Neuroprotective Strategies for Newborns

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Abstract

Perinatal brain injury is the leading cause of death and disability in children. Such damage can be induced by multiple factors, varies in severity between individuals, affects infants of different genetic backgrounds, and occurs at various stages of the physiological developmental program. This complexity creates innumerable difficulties in creating therapeutic agents. A wealth of experimental studies has engaged in the understanding of brain injury pathophysiology and in the development of strategies that may be beneficial for the neurological outcome of infants. Clinical trials have demonstrated the partial neuroprotective effects of hypothermia and magnesium sulfate in human neonates. Trials for the neuroprotective effects of the pluripotent hormone melatonin are ongoing. In the following chapter we review the experimental and clinical data on neuroprotective strategies.

Keywords

Traumatic Brain Injury Term Infant Mitochondrial Permeability Transition Pore Mitochondrial Permeability Transition Pore Placental Abruption 
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.

Abbreviations

AMPA

Alpha-3-amino-hydroxy-5-methyl-4-isoxazole propionic acid

ATP

Adenosine triphosphate

BBB

Blood brain barrier

CNS

Central nervous system

COX

Cyclooxygenase

EPO

Erythropoietin

iNOS

Inducible form of nitric oxide synthase

KA

Kainate

MMPs

Matrix metalloproteases

NAC

N-Acetylcysteine

NMDA

N-Methyl-d-aspartate

NO

Nitric oxide

NSAIDS

Nonsteroidal anti-inflammatory drugs

rEPO

Recombinant form of erythropoietin

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

TBI

Traumatic brain injury

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References

  1. Abraini J et al (2003) Gamma-aminobutyric acid neuropharmacological investigations on narcosis produced by nitrogen, argon, or nitrous oxide. Anesth Analg 96(3):746–749PubMedCrossRefGoogle Scholar
  2. Baburamani AA et al (2015) Mitochondrial Optic Atrophy (OPA) 1 processing is altered in response to neonatal hypoxic-ischemic brain injury. Int J Mol Sci 16(9):22509–22526PubMedPubMedCentralCrossRefGoogle Scholar
  3. Barrere-Lemaire S, Nargeot J, Piot C (2012) Delayed postconditioning: not too late? Trends Cardiovasc Med 22(7):173–179PubMedCrossRefGoogle Scholar
  4. Boardman JP et al (2006) Abnormal deep grey matter development following preterm birth detected using deformation-based morphometry. Neuroimage 32(1):70–78PubMedCrossRefGoogle Scholar
  5. Bouslama M et al (2007) Melatonin prevents learning disorders in brain-lesioned newborn mice. Neuroscience 150(3):712–719PubMedCrossRefGoogle Scholar
  6. Candelario-Jalil E (2008) Nimesulide as a promising neuroprotectant in brain ischemia: new experimental evidences. Pharmacol Res 57(4):266–273PubMedCrossRefGoogle Scholar
  7. Candelario-Jalil E et al (2007) Cyclooxygenase inhibition limits blood–brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. J Pharmacol Exp Ther 323(2):488–498PubMedCrossRefGoogle Scholar
  8. Carlsson Y et al (2011) Genetic inhibition of caspase-2 reduces hypoxic-ischemic and excitotoxic neonatal brain injury. Ann Neurol 70(5):781–789PubMedCrossRefGoogle Scholar
  9. Carlsson Y et al (2012) Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic-ischemic brain injury. Pediatr Res 71(5):566–572PubMedCrossRefGoogle Scholar
  10. Chaudhari T, McGuire W (2012) Allopurinol for preventing mortality and morbidity in newborn infants with hypoxic-ischaemic encephalopathy. Cochrane Database Syst Rev 7:CD006817PubMedGoogle Scholar
  11. Chauvier D et al (2011) Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor. Cell Death Dis 2:e203PubMedPubMedCentralCrossRefGoogle Scholar
  12. Coburn M et al (2005) Randomized controlled trial of the haemodynamic and recovery effects of xenon or propofol anaesthesia. Br J Anaesth 94(2):198–202PubMedCrossRefGoogle Scholar
