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Glucose and Intermediary Metabolism and Astrocyte–Neuron Interactions Following Neonatal Hypoxia–Ischemia in Rat

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Abstract

Neonatal hypoxia–ischemia (HI) and the delayed injury cascade that follows involve excitotoxicity, oxidative stress and mitochondrial failure. The susceptibility to excitotoxicity of the neonatal brain may be related to the capacity of astrocytes for glutamate uptake. Furthermore, the neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance for limiting this kind of injury. Also, in the neonatal brain, neurons depend upon de novo synthesis of neurotransmitters via pyruvate carboxylase in astrocytes to increase neurotransmitter pools during normal brain development. Several recent publications describing intermediary brain metabolism following neonatal HI have yielded interesting results: (1) Following HI there is a prolonged depression of mitochondrial metabolism in agreement with emerging evidence of mitochondria as vulnerable targets in the delayed injury cascade. (2) Astrocytes, like neurons, are metabolically impaired following HI, and the degree of astrocytic malfunction may be an indicator of the outcome following hypoxic and hypoxic-ischemic brain injury. (3) Glutamate transfer from neurons to astrocytes is not increased following neonatal HI, which may imply that astrocytes fail to upregulate glutamate uptake in response to the massive glutamate release during HI, thus contributing to excitotoxicity. (4) In the neonatal brain, the activity of the PPP is reduced following HI, which may add to the susceptibility of the neonatal brain to oxidative stress. The present review aims to discuss the metabolic temporal alterations observed in the neonatal brain following HI.

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References

  1. Johnston MV, Fatemi A, Wilson MA, Northington F (2011) Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol 10:372–382

    Article  PubMed  PubMed Central  Google Scholar 

  2. Rice JE 3rd, Vannucci RC, Brierley JB (1981) The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 9:131–141

    Article  PubMed  Google Scholar 

  3. Buckley EM, Patel SD, Miller BF, Franceschini MA, Vannucci SJ (2015) In vivo monitoring of cerebral hemodynamics in the immature rat: effects of hypoxia–ischemia and hypothermia. Dev Neurosci 37:407–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vannucci SJ, Hagberg H (2004) Hypoxia–ischemia in the immature brain. J Exp Biol 207:3149–3154

    Article  CAS  PubMed  Google Scholar 

  5. Vannucci RC, Lyons DT, Vasta F (1988) Regional cerebral blood flow during hypoxia–ischemia in immature rats. Stroke 19:245–250

    Article  CAS  PubMed  Google Scholar 

  6. Widerøe M, Havnes MB, Morken TS, Skranes J, Goa P-E, Brubakk A-M (2012) Doxycycline treatment in a neonatal rat model of hypoxia–ischemia reduces cerebral tissue and white matter injury: a longitudinal magnetic resonance imaging study. Eur J Neurosci 36:2006–2016

    Article  PubMed  Google Scholar 

  7. Morken TS, Widerøe M, Vogt C, Lydersen S, Havnes M, Skranes J, Goa PE, Brubakk AM (2013) Longitudinal diffusion tensor and manganese-enhanced MRI detect delayed cerebral gray and white matter injury after hypoxia–ischemia and hyperoxia. Pediatr Res 73:171–179

    Article  CAS  PubMed  Google Scholar 

  8. Widerøe M, Olsen O, Pedersen TB, Goa PE, Kavelaars A, Heijnen C, Skranes J, Brubakk AM, Brekken C (2009) Manganese-enhanced magnetic resonance imaging of hypoxic–ischemic brain injury in the neonatal rat. Neuroimage 45:880–890

    Article  PubMed  Google Scholar 

  9. Welsh FA, Vannucci RC, Brierley JB (1982) Columnar alterations of NADH fluorescence during hypoxia–ischemia in immature rat brain. J Cereb Blood Flow Metab 2:221–228

    Article  CAS  PubMed  Google Scholar 

  10. Storm-Mathisen J, Leknes AK, Bore AT, Vaaland JL, Edminson P, Haug FM, Ottersen OP (1983) First visualization of glutamate and GABA in neurones by immunocytochemistry. Nature 301:517–520

