ARTICLE
Auteur(s) : Michael R
Hoane, David R Gilbert, Adrianne B Barbre, Stacy A Harrison
Restorative Neuroscience Laboratory, Brain and Cognitive Science
Program, Department of Psychology, Southern Illinois University,
Carbondale, IL, USA
It is well established that Mg2+ is essential for
maintaining normal cellular functions such as glycolysis [1],
maintaining membrane structure and function [2], protein synthesis
and DNA replication [3, 4]. Mg2+ also plays a vital role
in the pathophysiological events that occur following injury to the
central nervous system (CNS). One of these events is the disruption
of normal Mg2+ homeostasis, which has been shown to be
very detrimental. Vink and colleagues were the first to identify
the disruption of Mg2+ homeostasis following CNS injury
[5-7]. These studies have shown that fluid percussion injury (FPI)
produced a rapid and severe decline in intra- and extracellular
Mg2+ levels, which correlated significantly with the
severity of the behavioral deficits observed following injury
[5-8]. Heath and Vink have also shown that after severe
impact-acceleration injury intracellular levels of free
Mg2+ decline for four days post-injury and reach
pre-injury levels again by the sixth day [9].
Mg2+ pharmacotherapy has been found to be an
effective treatment in models of ischemia, FPI and cortical
lesions. For example, it has been shown that administration of
magnesium chloride (MgCl2) following focal cortical
injuries significantly improved behavioral outcome and reduced the
amount of lesion induced tissue damage [10]. It has also been shown
that MgCl2 facilitated behavioral recovery following
lesions that produce chronic impairments. MgCl2 induced
recovery of forelimb placing following large cortical injuries that
produced chronic impairments in untreated animals [11, 12].
Similarly, previous research has found that rats treated with daily
injections of Mg2+ prior to an electrolytic lesion of
the sensorimotor cortex (SMC) exhibited improved recovery of
function when compared to those treated with saline [13].
Administration of magnesium sulphate (MgSO4) or
MgCl2 has also been shown to improve functional outcome
following FPI and diffuse axonal injury [5, 9, 14-19].
Given the fact that Mg2+ is a vital nutrient it might
be expected that manipulation of dietary Mg2+ levels
would have an impact on recovery of function following brain
injury. A hallmark study by McIntosh and colleagues administered a
Mg2+-deficient diet to rats for 14 days prior to FPI
[5]. It was found that this diet reduced brain Mg2+
levels by 15% and resulted in a 53% mortality in the
Mg2+-deficient group. It was also found that this diet
significantly impaired the functional neuroscore assessment for 4
weeks following the injury. A Mg2+-deficient diet has
also been shown to exacerbate alcohol-induced stroke fatalities
[20]. Furthermore, several recent studies have shown that
Mg2+ deficiency impairs fear conditioning. In these
studies, a Mg2+-deficient diet (2-3 weeks) resulted in
significant memory deficits in both contextual and cued
conditioning tests; as well as increasing N-methyl-d-aspartate
(NMDA) hyperfunction [21, 22]. This hyperfunctioning of the NMDA
receptor should result in worsened behavioral outcome following
TBI. Although, it has been shown that Mg2+ deficiency
prior to injury worsened behavioral outcome it has yet to be
determined how generalizable this effect is. For example, does it
disrupt multiple behavioral systems (sensorimotor, motor or
cognitive) and what is the neuropathological effect? Furthermore,
can a Mg2+-enriched diet improve functional outcome when
fed prior to injury?
The purpose of the present experiment was to examine the effect
of dietary Mg2+ manipulation on recovery of function.
Rats were placed on one of three different diets
(Mg2+-normal, Mg2+-enriched, or
Mg2+-deficient) for 2 weeks prior to receiving cortical
injuries. Behavioral testing was conducted to assess sensorimotor
and cognitive performance. This study will aid in the understanding
of the relationship between Mg2+ dietary manipulations
and behavioral outcome following brain injury.