  13. Dingley J et al (2006) Xenon provides short-term neuroprotection in neonatal rats when administered after hypoxia-ischemia. Stroke 37(2):501–506PubMedCrossRefGoogle Scholar
  14. Doyle LW et al (2009) Antenatal magnesium sulfate and neurologic outcome in preterm infants: a systematic review. Obstet Gynecol 113(6):1327–1333PubMedCrossRefGoogle Scholar
  15. Edwards AD et al (2010) Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 340:c363PubMedPubMedCentralCrossRefGoogle Scholar
  16. Ezzati M et al (2016) Immediate remote ischemic postconditioning after hypoxia ischemia in piglets protects cerebral white matter but not grey matter. J Cereb Blood Flow Metab 36(8):1396–1411Google Scholar
  17. Fahlenkamp A et al (2012) The noble gas argon modifies extracellular signal-regulated kinase 1/2 signaling in neurons and glial cells. Eur J Pharmacol 674(2–3):104–111PubMedCrossRefGoogle Scholar
  18. Faulkner S et al (2011) Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia. Ann Neurol 70(1):133–150PubMedCrossRefGoogle Scholar
  19. Favrais G et al (2007) Cyclooxygenase-2 mediates the sensitizing effects of systemic IL-1-beta on excitotoxic brain lesions in newborn mice. Neurobiol Dis 25(3):496–505PubMedCrossRefGoogle Scholar
  20. Fernandez-Gomez FJ et al (2005) Minocycline fails to protect cerebellar granular cell cultures against malonate-induced cell death. Neurobiol Dis 20(2):384–391PubMedCrossRefGoogle Scholar
  21. Fleiss B, Gressens P (2012) Tertiary mechanisms of brain damage: a new hope for treatment of cerebral palsy? Lancet Neurol 11(6):556–566PubMedCrossRefGoogle Scholar
  22. Fleiss B et al (2014) Stem cell therapy for neonatal brain injury. Clin Perinatol 41:133–148PubMedCrossRefGoogle Scholar
  23. Fleiss B et al (2015) Inflammation-induced sensitization of the brain in term infants. Dev Med Child Neurol 57(Suppl 3):17–28PubMedCrossRefGoogle Scholar
  24. Fox C et al (2005) Minocycline confers early but transient protection in the immature brain following focal cerebral ischemia-reperfusion. J Cereb Blood Flow Metab 25(9):1138–1149PubMedPubMedCentralCrossRefGoogle Scholar
  25. Franks NP et al (1998) How does xenon produce anaesthesia? Nature 396(6709):324PubMedCrossRefGoogle Scholar
  26. Garrido-Mesa N, Zarzuelo A, Galvez J (2013) Minocycline: far beyond an antibiotic. Br J Pharmacol 169(2):337–352PubMedPubMedCentralCrossRefGoogle Scholar
  27. Gonzalez JC et al (2007) Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca(2+) signalling in hippocampal neurons. Eur J Neurosci 26(9):2481–2495PubMedCrossRefGoogle Scholar
  28. Gonzalez-Burgos I et al (2007) Long-term study of dendritic spines from hippocampal CA1 pyramidal cells, after neuroprotective melatonin treatment following global cerebral ischemia in rats. Neurosci Lett 423(2):162–166PubMedCrossRefGoogle Scholar
  29. Goto T et al (1997) Xenon provides faster emergence from anesthesia than does nitrous oxide-sevoflurane or nitrous oxide-isoflurane. Anesthesiology 86(6):1273–1278PubMedCrossRefGoogle Scholar
  30. Gunes T et al (2007) Effect of allopurinol supplementation on nitric oxide levels in asphyxiated newborns. Pediatr Neurol 36(1):17–24PubMedCrossRefGoogle Scholar
  31. Hagberg H et al (2014) Mitochondria: hub of injury responses in the developing brain. Lancet Neurol 13(2):217–232PubMedCrossRefGoogle Scholar
  32. Hassell JK et al (2014) Argon augments hypothermic neuroprotection in a piglet model of perinatal asphyxia. In: Pediatric academic society meeting. Vancouver, CanadaGoogle Scholar
  33. Hobbs C et al (2008) Xenon and hypothermia combine additively, offering long-term functional and histopathologic neuroprotection after neonatal hypoxia/ischemia. Stroke 39(4):1307–1313PubMedCrossRefGoogle Scholar
