free and total magnesium in lymphocytes of migraine patients — effect of magnesium-rich mineral...

Clinica Chimica Acta 295 (2000) 63–75www.elsevier.com/ locate /clinchim

Free and total magnesium in lymphocytes ofmigraine patients — effect of magnesium-rich

qmineral water intake

a b b´Jean Thomas , Jean-Marc Millot , Stephane Sebille , Anne-c a bMarie Delabroise , Elisabeth Thomas , Michel Manfait , Maurice

c ,*J. Arnauda

´ ´Centre d’Exploration et de Traitement des Migraines et Cephalees, Vittel, Franceb ´Laboratoire de Spectroscopie Biomoleculaire, UFR Pharmacie, Reims, France

cWater Institute, Perrier Vittel, Vittel, France

Received 13 September 1999; received in revised form 6 December 1999; accepted 15 December 1999

Abstract

Dietary surveys performed in Western countries show magnesium intakes lower than therecommended dietary allowances, suggesting a large prevalence of magnesium deficiency. Lowbrain magnesium as well as impaired magnesium metabolism have also been reported in variousdiseases such as migraine. To detect these deficiencies, a non-invasive and sensitive test assessingmagnesium status is needed. Because magnesium is an intracellular cation, either total or ionized

21magnesium (Mg ) of blood cells were suggested as the most adequate tests. Total magnesium21levels in plasma, erythrocytes and lymphocytes and Mg in lymphocytes were analyzed in a

group of 29 migraine patients and 18 control subjects. Results show significantly lowerconcentrations of total magnesium in erythrocytes (50.764.7 vs. 53.562.9 mg/ l; P , 0.01) and of

21Mg in lymphocytes (12.063.5 vs. 14.263.8 mg/ l; P , 0.05) in migraine patients as comparedto controls. While a significant difference of mean values was noted between migraine patients andcontrols, an overlap of individual values was observed. These analyses were repeated on migrainepatients before and after a 2-week intake of a mineral water containing 110 mg/ l magnesium, anda significant increase in all intracellular magnesium concentrations with no effect on plasmamagnesium was observed. These increased intracellular magnesium concentrations demonstrate

qSome results of this study were presented as a Poster at the 16th International Congress of Nutrition, July´27–August 1, 1997, Montreal, in the session on mineral metabolism: balance and status.

*Corresponding author. Correspondence address: Institut de l’Eau Perrier Vittel, BP 101, F-88804 Vittel,Cedex, France. Tel.: 133-3-2908-7041; fax: 133-3-2908-7049.

E-mail address: [email protected] (M.J. Arnaud)

0009-8981/00/$ – see front matter 2000 Elsevier Science B.V. All rights reserved.PI I : S0009-8981( 00 )00186-8

64 J. Thomas et al. / Clinica Chimica Acta 295 (2000) 63 –75

21the bioavailability of magnesium from this mineral water. Among the analyzed parameters, Mgin lymphocytes appears to be the most sensitive index of magnesium deficiency with a 15%decrease in migraine patients when compared to controls and a 16% increase after 2 weeks of amagnesium-rich mineral water intake. 2000 Elsevier Science B.V. All rights reserved.

Keywords: Migraine; Ionized magnesium; Erythrocytes; Lymphocyte; Microspectrofluorimetry;Mineral water

1. Introduction

Most dietary surveys performed in Western countries show magnesiumintakes lower than recommended dietary allowances (RDAs) suggesting thatmagnesium deficiency would be more prevalent than previously. In addition,some pathologies such as migraine are associated with low brain magnesium[1,2], magnesium deficiency [3,4], impaired magnesium metabolism [5–7] andcan be relieved in some cases by magnesium administration [8–10]. A sensitiveand non-invasive clinical test for the assessment of magnesium status would beuseful for these patients and for the general population when deficiency issuspected.

Currently, the most accurate methods to assess magnesium status aremagnesium loading tests [11,12] as well as muscle biopsy magnesium analyses[13,14]. However, these methods are too invasive for patients and unavailablefor most clinicians.