    Article  CAS  PubMed  Google Scholar 

  11. Hagberg H, Mallard C, Rousset CI, Thornton C (2014) Mitochondria: hub of injury responses in the developing brain. Lancet Neurol 13:217–232

    Article  CAS  PubMed  Google Scholar 

  12. Mujsce DJ, Christensen MA, Vannucci RC (1990) Cerebral blood flow and edema in perinatal hypoxic–ischemic brain damage. Pediatr Res 27:450–453

    Article  CAS  PubMed  Google Scholar 

  13. Niatsetskaya ZV, Sosunov SA, Matsiukevich D, Utkina-Sosunova IV, Ratner VI, Starkov AA, Ten VS (2012) The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia–ischemia in neonatal mice. J Neurosci 32:3235–3244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Northington FJ, Ferriero DM, Graham EM, Traystman RJ, Martin LJ (2001) Early neurodegeneration after hypoxia–ischemia in neonatal rat is necrosis while delayed neuronal death is apoptosis. Neurobiol Dis 8:207–219

    Article  CAS  PubMed  Google Scholar 

  15. Vannucci RC, Towfighi J, Vannucci SJ (2004) Secondary energy failure after cerebral hypoxia–ischemia in the immature rat. J Cereb Blood Flow Metab 24:1090–1097

    Article  CAS  PubMed  Google Scholar 

  16. Yu AC, Drejer J, Hertz L, Schousboe A (1983) Pyruvate carboxylase activity in primary cultures of astrocytes and neurons. J Neurochem 41:1484–1487

    Article  CAS  PubMed  Google Scholar 

  17. Patel MS (1974) The relative significance of CO2-fixing enzymes in the metabolism of rat brain. J Neurochem 22:717–724

    Article  CAS  PubMed  Google Scholar 

  18. Sonnewald U (2014) Glutamate synthesis has to be matched by its degradation—where do all the carbons go? J Neurochem 131:399–406

    Article  CAS  PubMed  Google Scholar 

  19. Varoqui H, Zhu H, Yao D, Ming H, Erickson JD (2000) Cloning and functional identification of a neuronal glutamine transporter. J Biol Chem 275:4049–4054

    Article  CAS  PubMed  Google Scholar 

  20. Norenberg MD, Martinez-Hernandez A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 161:303–310

    Article  CAS  PubMed  Google Scholar 

  21. McKenna MC, Sonnewald U, Huang X, Stevenson J, Zielke HR (1996) Exogenous glutamate concentration regulates the metabolic fate of glutamate in astrocytes. J Neurochem 66:386–393

    Article  CAS  PubMed  Google Scholar 

  22. McKenna MC, Dienel GA, Sonnewald U, Waagepetersen HS, Schousboe A (2012) Energy metabolism of the brain. In: Basic Neurochemistry, 8 edn. Elsevier Inc, London, pp 224–253

    Google Scholar 

  23. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105

    Article  CAS  PubMed  Google Scholar 

  24. Nijboer CH, Heijnen CJ, Degos V, Willemen HLDM, Gressens P, Kavelaars A (2013) Astrocyte GRK2 as a novel regulator of glutamate transport and brain damage. Neurobiol Dis 54:206–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schousboe A (2000) Pharmacological and functional characterization of astrocytic GABA transport: a short review. Neurochem Res 25:1241–1244

    Article  CAS  PubMed  Google Scholar 

  26. Morken TS, Brekke E, Haberg A, Wideroe M, Brubakk AM, Sonnewald U (2014) Altered astrocyte–neuronal interactions after hypoxia–ischemia in the neonatal brain in female and male rats. Stroke 45:2777–2785

    Article  PubMed  Google Scholar 

  27. Berger HR, Morken TS, Vettukattil R, Brubakk AM, Sonnewald U, Widerøe M (2016) No improvement of neuronal metabolism in the reperfusion phase with melatonin treatment after hypoxic-ischemic brain injury in the neonatal rat. J Neurochem 136(2):339–350. doi:10.1111/jnc.13420

