ARTICLE
Auteur(s) : Liyuan Sun1,4, Yuki
Kosugi2, Emiko Kawakami1, Ying-Shan
Piao1, Tomoyo Hashimoto1,3, Kiyomitsu
Oyanagi1
1Department of Neuropathology, Tokyo
Metropolitan Institute for Neuroscience, Tokyo, Japan
2Department of Environmental Health
and Toxicology, Division of Environmental Health, Tokyo
Metropolitan Institute of Public Health, Tokyo, Japan
3Department of Safety and Health, Tokyo Gas,
Co., Ltd., Tokyo, Japan
4Department of Anatomy, College of Basic
Medical Sciences, Dalian Medical University, 116044 Dalian,
China
Magnesium (Mg) is essential for cell functions such as the
transport of calcium and potassium ions, and modulates signal
transduction, enzyme activities, nucleic acid and protein
synthesis, energy metabolism, and cell proliferation, and protects
biological membranes [1]. Mg deficiency has been reported to be
correlated with skeletal mal-development [2], stroke [1, 3, 4],
secondary tissue damage in brain trauma [5], ischemic heart
disease, cardiac arrhythmia, atherosclerosis, hypertension and
diabetes mellitus [1], and retinal function abnormality [6]. It is
also suggested to play a role in the pathogenesis of Parkinson’s
disease [7] and the parkinsonism-dementia complex (PDC) and
amyotrophic lateral sclerosis (ALS) of Guam [8-10]. In relation to
the pathogenesis of Parkinson’s disease and PDC, Mg deficiency over
generations induces selective loss of dopaminergic neurons in the
substantia nigra of rats [11].
Some clinical and experimental studies have shown that
intravenous Mg administration exerts a neuroprotective effect in
cases of traumatic brain injury, seizure, subarachnoid hemorrhage
and cerebral ischemia in humans and animals [1, 3, 12, 13], and
also lidocaine-induced seizures in rats [13]. These data indicate
that consumption of a Mg-deficient diet induces degeneration of
certain neurons in the brain, whereas an elevated Mg concentration
in serum has a therapeutic effect on neurons in the brain in
certain pathological conditions.
On the other hand, a number of studies have reported that serum
Mg enters the CSF, but that the ionic composition of the CSF
remains remarkably constant during changes in blood ionic
composition in humans [14, 15] and animals [13, 16-21] under normal
as well as pathologic conditions, or that only a slight increase in
the CSF Mg level occurs in human patients with brain injury or in
dogs with 2-4 times the normal level of serum Mg under
otherwise normal conditions [22, 23]. However, some studies have
indicated that the CFS Mg concentration is significantly increased
in patients with preeclampsia [24] and in rats with hippocampal
seizures [25], and that long-term Mg deficiency induces a decrease
of the CSF Mg concentration [21].
Mice are used as models of various neurological disorders, and
in studies of neuroprotective treatment using Mg. However, no
measurements of Mg concentration in the serum, CSF or brain have
been performed during chronic oral Mg administration to mice used
in the Parkinson’s disease model [26], and no significant increase
in the brain tissue concentration of Mg was reported during oral
intake of Mg pidolate in SOD (superoxide dismutase)-1 transgenic
(Tg) mice [19]. Also, no reports have indicated the normal
concentration of Mg in the CSF, nor its response to elevation of
the Mg level in serum. Here we report details of the normal Mg
concentration in the CSF in C57BL/6J (B6) and ICR mice, and
alteration of the Mg concentration in the CSF after intraperitoneal
injection of Mg sulfate in B6 mice.
Materials and methods
Animals
The present study was conducted in accordance with the Guidelines
for Experiment and approved by the Animal use and Care Committee of
Tokyo Metropolitan Institute for Neuroscience, and adequate
measures were taken to minimize pain and discomfort to the animals.
We used male B6 (n = 27, CLEA Japan, Inc., Tokyo, Japan) and
ICR mice (n = 11, CLEA Japan, Inc.) at 8 weeks of age,
weighing 21-24 g and 32-37 g, respectively. The content
of Mg in the diet for the mice used was 0.25 g/100 g.
Experimental groups
Normal levels of Mg in the serum and CSF were measured in both
B6 (n = 7) and ICR mice (n = 11), and alterations of the Mg
concentration were measured in the CSF and serum after
intraperitoneal injection of Mg sulfate (Conclyte-Mg,
MgSO4·7H2O, 1.23 g/kg body weight, Nipro
Pharma, Osaka, Japan) to B6 mice (n = 40).