The measurement of serum magnesium concentration is the most availableand commonly applied test to assess magnesium status. The observed values aregenerally stable, in the range 0.7–0.9 mmol / l. Serum values, which are under0.7 mmol / l, usually indicate a severe magnesium deficiency and are shown to beinduced, for example, by drug toxicity [15]. However, even in chronicmagnesium deficiency, serum magnesium concentration may be normal [16,17]since it would be compensated by the labile bone magnesium pool [18]. Becausemagnesium is an intracellular cation with less than 1% of the total body contentin extracellular fluid compartments, it is suggested that serum or extracellularmagnesium concentration does not reflect the intracellular content [19].

The total magnesium content or cellular tissue concentration such asleukocytes, red blood cells, peripheral lymphocytes, skeletal muscle and bonehas been assessed as an index of magnesium status. The leukocyte magnesiumconcentration seems a better indicator of magnesium status than serum valuesbut this test has not been correlated with other tissues [20]. The red blood cellmagnesium concentration was not shown to be correlated with other tissue poolsof magnesium, limiting the clinical usefulness of this test. This observation

J. Thomas et al. / Clinica Chimica Acta 295 (2000) 63 –75 65

could be explained by a possible genetic control [21] as well as age and sexdependence [22] of erythrocyte magnesium concentration. In a case of congeni-tal hypomagnesemia, it was observed that erythrocyte as well as plasmamagnesium concentrations did not accurately reflect magnesium status while theuse of accessible stable tissues such as temporary teeth and lymphocytesrevealed a marked deficiency in magnesium. The magnesium content ofperipheral lymphocytes seems to be a more accurate indicator of magnesiumstatus than serum concentration but was not sufficiently discriminatory todiagnose magnesium deficiency [23].

21Recent studies have determined ionized magnesium (Mg ) in red bloodcells, in platelets and in lymphocytes [24,25]. This parameter would be better

21correlated with magnesium balance suggesting that Mg reflects the mostimportant biologically-active magnesium fraction [26]. We report here the firstresults obtained on total and ionized magnesium analyzed in lymphocytes fromboth control subjects and in migraine patients, before and after magnesiumsupplementation. The observed variations on lymphocytes are compared withthose from plasma and erythrocytes to evaluate the most sensitive parameter.

2. Materials and methods

2.1. Migraine patients and controls

A total of 29 migraine patients and 18 controls subjects were recruited duringa spa treatment period. When coming for their medical examination, the protocolwhich is in accordance with the Helsinki Declaration of 1975 such as revised in1983, was thoroughly explained and informed consent was obtained by theirphysician (JT). Migraine patients met the clinical criteria laid down by the I.H.S.(International Headache Society) [27]. These criteria are: (i) at least five suddenheadache attacks; (ii) a 4–72 h duration; (iii) headache associated with anunilateral pulsation (moderate or acute) and worsened by physical activity; (iv)the presence of at least two criteria among nausea, photophobia, phonophobia.These patients presented these symptoms at least 5 years ago and had treatmentswithout durable effect (analgesics). Only patients and control subjects taking nomedication and without any diseases leading to increased magnesium losseswere included in the study. Other selection criteria including life style(sedentary) and dietary habits (adequate magnesium intakes) were considered.

The control group constituted 18 subjects who came for a routine check up,did not have any disorder and did not suffer from migraine. The distributions ofthe two groups were 26 women/3 men for the migraine patients with an averageof 46 years (range 22–69 years) and 14 women/5 men for control subjects withan average of 51 years (26–65 years).


2.2. Measurements

The following measurements on magnesium concentrations were carried outin the context of medical examinations performed under the responsibility of

21their medical doctor (JT): (i) free Mg concentration in lymphocytes (FL), (ii)total Mg concentration in lymphocytes (TL), (iii) total Mg concentration inserum (TS) and (iv) total Mg concentration in erythrocytes (TE). All de-terminations on migraine patients were performed out of a headache attack.