Materials and methods
Subjects
Forty male Sprague-Dawley rats (weighing 275-350 g) were used
as subjects. All experimental procedures were reviewed and approved
by the Institutional Animal Care and Use Committee. Rats were
maintained on a standard 12-h light/dark cycle with food and water
available ad libitum.
Diet Manipulation
Experimental diets were purchased from Harlan TEKLAD (Madison, WI).
The Mg2+-deficient diet (TD02373) was formulated with
0.0 g/kg of MgO. The Mg2+-normal diet (TD94253) was
formulated with 1.02 g/kg of MgO. The Mg2+-enriched diet
(TD02372) was formulated with 9.95 g/kg of MgO. All rats were
placed onto their formulated diets 2 weeks prior to injury and were
allowed to feed and drink ad libitum. All behavioral testing and
anatomical analyses were conducted without knowledge of the diet
assignment. Following surgery all animals were placed back onto
normal rodent diets.
Serum Mg2+ analysis
Immediately prior to injury, blood was collected from the tail vein
to be used for the determination of serum Mg2+ levels.
Samples were frozen and shipped to a clinical laboratory for
analysis using the ACE® magnesium reagent and NExCT™
clinical chemistry system (Schiapparelli Biosystems, Inc.,
Fairfield, NJ, USA).
Surgery
The surgical procedure was performed using aseptic procedures and
conditions. Animals were anesthetized with a cocktail of ketamine
(90 mg/kg, i.p.) and xylazine (10 mg/kg, i.p.) and then prepared
for surgery [23]. When the animal became unresponsive (no ocular or
pedal reflexes) it was shaved and scrubbed with 70% alcohol
followed by betadine and placed in a stereotaxic device. A midline
scalp incision was made in the skin and underlying fascia. A
circular craniotomy (5.0 mm) was then performed with a Dremel
hand drill and a specially designed drill bit that prevented
damaging the meninges or cortical tissue. The craniotomy was
unilateral and centered over the cortical region containing the
sensorimotor cortex (-0.5 mm posterior and 3.0 mm lateral
to bregma). The contusion injury was produced using a sterile,
stainless steel impactor tip (3.0 mm diameter) attached to a
piston activated with compressed air. The impactor tip was
positioned above the cortex and upon activation (2.75 m/s),
made contact with the cortex for 0.5 s, resulting in a
2.5 mm compression of the cortex. It should be noted that the
impactor tip did not actually penetrate the cortex, or the
meninges, but only momentarily compressed the tissue. Following the
contusion, the incision was closed with nylon suture material. The
animals were maintained on a heating pad (37°C) until they showed
locomotive behavior and were then returned to their home cage. Sham
animals were prepped for surgery, anesthetized, placed into the
stereotaxic device, given a midline scalp incision and craniotomy,
sutured and allowed to recover.
Behavioral analysis
Vibrissae- forelimb placing
This test measures sensorimotor dysfunction following cortical
injury and has been described in detail [24]. Each forelimb was
independently tested for placing reactions by touching the
vibrissae to a Plexiglas surface. Testing was conducted on
post-operative days 2, 4, 6, 10, 14, 21, 28, 35, and 42. In
un-injured animals, vibrissae stimulation elicits a placing
response. This response was observed when the animal placed its
forelimb on the surface after vibrissae contact. The rats received
10 trials for each forelimb per test day.
Bilateral tactile adhesive removal test
This test was used in order to examine sensorimotor deficits
following injury [24, 25]. The rats were removed from their cages
and gently held while a small adhesive patch
(121.5 mm2) was applied to the radial aspect of
each forelimb. The order of attachment varied between trials. The
rat was then returned to its cage and the order and latency of
removal was recorded. Each rat received two trials per test day and
was tested on post-operative days 2, 4, 6, 10, 14, 21, and 28. The
trial ended when the rat removed both stimuli or at the end of two
minutes.
