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Chapter 41 - Endogenous and Exogenous Neuroprotective Mechanisms after Hypoxic-Ischemic Injury

from Section 4 - Specific Conditions Associated with Fetal and Neonatal Brain Injury

Published online by Cambridge University Press:  13 December 2017

David K. Stevenson
Affiliation:
Stanford University, California
William E. Benitz
Affiliation:
Stanford University, California
Philip Sunshine
Affiliation:
Stanford University, California
Susan R. Hintz
Affiliation:
Stanford University, California
Maurice L. Druzin
Affiliation:
Stanford University, California
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Print publication year: 2017

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References

Low, JA, Lindsay, BG, Derrick, EJ. Threshold of metabolic acidosis associated with newborn complications. Am J Obstet Gynecol 1997; 177: 1391–4.Google Scholar
Gunn, AJ, Parer, JT, Mallard, EC, et al. Cerebral histologic and electrocorticographic changes after asphyxia in fetal sheep. Pediatr Res 1992; 31: 486–91.Google Scholar
George, S, Gunn, AJ, Westgate, JA, et al. Fetal heart rate variability and brainstem injury after asphyxia in preterm fetal sheep. Am J Physiol Regul Integr Comp Physiol 2004; 287: R925–33.Google Scholar
Gunn, AJ, Gunn, TR, de Haan, HH, et al. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997; 99: 248–56.CrossRefGoogle ScholarPubMed
Tan, WK, Williams, CE, During, MJ, et al. Accumulation of cytotoxins during the development of seizures and edema after hypoxic-ischemic injury in late gestation fetal sheep. Pediatr Res 1996; 39: 791–7.Google Scholar
Azzopardi, D, Wyatt, JS, Cady, EB, et al. Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res 1989; 25: 445–51.Google Scholar
Roth, SC, Baudin, J, Cady, E, et al. Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years. Dev Med Child Neurol 1997; 39: 718–25.Google Scholar
Lorek, A, Takei, Y, Cady, EB, et al. Delayed (“secondary”) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res 1994; 36: 699706.CrossRefGoogle ScholarPubMed
Blumberg, RM, Cady, EB, Wigglesworth, JS, et al. Relation between delayed impairment of cerebral energy metabolism and infarction following transient focal hypoxia-ischaemia in the developing brain. Exp Brain Res 1997; 113: 130–7.CrossRefGoogle ScholarPubMed
Bennet, L, Roelfsema, V, Pathipati, P, et al. Relationship between evolving epileptiform activity and delayed loss of mitochondrial activity after asphyxia measured by near-infrared spectroscopy in preterm fetal sheep. J Physiol 2006; 572: 141–54.Google Scholar
Vannucci, RC, Towfighi, J, Vannucci, SJ. Secondary energy failure after cerebral hypoxia-ischemia in the immature rat. J Cereb Blood Flow Metab 2004; 24: 1090–7.CrossRefGoogle ScholarPubMed
Tsuji, M, Naruse, H, Volpe, J, Holtzman, D. Reduction of cytochrome aa3 measured by near-infrared spectroscopy predicts cerebral energy loss in hypoxic piglets. Pediatr Res 1995; 37: 253–9.Google Scholar
Keogh, MJ, Drury, PP, Bennet, L, et al. Limited predictive value of early changes in EEG spectral power for neural injury after asphyxia in preterm fetal sheep. Pediatr Res 2012; 71: 345–53.CrossRefGoogle ScholarPubMed
Williams, CE, Gunn, A, Gluckman, PD. Time course of intracellular edema and epileptiform activity following prenatal cerebral ischemia in sheep. Stroke 1991; 22: 516–21.CrossRefGoogle ScholarPubMed
Gunn, AJ, Thoresen, M. Hypothermic neuroprotection. NeuroRx 2006; 3: 154–69.Google Scholar
Jacobs, SE, Berg, M, Hunt, R, et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; 1: CD003311.Google Scholar
Guillet, R, Edwards, AD, Thoresen, M, et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res 2012; 71: 205–9.Google Scholar
Azzopardi, D, Strohm, B, Marlow, N, et al. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med 2014; 371: 140–9.Google Scholar
