Abstract
Transient perinatal hypoxia-ischemia (HI) can lead to delayed cerebral damage beginning 8–24 h after resuscitation. Cerebroprotective therapies applied soon after HI may thus reduce the severity of brain injury. We have previously shown that MgSO4 administration to newborn piglets after HI fails to prevent the delayed global impairment in cerebral energy metabolism characteristic of severe brain damage. However, high extracellular concentrations of magnesium ions have been found to prevent specific excitotoxic neural cell death in vivo and in vitro. This study therefore examined the hypothesis that MgSO4 administration after HI reduces damage in some regions of the brain even though global energy metabolism is unaffected. Twelve newborn piglets were subjected to global cerebral HI by transient occlusion of both common carotid arteries and reduction of the inspired oxygen fraction to 0.12 until cerebral high-energy phosphates, measured by magnetic resonance spectroscopy, were significantly depleted. Subjects were randomly assigned to two groups of six: the first received MgSO4 (three doses, 400 mg/kg 1 h after resuscitation and 200 mg/kg at 12 and 24 h), and the second received placebo infusions. At 48 h after the start of the experiment, the piglets were killed and their brains were perfused, fixed, and embedded in paraffin wax. Five-micrometer sections were stained with hematoxylin and eosin to allow semiquantitative analysis of the severity and extent of injury to the hippocampus, cerebellum, cerebral cortex, caudate nucleus, thalamus, and striatum and the white matter tracts. There was no difference in the severity of tissue damage between the MgSO4-treated group and the placebo-treated animals in any brain region.
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
- EPP:
-
exchangeable phosphate pool
- H&E:
-
hematoxylin and eosin
- HI:
-
hypoxia-ischemia
- MRS:
-
magnetic resonance spectroscopy
- NMDA:
-
N-methyl-d-aspartate
- NTP:
-
nucleotide triphosphate
- PCr:
-
phosphocreatine
- Pi:
-
inorganic phosphate
References
Volpe JJ 1995 Neurology of the Newborn, 3rd Ed. WB Saunders, Philadelphia, 279–314.
Azzopardi D, Wyatt JS, Cady EB, Delpy DT, Baudin J, Stewart AL, Hope PL, Hamilton PA, Reynolds EO 1989 Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res 25: 445–451.
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: 285–295.
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.
Blumberg RM, Cady EB, Wigglesworth JS, McKenzie JE, Edwards AD 1996 Relation between delayed impairment of cerebral energy metabolism and infarction following transient focal hypoxia-ischaemia in the developing brain. Exp Brain Res 113: 130–137.
Thoresen M, Penrice J, Lorek A, Cady EB, Wylezinska M, Kirkbride V, Cooper CE, Brown GC, Edwards AD, Wyatt JS, Reynolds EOR 1995 Mild hypothermia after severe transient cerebral hypoxia-ischaemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 37: 667–670.
Rose K, Christine CW, Choi DW 1990 Magnesium removal induces paroxysmal neuronal firing and NMDA receptor-mediated neuronal degeneration in cortical cultures. Neurosci Lett 115: 313–317.
McDonald JW, Silverstein FS, Johnston MV 1990 Magnesium reduces N-methyl- d -aspartate (NMDA)-mediated brain injury in perinatal rats. Neurosci Lett 109: 234–238.
Penrice J, Amess PN, Punwani S, Wylezinska M, Tyszczuk L, D'Souza P, Edwards AD, Cady EB, Wyatt JS, Reynolds EOR 1997 Magnesium sulfate after transient hypoxia-ischemia fails to prevent delayed cerebral energy failure in the newborn piglet. Pediatr Res 41: 443–447.
Marret S, Gressens P, Gadisseux J-F, Evrard P 1995 Prevention by magnesium of excitotoxic neuronal death in the developing brain: an animal model for clinical intervention studies. Dev Med Child Neurol 37: 473–484.