Cognitive assessment
The Morris water maze was used to assess cognitive functioning
[25]. A blue fiberglass tank, 1.5 m in diameter and 76 cm
deep, was filled with water to a depth of 32 cm. A
10 cm2 Plexiglas platform was submerged 1.0 cm
below the surface of the water. A San Diego Instruments video
recording system with SMART tracking software was used to track and
record the movement of each rat as it traveled over the dark
background. Starting positions were randomly selected in the pool
for the reference memory task. Trials measuring reference memory
began on post-operative day 11 and continued for 4 days. The
submerged platform was always located in the center of quadrant 2,
halfway between the wall and the center of the tank. Rats were
placed into the water at one of four randomly chosen starting
points. Rats completed 4 trials on each test day, being released at
each of the starting points. All trials ended when the rat reached
the platform or after 90 seconds had elapsed. If the rat did not
reach the platform within 90 seconds, it was guided to the platform
and remained there for 10 seconds. Swim latency was recorded for
each trial.
Histology
At 45 days post-injury, rats were anesthetized with Nembutal, (100
mg/kg, i.p.) and transcardially perfused with 0.9% phosphate
buffered saline, followed by 4% paraformaldehyde. The brains were
carefully extracted from the cranium, post-fixed in 4%
paraformaldehyde and then cryopreserved in 30% sucrose for 3 days
prior to sectioning. The brain was sectioned frozen on a sliding
microtome through the extent of the injury cavity. Coronal slices
(40 μm thick) were collected in a cryopreservative solution
for storage. The extent of the lesion was analyzed with an Olympus
microscope (BX-51) and an Olympus 13.5 megapixel digital camera
(DP-70). Images of the sections throughout the extent of the injury
coordinates were captured using the digital capturing system and
area measures of the lesioned tissue were determined using
ImageTool software. The Calvalieri method was used to calculate the
volumes of the ipsilateral cortex and the contralateral cortex
[26]. The number of sections and the section thickness (40 μm)
were multiplied by the mean area of the lesion cavity (calculated
at five stereotaxic coordinates surrounding the lesion: 2.20, 1.20,
0.20, -1.20, -2.20 relative to bregma) [27]. The extent of cortical
injury was measured by calculating the percent reduction in the
ipsilateral cortex compared to the contralateral cortex using the
formula (1-(ipsi/contra) x 100) [24].
Statistical Analysis
Statistical evaluations were performed with SPSS v15.0 to determine
if the Mg2+ dietary condition modulated behavioral
recovery following injury. Data was analyzed for each behavioral
test using analysis of variance (ANOVA) tests following procedures
for general linear models with options for repeated measures when
appropriate. Huyn-Feldt (HFP) probabilities were used when
assessing the repeated measures factor. Post-hoc analyses were
performed with Tukey’s HSD tests.
Results
Initial behavioral analyses indicated that there were no
significant differences in performance between the animals that
received sham procedures and any of the dietary manipulations.
Analysis of forelimb placing data with a repeated measures ANOVA of
the sham-Mg2+-normal (n = 4)
sham-Mg2+-enriched (n = 5) and
sham-Mg2+-deficient (n = 4) revealed no significant
differences for group [F(2,10) = 0.61, p > 0.56], day
[F(1.37,13.69) = 0.78, p > 0.43], or the group x day interaction
[F(2.74,13.69) = 0.77, p > 0.52]. The same was also true for the
tactile removal data. The effects for group [F(2,10) = 0.03, p >
0.97] and the group x day interaction [F(6.48,832.38) = 0.62, p
> 0.72] were non-significant; however, the effect of day was
significant [F(3.24,32.38) = 0.64, p < 0.001]. Comparison of
swim latencies on the acquisition of reference memory revealed no
significant differences for group [F(2,10) = 1.29, p > 0.32] and
the group x day interaction [F(5.45,27.26) = 0.64, p > 0.68]
were not significant; however, the effect of day was significant
day [F(2.73,27.26) = 24.59, p < 0.001]. Thus, the groups were
combined to create a single sham-control group. Thus, all
subsequent analyses were conducted with the following groups:
Mg2+-enriched (n = 9), Mg2+-deficient (n =
9), Mg2+-normal (n = 9), and sham (n = 13).