2.3. Magnesium consumption of migraine patients

FL, TL, TS, TE were determined in migraine patients before and after an oral´supplementation of magnesium taken from a mineral water (Hepar containing

21 22 24.5 mmol / l Mg , 13.8 mmol / l SO , 6.6 mmol / l HCO ). Magnesium intakes4 3

estimated from dietary questionnaire range from 8.5 to 13 mmol per day in bothcontrol subjects and migraine patients. The quantity of magnesium supple-mentation is dependent on the individual drinking pattern but ranges from 7.4 to12 mmol per day for 15–18 days (mean 17.3 days). This supplement representsbetween 56 and 138% of the estimated intakes. At the term of this supple-mentation period, a second Mg determination was performed in lymphocytes,erythrocytes and plasma.

212.4. Determination of total Mg and Mg in lymphocytes

Total magnesium in lymphocytes, erythrocytes and serum was determined byatomic absorption spectrophotometry [28].

21For Mg analysis in lymphocytes, 5 ml of whole blood were obtained inyellow top vacutainer tubes containing citrate dextrose. All blood samples werecollected and maintained under anaerobic conditions. Living mononuclear cellswere isolated on Ficoll gradient from 5 ml of human blood [29]. Lymphocyteswere washed twice with Dulbecco’s modified Eagle’s medium without phenolred and were incubated in this medium containing the magnesium sensitive dyeMag-Indo-1 (2 mmol / l) in its acetoxymethylester form (Mag-Indo-1 /AM) for45 min at 378C. Cells were washed free of dye and a post-incubation wasperformed for 30 min to complete the hydrolysis of the dye. Under a 350-nm

1excitation (UV Ar laser Spectra Physics, Model 2065A), fluorescence emissionspectra from a living cell were recorded using a UV confocal microspec-trofluorometer (Dilor, Lille, France). These emission spectra were characterized

21by the ratio (R) of emission intensities at 410 and 500 nm. Free Mgconcentrations were determined according to the following equation [30]


21[Mg ] 5 bK (R 2 R ) /(R 2 R)i d min max

where b 52.57 corresponds to the emission intensity ratio of Mag-Indo-121emissions in saturated and free of Mg ; K 5 2.6 mmol / l is the dissociationd

21constant of Mag-Indo-1 for Mg ; R 5 0.24 and R 5 0.95 are, respective-min max21ly, the ratios for Mag-Indo-1 emissions in saturated and free of Mg conditions,

21both evaluated from Mg permeabilized cells.21The reproducibility of day-to-day Mg analysis using microspectrofl-

uorimetry was checked from aqueous solution (concentrations of 5, 10 and 2021mg/ l Mg ) with a relative standard deviation (R.S.D.) of less than 1%.

2.5. Statistical analysis

Significant differences of Mg from both groups of migraine patients andcontrols were determined by an unpaired Student’s t-test for two groupcomparison.

To show the influence of mineral water intake, individual differences betweenthe Mg concentrations before and after mineral water absorption were calcu-lated. Distributions of these variations are non-Gaussian, which prevents theapplication of a paired Student’s t-test. For each of the four parameters, eachpatient was classed among the two groups: a Mg increase or a Mg decrease.

2Sizes of both groups were compared by a x test.

3. Results

213.1. Reproducibility of intracellular Mg in lymphocytes

21For the intracellular Mg determination, all lymphocytes stained with 2mmol / l Mag-Indo-1 show homogeneous fluorescence distributions. R.S.D.values were ,1% from the same localisation of one lymphocyte; ,13% fromdifferent localisations of one lymphocyte; ,26% from different lymphocytes(n530) of a blood sample. Within-run R.S.D. values of means was ,10%, asdetermined from four fractions (30 analysed lymphocytes) of the same bloodsample.