  34. Homsi S et al (2010) Blockade of acute microglial activation by minocycline promotes neuroprotection and reduces locomotor hyperactivity after closed head injury in mice: a twelve-week follow-up study. J Neurotrauma 27(5):911–921PubMedCrossRefGoogle Scholar
  35. Husson I et al (2002) Melatoninergic neuroprotection of the murine periventricular white matter against neonatal excitotoxic challenge. Ann Neurol 51(1):82–92PubMedCrossRefGoogle Scholar
  36. Jacobs S et al (2007) Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 4:CD003311PubMedGoogle Scholar
  37. Kaandorp JJ et al (2015) Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed 100(3):F216–F223PubMedCrossRefGoogle Scholar
  38. Kaindl AM et al (2008) Erythropoietin protects the developing brain from hyperoxia-induced cell death and proteome changes. Ann Neurol 64(5):523–534PubMedCrossRefGoogle Scholar
  39. Kannan S et al (2012) Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model. Sci Transl Med 4(130):130ra46PubMedPubMedCentralCrossRefGoogle Scholar
  40. Kobayashi K et al (2013) Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis 4:e525PubMedPubMedCentralCrossRefGoogle Scholar
  41. Koistinaho M et al (2005) Minocycline protects against permanent cerebral ischemia in wild type but not in matrix metalloprotease-9-deficient mice. J Cereb Blood Flow Metab 25(4):460–467PubMedCrossRefGoogle Scholar
  42. Kumral A et al (2004) Selective inhibition of nitric oxide in hypoxic-ischemic brain model in newborn rats: is it an explanation for the protective role of erythropoietin? Biol Neonate 85(1):51–54PubMedCrossRefGoogle Scholar
  43. Kumral A et al (2007) Erythropoietin attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain. Neonatology 92(4):269–278PubMedCrossRefGoogle Scholar
  44. Lazarini F et al (2012) Early activation of microglia triggers long-lasting impairment of adult neurogenesis in the olfactory bulb. J Neurosci 32(11):3652–3664PubMedCrossRefGoogle Scholar
  45. Loetscher P et al (2009) Argon: neuroprotection in in vitro models of cerebral ischemia and traumatic brain injury. Crit Care 13(6):R206PubMedPubMedCentralCrossRefGoogle Scholar
  46. Ma D et al (2005) Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann Neurol 58(2):182–193PubMedCrossRefGoogle Scholar
  47. Ma D et al (2006) Xenon preconditioning reduces brain damage from neonatal asphyxia in rats. J Cereb Blood Flow Metab 26(2):199–208PubMedCrossRefGoogle Scholar
  48. Ma D et al (2009) Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1alpha activation. J Am Soc Nephrol 20(4):713–720PubMedPubMedCentralCrossRefGoogle Scholar
  49. Marret S et al (2007) Magnesium sulphate given before very-preterm birth to protect infant brain: the randomised controlled PREMAG trial*. BJOG 114(3):310–318PubMedCrossRefGoogle Scholar
  50. Martin JL et al (2007) Asynchronous administration of xenon and hypothermia significantly reduces brain infarction in the neonatal rat. Br J Anaesth 98(2):236–240PubMedCrossRefGoogle Scholar
  51. McKee JA et al (2005) Analysis of the brain bioavailability of peripherally administered magnesium sulfate: a study in humans with acute brain injury undergoing prolonged induced hypermagnesemia. Crit Care Med 33(3):661–666PubMedCrossRefGoogle Scholar
  52. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74(5):1124–1136PubMedCrossRefGoogle Scholar
  53. Natalucci G, Latal B, Koller B, Rﺰegger C, Sick B, Held L, Bucher HU, Fauchère JC, Swiss EPO Neuroprotection Trial Group (2016) Effect of early prophylactic high-dose recombinant human erythropoietin in very preterm infants on neurodevelopmental outcome at 2 years: a randomized clinical trial. JAMA 315(19):2079–2085. doi: 10.1001/jama.2016.5504
  54. Ng SY et al (2012) Attenuation of microglial activation with minocycline is not associated with changes in neurogenesis after focal traumatic brain injury in adult mice. J Neurotrauma 29(7):1410–1425PubMedCrossRefGoogle Scholar