Serum Mg2+ analysis
Serum Mg2+ analysis was analyzed in a one-way ANOVA
including group (Mg2+-normal, Mg2+-enriched,
Mg2+-deficient) prior to injury. Two weeks of dietary
manipulation of Mg2+ showed a diet-dependent change in
serum levels; the main effect for serum Mg2+ was
statistically significant, [F(2,27) = 31.05, p < 0.001] (figure 1). Post-hoc
comparisons with Tukey’s HSD tests were conducted to determine
significant differences within the group factor. Comparison of the
Mg2+-normal and Mg2+-enriched diets showed a
significant elevation in Mg2+ levels in the enriched
group 14 [HSD (16) = 1.10, p < 0.001]. Mg2+-deficient
diet showed a significant decrease in Mg2+ level
compared to the Mg2+-normal diet [HSD (16) = 1.08, p
< 0.001]. Thus, pre-surgical dietary manipulation of
Mg2+ resulted in significant alterations of
Mg2+ level prior to injury.
Vibrissae-forelimb placing test
The percentage of unsuccessful placing attempts was analyzed in a
repeated measures ANOVA including group (Mg2+-normal,
Mg2+-enriched, Mg2+-deficient, or Sham) and
post-injury test session as the repeated measure. Following injury,
the rats became more efficient in placing their contralateral
forelimbs on successive trials; the main effect for day was
statistically significant, [F(3.21,115.81) = 34.52, p < 0.001].
Unilateral contusions produced significant impairments in forelimb
placing; the main effect of group was statistically significant,
[F(3,36) = 78.74, p < 0.001] (figure 2). There was a
significant difference in the rate of recovery; the group x day
interaction was significant, [F(9.65,115.81) = 7.50, p < 0.001].
Post-hoc comparisons were conducted to determine differences within
the group factor. Comparison of the Mg2+-normal and
Mg2+-enriched diets showed no significant differences in
performance on any test day. The Mg2+-deficient diet
showed worse behavioral outcome compared to the
Mg2+-normal diet on days 14 [HSD (16) = 28.89, p <
0.01], 21 [HSD (16) = 42.22, p < 0.02], 28 [HSD (16) = 67.78, p
< 0.001], 35 [HSD (16) = 66.67, p < 0.001] and 42 [HSD (16) =
66.67, p < 0.001].
Bilateral tactile adhesive removal test
The latencies to remove the tactile stimuli were analyzed in a
repeated measures ANOVA, including group (Mg2+-normal,
Mg2+-enriched, Mg2+-deficient, or Sham) and
post-injury test session as the repeated measure. Following injury,
the rats became more efficient in removing the contralateral
stimuli on their forelimbs on successive trials; the main effect
for day was statistically significant, [F(2.94,105.99) = 57.28, p
< 0.001]. Unilateral contusions produced significant impairments
in stimuli removal; the main effect of group was statistically
significant, [F(3,36) = 11.50, p <0.001] (figure 3). There was a
significant difference in the rate of recovery; the group x day
interaction was significant, [F(8.83,105.99) = 2.33, p < 0.02].
Post-hoc comparisons were conducted to determine differences within
the group factor. Comparison of the Mg2+-normal and
Mg2+-enriched diets showed no significant differences in
performance on any test day (p > 0.05). The
Mg2+-deficient diet showed worse behavioral outcome
compared to the Mg2+-normal diet on days 6 [HSD (16) =
27.72, p < 0.05], 10 [HSD (16) = 39.11, p < 0.007], 14 [HSD
(16) = 45.61, p < 0.01], and 21 [HSD (16) = 33.33, p < 0.04].