    Article  CAS  PubMed  Google Scholar 

  28. Brekke EM, Morken TS, Widerøe M, Håberg AK, Brubakk AM, Sonnewald U (2014) The pentose phosphate pathway and pyruvate carboxylation after neonatal hypoxic-ischemic brain injury. J Cereb Blood Flow Metab 34(4):724–734. doi:10.1038/jcbfm.2014.8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Scafidi S, O’Brien J, Hopkins I, Robertson C, Fiskum G, McKenna M (2009) Delayed cerebral oxidative glucose metabolism after traumatic brain injury in young rats. J Neurochem 109(Suppl 1):189–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Robertson CL, Saraswati M, Scafidi S, Fiskum G, Casey P, McKenna MC (2013) Cerebral glucose metabolism in an immature rat model of pediatric traumatic brain injury. J Neurotrauma 30:2066–2072

    Article  PubMed  PubMed Central  Google Scholar 

  31. Clarke DD, Sokoloff L (1999) Circulation and energy metabolism. In: Siegel GJ, Agranoff BW, Albers DS, Fisher SK, Uhler MD (eds) Basic Neurochemistry, 6th edn. Lippincott Williams and Wilkins, Philadelphia

    Google Scholar 

  32. Cremer JE (1982) Substrate utilization and brain development. J Cereb Blood Flow Metab 2:394–407

    Article  CAS  PubMed  Google Scholar 

  33. McKenna MC, Scafidi S, Robertson CL (2015) Metabolic alterations in developing brain after injury: knowns and unknowns. Neurochem Res 40:2527–2543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bondy CA, Lee WH, Zhou J (1992) Ontogeny and cellular distribution of brain glucose transporter gene expression. Mol Cell Neurosci 3:305–314

    Article  CAS  PubMed  Google Scholar 

  35. Koehler-Stec EM, Simpson IA, Vannucci SJ, Landschulz KT, Landschulz WH (1998) Monocarboxylate transporter expression in mouse brain. Am J Physiol 275:E516–E524

    CAS  PubMed  Google Scholar 

  36. Vannucci SJ, Simpson IA (2003) Developmental switch in brain nutrient transporter expression in the rat. Am J Physiol Endocrinol Metab 285:E1127–E1134

    Article  CAS  PubMed  Google Scholar 

  37. Vannucci SJ (1994) Developmental expression of GLUT1 and GLUT3 glucose transporters in rat brain. J Neurochem 62:240–246

    Article  CAS  PubMed  Google Scholar 

  38. Vannucci SJ, Seaman LB, Brucklacher RM, Vannucci RC (1994) Glucose transport in developing rat brain: glucose transporter proteins, rate constants and cerebral glucose utilization. Mol Cell Biochem 140:177–184

    Article  CAS  PubMed  Google Scholar 

  39. Brekke E, Morken TS, Sonnewald U (2015) Glucose metabolism and astrocyte–neuron interactions in the neonatal brain. Neurochem Int 82:33–41

    Article  CAS  PubMed  Google Scholar 

  40. Vannucci R, Brucklacher R, Vannucci S (2005) Glycolysis and perinatal hypoxic–ischemic brain damage. Dev Neurosci 27:185–190

    Article  CAS  PubMed  Google Scholar 

  41. Yager JY, Brucklacher RM, Vannucci RC (1991) Cerebral oxidative metabolism and redox state during hypoxia–ischemia and early recovery in immature rats. Am J Physiol 261:H1102–H1108

    CAS  PubMed  Google Scholar 

  42. Yager JY, Brucklacher RM, Vannucci RC (1992) Cerebral energy metabolism during hypoxia–ischemia and early recovery in immature rats. Am J Physiol 262:H672–H677

    CAS  PubMed  Google Scholar 

  43. Palmer C, Brucklacher RM, Christensen MA, Vannucci RC (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

    Article  CAS  PubMed  Google Scholar 

  44. Vannucci SJ, Reinhart R, Maher F, Bondy CA, Lee W-H, Vannucci RC, Simpson IA (1998) Alterations in GLUT1 and GLUT3 glucose transporter gene expression following unilateral hypoxia–ischemia in the immature rat brain. Dev Brain Res 107:255–264

    Article  CAS  Google Scholar 

  45. Vannucci SJ, Seaman LB, Vannucci RC (1996) Effects of hypoxia–ischemia on GLUT1 and GLUT3 glucose transporters in immature rat brain. J Cereb Blood Flow Metab 16:77–81