Shankaran, S, Pappas, A, McDonald, SA, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012; 366: 2085–92.Google Scholar
Gunn, AJ, Gunn, TR, Gunning, MI, et al. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics 1998; 102: 1098–106.Google Scholar
Gunn, AJ, Bennet, L, Gunning, MI, et al. Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep. Pediatr Res 1999; 46: 274–80.Google Scholar
Sirimanne, ES, Blumberg, RM, Bossano, D, et al. The effect of prolonged modification of cerebral temperature on outcome after hypoxic-ischemic brain injury in the infant rat. Pediatr Res 1996; 39: 591–7.Google Scholar
Thoresen, M, Penrice, J, Lorek, A, et al. Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 1995; 37: 667–70.Google Scholar
Tooley, JR, Satas, S, Porter, H, et al. Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective. Ann Neurol 2003; 53: 6572.Google Scholar
Thoresen, M, Tooley, J, Liu, X, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology 2013; 104: 228–33.Google Scholar
Gluckman, PD, Wyatt, JS, Azzopardi, D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365: 663–70.Google Scholar
Westgate, JA, Gunn, AJ, Gunn, TR. Antecedents of neonatal encephalopathy with fetal acidaemia at term. Br J Obstet Gynaecol 1999; 106: 774–82.Google Scholar
Colbourne, F, Auer, RN, Sutherland, GR. Characterization of postischemic behavioral deficits in gerbils with and without hypothermic neuroprotection. Brain Res 1998; 803: 6978.CrossRefGoogle ScholarPubMed
Alonso-Alconada, D, Broad, KD, Bainbridge, A, et al. Brain cell death is reduced with cooling by 3.5°C to 5°C but increased with cooling by 8.5°C in a piglet asphyxia model. Stroke 2015; 46: 275–8.Google Scholar
Colbourne, F, Corbett, D. Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci 1995; 15: 7250–60.Google Scholar
Colbourne, F, Corbett, D, Zhao, Z, et al. Prolonged but delayed postischemic hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model. J Cereb Blood Flow Metab 2000; 20: 1702–8.Google Scholar
Davidson, JO, Wassink, G, Yuill, CA, et al. How long is too long for cerebral cooling after ischemia in fetal sheep? J Cereb Blood Flow Metab 2015; 35: 751–8.CrossRefGoogle Scholar
Shankaran, S, Laptook, AR, Pappas, A, et al. Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA 2014; 312: 2629–39.CrossRefGoogle ScholarPubMed
Johnston, MV. Excitotoxicity in perinatal brain injury. Brain Pathol 2005; 15: 234–40.Google Scholar
Bruno, VM, Goldberg, MP, Dugan, LL, et al. Neuroprotective effect of hypothermia in cortical cultures exposed to oxygen-glucose deprivation or excitatory amino acids. J Neurochem 1994; 63: 1398–406.Google Scholar
Wassink, G, Gunn, ER, Drury, PP, et al. The mechanisms and treatment of asphyxial encephalopathy. Front Neurosci 2014; 8: 40.Google Scholar
Northington, FJ, Zelaya, ME, O’Riordan, DP, et al. Failure to complete apoptosis following neonatal hypoxia-ischemia manifests as “continuum” phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain. Neuroscience 2007; 149: 822–33.Google Scholar
Edwards, AD, Yue, X, Squier, MV, et al. Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun 1995; 217: 1193–9.Google Scholar
Bennet, L, Roelfsema, V, George, S, et al. The effect of cerebral hypothermia on white and grey matter injury induced by severe hypoxia in preterm fetal sheep. J Physiol 2007; 578: 491506.Google Scholar
Hagberg, H, Mallard, C, Jacobsson, B. Role of cytokines in preterm labour and brain injury. BJOG. 2005; 112(Suppl 1): 1618.Google Scholar
Roelfsema, V, Bennet, L, George, S, et al. The window of opportunity for cerebral hypothermia and white matter injury after cerebral ischemia in near-term fetal sheep. J Cereb Blood Flow Metab 2004; 24: 877–86.Google Scholar
Welin, AK, Sandberg, M, Lindblom, A, et al. White matter injury following prolonged free radical formation in the 0.65 gestation fetal sheep brain. Pediatr Res 2005; 58: 100–5.Google Scholar
