ARTICLE
Auteur(s) : Naomi L Cook, Corinna Van Den Heuvel, Robert Vink
Discipline of Pathology, School of Medical Sciences,
The University of Adelaide, Australia
Traumatic brain injury
Traumatic injury to the central nervous system (CNS) is the leading
cause of death and disability in people under 40 years of age
[1]. Worldwide incidence rates of traumatic brain injuries (TBI)
are estimated at 150-200 cases per 100,000 population per
annum [2]. Motor vehicle accidents account for the majority of
moderate and severe TBI cases, whereas falls and sporting accidents
are responsible for most mild injuries [3]. Despite the major
public health significance of TBI, there is currently no effective
treatment regime and survivors are left with debilitating long-term
motor, cognitive and behavioural deficits.
TBI is defined as craniocerebral trauma associated with
decreased level of consciousness, amnesia, other neurological or
neuropsychological abnormalities, skull fracture, intracranial
lesions or death [4]. The neurological dysfunction resulting from
TBI is due to both direct, immediate mechanical damage to brain
tissue (the primary injury) and indirect, delayed (secondary)
injury mechanisms [5]. The primary event is irreversible and
includes both focal (e.g. contusion, laceration) and diffuse (e.g.
concussion, diffuse axonal injury) lesions [6]. In contrast,
secondary injury is comprised of a series of complex biochemical
changes that are triggered by the primary event and may continue
for days to weeks after the insult [7]. These changes include
disruption to the blood brain barrier (BBB), oedema, ischemia,
hypertension, inflammation, excitotoxicity and oxidative stress,
all of which can be deleterious to neuronal cells [6, 8, 9].
Magnesium decline following TBI
Magnesium has been implicated as a crucial component of the
secondary injury cascade that follows brain injury. Indeed, several
lines of evidence suggest that magnesium deficit is associated with
poor neurological outcome following TBI. A significant decline
in serum ionised magnesium (Mg2+) levels has been
measured in TBI patients, with the magnitude of Mg2+
decline being associated with the severity of TBI [10].
A decrease in brain intracellular free Mg2+
concentration has also been demonstrated after TBI in rats, and
this is associated with the development of neurological deficits
[11, 12]. Another study [13] examined the consequences of magnesium
deficiency prior to TBI in rats, and found that the
Mg2+-deficient group had significantly greater cortical
cell loss compared to the vehicle group, as well as cytoskeletal
alterations in cortical and hippocampal neurons.
Mg2+ deficiency in the absence of injury has been
shown to evoke an inflammatory response in rats, resulting in
leukocytosis, hyperplasia and increases in pro-inflammatory
cytokines and substance P [14]. Low Mg2+ caused lipid
peroxidation and activation of NF-KB in canine primary cerebral
vascular smooth muscle cells [15]. This is relevant to TBI since
lipid peroxidation can generate reactive oxygen species (ROS) and
reactive nitrogen species (RNS), thus activating multiple
signalling pathways that may result in cell death. Finally, low
Mg2+ diet in rats over generations led to a significant
loss of dopaminergic neurons in the substantia nigra, suggesting a
role of Mg2+ in the pathogenesis of Parkinson’s disease
[16].
Physiological role of magnesium
Mg2+ plays a vital role in a number of diverse
biological processes and is an essential co-factor required for the
function of numerous enzymes [17, 18]. Mg2+ is necessary
for all reactions that either consume or produce ATP, including
glycolysis, oxidative phosphorylation and cellular respiration
[19]. Mg2+ also plays an important role in protein
synthesis [20], the cell cycle and normal neuronal functioning [21]
and is often referred to as a physiological calcium blocker [22].
Furthermore, Mg2+ maintains the stability, integrity and
normal function of the cell membrane, and is essential for the
activity of the membrane Na+/K+-ATPase [23].
Mg2+ also modulates other ion transport pumps, carriers
and channels, and therefore is likely to be involved in the
regulation of signal transduction and the intracellular
concentrations of ions such as K+ and Ca2+
[24].