    Article  CAS  PubMed  Google Scholar 

  46. Vannucci SJ, Vannucci RC (1980) Glycogen metabolism in neonatal rat brain during anoxia and recovery. J Neurochem 34:1100–1105

    Article  CAS  PubMed  Google Scholar 

  47. Vannucci RC, Yager JY, Vannucci SJ (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

    Article  CAS  PubMed  Google Scholar 

  48. Dombrowski GJ Jr, Swiatek KR, Chao KL (1989) Lactate, 3-hydroxybutyrate, and glucose as substrates for the early postnatal rat brain. Neurochem Res 14:667–675

    Article  CAS  PubMed  Google Scholar 

  49. Halestrap AP, Meredith D (2004) The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447:619–628

    Article  CAS  PubMed  Google Scholar 

  50. Vannucci RC, Duffy TE (1976) Carbohydrate metabolism in fetal and neonatal rat brain during anoxia and recovery. Am J Physiol 230:1269–1275

    CAS  PubMed  Google Scholar 

  51. Vannucci RC, Brucklacher RM, Vannucci SJ (1996) The effect of hyperglycemia on cerebral metabolism during hypoxia–ischemia in the immature rat. J Cereb Blood Flow Metab 16:1026–1033

    Article  CAS  PubMed  Google Scholar 

  52. Dietrich WD, Alonso O, Busto R (1993) Moderate hyperglycemia worsens acute blood–brain barrier injury after forebrain ischemia in rats. Stroke 24:111–116

    Article  CAS  PubMed  Google Scholar 

  53. Folbergrova J, Zhao Q, Katsura K, Siesjo BK (1995) N-tert-butyl-alpha-phenylnitrone improves recovery of brain energy state in rats following transient focal ischemia. Proc Natl Acad Sci USA 92:5057–5061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xu L, Sapolsky RM, Giffard RG (2001) Differential sensitivity of murine astrocytes and neurons from different brain regions to injury. Exp Neurol 169:416–424

    Article  CAS  PubMed  Google Scholar 

  55. Håberg A, Qu H, Sather O, Unsgard G, Haraldseth O, Sonnewald U (2001) Differences in neurotransmitter synthesis and intermediary metabolism between glutamatergic and GABAergic neurons during 4 h of middle cerebral artery occlusion in the rat: the role of astrocytes in neuronal survival. J Cereb Blood Flow Metab 21:1451–1463

    Article  PubMed  Google Scholar 

  56. Sonnewald U, Muller TB, Westergaard N, Unsgard G, Petersen SB, Schousboe A (1994) NMR spectroscopic study of cell cultures of astrocytes and neurons exposed to hypoxia: compartmentation of astrocyte metabolism. Neurochem Int 24:473–483

    Article  CAS  PubMed  Google Scholar 

  57. Demarest TG, Schuh RA, Waddell J, McKenna MC, Fiskum G (2016) Sex-dependent mitochondrial respiratory impairment and oxidative stress in a rat model of neonatal hypoxic–ischemic encephalopathy. J Neurochem 137:714–729

    Article  CAS  PubMed  Google Scholar 

  58. Kreis R, Hofmann L, Kuhlmann B, Boesch C, Bossi E, Huppi PS (2002) Brain metabolite composition during early human brain development as measured by quantitative in vivo 1 H magnetic resonance spectroscopy. Magn Reson Med 48:949–958

    Article  CAS  PubMed  Google Scholar 

  59. Pouwels PJ, Brockmann K, Kruse B, Wilken B, Wick M, Hanefeld F, Frahm J (1999) Regional age dependence of human brain metabolites from infancy to adulthood as detected by quantitative localized proton MRS. Pediatr Res 46:474–485

    Article  CAS  PubMed  Google Scholar 

  60. Tkac I, Rao R, Georgieff MK, Gruetter R (2003) Developmental and regional changes in the neurochemical profile of the rat brain determined by in vivo 1 H NMR spectroscopy. Magn Reson Med 50:24–32

    Article  CAS  PubMed  Google Scholar 

  61. Morken TS, Brekke E, Håberg A, Widerøe M, Brubakk AM, Sonnewald U (2014) Neuron-astrocyte interactions, pyruvate carboxylation and the pentose phosphate pathway in the neonatal rat brain. Neurochem Res 39(3):556–569. doi:10.1007/s11064-013-1014-3

