) Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J. Cereb. Blood Flow Metab. 24, 458–466.PubMedGoogle Scholar
  111. Pu Y., Li Q. F., Zeng C. M., et al. (2000) Increased detectability of alpha brain glutamate/glutamine in neonatal hypoxic-ischemic encephalopathy. AJNR Am. J. Neuroradiol. 21, 203–212.PubMedGoogle Scholar
  112. Puka-Sundvall M., Gajkowska B., Cholewinski M., Blomgren K., Lazarewicz J. W., and Hagberg H. (2000) Subcellular distribution of calcium and ultrastructural changes after cerebral hypoxia-ischemia in immature rats. Brain Res. Dev. Brain Res. 125, 31–41.PubMedGoogle Scholar
  113. Reiss A. L., Kesler S. R., Vohr B., et al. (2004) Sex differences in cerebral volumes of 8-year-olds born preterm. J. Pediatr. 145, 242–249.PubMedGoogle Scholar
  114. Riikonen R. S., Kero P. O., and Simell O. G. (1992) Excitatory amino acids in cerebrospinal fluid in neonatal asphyxia. Pediatr. Neurol. 8, 37–40.PubMedGoogle Scholar
  115. Roland E. H. and Hill A. (2003) Germinal matrix-intraventricular hemorrhage in the premature newborn: management and outcome. Neurol. Clin. 21, 833–851.PubMedGoogle Scholar
  116. Rosenberg P. A., Dai W., Gan X. D. et al. (2003) Mature myelin basic protein-expressing oligodendrocytes are insensitive to kainate toxicity. J. Neurosci. Res. 71, 237–245.PubMedGoogle Scholar
  117. Salter M. G. and Fern R. (2005) NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 438, 1167–1171.PubMedGoogle Scholar
  118. Shankaran S., Laptook A. R., Ehrenkranz R. A., et al. (2005) Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N. Engl. J. Med. 353, 1574–1584.PubMedGoogle Scholar
  119. Silverstein F. S., Buchanan K., and Johnston M. V. (1986) Perinatal hypoxia-ischemia disrupts striatal high-affinity [3H]glutamate uptake into synaptosomes. J. Neurochem. 47, 1614–1619.PubMedGoogle Scholar
  120. Tahraoui S. L., Marret S., Bodenant C., et al. (2001) Central role of microglia in neonatal excitotoxic lesions of the murine periventricular white matter. Brain Pathol. 11, 56–71.PubMedCrossRefGoogle Scholar
  121. Tanaka S., Takehashi M., Iida S., et al. (2005) Mitochondrial impairment induced by poly (ADP-ribose) polymerase-1 activation in cortical neurons after oxygen and glucose deprivation. J. Neurochem. 95, 179–190.PubMedGoogle Scholar
  122. Thomas B., Eyssen M., Peeters R., et al. (2005) Quantitative diffusion tensor imaging in cerebral palsy due to periventricular white matter injury. Brain 128, 2562–2577.PubMedGoogle Scholar
  123. Thoresen M., Satas S., Puka-Sundvall M., et al. (1997) Post-hypoxic hypothermia reduces cerebrocortical release of NO and excitotoxins. Neuroreport 8, 3359–3362.PubMedGoogle Scholar
  124. Utiger R. D. (1999) Maternal hypothyroidism and fetal development (Editorial). N. Engl. J. Med. 341, 601–602.PubMedGoogle Scholar
  125. Volpe J. (2003) Cerebral white matter injury of the premature infant—more common than you think. Pediatrics 112, 176–180.PubMedGoogle Scholar
  126. Volpe J. J. (2001) Neurobiology of periventricular leukomalacia in the premature infant. Pediatr. Res. 50, 553–562.PubMedGoogle Scholar
  127. Willoughby R. E. and Nelson K. B. (2002) Chorioamnionitis and brain injury. Clin. Perinatol. 29, 603–621.PubMedGoogle Scholar
  128. Woodward L. J., Edgin J. O., Thompson D., and Inder T. E. (2005) Object working memory deficits predicted by early brain injury and development of the preterm infant. Brain. 128, 2578–2587.PubMedGoogle Scholar
  129. Xu Y., Huang S., Liu Z. G., and Han J. (2006) Poly (ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. J. Biol. Chem. 281, 8788–8795.PubMedGoogle Scholar
  130. Yamaguchi S., Endo K., Kitajima T., Ogata H., and Hori Y. (1998) Involvement of the glutamate transporter and the sodium-calcium exchanger in the hypoxia-induced increase in intracellular Ca2+ in rat hippocampal slices. Brain Res. 813, 351–358.PubMedGoogle Scholar
  131. Zhu C., Qiu L., Wang X., et al. (2003) Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain. J. Neurochem. 86, 306–317.PubMedGoogle Scholar
  132. Zhu C., Xu F., Wang X., et al. (2006) Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia-ischaemia. J. Neurochem. 96, 1016–1027.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2006

Authors and Affiliations

  1. 1.Kennedy Krieger Institute and Departments of Neurology and PediatricsJohns Hopkins University School of MedicineBaltimore

Personalised recommendations