21The stability of [Mg ] in lymphocytes was checked for the duration ofi

blood transport (up to 1 day) either in sodium citrate or in heparin (Table 1).21After Indo-1 staining, both [Mg ] determinations were not significantlyi

different. However, only the citrate conservation makes it possible to verify 121day of [Mg ] stability in lymphocytes.i


Table 121 aStability of [Mg ] in lymphocytesi

21[Mg ] (mg/ l)i

Fresh After 1 day

Blood collected in citrate 8.860.8 9.060.7Blood collected in heparin 8.260.5 10.361.4

a Values are expressed as mean6S.D.

3.2. Intracellular and plasma Mg concentrations from migraine patients andcontrols

21Mean values of [Mg ] from both groups (30 lymphocytes / sample) werei21significantly different (P,0.05). [Mg ] from lymphocytes of migraine patientsi

was 15% lower (Table 2). However, the total Mg from lymphocytes (TL) showsonly a 7% lower value for migraine patients than for controls (no significant

21difference; Table 2). Thus, among the intracellular Mg, the free Mg fractionwas more sensitive to migraine pathology, than the magnesium bound tointracellular molecules.

From the total Mg, the same level of difference (migraine patients vs.controls) was noted in erythrocytes as well as for lymphocytes. However, thislevel of difference is significant for TE (P,0.01), due to a lower intra-groupvariability of this parameter. For both FL and TE parameters, an overlap ofindividual values was observed between migraine patients and controls (Fig. 1).However, significant differences between mean values were noted (Table 2).

Table 2aMagnesium determinations from migraine patients and controls

FL TL TP TE6(mg/ l) (ng /10 cells) (mg/ l) (mg/ l)

Migraine patients (n529) 12.063.5 68.1610.7 2361.6 50.764.7Controls (n518) 14.263.8 73.3611.8 22.561.4 53.562.9Difference of means (%) 15.4 7.1 2 2.1 5.3migraine patients /controlsComparison of P,0.05 NS NS P,0.01

bmigraine patients /controlsa 21FL (free Mg in lymphocytes), TL (total magnesium in lymphocytes), TP (total magnesium

in plasma), TE (total magnesium in erythrocytes). In the migraine patient group, Mg con-centrations were determined before water absorption. Values are expressed as mean6S.D.

b Student’s t-test.


21Fig. 1. Individual magnesium concentration values of free Mg in lymphocytes and totalmagnesium in erythrocytes from controls (j) and migraine patients (s). Ellipses of tolerance

]]]]]include 95% of control values ( ) and of migraine patients (- - -).

There was no difference of total plasmatic Mg between controls and migrainepatients.

3.3. Influence of a mineral water intake on Mg concentrations in migrainepatients

Individual variations of FL, TL, TP and TE in migraine patients werecalculated from Mg determinations analysed before and after mineral watersupplementation (Fig. 2). Most FL, TL (Fig. 2A) and TE (Fig. 2B) values ofindividual variations (post- minus pre-Mg intake) were positive and displayedincreases in intracellular Mg content after mineral water absorption.Variations ofFL and TL, both from lymphocytes, displayed non-normal distributions due to2–3 isolated cases, which prevented the comparison of means (6S.D.) using aStudent’s t-test of paired data (Table 3). Thus, the number of cases showingeither a Mg increase or a Mg decrease is reported in Fig. 3. Both class sizes (Mg

2increase /Mg decrease) were compared using a x test in order to display theinfluence of mineral water supplementation. Intracellular Mg concentrations


Fig. 2. Variations of Mg concentrations from 29 migraine patients after the oral supplementation21of mineral water. (A) Individual variations of free Mg and total Mg in lymphocytes; (B)

individual variations of Mg in plasma and in erythrocytes.


Table 3aInfluence of a mineral water intake on Mg concentrations

FL TL TP TE6(mg/ l) (ng /10 cells) (mg/ l) (mg/ l)

Before Mg intake (n529) 12.063.5 68.1610.7 23.061.6 50.764.7After Mg intake (n529) 14.063.8 72.6614.6 22.861.7 52.964.8Increase (%) 16 6.6 20.8 4.3

a 21FL, free Mg in lymphocytes; TL, total magnesium in lymphocytes; TP, total magnesium inplasma; TE, total magnesium in erythrocytes. Values are expressed as mean6S.D.