    Article  CAS  PubMed  Google Scholar 

  62. Represa A, Tremblay E, Ben-Ari Y (1989) Transient increase of NMDA-binding sites in human hippocampus during development. Neurosci Lett 99:61–66

    Article  CAS  PubMed  Google Scholar 

  63. Tremblay E, Roisin MP, Represa A, Charriaut-Marlangue C, Ben-Ari Y (1988) Transient increased density of NMDA binding sites in the developing rat hippocampus. Brain Res 461:393–396

    Article  CAS  PubMed  Google Scholar 

  64. Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ (2013) Brain development in rodents and humans: identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol 106–107:1–16

    Article  PubMed  Google Scholar 

  65. Jantzie LL, Talos DM, Jackson MC, Park HK, Graham DA, Lechpammer M, Folkerth RD, Volpe JJ, Jensen FE (2015) Developmental expression of N-methyl-d-aspartate (NMDA) receptor subunits in human white and gray matter: potential mechanism of increased vulnerability in the immature brain. Cereb Cortex 25:482–495

    Article  PubMed  Google Scholar 

  66. Furuta A, Rothstein JD, Martin LJ (1997) Glutamate transporter protein subtypes are expressed differentially during rat CNS development. J Neurosci 17:8363–8375

    CAS  PubMed  Google Scholar 

  67. Johnston MV (2005) Excitotoxicity in perinatal brain injury. Brain Pathol 15:234–240

    Article  CAS  PubMed  Google Scholar 

  68. Puka-Sundvall M, Sandberg M, Hagberg H (1997) Brain injury after hypoxia–ischemia in newborn rats: relationship to extracellular levels of excitatory amino acids and cysteine. Brain Res 750:325–328

    Article  CAS  PubMed  Google Scholar 

  69. Kusaka T, Matsuura S, Fujikawa Y, Okubo K, Kawada K, Namba M, Okada H, Imai T, Isobe K, Itoh S (2004) Relationship between cerebral interstitial levels of amino acids and phosphorylation potential during secondary energy failure in hypoxic–ischemic newborn piglets. Pediatr Res 55:273–279

    Article  CAS  PubMed  Google Scholar 

  70. Puka-Sundvall M, Gilland E, Bona E, Lehmann A, Sandberg M, Hagberg H (1996) Development of brain damage after neonatal hypoxia–ischemia: excitatory amino acids and cysteine. Metab Brain Dis 11:109–123

    Article  CAS  PubMed  Google Scholar 

  71. Chowdhury GMI, Patel AB, Mason GF, Rothman DL, Behar KL (2007) Glutamatergic and GABAergic neurotransmitter cycling and energy metabolism in rat cerebral cortex during postnatal development. J Cereb Blood Flow Metab 27:1895–1907

    Article  CAS  PubMed  Google Scholar 

  72. Wilbur DO, Patel MS (1974) Development of mitochondrial pyruvate metabolism in rat brain. J Neurochem 22:709–715

    Article  CAS  PubMed  Google Scholar 

  73. Kunnecke B, Cerdan S, Seelig J (1993) Cerebral metabolism of [1,2-13C2]glucose and [U-13C4]3-hydroxybutyrate in rat brain as detected by 13 C NMR spectroscopy. NMR Biomed 6:264–277

    Article  CAS  PubMed  Google Scholar 

  74. Vannucci RC, Brucklacher RM, Vannucci SJ (1999) CSF glutamate during hypoxia–ischemia in the immature rat. Dev Brain Res 118:147–151

    Article  CAS  Google Scholar 

  75. McKenna MC, Tildon JT, Stevenson JH, Huang X, Kingwell KG (1995) Regulation of mitochondrial and cytosolic malic enzymes from cultured rat brain astrocytes. Neurochem Res 20:1491–1501

    Article  CAS  PubMed  Google Scholar 

  76. Cruz F, Scott SR, Barroso I, Santisteban P, Cerdan S (1998) Ontogeny and cellular localization of the pyruvate recycling system in rat brain. J Neurochem 70:2613–2619