Mg2+ neuroprotection in TBI
Since magnesium is crucial to so many physiological processes, it
is clear that a decline in Mg2+ concentration, such as
that resulting from TBI, will adversely affect normal cellular
functioning, the maintenance of membrane potential and the capacity
for cells to undergo repair [25]. Indeed, several groups have
investigated Mg2+ as a potential multifactorial therapy
for TBI, since it is able to modulate many processes of the
secondary injury cascade. For example, magnesium ions are able to
regulate excitotoxic processes by blocking voltage- and
ligand-gated Ca2+ channels, including
N-methyl-D-aspartate (NMDA) receptors [26] and other voltage-gated
calcium channels [27], thus acting as a Ca2+ antagonist.
Mg2+ may also have protective effects on the BBB,
thereby reducing the formation of vasogenic oedema [19]. It has
also been demonstrated that Mg2+ inhibits the formation
of reactive oxygen species [28] and potentiates presynaptic
adenosine and relaxes vascular smooth muscle cells [29]. Adenosine
stimulation has been reported to reduce neuronal damage and
mortality in stroke [30]. Finally, Mg2+ preserves
mitochondrial membrane potential and has been shown to improve
oxidative phosphorylation and decrease lactic acid production when
administered post-TBI [19]. Additional properties that render
magnesium an attractive therapeutic agent are its low cost, ease of
use, low risk of adverse effects and its ability to penetrate the
BBB [27].
It is therefore not surprising that several groups have
investigated whether Mg2+ administration reduces the
mortality and morbidity associated with TBI. Post-TBI
Mg2+ administration in rats significantly reduced
cortical cell loss compared to the vehicle group [13] and was also
shown to reduce apoptosis and the expression of the
apoptosis-regulating proteins, p53 [31], Bax and Bcl-2 [32].
Another study [33] showed that magnesium chloride attenuated the
neurological motor deficits in brain-injured rats. Research
conducted in our own laboratory with magnesium salts [34] has also
demonstrated a neuroprotective effect of Mg2+ following
TBI. Mg2+ has been shown to improve neurological outcome
when administered up to 24 hours after injury [35], however,
the best results have been achieved when the therapeutic window is
restricted to 12 hours [25]. The study by Heath and Vink [11]
found that the Mg2+ decline persisted for at least
4 days after injury. However, the concentration of
Mg2+ in CNS injury has been shown never to fall below
0.2 mM [12]. Thus, it is likely that the length of time for
which free Mg2+ concentration is reduced, rather than
the magnitude of decline, is the parameter that influences
neurological outcome [25]. It is clear that there exists
substantial evidence that Mg2+ deficiency plays a role
in the secondary injury cascade of TBI and that administration of
magnesium salts is neuroprotective in experimental TBI.
Despite the positive results obtained using Mg2+ as a
therapy for TBI in animal models, a recent phase III clinical trial
[36] found that MgSO4 given to patients for 5 days
after traumatic brain injury was not neuroprotective and possibly
even had a negative effect on outcome. Given that all patients
(including the control group) received magnesium to restore
depleted serum levels to normal, it is unclear whether this
restoration of serum magnesium level was sufficient to confer
positive effects in all patients irrespective of the treatment
group. This result was in marked contrast to the clinical trial
reported by [37] which reported that acute Mg administration (less
than 24 h) resulted in significant improvements in Glasgow
outcome scores at 3 months, as well as in post-operative brain
swelling and 1-month mortality. While differences in trial results
have been ascribed to possible limitations in central magnesium
transport [38], the potential role of the more recently described
magnesium transporters in brain magnesium homeostasis and neuronal
cell death has not been critically assessed.