Fraser, M, Bennet, L, van Zijl, PL, et al. Extracellular amino acids and peroxidation products in the periventricular white matter during and after cerebral ischemia in preterm fetal sheep. J Neurochem 2008; 105: 2214–23.Google Scholar
Tan, WK, Williams, CE, Gunn, AJ, et al. Suppression of postischemic epileptiform activity with MK-801 improves neural outcome in fetal sheep. Ann Neurol 1992; 32: 677–82.CrossRefGoogle ScholarPubMed
George, SA, Barrett, RD, Bennet, L, et al. Nonadditive neuroprotection with early glutamate receptor blockade and delayed hypothermia after asphyxia in preterm fetal sheep. Stroke 2012; 43: 3114–7.Google Scholar
Bennet, L, Dean, JM, Wassink, G, Gunn, AJ. Differential effects of hypothermia on early and late epileptiform events after severe hypoxia in preterm fetal sheep. J Neurophysiol 2007; 97: 572–8.CrossRefGoogle ScholarPubMed
Biagioni, E, Bartalena, L, Boldrini, A, et al. Electroencephalography in infants with periventricular leukomalacia: prognostic features at preterm and term age. J Child Neurol 2000; 15: 16.CrossRefGoogle ScholarPubMed
Dean, JM, George, SA, Wassink, G, et al. Suppression of post hypoxic-ischemic EEG transients with dizocilpine is associated with partial striatal protection in the preterm fetal sheep. Neuropharmacology 2006; 50: 491503.Google Scholar
Bennet, L, Booth, L, Gunn, AJ. Potential biomarkers for hypoxic-ischemic encephalopathy. Semin Fetal Neonatal Med 2010; 15: 253–60.CrossRefGoogle ScholarPubMed
Jensen, EC, Bennet, L, Hunter, CJ, et al. Post-hypoxic hypoperfusion is associated with suppression of cerebral metabolism and increased tissue oxygenation in near-term fetal sheep. J Physiol 2006; 572: 131–9.CrossRefGoogle ScholarPubMed
Elstad, M, Whitelaw, A, Thoresen, M. Cerebral resistance index is less predictive in hypothermic encephalopathic newborns. Acta Paediatr 2011; 100: 1344–9.Google Scholar
Laptook, AR, Corbett, RJ, Sterett, R, et al. Quantitative relationship between brain temperature and energy utilization rate measured in vivo using 31P and 1H magnetic resonance spectroscopy. Pediatr Res 1995; 38: 919–25.Google Scholar
Lotgering, FK, Bishai, JM, Struijk, PC, et al. Ten-minute umbilical cord occlusion markedly reduces cerebral blood flow and heat production in fetal sheep. Am J Obstet Gynecol 2003; 189: 233–8.Google Scholar
Hunter, CJ, Bennet, L, Power, GG, et al. Key neuroprotective role for endogenous adenosine A1 receptor activation during asphyxia in the fetal sheep. Stroke 2003; 34: 2240–5.CrossRefGoogle ScholarPubMed
Mortola, JP. Implications of hypoxic hypometabolism during mammalian ontogenesis. Respir Physiol Neurobiol 2004; 141: 345–56.Google Scholar
Guan, J, Bennet, L, Gluckman, PD, Gunn, AJ. Insulin-like growth factor-1 and post-ischemic brain injury. Prog Neurobiol 2003; 70: 443–62.Google Scholar
Clawson, TF, Vannucci, SJ, Wang, GM, et al. Hypoxia-ischemia-induced apoptotic cell death correlates with IGF-I mRNA decrease in neonatal rat brain. Biol Signals Recept 1999; 8: 281–93.Google Scholar
Guan, J, Bennet, L, George, S, et al. Insulin-like growth factor-1 reduces postischemic white matter injury in fetal sheep. J Cereb Blood Flow Metab 2001; 21: 493502.Google Scholar
George, SA, Bennet, L, Weaver-Mikaere, L, et al. White matter protection with insulin like-growth factor 1 (IGF-1) and hypothermia is not additive after severe reversible cerebral ischemia in term fetal sheep. Dev Neurosci 2011; 33: 280–7.Google Scholar
Cao, Y, Gunn, AJ, Bennet, L, et al. Insulin-like growth factor (IGF)-1 suppresses oligodendrocyte caspase-3 activation and increases glial proliferation after ischemia in near-term fetal sheep. J Cereb Blood Flow Metab 2003; 23: 739–47.CrossRefGoogle ScholarPubMed