Collection of samples from serum and CSF
The animals were anesthetized with Nembutal (50 mg/kg,
Dainippon Pharmaceutical Co., Ltd.). For collection of serum, a cut
was made in the tail about 1-1.5 cm from the tip, and blood
from the wound was collected in a polypropylene tube (catalog No.
430791, Corning, NY, USA) using polypropylene tips (catalog no.
RS-200Y, Renover Science, Co., Ltd., Tokyo, Japan). The serum was
then separated by centrifugation of the tubes at 1,500 rpm.
CSF was obtained from the cisterna magna. After separating the
skin and muscle in the neck, the CSF was aspirated by penetrating
the exposed dura mater and the arachnoid membrane using a butterfly
needle (27 G x 1/2, 0.4 x 13 mm, TOP Co., Tokyo,
Japan). Samples were collected from a normal control, and from
C57 mice at 20 min, 40 min, 2 h and 4 h
after intraperitoneal injection of Mg sulfate. The samples were
diluted 1,000-fold with milliQ water.
Measurement of Mg concentration
Mg concentration was measured using quadrupole ICP-MS (inductively
coupled plasma mass spectrometry; 7500 Series, Agilent
Technologies, Tokyo, Japan). Yttrium (Kanto Kagaku, Co., Ltd.,
Tokyo, Japan), for internal standardization, in 1% nitric acid was
added to the samples and standards at a final concentration of
10 μg L-1. The instrument was flushed with milliQ
water before the introduction of each sample or standard. Operating
conditions of the instrument for ICP-MS were as follows: ICP rf
power, 1,500 W; cooling chamber temperature, 2oC;
argon gas flow rate, plasma 0.7 L/min, carrier
0.35 L/min; hydrogen gas flow rate, 0.4; scanning mass, Mg m/z
= 25, Y m/z = 89. Each sample and standard solution was subjected
to measurement three times.
Statistical analysis
Data were analyzed by repeated-measures analysis of variance
(ANOVA) with treatment group and day of testing as independent
variables, followed by the Bonferroni post hoc test for multiple
comparisons between groups using Excel software (Microsoft Ltd.).
The level of statistical significance was set at p < 0.05. All
values are presented as mean ± SD.
Results
Mg levels in the milliQ water were within the range 0.14 ±
0.12 mM (n = 11). Since these values were considered to be
within an acceptable error range, no correction was made for the Mg
concentration in the serum and CSF. Mg concentrations were 0.89 ±
0.11 mM in CSF (n = 7) and 1.38 ± 0.12 mM in serum (n =
7) from normal B6 mice, and 1.00 ± 0.12 mM in CSF (n =
11), and 1.10 ± 0.09 mM in serum (n = 11) from normal ICR mice
(table 1). No significant alteration was
found in the CSF of B6 mice that had been injected
intraperitoneally with Mg, even though the magnesium concentration
in the serum was significantly increased from 1.38 ± 0.12 mM
(normal level; n = 5) to 8.68 ± 1.85 mM (20 min after
injection; n = 5), to 7.58 ± 0.67 mM (40 min after; n =
5) and 3.56 ± 0.96 mM (2 h after; n = 5), and decreased
to the normal level at 4 h after (n = 5, figure 1).
Table 1 Normal magnesium (Mg) concentration in plasma
and cerebrospinal fluid and the response of Mg concentration in the
CSF/brain tissue after systemic administration of Mg in various
species reported previously.