Transient receptor potential melastatin (TRPM) channels
Of all the potential eukaryotic magnesium transporters that have
been identified to date, the recent discovery and description of
the magnesium transporting transient receptor potential (TRP)
channel family has generated the most interest. The TRP channel
family is a diverse group of ion channels consisting of about
30 known members. The general properties of TRP channels are
discussed in a number of excellent general reviews [39-43] and will
not be discussed in detail here. Of interest to this review is the
TRP melastatin (TRPM) subfamily that contains eight members,
designated TRPM1-TRPM8. TRPM proteins are a heterogeneous group of
ion channels with diverse expression patterns, permeabilities,
activation mechanisms and physiological functions [44-46]. The
ubiquitously expressed TRPM7 is permeable to a wide range of
divalent metal ions, including Zn2+, Ni2+,
Ba2+, Co2+, Mg2+, Mn2+,
Sr2+, Cd2+ and Ca2+ [47], and is
one of only a few identified mammalian Mg2+ transporters
(see [48] for review). It consists of an ion channel fused to a
protein kinase domain [49] and has been implicated in many cellular
processes including synaptic transmission [50], the cell cycle
[51], normal growth and development [52], regulation of vascular
smooth muscle cells [53] and the proliferation of human
retinoblastoma cells [54]. While deletion of TRPM7 has been
shown to disrupt embryonic development without altering
Mg2+ homeostasis [55], evidence from a number of other
studies suggests that TRPM7 is necessary both for cell
survival and potentially for magnesium homeostasis. Genetic
deletion of TRPM7 in DT-40 chicken lymphocytes resulted
in non-viable cells [49]. In another study [56], TRPM7-deficient
cells were Mg2+-deficient and growth arrested, but the
viability and proliferation of these cells were rescued by
supplementation of extracellular Mg2+. The addition of
high levels of other cations was ineffective in substituting for
the loss of TRPM7, suggesting that TRPM7 regulates
Mg2+ homeostasis in eukaryotic cells.
TRPM7 activity is inhibited by free intracellular
Mg2+ and Mg. ATP complexes, and is strongly activated
when intracellular Mg.ATP and Mg2+ concentrations are
depleted [49, 57-60]. TRPM7 may also be regulated by
G-protein-coupled receptors, either via the cyclic AMP (cAMP) and
protein kinase A (PKA) pathway [61], or the phospholipase C
(PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate
(PIP2) [62]. Considering the vital role fulfilled by
TRPM7 with regard to cell viability and Mg2+
homeostasis, mutations in TRPM7 could be expected to result in
severe pathological consequences [63]. Indeed, the zebrafish
touchtone/nutria phenotype, resulting from mutations in the
TRPM7 gene, displayed growth retardation and serious
alterations in skeletal development [52].
The pathogenesis of complex neurodegenerative disorders is
believed to involve both genetic and environmental factors [64].
Two such disorders, amyotrophic lateral sclerosis and
Parkinsonism-dementia complex of Guam (ALS-G and PD-G,
respectively), have been found with a relatively high incidence on
islands in the Western Pacific. Environmental factors such as
deficiencies in dietary Ca2+ and Mg2+, toxins
from the cycad plant and high exposure to aluminium, manganese and
other toxic metals may act as triggers for these diseases [65].
With regard to genetic factors, Hermosura et al. [66] reported
a missense mutation in the TRPM7 gene, Thr1482Ile, in a
subgroup of ALS-G and PD-G patients but not in matched controls.
The protein encoded by this variant displays a higher sensitivity
to inhibition by levels of intracellular Mg2+. Thr1482,
which lies between the channel and kinase domains of TRPM7 is
evolutionarily conserved between many species, and phosphorylation
of Thr in this position is likely to be important for channel
function. Isoleucine cannot be phosphorylated, therefore, the
mutant allele found in ALS-G and PD-G patients could potentially
confer a functional deficit. Since TRPM7 is important in
maintaining homeostasis of Mg2+ and Ca2+, the
authors propose that the higher sensitivity to Mg2+ of
the TRPM7 variant, combined with the Mg2+- and
Ca2+-deficient environment, could result in severe
cellular deficiencies of these metal ions, which may contribute to
the aetiology of diseases such as ALS-G and PD-G [66]. The same
group has recently reported a missense mutation of the
TRPM2 gene (Pro1018Leu) in ALS-G and PD-G patients, which
resulted in TRPM2 channels that were unable to sustain ion
influx [65].
TRPM6 is the closest relative of TRPM7, with which it
shares 50% homology at the amino acid level [67]. TRPM6 is
able to form homomeric channels, as well as heteromeric channels
with TRPM7, which are biophysically and pharmacologically
distinguishable [68]. TRPM6 is mainly expressed in the kidney
and small intestine [69], but has also been localised in the brain
[70]. Mutations in the TRPM6 gene have been identified as the
cause of hypomagnesaemia with secondary hypocalcaemia (HSH) [69,
71, 72], an autosomal recessive disorder characterised by low serum
levels of Mg2+ and Ca2+ [73]. TRPM7 and
TRPM6 contain serine/threonine protein kinase domains
resembling elongation factor 2 (eEF-2) kinase and other
atypical alpha-kinases [74]. The protein kinase domain of
TRPM7 is able to phosphorylate serine and threonine residues
of various substrates, as well as to undergo autophosphorylation
[75]. Interestingly, TRPM6 is able to phosphorylate TRPM7, but
not vice versa [76].
