ARTICLE
Auteur(s) : Robert Vink, Naomi L Cook,
Corinna van den Heuvel
Discipline of Pathology, School of Medical Sciences,
University of Adelaide, Australia
Brain magnesium levels have now been shown to decline in a
number of acute and chronic pathologies of the brain including
traumatic brain injury [1], migraine [2], cocaine exposure [3],
ethanol intoxication [4, 5], stroke [6] and subarachnoid hemorrhage
[7], with mounting evidence supporting similar declines in
depression and neurodegeneration [8-11]. Accordingly, there has
been a considerable research effort directed toward establishing
the mechanisms of such decline and the potential for magnesium
administration as a therapeutic intervention. While a number of
excellent reviews have previously summarized progress in this field
of magnesium research [12-14], few have covered a spectrum of acute
and chronic brain pathologies. The current review therefore
highlights recent progress in brain magnesium research focusing on
advances of relevance to various pathologies.
Traumatic brain injury
Despite the considerable pre-clinical evidence from rodent models
that magnesium therapy improves outcome after traumatic brain
injury [12], magnesium therapy has failed in a recent clinical
trial of trauma [15]. Although the standard care in the clinical
trial was to correct plasma magnesium concentration in all
patients, those in the magnesium treatment group received
additional magnesium to at least double plasma magnesium
concentration. At this concentration, magnesium did not deliver any
improvement in outcome and actually was deleterious with respect to
placebo on a number of markers. While reflecting the general
dose-response characteristics previously described for magnesium
administration in the pre-clinical studies [16], attention has
nonetheless been drawn to the fact that in human TBI, intravenous
magnesium administration only marginally increases CSF magnesium
concentration [17]. Whether this small increase in CSF
concentration is sufficient to increase brain cellular free
magnesium concentration is critical given that the increase in
brain free magnesium concentration is essential to confer
neuroprotection [16]. Entry of magnesium into the CNS is dependent
on the integrity of the blood brain barrier. While animal models of
trauma produce extensive opening of the blood brain barrier that
facilitates magnesium entry into the CNS for at least 24 h
[18, 19], such an opening is not always present in human trauma
[20]. Therefore magnesium may not have entered as it did in the
pre-clinical studies and, under these circumstances, peripheral
effects of magnesium administration may dominate over central
effects, which in brain injury would be deleterious to critical
parameters such as blood pressure and cerebral perfusion.
A better understanding of magnesium entry into the human CNS
is required to overcome this barrier to therapy.
Stroke
Magnesium therapy has also been described in the clinical stroke
literature [21], with similar negative results as in the trauma
trial. However, unlike the trauma trial, magnesium was shown to be
beneficial in a subgroup of patients with noncortical, or lacunar
strokes. It is well known that the blood brain barrier around
infarcted tissue is highly permeable, thus potentially facilitating
local magnesium entry to the injured tissue. Subsequent analysis of
the original trial data indicated that the beneficial effects of
magnesium on lacunar strokes could not be attributed to other
baseline factors such as severity of stroke, blood pressure or time
to treatment [22], although there was a strong correlation with age
of patient. The authors were unable to rule out that the positive
findings may have been influenced by such other confounding factors
and have therefore recommended that a large clinical trial of
magnesium in lacunar clinical syndromes be conducted.
Of interest has been the subsequent pre-clinical study examining
the effects of magnesium on lacunar strokes. Despite reducing blood
pressure and improving motor outcome, magnesium did not
significantly reduce infarct size [23], which is contrary to
expectations that infarct size correlates with neurological
outcome. Whether this indicates that infarct size is not as
important as synaptic connectivity is yet to be determined.