    Article  CAS  PubMed  Google Scholar 

  77. McKenna MC, Stevenson JH, Huang X, Tildon JT, Zielke CL, Hopkins IB (2000) Mitochondrial malic enzyme activity is much higher in mitochondria from cortical synaptic terminals compared with mitochondria from primary cultures of cortical neurons or cerebellar granule cells. Neurochem Int 36:451–459

    Article  CAS  PubMed  Google Scholar 

  78. Ben-Ari Y, Woodin MA, Sernagor E, Cancedda L, Vinay L, Rivera C, Legendre P, Luhmann HJ, Bordey A, Wenner P, Fukuda A, van den Pol AN, Gaiarsa JL, Cherubini E (2012) Refuting the challenges of the developmental shift of polarity of GABA actions: GABA more exciting than ever! Front Cell Neurosci 6:35. doi:10.3389/fncel.2012.00035

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA, Delpire E, Jensen FE, Staley KJ (2005) NKCC1 transporter facilitates seizures in the developing brain. Nat Med 11:1205–1213

    Article  CAS  PubMed  Google Scholar 

  80. Wang DD, Kriegstein AR (2009) Defining the role of GABA in cortical development. J Physiol 587:1873–1879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yan XX, Zheng DS, Garey LJ (1992) Prenatal development of GABA-immunoreactive neurons in the human striate cortex. Brain Res Dev Brain Res 65:191–204

    Article  CAS  PubMed  Google Scholar 

  82. Tyzio R, Represa A, Jorquera I, Ben-Ari Y, Gozlan H, Aniksztejn L (1999) The establishment of GABAergic and glutamatergic synapses on CA1 pyramidal neurons is sequential and correlates with the development of the apical dendrite. J Neurosci 19:10372–10382

    CAS  PubMed  Google Scholar 

  83. Micheva KD, Beaulieu C (1995) Postnatal development of GABA neurons in the rat somatosensory barrel cortex: a quantitative study. Eur J Neurosci 7:419–430

    Article  CAS  PubMed  Google Scholar 

  84. Vitellaro-Zuccarello L, Calvaresi N, Biasi S (2003) Expression of GABA transporters, GAT-1 and GAT-3, in the cerebral cortex and thalamus of the rat during postnatal development. Cell Tissue Res 313:245–257

    Article  CAS  PubMed  Google Scholar 

  85. Sipilä S, Huttu K, Voipio J, Kaila K (2004) GABA uptake via GABA transporter-1 modulates GABAergic transmission in the immature hippocampus. J Neurosci 24:5877–5880

    Article  PubMed  CAS  Google Scholar 

  86. Wallin C, Puka-Sundvall M, Hagberg H, Weber SG, Sandberg M (2000) Alterations in glutathione and amino acid concentrations after hypoxia–ischemia in the immature rat brain. Dev Brain Res 125:51–60

    Article  CAS  Google Scholar 

  87. Nehlig A (2004) Brain uptake and metabolism of ketone bodies in animal models. Prostaglandins Leukot Essent Fatty Acids 70:265–275

    Article  CAS  PubMed  Google Scholar 

  88. Ben-Yoseph O, Boxer P, Ross B (1996) Noninvasive assessment of the relative roles of cerebral antioxidant enzymes by quantitation of pentose phosphate pathway activity. Neurochem Res 21:1005–1012

    Article  CAS  PubMed  Google Scholar 

  89. Lenaz G (2001) The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life 52:159–164

    Article  CAS  PubMed  Google Scholar 

  90. Starkov AA, Fiskum G, Chinopoulos C, Lorenzo BJ, Browne SE, Patel MS, Beal MF (2004) Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 24:7779–7788

    Article  CAS  PubMed  Google Scholar 

  91. Maltepe E, Saugstad OD (2009) Oxygen in health and disease: regulation of oxygen homeostasis-clinical implications. Pediatr Res 65:261–268

    Article  CAS  PubMed  Google Scholar 

  92. Fullerton HJ, Ditelberg JS, Chen SF, Sarco DP, Chan PH, Epstein CJ, Ferriero DM (1998) Copper/zinc superoxide dismutase transgenic brain accumulates hydrogen peroxide after perinatal hypoxia ischemia. Ann Neurol 44:357–364