TRPM channels and ischemic cell death
Over recent years, TRPM channels have gained attention as possible
therapeutic targets for ischemia. TRPM7 and TRPM2 have
been implicated in playing direct roles in Ca2+-mediated
neuronal death [77], although the exact mechanism by which this
occurs requires further investigation. It has been proposed that
TRPM7 mediates cell death via a positive feedback loop whereby
Ca2+ entry into cells as a result of injury causes the
production of free radicals, which activate TRPM7, leading to
further Ca2+ influx and additional free radical
production [78]. Indeed, the activation of TRPM7 during
ischemia is proposed to be a key factor contributing to
excitotoxicity and other deleterious processes [79]. Consistent
with this proposal, suppressing TRPM7 expression in
CA1 hippocampal neurons has been shown to be protective
against damage following ischemia [80].
TRPM2 is a non-selective cation channel, which is highly
permeable to Ca2+, and expressed in a wide range of
human tissues, including immune cells and brain [81-83].
TRPM2 is activated in response to oxidative and nitrosative
stress, and several groups have shown that activation of
TRPM2 by reactive oxygen species, such as hydrogen peroxide,
results in cell death via unregulated Ca2+ influx
[84-86]. TRPM2 is also activated by ADP-ribose [87], levels of
which are elevated in response to oxidative stress (for review, see
[88]). TRPM2 has recently been shown to aggravate
inflammation, specifically as a key participant in monocyte
chemokine production induced by H2O2 [89].
TRPM2 may form multimers with TRPM7, however this has yet to
be demonstrated conclusively. Interestingly, silencing of
TRPM7 also resulted in the silencing of TRPM2, suggesting that
the expression of these proteins may be co-regulated [77, 78]. The
role of TRPM2 and TRPM7 in ischemic neuronal cell death
has been comprehensively reviewed in several articles [78, 90, 91].
The role of TRPM6 in these processes is currently unclear,
however, given its localisation in the brain, its permeability to
Mg2+, ability to form functional heteromers with, and to
phosphorylate, TRPM7, it too may be a mediator of cell death.
TRPM channels and TBI
There are a number of secondary injury factors that contribute to
neuronal cell death after TBI. Excitotoxicity resulting from
Ca2+ influx through n-methyl-D-aspartate (NMDA)
receptors is one mechanism of delayed cell death following CNS
injury [79]. Several other secondary injury processes including
oxidative stress, oedema formation, apoptosis and necrosis also
require, to some extent, the influx of cations into neurons [92].
Therefore, non-selective cation channels, including TRPM channels,
have gained attention as potential contributors to neuronal cell
death.
There are several ways in which TRPM channels could contribute
to cell death following TBI (figure 1). The role of
TRPM2 and TRPM7 in ischemic neuronal death, as discussed
in the previous section, is clearly established and is extremely
relevant to TBI. Oxidative stress and the production of free
radicals have been demonstrated to be key secondary injury factors
in TBI [8, 9]. Since both TRPM2 and TRPM7 are activated
by reactive oxygen and nitrogen species (ROS and RNS,
respectively), oxidative stress could lead to the production of
positive feedback loops, whereby unregulated Ca2+ influx
via TRPM2 and TRPM7 channels stimulate secondary
signalling pathways that further enhances oxidative stress, leading
to tissue damage and cell death.
Deficits in Mg2+ concentration, as have been
demonstrated following TBI, can also lead to the generation of ROS
and RNS [15], further activating TRPM7 and TRPM2, thereby
enhancing inflammation, oxidative stress and cell death. ATP is
also depleted as a result of severe brain injury [9]. As discussed,
low intracellular Mg2+ and Mg.ATP levels strongly
activate TRPM7 [47, 49, 93]. Given that Mg2+ levels
remain suppressed for several days following injury [11], this is
potentially a critical and persistent pathway leading to cell death
after TBI. Furthermore, free radicals increase microvascular
permeability, and have been shown to cause blood-brain barrier
disruption and oedema following ischemia [94]. Indeed, oedema is
one of the most important secondary injury factors in TBI with
respect to patient outcome [95]. Changes in extracellular
Ca2+ concentrations as a result of injury also activate
TRPM7 [90] and TRPM2 [96]. All of these factors could potentiate
the cell death process by the generation of free radicals and
causing the sustained activation of TRPM2, TRPM7 and
TRPM2/TRPM7 multimers. TRPM6 may also be involved in
these processes, either alone or by association with TRPM7,
however, this requires further investigation.