Neonatal brain injury
A number of studies have suggested that maternal magnesium
administration may be of benefit to pediatric outcome, although
this view is not universally held [24]. A recent meta-analysis
of all trials has nonetheless recommended the use of magnesium for
neuroprotection in the preterm fetus [25]. These studies have
clearly shown that low-dose prenatal magnesium is beneficial for
outcome in very preterm infants and that its administration does
not increase mortality. The dose is particularly significant given
that high prenatal doses of magnesium have been shown to be
deleterious to neonatal outcome [24]. While the reasons for this
dose effect are unclear, administration of high doses of magnesium
have been purported to be detrimental to the fetal brain in
critical periods of neurodevelopment, in part by inducing apoptotic
cell death [26].
Beneficial effects of magnesium administration are not limited
to the prenatal period with recent studies demonstrating that
postnatal magnesium administration also improves neurological
outcome in term neonates with perinatal asphyxia at discharge [27]
as well as at 18 months [28]. Pre-clinical studies suggest that
these results should be interpreted with caution given that the
protective effects of magnesium in animals have only been observed
in mild to moderate brain injury, with no positive effects observed
following severe brain injury [29].
Combination treatment in acute injury
A number of reports have supported combination therapy with
magnesium, which is unsurprising given that brain injury is widely
considered to be the result of multiple injury factors that combine
to culminate in neuronal cell death. Targeting an individual injury
factor is therefore unlikely to result in a beneficial outcome, and
multipotential therapies that target more than one injury factor
are gaining increasing attention [30]. To date, various
combinations with magnesium have been examined in stroke and
traumatic CNS injury including magnesium with glutamate antagonists
[31], growth factors [32], B vitamins [33], antioxidants [34, 35],
immunosuppressants [36] or hypothermia [34, 37]. The studies have
produced mixed results in preclinical studies, although the
combination of magnesium and hypothermia has produced promising
results. Clinical trials examining the efficacy of combined
hypothermia and magnesium have been recommended for stroke.
Neurodegeneration
With respect to chronic brain injury and neurodegeneration, a
critical role for magnesium has been implicated in Alzheimer’s
disease [8], Huntington’s disease [11], mitochondrial cytopathies
[38] and depression [10], although most recent studies have focused
on Parkinson’s disease. These recent reports have shown that
magnesium deficient mice are susceptible to developing Parkinson’s
disease [39], and that magnesium administration is beneficial in an
in vitro model of Parkinson’s disease [40]. In effect, they
describe that magnesium concentration is critical in disease onset,
which is consistent with the earlier finding that magnesium
deficiency over a number of generations is associated with the
development of Parkinson’s disease [41]. While the exact mechanisms
by which magnesium is associated with Parkinson’s disease are
unknown, the appearance of variants of the TRPM channels [42] that
are linked with magnesium transport suggest that magnesium
transporters may play a role in disease onset under some
circumstances. This hypothesis is supported by our own studies
(unpublished results) that have shown that Parkinson’s disease is
associated with reduced TRPM2 and TRPM7 channel mRNA expression.
Whether this reduced magnesium transport initiates the inflammation
and oxidative stress that have been widely reported in Parkinson’s
disease is yet to be investigated. Aside from disease onset,
magnesium has also been shown to reduce dyskinesia (abnormal motor
movements) in Parkinson’s disease [43], suggesting some interaction
between neurotransmitter release and magnesium levels.
Conclusion
Magnesium continues to be of interest to those who study acute and
chronic brain injury. Clear associations have now been described
between magnesium homeostasis and functional outcome in acute
injury, as well as in disease onset and progression in chronic
injury and neurodegeneration. However, it is also apparent that
just administering magnesium as a therapeutic intervention is a
simplistic approach that does not always achieve desired outcomes.
Several barriers exist to successful therapeutic intervention, not
the least being that experimental models of CNS disease and injury
do not always fully replicate the human condition. The role and
characterization of magnesium transporters is also becoming
increasingly important, particularly in neurodegeneration. While
significant progress has been made in understanding the role of
magnesium in these various brain pathologies, its therapeutic
potential as well the mechanisms associated with its decline, there
is still much to be done to fully capitalize the potential of this
important ion.
Acknowledgments
Supported, in part, by the Neurosurgical Research Foundation of
Australia.
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