Corley, SM, Ladiwala, U, Besson, A, Yong, VW. Astrocytes attenuate oligodendrocyte death in vitro through an alpha(6) integrin-laminin-dependent mechanism. Glia 2001; 36: 281–94.Google Scholar
Ohlsson, A, Aher, SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006; 3: CD004863.Google Scholar
Digicaylioglu, M, Lipton, SA. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-κB signalling cascades. Nature 2001; 412: 641–7.Google Scholar
Statler, PA, McPherson, RJ, Bauer, LA, et al. Pharmacokinetics of high-dose recombinant erythropoietin in plasma and brain of neonatal rats. Pediatr Res 2007; 61: 671–5.Google Scholar
Robertson, NJ, Tan, S, Groenendaal, F, et al. Which neuroprotective agents are ready for bench to bedside translation in the newborn infant? J Pediatr 2012; 160: 544–52.Google Scholar
Nadam, J, Navarro, F, Sanchez, P, et al. Neuroprotective effects of erythropoietin in the rat hippocampus after pilocarpine-induced status epilepticus. Neurobiol Dis 2006; 2: 412–26.Google Scholar
Drury, PP, Davidson, JO, van den Heuij, LG, et al. Status epilepticus after prolonged umbilical cord occlusion is associated with greater neural injury in fetal sheep at term-equivalent. PLoS One 2014; 9: e96530.Google Scholar
Fang, AY, Gonzalez, FF, Sheldon, RA, Ferriero, DM. Effects of combination therapy using hypothermia and erythropoietin in a rat model of neonatal hypoxia-ischemia. Pediatr Res 2013; 73: 12–7.Google Scholar
Fan, X, van Bel, F, van der Kooij, MA, et al. Hypothermia and erythropoietin for neuroprotection after neonatal brain damage. Pediatr Res 2013; 73: 1823.Google Scholar
Traudt, CM, McPherson, RJ, Bauer, LA, et al. Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia. Dev Neurosci 2013; 35: 491503.CrossRefGoogle Scholar
Wang, H, Zhang, L, Jin, Y. A meta-analysis of the protective effect of recombinant human erythropoietin (rhEPO) for neurodevelopment in preterm infants. Cell Biochem Biophys 2015; 71: 795802.CrossRefGoogle ScholarPubMed
Zhu, C, Kang, W, Xu, F, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics 2009; 124: e218–26.Google Scholar
Elmahdy, H, El-Mashad, AR, El-Bahrawy, H, et al. Human recombinant erythropoietin in asphyxia neonatorum: pilot trial. Pediatrics 2010; 125: e1135–42.Google Scholar
Yawno, T, Castillo-Melendez, M, Jenkin, G, et al. Mechanisms of melatonin-induced protection in the brain of late gestation fetal sheep in response to hypoxia. Dev Neurosci 2012; 34: 543–51.Google Scholar
Drury, PP, Davidson, JO, Bennet, L, et al. Partial neural protection with prophylactic low-dose melatonin after asphyxia in preterm fetal sheep. J Cereb Blood Flow Metab 2014; 34: 126–35.Google Scholar
Welin, AK, Svedin, P, Lapatto, R, et al. Melatonin reduces inflammation and cell death in white matter in the mid-gestation fetal sheep following umbilical cord occlusion. Pediatr Res 2007; 61: 153–8.Google Scholar
Robertson, NJ, Faulkner, S, Fleiss, B, et al. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain 2013; 136: 90105.Google Scholar
Gitto, E, Romeo, C, Reiter, RJ, et al. Melatonin reduces oxidative stress in surgical neonates. J Pediatr Surg 2004; 39: 184–9; discussion 189.Google Scholar
Bennet, L, Tan, S, Van den Heuij, L, et al. Cell therapy for neonatal hypoxia-ischemia and cerebral palsy. Ann Neurol 2012; 71: 589600.Google Scholar
Drobyshevsky, A, Cotten, CM, Shi, Z, et al. Human umbilical cord blood cells ameliorate motor deficits in rabbits in a cerebral palsy model. Dev Neurosci 2015; 37(4–5): 349–62.Google Scholar
Park, WS, Sung, SI, Ahn, SY, et al. Hypothermia augments neuroprotective activity of mesenchymal stem cells for neonatal hypoxic-ischemic encephalopathy. PLoS One 2015; 10: e0120893.Google Scholar
Min, K, Song, J, Kang, JY, et al. Umbilical cord blood therapy potentiated with erythropoietin for children with cerebral palsy: a double-blind, randomized, placebo-controlled trial. Stem Cells 2013; 31: 581–91.Google Scholar