TBI results in massive influxes of Zn2+ ions to
neurons, which is a major factor in neuronal cell toxicity and
death [97, 98]. While voltage-gated calcium channels have been
proposed to carry this current, zinc could also enter cells through
TRPM7 channels, which is permeable to a wide range of divalent
cations including Zn2+. Although trace metal ions are
necessary for the catalytic function of enzymes and normal cellular
function, their accumulation above trace levels is highly toxic
[47]. Precise regulation of ion channels such as TRPM7 is
vital to maintain normal physiological conditions and their
overactivation in pathological processes like TBI may lead to cell
death. TRPM7 has a low, constitutive activity in resting cells
that is likely to provide a constant flow of Mg2+ and
Ca2+ into the cell [46]. TRPM7 channel activity is
strongly activated when Mg2+ is decreased. Therefore,
the depletion of Mg2+ following TBI combined with
increases in ROS and RNS, which further stimulate TRPM7 in a
positive feedback loop, may result in impaired inhibition of
TRPM7 activity. The resultant overactivation of
TRPM7 could therefore result in extensive entry of cations
other that magnesium into the cell thus resulting in significant
cell death.
TRPM7 has also been implicated in the pathological response
to vessel wall injury, which may be relevant to both the primary
and secondary injury processes of TBI. At the time of insult,
shearing of nerve fibres results in massive ion fluxes across cell
membranes, loss of membrane potential and rapid release of
neurotransmitters from damaged neurons. This results in
excitotoxicity and evokes an inflammatory response, which
stimulates further pathological processes, eventually leading to
apoptosis and necrosis [99]. In response to shear stress, which
results in an increase in fluid flow, a significant number of
TRPM7 channels accumulated at the plasma membrane in less than
2 minutes, and an increase in TRPM7 current was detected
in vascular smooth muscle cells [100]. This rapid response by
TRPM7 most likely makes it one of the first molecules to react
to shear stress. TRPM7 was also identified as the
stretch-activated channel that is activated by osmotic swelling in
epithelial cells, and is involved in cellular volume regulation by
providing a Ca2+-influx pathway [101], which may be
relevant to cerebral oedema following TBI.
TRPM7 could also participate in cell death after TBI is by
responding to changes in extracellular pH [102, 103]. High
concentrations of protons may be generated in pathological
processes like TBI, leading to an acidic (pH < 6.0) state and
thus enhancing TRPM7 activity. Finally, the TRPM7 kinase
domain is able to phosphorylate annexin I, a Ca2+- and
phospholipid-binding protein originally described as a mediator of
the anti-inflammatory actions of glucocorticoids [104]. The
biological function of annexin I phosphorylation by TRPM7 is
currently unknown, but may have relevance to TBI since both
TRPM7 and annexin I have been implicated in cell death.
Conclusion
The secondary injury cascade resulting from traumatic brain injury
involves numerous pathological processes that can lead to cell
death. Deficits in intracellular Mg2+ concentration
occurring following TBI are associated with poor neurological
outcome, but despite promising experimental studies,
Mg2+ has not been proven clinically effective. It is
unlikely that targeting a single factor will result in a
significant improvement in outcome. Members of the TRPM channel
family have been implicated in ischemic neuronal death and may also
play a role in the injury processes occurring after TBI. In
particular, TRPM7, which is crucial to Mg2+ homeostasis
and cell survival, could be a critical mediator of cell death
following TBI. However, their role in magnesium transport seems
less important than their facilitation of other cation fluxes, as
well as the kinase role in inflammatory processes. TRPM channels
may therefore represent novel therapeutic targets as part of a
multifactorial treatment strategy for TBI, although not likely a
major target for regulating brain magnesium homeostasis.
Acknowledgments
Supported, in part, by the Neurosurgical Research Foundation of
Australia (RV) and a National Health and Medical Research Council
postgraduate research award (NLC).
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