Reference memory
The swim latencies to find the hidden platform in the MWM was
analyzed in a repeated measures ANOVA including group
(Mg2+-normal, Mg2+-enriched,
Mg2+-deficient, or Sham) and post-injury test session as
the repeated measure. Following injury, the rats became more
efficient at finding the platform on successive days; the main
effect for day was statistically significant, [F(3.00,108.00) =
34.46, p < 0.001]. Unilateral contusions produced significant
impairments in overall performance; the main effect of group was
statistically significant, [F(3,36) = 5.14, p < 0.005] (figure 4). However,
there was not a significant difference in the rate of recovery; the
group x day interaction was not significant, [F(9.00,108.00) =
0.60, p > 0.80]. Post-hoc comparisons demonstrated that the
performance on the task between the sham group and the
Mg2+-normal group was not significant on any of the 4
test days (p > 0.05). This was also the case between the
Mg2+-normal group and either the
Mg2+-enriched, or -deficient groups (p > 0.05). The
Mg2+-deficient diet showed worse behavioral outcome
compared to the sham group on days 11 [HSD (18) = 15.74, p <
0.009] and 14 [HSD (18) = 22.75, p < 0.008]; whereas, the
Mg2+-enriched group was significant different from the
sham group on days 11 [HSD (18) = 20.71, p < 0.001], 13 [HSD
(18) = 19.97, p < 0.03], and 14 [HSD (18) = 22.23, p <
0.009].
Lesion analysis
The percent reduction of the injured cortex compared to the
non-injured cortex was analyzed in a one-way ANOVA including group
(Mg2+-normal, Mg2+-enriched,
Mg2+-deficient, or Sham) as the factor in the analysis.
There were significant differences in lesion size between groups,
the analysis of remaining tissue surrounding the lesion cavity was
significant, [F(3,39) = 21.43, p > 0.001] (figure 5). Post-hoc
comparisons with Tukey’s LSD test were conducted to determine
significant differences within the group factor. Comparison of the
Mg2+-normal and Mg2+-deficient diets showed a
significant increase in lesion severity in the deficient group [HSD
(16) = 10.06, p < 0.01]. There was a strong trend toward a
reduction in lesion severity in the Mg2+-enriched group
compared to the Mg2+-normal group [HSD (16) = 6.47, p
> 0.09].
Discussion
The purpose of the present study was to examine the effect of
dietary Mg2+ manipulations on recovery of function.
After 2 weeks of diet manipulation a serum analysis was conducted
at the time of cortical injury and showed that the experimental
diets significantly modulated the level of circulating serum
Mg2+. A strong diet-dependent effect was observed. Rats
fed the Mg2+-normal diet were found to have on average
2.0 mEq/L of serum Mg2+; whereas, the
Mg2+-deficient group had 0.9 mEq/L and the
Mg2+-enriched had 3.1 mEq/L of serum Mg2+.
Thus, the diet manipulations significantly altered serum
Mg2+ levels and allowed us to determine if these dietary
manipulations had any effect on recovery of function following
cortical injuries.
It was found that manipulation of dietary Mg2+ did
have significant effects on recovery of function. Rats fed a 2 week
diet deficient in Mg2+ were significantly worse on the
bilateral tactile adhesive removal and vibrissae-forelimb placing
tests compared to injured rats feed a standard laboratory diet. The
recovery curve of the Mg2+-deficient group showed that
very little recovery of function occurred following the cortical
lesions. In fact, on day 42 the average degree of impairment in
this group was still at 80%, compared to 10% in the
Mg2+-normal diet. Likewise, the recovery curve for the
Mg2+-deficient group on the bilateral tactile removal
test also showed severe impairments up to 28 days following
cortical injury. Interestingly, during the assessment of reference
memory performance it was found that the Mg2+-deficient
diet was significantly worse compared to the non-injured, sham
group, comparatively, the Mg2+-normal group was not
significantly different than the sham group. Thus, the
Mg2+ deficient diet produced a significant injury
deficit in the MWM when there was no deficit in the injured
Mg2+-normal group. Thus, the Mg2+-deficient
diet worsened recovery of function on both the sensorimotor tests
and on the acquisition of a reference memory task in the MWM.