  55. Nijboer CH et al (2011) Targeting the p53 pathway to protect the neonatal ischemic brain. Ann Neurol 70(2):255–264PubMedCrossRefGoogle Scholar
  56. Nijboer CH et al (2013) Mitochondrial JNK phosphorylation as a novel therapeutic target to inhibit neuroinflammation and apoptosis after neonatal ischemic brain damage. Neurobiol Dis 54:432–444PubMedCrossRefGoogle Scholar
  57. Northington FJ et al (2007) Failure to complete apoptosis following neonatal hypoxia-ischemia manifests as :“continuum” phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain. Neuroscience 149(4):822–833PubMedPubMedCentralCrossRefGoogle Scholar
  58. O’Gorman RL et al (2015) Tract-based spatial statistics to assess the neuroprotective effect of early erythropoietin on white matter development in preterm infants. Brain 138(Pt 2):388–397CrossRefGoogle Scholar
  59. Ohls RK et al (2004) Neurodevelopmental outcome and growth at 18 to 22 months’ corrected age in extremely low birth weight infants treated with early erythropoietin and iron. Pediatrics 114(5):1287–1291PubMedCrossRefGoogle Scholar
  60. Osredkar D et al (2014) Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic-ischemic brain injury. Resuscitation 85(4):567–572PubMedCrossRefGoogle Scholar
  61. Osredkar D et al (2015) Hypothermia does not reverse cellular responses caused by lipopolysaccharide in neonatal hypoxic-ischaemic brain injury. Dev Neurosci 37(4–5):390–397PubMedCrossRefGoogle Scholar
  62. Paintlia MK et al (2004) N-acetylcysteine prevents endotoxin-induced degeneration of oligodendrocyte progenitors and hypomyelination in developing rat brain. J Neurosci Res 78(3):347–361PubMedCrossRefGoogle Scholar
  63. Perlman JM (2006) Intervention strategies for neonatal hypoxic-ischemic cerebral injury. Clin Ther 28(9):1353–1365PubMedCrossRefGoogle Scholar
  64. Pignataro G et al (2008) In vivo and in vitro characterization of a novel neuroprotective strategy for stroke: ischemic postconditioning. J Cereb Blood Flow Metab 28(2):232–241PubMedCrossRefGoogle Scholar
  65. Preckel B et al (2002) Xenon produces minimal haemodynamic effects in rabbits with chronically compromised left ventricular function. Br J Anaesth 88(2):264–269PubMedCrossRefGoogle Scholar
  66. Puka-Sundvall M et al (2000) Subcellular distribution of calcium and ultrastructural changes after cerebral hypoxia-ischemia in immature rats. Brain Res Dev Brain Res 125(1–2):31–41PubMedCrossRefGoogle Scholar
  67. Ren C et al (2009) Limb remote ischemic postconditioning protects against focal ischemia in rats. Brain Res 1288:88–94PubMedPubMedCentralCrossRefGoogle Scholar
  68. Robertson NJ et al (2013) Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain 136(Pt 1):90–105PubMedCrossRefGoogle Scholar
  69. Roumier A et al (2008) Prenatal activation of microglia induces delayed impairment of glutamatergic synaptic function. PLoS One 3(7):e2595PubMedPubMedCentralCrossRefGoogle Scholar
  70. Ryang Y et al (2011) Neuroprotective effects of argon in an in vivo model of transient middle cerebral artery occlusion in rats. Crit Care Med 39(6):1448–1453PubMedCrossRefGoogle Scholar
  71. Sanchez Mejia RO et al (2001) Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery 48(6):1393–1399; discussion 1399–1401PubMedGoogle Scholar
  72. Sanderson TH, Raghunayakula S, Kumar R (2015) Neuronal hypoxia disrupts mitochondrial fusion. Neuroscience 301:71–78PubMedPubMedCentralCrossRefGoogle Scholar
  73. Schang AL, Gressens P, Fleiss B (2014) Revisiting thyroid hormone treatment to prevent brain damage of prematurity. J Neurosci Res 92:1609–1610PubMedCrossRefGoogle Scholar
  74. Sfaello I et al (2005) Topiramate prevents excitotoxic damage in the newborn rodent brain. Neurobiol Dis 20(3):837–848PubMedCrossRefGoogle Scholar
  75. Sifringer M et al (2012) Prevention of neonatal oxygen-induced brain damage by reduction of intrinsic apoptosis. Cell Death Dis 3:e250PubMedPubMedCentralCrossRefGoogle Scholar
