Abstract
Free iron chelation after hypoxia-ischemia can reduce free radical-induced damage to brain cell membranes and preserve electrical brain activity. We investigated whether chelation of free iron with deferoxamine (DFO) preserved cortical cell membrane activity of Na+,K+-ATPase and electrocortical brain activity (ECBA) of newborn lambs during early reperfusion after severe hypoxia-ischemia. Hypoxia was induced in 16 lambs by decreasing the fraction of inspired oxygen to 0.07 for 30 min, followed by a 5-min period of hypotension (mean arterial blood pressure <35 mm Hg). ECBA (in microvolts) was measured using a cerebral function monitor. Immediately after hypoxia and additional ischemia, eight lambs received DFO (2.5 mg/kg, i.v.), and seven lambs received a placebo (PLAC). Two lambs underwent sham operation. One hundred eighty minutes after completion of hypoxia and ischemia, the brains were obtained and frozen. Na+,K+-ATPase activity was measured in the P2 fraction of cortical tissue. Na+,K+-ATPase activity was 35.1 ± 7.4, 42.0 ± 7.6, and 40.7 ± 1.4 μmol inorganic phosphate/mg protein per hour in PLAC-treated, DFO-treated, and sham-operated lambs, respectively (p < 0.05: DFO versus PLAC). ECBA was 11.2 ± 6.1, 14.8 ± 4.8, and 17.5±.0.5 μV in PLAC-treated, DFO-treated, and sham-operated lambs, respectively (p = 0.06: DFO versus PLAC). Na+,K+-ATPase activity correlated with ECBA at 180 min of reperfusion (r = 0.85, p < 0.001). We conclude that Na+,K+-ATPase activity of cortical brain tissue was higher in DFO-treated lambs compared with PLAC-treated animals during the early reperfusion phase after severe hypoxia-ischemia, suggesting a reduction of free radical formation by DFO. Furthermore, a positive relationship was found between Na+,K+-ATPase activity and ECBA.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- DFO:
-
deferoxamine
- ECBA:
-
electrocortical brain activity
- PLAC:
-
placebo
- V˙car:
-
carotid blood flow
- SHAM:
-
sham-operated animals
- MRS:
-
magnetic resonance spectroscopy
- Pi:
-
inorganic phosphate
References
Saugstad OD, Aasen AO 1986 Plasma hypoxanthine concentrations in pigs: a prognostic aid in hypoxia. Eur Surg Res 12: 123–129
McCord JM 1985 Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 312: 159–163
Halliwell B 1992 Reactive oxygen species and central nervous system. J Neurochem 59: 1609–1623
Shadid M, Moison RMW, Steendijk P, Hiltermann L, Berger HM, van Bel F 1998 The effect of antioxidative combination therapy on post hypoxic-ischemic perfusion, metabolism, and electrical activity of the newborn brain. Pediatr Res 44: 119–124
Van Bel F, Shadid M, Moison RMW, Dorrepaal CA, Fontijn J, Monteiro L, Van de Bor M, Berger HM 1998 Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics and electrical brain activity. Pediatrics 101: 185–193
Shadid M, Buonocore G, Groenendaal F, Moison RWM, Ferrali M, Berger HM, Van Bel F 1998 Effect of deferoxamine and allopurinol on non-protein-bound iron concentrations in plasma and cortical brain tissue of newborn lambs following hypoxia-ischemia. Neurosci Lett 248: 5–8
Mishra OP, Delivoria-Papadopoulos M 1988 Na+,K+-ATPase in developing fetal guinea pig brain and the effect of maternal hypoxia. Neurochem Res 13: 765–770
DiGiacomo JE, Pane CR, Gwiazdowski S, Mishra OP, Delivoria-Papadopoulos M 1992 Effect of graded hypoxia on brain cell membrane injury in newborn piglets. Biol Neonate 61: 25–32
Dobsen AD, Sellers AF, McLeod FD 1986 Performance of a cuff-type blood flowmeter in vivo. J Appl Physiol 21: 1642–1648
Van Bel F, Roman C, Klautz RJM, Teitel DF, Rudolph AM 1994 Relationship between brain blood flow and carotid arterial flow in the sheep fetus. Pediatr Res 35: 329–333
Prior PF 1979 Monitoring Cerebral Function: Long-Term Recordings of Cerebral Electrical Activity. North Holland Biomedical Press, Amsterdam, pp 45–301
Hellstrom-Westas L, Rosen I, Svenningsen HW 1995 Predictive value of early continuous amplitude integrated EEG recordings on outcome after severe birth asphyxia in full term infants. Arch Dis Child 72: F34
Harik SI, Doull GH, Dick APK 1985 Specific ouabain binding to brain microvessels and choroid plexus. J Cereb Blood Flow Metab 5: 156–160
Mishra OP, Delivoria-Papadopoulos M, Cahillane G, Wagerle LC 1989 Lipid peroxidation as the mechanism of modification of the affinity of the Na+,K+-ATPase active sites for ATP, K+, Na+ and strophanthin in vitro. Neurochem Res 14: 845–851
