Stroke

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For 15 years many neuroprotective agents have been described as effective in the treatment of ischaemic stroke, i.e. an infarct of brain tissue which is different from haemorrhagic stroke, i.e. an haemorrhagia in the context of brain tissue. Magnesium sulphate is currently undergoing clinical trials in the treatment of acute stroke. It is well known how Mg2+ plays a physiological role in processes pertinent to ischaemia. In the brain it is complexed with ATP and is an important cofactor in cellular energy metabolism and protein synthesis.38 Brain magnesium concentrations are regulated by active blood-brain barrier transport that maintains cerebrospinal fluid (CSF) concentrations higher than those in serum, typically 1.1 mmol/l compared to 0.8mmol/l. Magnesium concentration increases in situations of focal ischaemia and seizures in animal models.39,40 Intracellular ionized magnesium concentrations increase in ischaemic stroke presumably because of a decrease in cellular ATP, the main intracellular buffer of magnesium.41

Magnesium is an attractive therapeutic agent because it is inexpensive, widely available and intravenous, and intramuscular administration yields predictable serum concentrations. Magnesium is normally excreted by the kidneys with a half life of 4 hours or less and adverse effects generally are restricted to patients with advanced renal failure. Overdose can be detected clinically by loss of deep tendon reflexes and administration of calcium gluco-nate generally avoids further problems. The wide therapeutic index of magnesium contrasts with the majority of neuroprotective agents which have been associated with important side effects. There are a number of possible mechanisms of action of magnesium in the protection of neurones and glia (i.e. the connective tissue in the central nervous system) from ischaemic damage. Reduction of infarct size by magnesium may be the consequence of an effect on blood flow or a direct neuroprotective effect or a combination of both. After cerebral artery occlusion, a core region rapidly necroses. A surrounding region of ischaemia is known as ischaemic penumbra which may also proceed towards necroses following a complex range of metabolic reactions. These processes include excessive release of neurotransmitters such as glutamate, excessive activation of glutamate receptors, excessive sodium and calcium entry into the cell via receptor-operated and voltage-dependent channels, and activation of calcium-dependent enzymes that lead to free-radical production. This latter phenomenon leads to membrane lipid breakdown, proteolysis and initiation of apoptosis and inflammatory response (for review see Ref. 42).

Magnesium may act at different levels in this complex chain of reactions. It may inhibit ischaemia-induced glutamate release, an excitatory amino acid neurotransmitter,43 and has antagonist properties at the N-methyl-D-aspartate (NMDA) receptor ion channel level44,45 leading to increased Ca2+ intracellular concentrations. Magnesium antagonizes calcium entry via voltage-gated channels, antagonizes mitochondrial calcium overload and may prevent cellular ATP depletion.46 Despite doubts about brain penetration by systemically administered magnesium, preclinical and clinical studies show slow entrance of magnesium into the CSF and brain tissue.47 The beneficial effects of magnesium administration in animal models of ischaemia are numerous. Magnesium ameliorates brain injury induced by injection of NMDA,48 prevents NMDA-induced seizures,49 increases ionized magnesium after head trauma50 and induces modifications of NMDA binding properties.51 In addition to neuronal effects, magnesium also has a number of vascular effects that may be important, particularly increased cerebral blood supply52 and antagonism of vasoconstrictor substances.41

A series of six randomized controlled trials on magnesium in stroke were recently performed but only four are suitable for meta-analysis.53 All trials have reported a reduction in the end-point of mortality but the small number of patients has hampered the true significance of these studies.54,55 Most clinical trials have administered magnesium as an intravenous loading infusion usually over 15min followed by a maintenance infusion of about 24 hours. Overall the results of these small trials are encouraging and have constituted the basis for a large ongoing trial, the intravenous magnesium efficacy in stroke (IMAGES) trial. IMAGES is a multicentric study involving over 130 centres and designed to detect a 5.5% absolute difference in death and disability 3 months after stroke.56 A substudy of IMAGES, MR-IMAGES, utilizes magnetic resonance imaging to compare lesion size at acute and later time points.

Clinical data are presently too limited to permit definite conclusions on the effects of magnesium in patients with stroke. Magnesium has a profile comparable with or superior to synthetic neuroprotective drugs. Nevertheless, no neuroprotective agent has so far been successful in clinical trials and there have been a large number of failures with promising compounds.

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