  76. Soghier LM, Brion LP (2006) Cysteine, cystine or N-acetylcysteine supplementation in parenterally fed neonates. Cochrane Database Syst Rev 4:CD004869PubMedGoogle Scholar
  77. Soldatov P et al (2008) Physiologically active argon-based gas mixtures as a means of creating fire-safe gaseous environments in pressurized modules of varying purpose. Aviakosm Ekolog Med 42(2):45–52PubMedGoogle Scholar
  78. Sriram K, Miller DB, O’Callaghan JP (2006) Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha. J Neurochem 96(3):706–718PubMedCrossRefGoogle Scholar
  79. Stippler M et al (2007) Serum and cerebrospinal fluid magnesium in severe traumatic brain injury outcome. J Neurotrauma 24(8):1347–1354PubMedCrossRefGoogle Scholar
  80. Sugimoto J et al (2012) Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism. J Immunol 188(12):6338–6346PubMedCrossRefGoogle Scholar
  81. Sun J et al (2012) Protective effect of delayed remote limb ischemic postconditioning: role of mitochondrial K(ATP) channels in a rat model of focal cerebral ischemic reperfusion injury. J Cereb Blood Flow Metab 32(5):851–859PubMedPubMedCentralCrossRefGoogle Scholar
  82. Temkin NR et al (2007) Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial. Lancet Neurol 6(1):29–38PubMedCrossRefGoogle Scholar
  83. Thoresen M (2000) Cooling the newborn after asphyxia – physiological and experimental background and its clinical use. Semin Neonatol 5(1):61–73PubMedCrossRefGoogle Scholar
  84. Thoresen M et al (2009) Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia. J Cereb Blood Flow Metab 29(4):707–714PubMedCrossRefGoogle Scholar
  85. Vawda R et al (2007) Stem cell therapies for perinatal brain injuries. Semin Fetal Neonatal Med 12(4):259–272PubMedCrossRefGoogle Scholar
  86. Vinten-Johansen J, Yellon DM, Opie LH (2005a) Postconditioning: a simple, clinically applicable procedure to improve revascularization in acute myocardial infarction. Circulation 112(14):2085–2088PubMedCrossRefGoogle Scholar
  87. Vinten-Johansen J et al (2005b) Postconditioning – a new link in nature’s armor against myocardial ischemia-reperfusion injury. Basic Res Cardiol 100(4):295–310PubMedCrossRefGoogle Scholar
  88. Wang J et al (2004) Minocycline up-regulates Bcl-2 and protects against cell death in mitochondria. J Biol Chem 279(19):19948–19954PubMedCrossRefGoogle Scholar
  89. Wang X et al (2007) N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury. Ann Neurol 61(3):263–271PubMedCrossRefGoogle Scholar
  90. Wang X et al (2010) Neuroprotective effect of Bax-inhibiting peptide on neonatal brain injury. Stroke 41(9):2050–2055PubMedCrossRefGoogle Scholar
  91. Xiong Y, Chopp M, Lee CP (2009) Erythropoietin improves brain mitochondrial function in rats after traumatic brain injury. Neurol Res 31(5):496–502Google Scholar
  92. Zhao ZQ, Vinten-Johansen J (2006) Postconditioning: reduction of reperfusion-induced injury. Cardiovasc Res 70(2):200–211PubMedCrossRefGoogle Scholar
  93. Zhou Y et al (2011) Remote limb ischemic postconditioning protects against neonatal hypoxic-ischemic brain injury in rat pups by the opioid receptor/Akt pathway. Stroke 42(2):439–444PubMedCrossRefGoogle Scholar
  94. Zhuang L et al (2012) The protective profile of argon, helium, and xenon in a model of neonatal asphyxia in rats. Crit Care Med 40(6):1724–1730PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Bobbi Fleiss
    • 1
    • 2
  • Claire Thornton
    • 2
  • Pierre Gressens
    • 1
    • 2
  1. 1.UMR1141Insem-Paris Diderot University, Hôpital Robert DebréParisFrance
  2. 2.Centre for the Developing Brain, Department of Perinatal Imaging and Health, Division of Imaging Sciences and Biomedical EngineeringKing’s College London, King’s Health Partners, St. Thomas’ HospitalLondonUK

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