|
Species
|
Strain
|
Age
|
Sex
|
Normal Mg concentration
|
Response of
|
Methods for
|
Citation
|
|
|
|
|
Plasma
|
CSF
|
Mg concentration in CSF/brain tissue
|
Mg
|
|
|
|
|
|
|
|
after systemic Mg administration
|
concentration measurement
|
|
|
Mouse
|
C57BK/6J
|
8 weeks
|
M
|
1.38 ± 0.12 mM
|
0.89 ± 0.11 mM
|
No significant response in CSF
|
ICP-MS
|
Present study
|
|
C57BK/6J
|
|
M
|
2.8 ± 0.1 mg/dL
|
|
|
AAS
|
Marie et al. 1983 [27]
|
|
ICR
|
8 weeks
|
M
|
1.10 ± 0.09 mM
|
1.00 ± 0.12 mM
|
|
ICP-MS
|
Present study
|
|
SOD-1 Tg
|
|
|
|
|
No significant response in brain tissue
|
ICP-MS
|
Pamphlett et al. 2003 [19]
|
|
A/J
|
adult
|
M
|
17000 μg/mL
|
|
|
ICP-MS
|
Funseth et al. 2000 [28]
|
|
Balb/c
|
|
F
|
24284 ng/g wet weight
|
|
|
ICP-MS
|
Ilbäck et al. 2003 [29]
|
|
Rat
|
Wistar
|
|
F
|
1.96 ± 0.24 mg/dL
|
2.06 ± 0.16 mg/dL
|
|
AAS
|
Hoffman et al. 1990 [33]
|
|
Sprague-Dawley
|
|
|
2.0 ± 0.1 mg/dL
|
|
No significant response in brain tissue
|
calmagite dye
|
Choi et al. 1991 [16]
|
|
Long-Evans
|
|
F
|
2.4 ± 0.25 mg/dL
|
2.41 ± 0.14 mg/dL
|
Significant response in CSF
|
Colorimetry
|
Hallak et al. 1992 [25]
|
|
Guinea pig
|
|
|
|
0.97 mM
|
0.81 mM
|
|
AAS
|
Scheibe et al. 1999 [30]
|
|
Cat
|
|
|
|
1.35 mM/kg H2O
|
1.33 mM/kg H2O
|
|
Colorimetry
|
Ames III et al. 1964 [31]
|
|
Rabbit
|
White rabbit
|
adult
|
|
2.09 ± 0.36 mEq/L
|
|
No significant response in brain tissue
|
AAS
|
Hilmy et al. 1968 [18]
|
|
|
|
|
0.72 ± 0.13 mM
|
0.90 ± 0.20 mM
|
|
HPLC
|
Frosini et al. 1993 [34]
|
|
Dog
|
Mongrel
|
|
|
1.61 (1.33-2.0) mEq/L
|
2.16 (1.93-2.9) mEq/L
|
Slight increase in CSF
|
FS
|
Oppelt et al. 1963 [23]
|
|
Swine
|
Miniswine
|
2 & 40-day
|
|
|
No significant response in brain tissue
|
PMRS
|
Gee et al. 2001 [17]
|
|
Goat
|
|
|
|
2.24 ± 0.12 mEq/kg H2O
|
1.93 ± 0.06 mEq/kg H2O
|
ES
|
Pappenheimer et al. 1962 [32]
|
|
Human
|
Normal
|
adult
|
F
|
1.44 ± 0.16 mg/dL
|
2.56 ± 0.19 mg/dL
|
Slight but significant response in CSF
|
modified MBCP
|
Thurnau et al. 1987 [24]
|
|
Control
|
adult
|
|
1.69 ± 0.14 mEq/L
|
2.29 ± 0.1 mEq/L
|
|
AAS
|
Heipertz et al. 1979 [35]
|
|
Postop. patient
|
adult
|
|
1.91 ± 0.26 mg/dL
|
2.67 ± 0.44 mg/dL
|
No significant response in CSF
|
CPN
|
Ko et al. 2001 [15]
|
|
Patients
|
18-89 y.o.
|
M/F
|
Mg2+: 0.92 ± 0.18 mM
|
Mg2+: 1.25 ± 0.14 mM
|
Slight but significant response in CSF
|
ACCA
|
McKee et al. 2005 [22]
|
|
Hypertension
|
adult
|
|
0.58 ± 0.05 mM
|
0.82 ± 0.06 mM
|
No significant response in CSF
|
EA
|
Brewer et al. 2001 [14]
|
Discussion
The present study clarified the normal concentration of Mg in the
CSF and its response to changes in the serum concentration of Mg in
mice. The normal Mg concentration in the CSF was 0.89 ±
0.11 mM in B6 mice and 1.00 ± 0.12 mM in ICR mice,
and the Mg concentration in the CSF of B6 mice did not change
in response to an increase in the concentration of Mg in serum. The
Mg concentrations in B6 mice were 1.38 mM in plasma but
0.89 mM in CSF, and those in ICR mice were 1.10 mM in
plasma and 1.00 mM in CSF. It is unclear why there was such a
large difference in Mg concentrations between B6 mice and ICR
mice, particularly with respect to the values in CSF and serum in
B6, but not in ICR mice.
The Mg concentration in the plasma of mice was slightly higher
[27-29] than that reported for other species (table 1). The Mg concentration in the CSF was
lower than that reported in the serum of mice, guinea pigs [30],
cats [31], and goats [32], but higher than that reported in the
serum of rats [16, 25, 33], rabbits [34], dogs [23] and humans [14,
15, 22, 24, 35] (table 1). The reason
for the differences in serum Mg concentrations among species is
unclear.