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ 1951 Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275
Halliwell B, Chirico S 1993 Lipid peroxidation: its mechanism, measurements and significance. Am J Clin Nutr 57: 715S–725S
Hurn PD, Koehler RC, Blizzard KK, Traystman RJ 1995 Deferoxamine reduces early metabolic failure associated with severe cerebral ischemic acidosis in dogs. Stroke 26: 688–695
Mishra OP, Delivoria-Papadopoulos M, Cahillane G, Wagerle LC 1990 Lipid peroxidation as the mechanism of modification of brain 5′-nucleotidase activity in vitro. Neurochem Res 15: 237–242
Razdan B, Marro PJ, Tammela O, Goel R, Mishra OP, Delivoria-Papadopoulos M 1993 Selective sensitivity of synaptosomal membrane function to cerebral cortical hypoxia in newborn piglets. Brain Res 600: 308–314
Kovachich GB, Mishra OP 1981 Partial inactivation of Na+,K+-ATPase in cortical brain slices incubated in normal Krebs-Ringer phosphate medium at 1 and 10 atm oxygen pressures. J Neurochem 36: 333–335
Bertorello AM, Aperia A, Walaas SI, Nairn AC, Greengard P 1991 Phosphorylation of the catalytic subunit of Na+,K+-ATPase inhibits the activity of the enzyme. Proc Natl Acad Sci USA 88: 11359–11362
Siesjo BK, Siesjo P 1996 Mechanisms of secondary brain injury. Eur J Anaesthesiol 13: 247–268
Hayashi T, Sakurai M, Itoyma Y, Abe K 1999 Oxidative damage and breakage of DNA in rat brain after transient MCA occlusion. Brain Res 832: 159–163
Saugstad OD 1990 Oxygen toxicity in the neonatal period. Acta Paediatr 79: 881–892
Traystman RJ, Kirch JR, Koehler RC 1991 Oxygen radical mechanisms of brain injury following ischemia and reperfusion. J Appl Physiol 71: 1185–1195
Dorrepaal CA, Berger HM, Benders MJNL, Van Zoeren-Grobben D, Van De Bor M, Van Bel F 1996 Non protein bound iron in postasphyxial reperfusion injury of the newborn. Pediatrics 98: 883–889
Lorek A, Takei Y, Cady EB, Wyatt JS, Penrice J, Edwards AD, Peebles D, Wylezinska M, Owen-Reece H, Kirkbride V, Cooper CE, Aldridge RF, Roth SC, Brown G, Delpy DT, Reynolds EOR 1994 Delayed (“secondary”) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res 36: 699–706
Groenendaal F, de Graaf RA, van Vliet G, Nicolay K 1999 Effects of hypoxia-ischemia and inhibition of nitric oxide synthase on cerebral energy metabolism in newborn piglets. Pediatr Res 45: 827–833
Mintorovitch J, Yang GY, Shimuzu H, Kucharczyk J, Chan PH, Weinstein PR 1994 Diffusion-weighted magnetic resonance imaging of acute focal cerebral ischemia: comparison of signal intensity with changes in brain water and Na+,K+-ATPase activity. J Cereb Blood Flow Metab 14: 332–336
Allen KL, Busza AL, Proctor E, Williams SR, Van Bruggen N, Gadian DG, Crockard HA 1990 Restoration of energy metabolism and resolution of oedema following profound ischaemia. Acta Neurochir Suppl Wien 51: 171–173
Williams CE, Gunn AJ, Mallard EC, Gluckman PD 1991 Outcome after ischemia in the developing sheep brain: an electro-encephalographic and histological study. Ann Neurol 31: 14–21
Hossmann KA 1993 Ischemia mediated neuronal injury. Resuscitation 26: 225–235
Van Bel F, Dorrepaal CA, Benders MJNL, Zeeuw PEM, Van De Bor M, Berger HM 1993 Changes in cerebral hemodynamics and oxygenation in the first 24 hours after birth asphyxia. Pediatrics 92: 365–372
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Groenendaal, F., Shadid, M., McGowan, J. et al. Effects of Deferoxamine, a Chelator of Free Iron, on Na+,K+-ATPase Activity of Cortical Brain Cell Membrane during Early Reperfusion after Hypoxia-Ischemia in Newborn Lambs. Pediatr Res 48, 560–564 (2000). https://doi.org/10.1203/00006450-200010000-00023
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-200010000-00023
This article is cited by
-
Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets
Signal Transduction and Targeted Therapy (2024)
-
Prophylactic inhibition of NF-κB expression in microglia leads to attenuation of hypoxic ischemic injury of the immature brain
Journal of Neuroinflammation (2020)
-
Iron overload impact on P-ATPases
Annals of Hematology (2018)
-
Critical Evaluation of the Changes in Glutamine Synthetase Activity in Models of Cerebral Stroke
Neurochemical Research (2015)
-
Iron metabolism and lipid peroxidation products in infants with hypoxic ischemic encephalopathy
Journal of Perinatology (2008)