Bae, SH, Lee, HS, Kang, MS, et al. The levels of pro-inflammatory factors are significantly decreased in cerebral palsy patients following an allogeneic umbilical cord blood cell transplant. Int J Stem Cells 2012; 5: 31–8.Google Scholar
Dickinson, R, Peterson, BK, Banks, P, et al. Competitive inhibition at the glycine site of the N-methyl-d-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology. Anesthesiology 2007; 107: 756–67.Google Scholar
Lobo, N, Yang, B, Rizvi, M, Ma, D. Hypothermia and xenon: novel noble guardians in hypoxic-ischemic encephalopathy? J Neurosci Res 2013; 91: 473–8.CrossRefGoogle ScholarPubMed
Chakkarapani, E, Dingley, J, Liu, X, et al. Xenon enhances hypothermic neuroprotection in asphyxiated newborn pigs. Ann Neurol 2010; 68: 330–41.Google Scholar
Faulkner, S, Bainbridge, A, Kato, T, et al. Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia. Ann Neurol 2011; 70: 133–50.Google Scholar
Faulkner, SD, Downie, NA, Mercer, CJ, et al. A xenon recirculating ventilator for the newborn piglet: developing clinical applications of xenon for neonates. Eur J Anaesthesiol 2012; 29: 577–85.Google Scholar
Galinsky, R, Bennet, L, Groenendaal, F, et al. Magnesium is not consistently neuroprotective for perinatal hypoxia-ischemia in term-equivalent models in preclinical studies: a systematic review. Dev Neurosci 2014; 36: 7382.Google Scholar
Doyle, LW, Crowther, CA, Middleton, P, Marret, S. Antenatal magnesium sulfate and neurologic outcome in preterm infants: a systematic review. Obstet Gynecol 2009; 113: 1327–33.Google Scholar
Doyle, LW, Anderson, PJ, Haslam, R, et al. School-age outcomes of very preterm infants after antenatal treatment with magnesium sulfate vs placebo. JAMA 2014; 312: 1105–13.Google Scholar
Thornton, JS, Ordidge, RJ, Penrice, J, et al. Temporal and anatomical variations of brain water apparent diffusion coefficient in perinatal cerebral hypoxic-ischemic injury: relationships to cerebral energy metabolism. Magn Reson Med 1998; 39: 920–7.Google Scholar
Davidson, JO, Green, CR, Bennet, L, Gunn, AJ. Battle of the hemichannels: connexins and pannexins in ischemic brain injury. Int J Dev Neurosci 2014; 45: 6674.Google Scholar
Orellana, JA, Hernandez, DE, Ezan, P, et al. Hypoxia in high glucose followed by reoxygenation in normal glucose reduces the viability of cortical astrocytes through increased permeability of connexin 43 hemichannels. Glia 2010; 58: 329–43.Google Scholar
O’Carroll, SJ, Alkadhi, M, Nicholson, LF, Green, CR. Connexin 43 mimetic peptides reduce swelling, astrogliosis, and neuronal cell death after spinal cord injury. Cell Commun Adhes 2008; 15: 2742.Google Scholar
Davidson, JO, Green, CR, Nicholson, LF, et al. Connexin hemichannel blockade improves outcomes in a model of fetal ischemia. Ann Neurol 2012; 71: 121–32.Google Scholar
Davidson, JO, Drury, PP, Green, CR, et al. Connexin hemichannel blockade is neuroprotective after asphyxia in preterm fetal sheep. PLoS One. 2014; 9: e96558.Google Scholar
Davidson, JO, Green, CR, Nicholson, LF, et al. Connexin hemichannel blockade is neuroprotective after, but not during, global cerebral ischemia in near-term fetal sheep. Exp Neurol 2013; 248: 301–8.Google Scholar
Gunn, AJ, Thoresen, M. Animal studies of neonatal hypothermic neuroprotection have translated well in to practice. Resuscitation 2015; 97: 8890.Google Scholar
Dean, JM, Gunn, AJ, Wassink, G, et al. Endogenous α(2)-adrenergic receptor–mediated neuroprotection after severe hypoxia in preterm fetal sheep. Neuroscience 2006; 142: 615–28.Google Scholar
Guan, J, Bennet, L, George, S, et al. Selective neuroprotective effects with insulin-like growth factor-1 in phenotypic striatal neurons following ischemic brain injury in fetal sheep. Neuroscience 2000; 95: 831–9.Google Scholar

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