With regard to the correlation of Mg levels between CSF and
serum, it has been reported that the Mg concentration in CSF does
not increase even if the serum concentration is about 200% of
normal in humans [14, 15] and in animals [21]. In addition, the Mg
concentration in brain tissue was reportedly not increased in
newborn pigs after intravenous infusion of Mg sulfate [17] or in
SOD-1 Tg mice after oral Mg supplementation [19] (table 1).
In contrast, a few studies have reported significant increases
in the CSF concentration of Mg after an increase in the serum Mg
concentration. In rats, after intraperitoneal injection of Mg
sulfate, an increase in the CSF level of Mg was found, in parallel
with a significant elevation of the serum level, and the levels of
Mg in both the CSF and serum decreased 2 hours later [25].
Oppelt et al. reported that serum Mg enters the CSF, and that
the Mg concentration in CSF increases to 121% of the control level
if the serum Mg concentration remains elevated for 3-4 hours
[23]. Thurnau et al. reported that the CSF Mg level increased
to 119% of the control after intravenous of magnesium sulfate in
patients with pre-eclampsia, resulting in a concentration 400-500%
of the normal one [24]. McKee et al. reported a slight but
significant elevation of the Mg concentration in CSF after systemic
Mg administration to patients who had suffered from various
disorders [22]. On the other hand, changes in CSF Mg concentration
have also been described in cases of severe long-term
hypomagnesemia [21]. Our present results confirmed that, in normal
mice, the CSF Mg concentration did not respond to an increase in
the serum Mg concentration (table 1,
figure 1).
With regard to the mechanism of Mg concentration homeostasis in
the CSF, Oppelt et al. considered that, in the normal dog, the
intact blood-CSF barrier was impermeable to Mg [23]. Hilmy
et al. concluded that, in the normal rabbit, the brain was
protected by the BBB and that a regulatory mechanism ensured that
the CSF Mg level remained constant [18]. However, under conditions
of brain damage, such as trauma, SAH or stroke, the mechanism
responsible for maintaining CSF Mg homeostasis might be disrupted
[36-41].
In mice, there have been some attempts to treat
neurodegenerative disorders with Mg. In a murine model of
amyotrophic lateral sclerosis (SOD-1 transgenic), oral
supplementation of Mg elicited no effect, and the Mg concentration
in brain tissue was not increased [19]. In a murine model with
Parkinson’s disease, oral supplementation of Mg produced an
improvement in behavior, although striatal dopamine was decreased
[26]. When taken together, the present and previous findings
suggest that, for the treatment of neurological disorders in murine
models, direct Mg administration into brain tissue or the
subarachnoid space/ventricles would be necessary.
Conclusion
Mg concentrations were 0.89 ± 0.11 mM in the CSF, and 1.38 ±
0.12 mM in the serum of normal 8-week-old male C57BL/6J (B6)
mice, and 1.00 ± 0.12 mM in the CSF, and 1.10 ± 0.09 mM
in the serum of normal 8-week-old male ICR mice. No significant
alteration was found in the CSF of B6 mice injected
intraperitoneally with Mg, even though the Mg concentration in
serum was significantly increased.
Acknowledgments
The authors are indebted to Dr H. Mochizuki and Dr Y. R. Ren,
Research Institute for Diseases of Old Age, Juntendo University
School of Medicine, Tokyo, Japan; Dr N. P. Murphy and Mr K.
Sakoori, Neuronal Circuit Mechanisms Research Group, RIKEN Brain
Science Institute, Saitama, Japan; Dr A. Furuta and Dr D. Yamada,
Department of Degenerative Neurological Diseases, National
Institute of Neuroscience, National Center of Neurology and
Psychiatry, Tokyo, Japan. The authors also thank Dr M. Takada,
Department of System Neuroscience, and Dr M. Yamayoshi and Dr S.
Koike, Department of Microbiology, Tokyo Metropolitan Institute for
Neuroscience, Mr Koshi Oyanagi, Department of Chemistry and
Biological Science, College of Science and Engineering, Aoyama
Gakuin University, Sagamihara, Kanagawa, Japan, and Dr M. Hashiba,
Course of Paramedic, Niigata Collage of Medical Technology,
Niigata, Japan, for their valuable advice and technical assistance.
This work was supported in part by grants from the Japanese
Ministry of Education, Science, Sports and Culture (Basic Research
(C) #20500330 to TH), and a Yujin Memorial Grant (to KO).
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