Fig. 3. Number of migraine patients that show either a Mg increase (j), or a Mg decrease (h),21after a mineral water intake. FL (free Mg in lymphocytes), TL (total magnesium in

lymphocytes), TP (total magnesium in plasma), TE (total magnesium in erythrocytes). The size ofthe Mg increase group was compared with the size of Mg decrease group.


(FL, TL, TE) showed significant increases. However, no variation has beennoted on the plasmatic Mg.

4. Discussion

4.1. Magnesium metabolism in migraine patients

This study confirms previous investigations which showed the relationshipbetween migraine and magnesium metabolism [1–7]. The implication ofmagnesium in headache attacks has been previously displayed by NMR analysis,in which the total magnesium in brain decreases between successive attacks [1].Moreover, clinical studies have shown that magnesium sulfate administrationdecreases the clinical signs of migraine and prevents convulsions in eclampticfits [10,31]. This study shows significant decreases in cellular Mg concentrationsin migraine patients as compared to controls. In spite of significant differencesof mean FL and TE values between control and migraine patients, there is anoverlap of individual values. This suggests that migraine patients with low levelsmay benefit more from magnesium supplements such as magnesium-richmineral water. The results show that consumption of a magnesium-rich mineralwater restores magnesium intracellular concentrations, initially lower in mi-graine patients. The rapid increase in intracellular magnesium concentrationsconfirms the bioavailability of magnesium from mineral waters already reportedin animal models [32,33].

The relatively limited number of migraine patients and the short-termtreatment described here do not allow conclusions to be drawn about the specificeffect of magnesium on a migraine attack. In addition, bias in the interpretationmay be introduced by other effects of spa treatments e.g., changes in physicaland sport activities, changes in eating pattern and food choice as well asenvironmental and climatic changes.

4.2. Free lymphocyte magnesium as a sensitive index of magnesium status

21This study reports for the first time the analysis of intracellular free Mgmeasured in lymphocytes. Microspectrofluorimetry is already used for therapeu-tic monitoring of cancer drugs [34]. This new method applied to the de-termination of intracellular free magnesium in migraine patients showed that

21intra-lymphocyte free Mg was lower when compared to control subjects andthat an oral intake of magnesium provided by mineral water increased the valueto that of the controls.

Our study seems to indicate that ionized magnesium is a more sensitive indexof magnesium intake when compared to total cell magnesium and to total


plasma magnesium, which was unchanged. To keep the benefit of plasmaavailability and the sensitivity of ionized magnesium, new instruments have

21been developed which are capable of measuring free plasma Mg using specificelectrodes. However, high ionized magnesium levels were recently reported inserum of patients who developed transient severe or profound hypomagnesemia,displaying in these cases the inadequacy of this method for the evaluation ofmagnesium status [35]. Currently, none of the methods based on free ionizedmagnesium measured either in plasma, lymphocytes or erythrocytes has beenvalidated with the reference method which is the loading dose followed by a24-h balance of magnesium. This method of reference is time consuming andrequires a well-controlled study and staff expertise. For the establishment ofrecommended magnesium intake it will be necessary in the near future to apply

21these new methods using ionized Mg and to compare their results with thoseof the loading dose in circumstances under which deficiency is well known suchas in patients subjected to ileal resection for Crohn’s disease [36] or inpopulations with low magnesium intake [37].

Whether migraine patients with low intracellular Mg levels may benefit fromlong-term magnesium supplementation and have their symptoms reduced isunknown and needs to be further studied.

Acknowledgements

The authors wish to thank C. Schwartz for reviewing the manuscript. Thisstudy was supported by the Water Institute, Perrier Vittel, Vittel, France.

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free and total magnesium in lymphocytes of migraine patients — effect of magnesium-rich mineral...

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