In the present study, a Mg2+-enriched diet was also
used to examine the effect of dietary supplementation on recovery
of function. It was found on both the vibrissae-forelimb placing
and bilateral tactile adhesive removal tests that Mg2+
enrichment significantly improved recovery of function compared to
the Mg2+-deficient group. However, there were no
statistical differences between the Mg2+-enriched and
Mg2+-normal groups. This was unexpected, especially
given the high serum levels of Mg2+ in the enriched
group. It is possible that the levels of Mg2+ were not
high enough to facilitate the recovery of function seen with these
behaviors following systemic post-injury administrations [5,
28-30]. Given that serum levels of Mg2+ do not correlate
well with brain tissue levels, this may also have contributed to
the diminished effect in the Mg2+-enriched diet. It may
also be the case that the pre-injury enriched diet might not offset
the injury-induced Mg2+ decline and subsequent
behavioral impairments to the same degree as post-injury systemic
administrations [28-30]. The Mg2+-enriched diet appears
to have impaired performance in the reference memory task to about
the same extent as in the Mg2+-deficient group. At first
this seems paradoxical; however, we have recently shown that daily
administration of MgCl2 impaired the acquisition of
reference memory in the MWM [29]. In that study, un-injured rats
were given daily injections of 1 or 2 mmol/kg of MgCl2
30 minutes prior to their running in the MWM [29]. The timing of
these administrations contrasts drastically to the present study,
diet enrichment was discontinued at the time of injury (11 days
prior to MWM testing) and the rats were placed back on the standard
laboratory diet, compared to daily systemic injections prior to the
MWM. Unfortunately, we do not have a serum analysis for
Mg2+ at this time point; however, at the time of injury
the levels were extremely high in the enriched diet group, it then
must be inferred that the Mg2+ levels were high enough
to interfere with maze learning. This data suggests that caution is
needed with Mg2+ supplementation and learning/cognitive
based tests. However, this effect only occurred in the injured
animals, there were no significant impairments in learning in the
Mg2+-enriched sham group.
The histological analysis revealed a diet-dependent effect on
the percent reduction in the injured cortex, compared to the
un-injured, contralateral cortex. The Mg2+-deficient
diet showed a significantly increased reduction in the injured
cortex (29.5%) compared to the contralateral cortex. This group
showed the greatest extent of injury compared to all other injured
groups. The Mg2+-normal group had a 21% reduction in
cortical volume. The Mg2+-enriched group had the
smallest lesions with a 13% reduction in cortical volume. Thus, not
only do Mg2+ diet manipulations modulate recovery of
function following cortical injuries but they also differentially
affect lesion size.
The results of the Mg2+-deficient diet from the
present study are in agreement with those reported by McIntosh and
colleagues [5]. The neuroscore is a battery of 5 different tests
that measure various reflexive motor and balance tasks and was
shown to be significantly impaired in the Mg2+-deficient
rats following FPI [5]. In the present study, we found that
following CCI the deficient diet significantly impaired recovery of
function on 2 different sensorimotor tests and on the acquisition
of a reference memory task in the MWM. The biggest difference
between these 2 studies is in post-injury mortality. Following FPI,
a 53% mortality was observed; whereas, following CCI we found no
mortality. Given the differences between FPI and CCI (FPI usually
shows greater mortality compared to CCI), this result is not
surprising.
Conclusion
The results of this study have demonstrated that manipulating
dietary Mg2+ levels prior to injury had dramatic effects
on recovery of function and extent of injury. A
Mg2+-deficient diet significantly reduced the serum
levels of Mg2+ and significantly exacerbated
sensorimotor and cognitive deficits following cortical injuries.
The Mg2+-enriched diet increased the serum level of
Mg2+ prior to injury but did not significantly improve
sensorimotor performance compared to the Mg2+-control
diet; however, cognitive performance in the MWM was impaired. In
general, the results of this study suggest that dietary status
(especially concerning Mg2+) is an important factor in
recovery of function following injury and warrants more
experimental consideration.
Acknowledgments
This research supported by grant from the University of North
Carolina Institute of Nutrition.
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