Original Articles
Therapeutic potential of magnesium in the treatment of acute stroke,☆☆

https://doi.org/10.1053/jscd.2000.20669Get rights and content

Abstract

Magnesium is a key cation in multiple biological processes, including membrane excitability, protein synthesis, and cellular bioenergetics. Parenterally administered magnesium crosses the blood-brain barrier, raises brain concentrations to supraphysiological levels, and is neuroprotective in preclinical models of cerebral and spinal cord ischemia, excitotoxic injury, and head trauma. Neuronal and vascular effects of therapeutic magnesium may be pertinent, including inhibition of presynaptic release of excitatory neurotransmitters, presynaptic potentiation of adenosine, blockade of the N-methyl D-aspartate receptor, block of voltage-gated calcium channels, relaxation of vascular smooth muscle with vasodilatation of large and small vessel vascular beds causing increased cerebral blood flow, antagonism of endothelin-1 and other vasoconstrictors, enhanced postischemic recovery of tissue adenosine triphosphate, buffering of intracellular calcium ions (especially antagonism of mitochondrial calcium entry), and inhibition of deleterious ion shifts in white matter. Wide clinical experience in obstetrics and myocardial infarction confirms safety and tolerability as a therapeutic agent. Clinical trials in stroke are ongoing following encouraging results of pilot studies.

References (107)

  • LT Iseri et al.

    Magnesium: Nature's physiologic calcium blocker

    Am Heart J

    (1984)
  • M Favaron et al.

    Tissue-specific modulation of the mitochondrial calcium uniporter by magnesium ions

    FEBS Lett

    (1985)
  • PK Stys et al.

    Effects of polyvalent cations and dihydropyridine calcium channel blockers on recovery of CNS white matter from anoxia

    Neurosci Lett

    (1990)
  • RA Reinhart

    Clinical correlates of the molecular and cellular actions of magnesium on the cardiovascular system

    Am Heart J

    (1991)
  • MI Lee et al.

    The effects of magnesium sulfate infusion on blood pressure and vascular responsiveness during pregnancy

    Am J Obstet Gynecol

    (1984)
  • E Alborch et al.

    Comparison of the anticonstrictor action of dihydropyridines (nimodipine and nicardipine) and Mg2+ in isolated human cerebral arteries

    Eur J Pharmacol

    (1992)
  • T Tsuda et al.

    Mg2+ administered up to twenty-four hours following reperfusion prevents ischemic damage of the CA1 neurons in the rat hippocampus

    Neuroscience

    (1991)
  • JW McDonald et al.

    Magnesium reduces N-methyl-D-aspartate (NMDA)-mediated brain injury in perinatal rats

    Neurosci Lett

    (1990)
  • TK McIntosh et al.

    Magnesium protects against neurological deficit after brain injury

    Brain Res

    (1989)
  • DH Smith et al.

    Magnesium and ketamine attenuate cognitive dysfunction following experimental brain injury

    Neurosci Lett

    (1993)
  • MR Hoane et al.

    Preoperative regimens of magnesium facilitate recovery of function and prevent subcortical atrophy following lesions of the rat sensorimotor cortex

    Brain Res Bull

    (1998)
  • BM Altura et al.

    Role of brain [Mg2+]i in alcohol-induced hemorrhagic stroke in a rat model: A 31P-NMR in vivo study

    Alcohol

    (1995)
  • QF Huang et al.

    Magnesium ions prevent phencyclidine-induced cerebrovasospasms and rupture of cerebral microvessels: Direct in-vivo microcirculatory studies on the rat brain

    Neurosci Lett

    (1990)
  • BM Altura et al.

    Cocaine induces rapid loss of intracellular free Mg2+ in cerebral vascular smooth muscle cells

    Eur J Pharmacol

    (1993)
  • M Kynczl-Leisure et al.

    Increased bleeding time after magnesium sulfate infusion

    Am J Obstet Gynecol

    (1996)
  • KL Woods et al.

    Long-term outcome after intravenous magnesium sulphate in suspected acute myocardial infarction: The second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2)

    Lancet

    (1994)
  • BM Sibai et al.