    Article  CAS  PubMed  Google Scholar 

  93. Sheldon RA, Jiang X, Francisco C, Christen S, Vexler ZS, Tauber MG, Ferriero DM (2004) Manipulation of antioxidant pathways in neonatal murine brain. Pediatr Res 56:656–662

    Article  CAS  PubMed  Google Scholar 

  94. McQuillen PS, Ferriero DM (2004) Selective vulnerability in the developing central nervous system. Pediatr Neurol 30:227–235

    Article  PubMed  Google Scholar 

  95. Hertz L, Zielke HR (2004) Astrocytic control of glutamatergic activity: astrocytes as stars of the show. Trends Neurosci 27:735–743

    Article  CAS  PubMed  Google Scholar 

  96. Liu J, Sheldon RA, Segal MR, Kelly MJ, Pelton JG, Ferriero DM, James TL, Litt L (2013) 1 H nuclear magnetic resonance brain metabolomics in neonatal mice after hypoxia–ischemia distinguished normothermic recovery from mild hypothermia recoveries. Pediatr Res 74:170–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Xu S, Waddell J, Zhu W, Shi D, Marshall AD, McKenna MC, Gullapalli RP (2015) In vivo longitudinal proton magnetic resonance spectroscopy on neonatal hypoxic–ischemic rat brain injury: neuroprotective effects of acetyl-l-carnitine. Magn Reson Med 74:1530–1542

    Article  CAS  PubMed  Google Scholar 

  98. Dusick JR, Glenn TC, Lee WN, Vespa PM, Kelly DF, Lee SM, Hovda DA, Martin NA (2007) Increased pentose phosphate pathway flux after clinical traumatic brain injury: a [1,2-13C2]glucose labeling study in humans. J Cereb Blood Flow Metab 27:1593–1602

    Article  CAS  PubMed  Google Scholar 

  99. Bartnik BL, Sutton RL, Fukushima M, Harris NG, Hovda DA, Lee SM (2005) Upregulation of pentose phosphate pathway and preservation of tricarboxylic acid cycle flux after experimental brain injury. J Neurotrauma 22:1052–1065

    Article  PubMed  Google Scholar 

  100. Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP (2009) The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol 11:747–752

    Article  CAS  PubMed  Google Scholar 

  101. Rodriguez-Rodriguez P, Fernandez E, Almeida A, Bolanos JP (2012) Excitotoxic stimulus stabilizes PFKFB3 causing pentose-phosphate pathway to glycolysis switch and neurodegeneration. Cell Death Differ 19:1582–1589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Liu J, Litt L, Segal MR, Kelly MJ, Yoshihara HA, James TL (2011) Outcome-related metabolomic patterns from 1H/31P NMR after mild hypothermia treatments of oxygen-glucose deprivation in a neonatal brain slice model of asphyxia. J Cereb Blood Flow Metab 31:547–559

    Article  PubMed  CAS  Google Scholar 

  103. Taylor DL, Mehmet H, Cady EB, Edwards AD (2002) Improved neuroprotection with hypothermia delayed by 6 h following cerebral hypoxia–ischemia in the 14-day-old rat. Pediatr Res 51:13–19

    Article  PubMed  Google Scholar 

  104. Williams GD, Dardzinski BJ, Buckalew AR, Smith MB (1997) Modest hypothermia preserves cerebral energy metabolism during hypoxia–ischemia and correlates with brain damage: a 31P nuclear magnetic resonance study in unanesthetized neonatal rats. Pediatr Res 42:700–708

    Article  CAS  PubMed  Google Scholar 

  105. Laptook AR, Corbett RJ, Sterett R, Garcia D, Tollefsbol G (1995) Quantitative relationship between brain temperature and energy utilization rate measured in vivo using 31P and 1 H magnetic resonance spectroscopy. Pediatr Res 38:919–925

    Article  CAS  PubMed  Google Scholar 

  106. Dehaes M, Aggarwal A, Lin PY, Rosa Fortuno C, Fenoglio A, Roche-Labarbe N, Soul JS, Franceschini MA, Grant PE (2014) Cerebral oxygen metabolism in neonatal hypoxic ischemic encephalopathy during and after therapeutic hypothermia. J Cereb Blood Flow Metab 34:87–94