Mehmet H, Yue X, Squier MV, Lorek A, Cady E, Penrice J, Sarraf C, Wylezinska M, Kirkbride V, Cooper C, Brown GC, Wyatt JS, Reynolds EOR, Edwards AD 1994 Increased apoptosis in the cingulate sulcus of newborn piglets following transient hypoxia-ischaemia is related to the degree of high energy phosphate depletion during insult. Neurosci Lett 181: 121–125.
Yoshikawa Tetsuo 1968 Part V. The brain of the pig. In: Atlas of the Brains of Domestic Animals. University of Tokyo Press, Tokyo, 6–8, 16
Wyllie AH, Duvall E 1992 Oxford Textbook of Pathology. Vol 26. Oxford University Press, Oxford, 141–193.
Hockenbery D 1995 Defining apoptosis. Am J Pathol 146: 16–19.
Yue X, Mehmet H, Penrice J, Cooper C, Cady E, Wyatt JS, Reynolds EOR, Edwards AD, Squier MV 1997 Apoptosis and necrosis in the newborn piglet brain following transient hypoxia-ischaemia. Neuropathol Appl Neurobiol 23: 16–25.
Edwards AD, Yue X, Squier MV, Thoresen M, Cady EB, Penrice J, Cooper CE, Wyatt JS, Reynolds EOR, Mehmet H 1995 Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun 217: 1193–1199.
Levene M, Blennow M, Whitelaw A, Hanko E, Fellman V, Hartley R 1995 Acute effects of two different doses of magnesium sulphate in infants with birth asphyxia. Arch Dis Child 73: F174–1441.
Heath DL, Vink R 1997 Magnesium sulphate improves neurologic outcome following severe closed head injury in rats. Neurosci Lett 228: 175–178.
Gluckman PD, Williams CE 1992 When and why do brain cells die?. Dev Med Child Neurol 34: 1010
Thordstein M, Bågenholm R, Thiringer K, Kjellmar I 1993 Scavengers of free oxygen radicals with magnesium ameliorate perinatal hypoxic-ischemic brain damage in the rat. Pediatr Res 34: 23–26.
Hoffman DJ, Marro PJ, McGowan JE, Mishra OP, Delivoria-Papadopoulis M 1994 Protective effect of MgSO4 infusion on NMDA receptor binding characteristics during cerebral cortical hypoxia in the newborn piglet. Brain Res 644: 144–149.
Wu TJ, Teng RJ, Yau K-IT 1995 Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates. Pediatrics 96: 472–474.
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.
Galvin KA, Oorschot DE 1998 Post injury magnesium sulfate treatment is not markedly neuroprotective for striatal medium spiny neurons after perinatal hypoxia/ischemia in the rat. Pediatr Res 44: 740–745.
Author information
Authors and Affiliations
Additional information
Supported by The Sir Jules Thorn Charitable Trust, the Medical Research Council, UK, the Wellcome Trust, University College London Hospitals Trust, and Garfield Weston Foundation.
Rights and permissions
About this article
Cite this article
Greenwood, K., Cox, P., Mehmet, H. et al. Magnesium Sulfate Treatment after Transient Hypoxia-Ischemia in the Newborn Piglet Does Not Protect against Cerebral Damage. Pediatr Res 48, 346–350 (2000). https://doi.org/10.1203/00006450-200009000-00014
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-200009000-00014
This article is cited by
-
Magnesium sulfate: a last roll of the dice for anti-excitotoxicity?
Pediatric Research (2019)
-
Disorganization of Oligodendrocyte Development in the Layer II/III of the Sensorimotor Cortex Causes Motor Coordination Dysfunction in a Model of White Matter Injury in Neonatal Rats
Neurochemical Research (2018)
-
Magnesium treatment for neuroprotection in ischemic diseases of the brain
Experimental & Translational Stroke Medicine (2013)
-
Brain lesions in newborns exposed to high-dose magnesium sulfate during preterm labor
Journal of Perinatology (2006)
-
Antenatal Risk Factors Associated with the Development of Lenticulostriate Vasculopathy (LSV) in Neonates
Journal of Perinatology (2005)
