Experimental Brain Research

, Volume 113, Issue 1, pp 130–137 | Cite as

Relation between delayed impairment of cerebral energy metabolism and infarction following transient focal hypoxia-ischaemia in the developing brain

  • R. M. Blumberg
  • E. B. Cady
  • J. S. Wigglesworth
  • J. E. McKenzie
  • A. D. Edwards
Research Article

Abstract

Phosphorus magnetic resonance spectroscopy (31P MRS) was used to determined whether focal cerebral injury caused by unilateral carotid artery occlusion and graded hypoxia in developing rats led to a delayed impairment of cerebral energy metabolism and whether the impairment was related to the magnitude of cerebral infarction. Forty-two 14-day-old Wistar rats were subjected to right carotid artery ligation, followed by 8% oxygen for 90 min. Using a 7T MRS system,31P brain spectra were collected during the period from before until 48 h after hypoxia-ischaemia. Twenty-eight control animals were studied similarly. In controls, the ratio of the concentration of phosphocreatine ([PCr]) to inorganic orthophosphate ([Pi]) was 1.75 (SD 0.34) and nucleotide triphosphate (NTP) to total exchangeable phosphate pool (EPP) was 0.20 (SD 0.04): both remained constant. In animals subjected to hypoxia-ischaemia, [PCr] to [Pi] and [NTP] to [EPP] were lower in the 0- to 3-h period immediately following the insult: 0.87 (0.48) and 0.13 (0.04), respectively. Values then returned to baseline level, but subsequently declined again: [PCr] to [Pi] at −0.02 h−1 (P<0.0001). [PCr] to [Pi] attained a minimum of 1.00 (0.33) and [NTP] to [EPP] a minimum of 0.14 (0.05) at 30–40 h. Both ratios returned towards baseline between 40 and 48 h. The late declines in high-energy phosphates were not associated with a fall in pHi. There was a significant relation between the extent of the delayed impairment of energy metabolism and the magnitude of the cerebral infarction (P<0.001). Transient focal hypoxia-ischaemia in the 14-day-old rat thus leads to a biphasic disruption of cerebral energy metabolism, with a period of recovery after the insult being followed by a secondary impaiment some hours later.