    A comparison of intravenous and intramuscular magnesium sulfate regimens in preeclampsia

    Am J Obstet Gynecol

    (1984)
  • GR Thurnau et al.

    Cerebrospinal fluid levels of magnesium in patients with preeclampsia after treatment with intravenous magnesium sulfate: A preliminary report

    Am J Obstet Gynecol

    (1987)
  • MA Belfort et al.

    Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: A randomized, placebo-controlled study

    Am J Obstet Gynecol

    (1992)
  • A Fuentes et al.

    Angiotensin-converting enzyme activity in hypertensive subjects after magnesium sulfate therapy

    Am J Obstet Gynecol

    (1987)
  • JR Barton et al.

    Magnesium sulfate therapy in preeclampsia is associated with increased urinary cyclic guanosine monophosphate excretion

    Am J Obstet Gynecol

    (1992)
  • DS Mastrogiannis et al.

    Effect of magnesium sulfate on plasma endothelin-1 levels in normal and preeclamptic pregnancies

    Am J Obstet Gynecol

    (1992)
  • SM Cox et al.

    Randomized investigation of magnesium sulfate for prevention of preterm birth

    Am J Obstet Gynecol

    (1990)
  • H Ebel et al.

    Magnesium metabolism: A review

    J Clin Chem Clin Biochem

    (1980)
  • WW Oppelt et al.

    Magnesium exchange between blood and cerebrospinal fluid

    Am J Physiol

    (1963)
  • KA Hossmann et al.

    Regional pH and electrolyte homeostasis of cat brain after prolonged ischemia

    Neurochem Pathol

    (1988)
  • JA Helpern et al.

    Acute elevation and recovery of intracellular [Mg2+] following human focal cerebral ischemia

    Neurology

    (1993)
  • SM Rothman

    Synaptic activity mediates death of hypoxic neurons

    Science

    (1983)
  • IS Kass et al.

    Magnesium and cobalt, not nimodipine, protect neurons against anoxic damage in the rat hippocampal slice

    Anesthesiology

    (1988)
  • DAS Smith et al.

    Effect of changing extracellular levels of magnesium on spontaneous activity and glutamate release in the mouse neocortical slice

    Br J Pharmacol

    (1989)
  • RH Evans et al.

    Selective antagonism by Mg2+ of amino acid-induced depolarization of spinal neurones

    Experientia

    (1977)
  • L Nowak et al.

    Magnesium gates glutamate-activated channels in mouse central neurones

    Nature

    (1984)
  • T Yamakura et al.

    Different sensitivities of NMDA receptor channel subtypes to non-competitive antagonists

    NeuroReport

    (1993)
  • N Burnashev et al.

    Control by asparagine residues of calcium permeability and magnesium blockade in the NMDA receptor

    Science

    (1992)
  • H Mori et al.

    Identification by mutagenesis of a Mg2+-block site of the NMDA receptor channel

    Nature

    (1992)
  • S Kawajiri et al.

    Multiple structural determinants of voltage-dependent magnesium block in recombinant NMDA receptors

    Neuropharmacology

    (1993)
  • T Kuner et al.

    Multiple structural elements determine subunit specificity of Mg2+ block in NMDA receptor channels

    J Neurosci

    (1996)
  • A Frandsen et al.

    Effect of magnesium on NMDA mediated toxicity and increases in [Ca2+]i and cGMP in cultured neocortical neurons: Evidence for distinct regulation of different responses

    Neurochem Int

    (1994)
  • NL Harrison et al.

    Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex

    Br J Pharmacol

    (1985)
  • P Ascher et al.

    The role of divalent cations in the N-methyl-D-aspartate responses of mouse central neurones in culture

    J Physiol (Lond)

    (1988)
  • K.W.M. is coprincipal investigator in the Intravenous Magnesium Efficacy in Stroke (IMAGES) trial, which is funded by the UK Medical Research Council.

    ☆☆

    Address reprint requests to Keith W. Muir, MD, MRCP, Department of Neurology, Southern General Hospital, Glasgow G51 4TF, Scotland.

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