    Article  CAS  PubMed  Google Scholar 

  107. Wisnowski JL, Wu TW, Reitman AJ, McLean C, Friedlich P, Vanderbilt D, Ho E, Nelson MD, Panigrahy A, Bluml S (2016) The effects of therapeutic hypothermia on cerebral metabolism in neonates with hypoxic–ischemic encephalopathy: An in vivo 1H-MR spectroscopy study. J Cereb Blood Flow Metab 36:1075–1086

    Article  CAS  PubMed  Google Scholar 

  108. Corbo ET, Bartnik-Olson BL, Machado S, Merritt TA, Peverini R, Wycliffe N, Ashwal S (2012) The effect of whole-body cooling on brain metabolism following perinatal hypoxic–ischemic injury. Pediatr Res 71:85–92

    Article  CAS  PubMed  Google Scholar 

  109. Thoresen M, Satas S, Puka-Sundvall M, Whitelaw A, Hallstrom A, Loberg EM, Ungerstedt U, Steen PA, Hagberg H (1997) Post-hypoxic hypothermia reduces cerebrocortical release of NO and excitotoxins. Neuroreport 8:3359–3362

    Article  CAS  PubMed  Google Scholar 

  110. Drury PP, Bennet L, Gunn AJ (2010) Mechanisms of hypothermic neuroprotection. Semin Fetal Neonatal Med 15:287–292

    Article  PubMed  Google Scholar 

  111. Brooks KJ, Hargreaves I, Bhakoo K, Sellwood M, O’Brien F, Noone M, Sakata Y, Cady E, Wylezinska M, Thornton J, Ordidge R, Nguyen Q, Clemence M, Wyatt J, Bates TE (2002) Delayed hypothermia prevents decreases in N-acetylaspartate and reduced glutathione in the cerebral cortex of the neonatal pig following transient hypoxia–ischaemia. Neurochem Res 27:1599–1604

    Article  CAS  PubMed  Google Scholar 

  112. Liu J, Segal MR, Kelly MJ, Pelton JG, Kim M, James TL, Litt L (2013) 13 C NMR metabolomic evaluation of immediate and delayed mild hypothermia in cerebrocortical slices after oxygen-glucose deprivation. Anesthesiology 119:1120–1136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Borges K, Sonnewald U (2012) Triheptanoin–a medium chain triglyceride with odd chain fatty acids: a new anaplerotic anticonvulsant treatment? Epilepsy Res 100:239–244

    Article  CAS  PubMed  Google Scholar 

  114. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG (2013) Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 1:CD003311

    Google Scholar 

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Authors and Affiliations

  1. Department of Neuroscience, Norwegian University of Science and Technology (NTNU), 7489, Trondheim, Norway

    Eva Brekke & Ursula Sonnewald

  2. Department of Neurology, Bodø Hospital, Bodø, Norway

    Eva Brekke

  3. Department of Laboratory Medicine, Children’s and Women’s Health, NTNU, 7489, Trondheim, Norway

    Hester Rijkje Berger & Tora Sund Morken

  4. Department of Pediatrics, St. Olavs Hospital, Trondheim University Hospital, 7006, Trondheim, Norway

    Hester Rijkje Berger

  5. Department of Circulation and Medical Imaging, NTNU, 7489, Trondheim, Norway

    Marius Widerøe

  6. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark

    Ursula Sonnewald

  7. Department of Ophthalmology, St. Olavs Hospital, Trondheim University Hospital, 7006, Trondheim, Norway

    Tora Sund Morken

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  1. Eva Brekke
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  2. Hester Rijkje Berger
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  3. Marius Widerøe
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  4. Ursula Sonnewald
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  5. Tora Sund Morken
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Correspondence to Tora Sund Morken.

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Brekke, E., Berger, H.R., Widerøe, M. et al. Glucose and Intermediary Metabolism and Astrocyte–Neuron Interactions Following Neonatal Hypoxia–Ischemia in Rat. Neurochem Res 42, 115–132 (2017). https://doi.org/10.1007/s11064-016-2149-9

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  • DOI: https://doi.org/10.1007/s11064-016-2149-9

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