Key words

Hypoxia-ischaemia Magnetic resonance spectroscopy Cerebral energy metabolism Newborns Rat 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abe K, Kawagoe J, Kogure K (1993) Early disturbance of mitochondrial DNA expression in gerbil hippocampus after transient forebrain ischemia. Neurosci Lett 153: 173–176PubMedCrossRefGoogle Scholar
  2. Azzopardi D, Wyatt JS, Cady EB, Delpy DT, Baudin J, Stewart AL, Hope PL, Hamilton PA, Reynolds EOR (1989) Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res 25: 445–451PubMedGoogle Scholar
  3. BOoth RFG, Patel TB, Clark JB (1980) The development of enzymes of energy metabolism in the brain of a precocial (guinea pig) and non-precocial (rat) species. J Neurochem 34: 17–25PubMedGoogle Scholar
  4. Brown GC, Cooper CE (1994) Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Lett 356(2–3): 295–298PubMedCrossRefGoogle Scholar
  5. Cady EB, Roth SC, Azzopardi D, Aldridge R, Delpy DT, Wylezinska M, Reynolds EOR (1992) Delayed onset intracellular alkalosis and outcome following birth asphyxia (abstract). Proceedings of the Society of Magnetic Resonance in Medicine, 11th annual meeting, Berlin, 2011Google Scholar
  6. Cleeter MW, Cooper JM, Darley-Usmar VM, Moncada S, Schapira AHV (1994) Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative disease. FEBS Lett 345(1): 50–54PubMedCrossRefGoogle Scholar
  7. Dawson VL (1995) Nitric oxide: role in neurotoxicity. Clin Exp Pharmacol Physiol 22: 305–308PubMedGoogle Scholar
  8. Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH (1991) Nitric oxide mediates gluamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 88: 6368–6371PubMedCrossRefGoogle Scholar
  9. Glantz SA, Slinker BK (1990) Primer of applied regression and analysis of variance. McGraw-Hill, New YorkGoogle Scholar
  10. Hamilton PA, Cady EB, Wyatt JS, Hope PL, Delpy DT, Reynolds EOR (1986) Impaired energy metabolism in brains of newborn infants with increased cerebral echodensities. Lancet 1: 1242–1246PubMedCrossRefGoogle Scholar
  11. Hanrahan D, Sargentoni J, Azzopardi D, Manji K, Cowan F, Rutherford MA, Cox IJ, Bell JD, Bryant D, Edwards AD (1996) Cerebral metabolism within 18 h of birth asphyxia: a proton magnetic resonance spectroscopy study. Pediatr Res 39(4): 584–590PubMedGoogle Scholar
  12. Hope PL, Costello AM, Cady EB, Delpy DT, Tofts PS, Chu A, Hamilton PA, Reynolds EO, Wilkie DR (1984) Cerebral energy metabolism studied with phosphorus NMR spectroscopy in normal and birth-asphyxiated infants. Lancet 2: 366–370PubMedCrossRefGoogle Scholar
  13. Ikonomidou C, Mosinger JL, Salles KS, Labruyere J, Olney JW (1989) Sensitivity of the developing rat brain to hypobaric/ischemic damage parallels sensitivity toN-methyl-aspartate neurotoxicity. J Neurosci 9: 2809–2818PubMedGoogle Scholar
  14. Levine S (1960) Anoxic-ischemic encephalopathy in rats. Am J Pathol 36: 1–17PubMedGoogle Scholar
  15. Lorek A, Takei Y, Cady EB, Wyatt JS, Penrice J, Edwards AD, Peebles DM, Wylezinska M, Owen-Rees H, Kirkbride V, Cooper C, Aldridge RF, Roth SC, Brown G, Delpy DT, Reynolds EOR (1994) Delayed (“secondary”) cerebral energy failure following acute hypoxia-ischaemia in the newborn piglet: continuous 48-hour studies by31P magnetic resonance spectroscopy. Pediatr Res 36: 699–706PubMedGoogle Scholar
  16. Marks KA, Mallard EC, Roberts I, Williams CE, Sirimanne ES, Johnston BM, Gluckman PD, Edwards AD (1996) Delayed vasodilation and altered oxygenation following cerebral ischaemia in fetal sheep. Pediatr Res 39(4): 48–54PubMedGoogle Scholar
  17. Mujsce DJ, Christensen MA, Vannucci RC (1990) Cerebral blood flow and edema in perinatal hypoxic-ischemic brain damage. Pediatr Res 27: 450–453PubMedGoogle Scholar
  18. Nelson C, Silverstein FS (1994) Acute disruption of cytochrome oxidase activity in brain in a perinatal rat stroke model. Pediatr Res 36: 12–19PubMedGoogle Scholar
  19. Petroff OAC, Prichard JW (1985) Cerebral intracellular pH by31P nuclear magnetic resonance spectroscopy. Neurology 35: 781–788PubMedGoogle Scholar
  20. Pryds O, Greisen G, Lou H, Friis Hansen B (1990) Vasoparalysis associated with brain damage in asphyxiated term infants. J Pediatr 117: 119–125PubMedCrossRefGoogle Scholar
  21. Qury TD, Ho Y-S, Piantadosi CA, Crapo JD (1992) Extracellular superoxide dismutase, nitric oxide, and central nervous toxicity. Proc Natl Acad Sci USA 89: 9715–9719CrossRefGoogle Scholar
  22. Rice E, Vannucci RC, Brierly JB (1981) The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 9: 131–141PubMedCrossRefGoogle Scholar
  23. Romijn HJ, Hofman MJ, Gramsbergen A (1991) At what age is the developing cortex of the rat comparable to that of the full term newborn baby? Early Hum Dev 26: 61–67PubMedCrossRefGoogle Scholar
  24. Roth SC, Azzopardi D, Aldridge R, Cady E, Edwards AD, McCormick DC, Thornton J, Wylezinska M, Wyatt JS, Delpy DT, Reynolds EOR (1991) Progression of changes in cerebral energy metabolism in newborn infants studied by31P magnetic resonance spectroscopy following birth asphyxia (abstract). Neuropediatric 22: 169Google Scholar
  25. Roth SC, Edwards AD, Cady EB, Delpy DT, Wyatt JS, Azzopardi D, Baudin J, Townsend J, Stewart AL, Reynolds EOR (1992) Relation between cerebral oxidative metabolism following birth asphyxia and neurodevelopmental outcome and brain growth at one year. Dev Med Child Neurol 34: 285–295PubMedCrossRefGoogle Scholar
  26. Sherwood NM, Timiras PS (1970) A Stereotaxic Atlas of the Developing Rat Brain. Univeristy of California Press, Berkley and Los Angeles, California, pp 110–115Google Scholar
  27. Siesjö BK, Katsura K, Mellergard P (1993) Acidosis related brain damage. Prog Brain Res 96: 23–48.PubMedGoogle Scholar
  28. Sirimanne ES, Guan J, Williams CE, Gluckman PD (1994) Two models for determining the mechanisms of damage and repair after hypoxic-ischemic injury in the developing rat brain. J Neurosci Methods 55: 7–14PubMedCrossRefGoogle Scholar
  29. Szatkowski M, Attwell D (1994) Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate release by different mechanisms. Trends Neurosci 17: 359–365PubMedCrossRefGoogle Scholar
  30. Williams CE, Gunn AJ, Mallard C, Gluckman PD (1992) Outcome after ischemia in the developing sheep brain: an electroencephalographic and histological study. Ann Neurol 31: 14–21PubMedCrossRefGoogle Scholar
  31. Williams GD, Towfighi J, Smith MB (1994) Cerebral energy metabolism during hypoxia-ischemia correlates with brain damage: a31P NMR study in unanesthetized immature rats. Neurosci Lett 170: 31–34PubMedCrossRefGoogle Scholar
  32. 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-H1108PubMedGoogle Scholar
  33. Yager JY, Brucklacher RM, Vannucci RC (1992) Cerebral energy metabolism during hypoxia-ischaemia and early recovery in immature rats. Am J Physiol 262: H672-H677PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • R. M. Blumberg
    • 1
  • E. B. Cady
    • 2
  • J. S. Wigglesworth
    • 3
  • J. E. McKenzie
    • 4
  • A. D. Edwards
    • 1
  1. 1.Department of Paediatrics and Neonatal MedicineRoyal Postgraduate Medical SchoolLondonUK
  2. 2.Department of Medical Physics and BioengineeringUniversity CollegeLondonUK
  3. 3.Department of HistopathologyRoyal Postgraduate Medical SchoolLondonUK
  4. 4.Department of PsychiatryCharing Cross and Westminster Medical SchoolLondonUK

Personalised recommendations