Mg Acetyltaurinate as a photic inhibitor in

photosensitive magnesium depletion: a

physiological pathway in headache with
photophobia treatment.
J. Durlach(1) ; P. Bac(2); N. Pagès(2-3);
P. Maurois(2) ; J. Vamecq(2) ; M. German Fattal (2);
V. Durlach(4, ); Ph. Danhier(5)

1.
Tri-Inov, 64 rue de longchamp 92200 Neuilly sur Seine [email protected]
2.
Laboratoire de Neuropharmacologie. Faculté de Pharmacie.
Paris XI Chatenay-Malabry
3.
Laboratoire de Toxicologie, Faculté de Pharmacie, Strasbourg,
Illkirch.
4.
Laboratoire de Thérapeutique .Faculté de Médecine .Reims
5.
SDRM

ETHANE SULFONIC ACID (ACETYLAMINO)MAGNESIUM 2-1.

ATA Mg®; Acetyltaurinate magnesium dihydrate; Magnesium acetyltaurate.
CAS Number : 75350-40-2 (Monograph on request by Synapharm)

Mg Acetyltaurinate as a photic inhibitor in photosensitive

magnesium depletion: a physiological pathway in
headache with photophobia treatment.

1
INTRODUCTION

We previously described an actimetry-based test of

photosensitization in mice, which can be used for a rapid and
efficient screening of drugs of interest for photic cephalalgia and
other photosensitive diseases (1, 2). In summary, in absence of
photostimulation, control mice had a basic motor activity
(around 180 crossings per 5 minutes of an actimeter photocell)
whereas magnesium-deficient mice suffered nervous
hyperactivity (NHE) with increased motor activity. While in
each group, control and magnesium-deficient mice, were
submitted to photostimulation using a stroboscope, control
mice developed the phenomenon of habituation (i.e. a gradual
decrease in the responses to repetitive stimuli) whereas
magnesium-deficient mice presented both sensitization with
higher NHE and generalization, involving hypersensitivity to
other type of stimuli. In the present study, we studied the
efficiency of a new magnesium salt, which was not yet
commercially available, magnesium N-acetyltaurinate (ATA
Mg) on senzitisation suppression suggesting a possible
therapeutic use in photosensitive diseases.

ETHANE SULFONIC ACID (ACETYLAMINO)MAGNESIUM 2-1.

ATA Mg®; Acetyltaurinate magnesium dihydrate; Magnesium acetyltaurate.
CAS Number : 75350-40-2 (Monograph on request by Synapharm)

2
MATERIALS AND METHODS

● Female Swiss OF1 mice, 6 weeks old (Janvier, France) were

fed either:
○ a standard magnesium-diet (950 ± 50 ppm mg/kg)
○ or a magnesium-deficient diet prepared as previously
described (50 ± 5 mg/kg).
● Magnesium deficient mice were or not intraperitoneally
injected 30 minutes before photostimulation with ATA Mg
(100 mg/kg). They were compared to groups exposed to
either MgCl 2 (59 mg/kg), taurine (100 mg/kg) or ATA Na
(100 mg/kg).
● Photostimulation test was done as previously described.
Briefly, after acclimatization to darkness, individually caged
mice were exposed to repeated light stimulation via a
stroboscope for 15 min (1000 lumens, 50 Hz frequency).
● Then, locomotor activity was measured for 5 min by the
crossing of a photocell actimeter (Appelex type 01-1668B).

● Five groups of mice were compared:

○ Group A : non magnesium-deficient,

nonphotostimulated;
○ Group B: non magnesium-deficient, subjected to
photostimulation;
○ Group C: magnesium-deficient, nonphotostimulated;
○ Group D: magnesium-deficient, subjected to
photostimulation;
○ Groups E: magnesium-deficient, subjected to
photostimulation and treated with 100 mg/kg ATAMg.

RESULTS

Plasmatic magnesium concentrations of magnesium deficient

groups were about 5.7 +/- 0.51 mg/L, i.e., reduction of 73.5%
compared to the control groups (21.53 +/- 1.26 mg/L).

3
The effect of ATA-Mg in the actimetry-based test is reported in
table 1.

Table 1: Effect of 100 mg/kg ATA-Mg in magnesium-deficient,

photostimulated mice

Magnesium Photostimulation ATA-Mg Results

status treatment
Normal No No 181.8 ± 17.1
Yes No 66.9 ± 19.4***
No No 267.6 ± 30.1***
Depletion
Yes No 458.0 ± 86.5**
Yes 100 mg/kg 210.2 ± 17.4
***Statistically different from controls (p <0.001);

DISCUSSION

The phenomenon of habituation was checked; group B mice

(non magnesium-deficient, non-treated, but photostimulated)
had a lower motor activity (66.9 ± 19.4) than the control group
(non magnesium-deficient, non-treated, non-photostimulated)
(181.8 ± 17.2). Magnesium-deficient mice presented the
classical NHE in absence of photostimulation (267.6 ± 36.1) and
severe NHE after photostimulation (458 ± 86.5), which
corresponds to the phenomenon of potentiation
(hypersensitivity).

In the E group (magnesium-deficient, ATA-Mg-treated at dose

of 100 mg/kg and photostimulated) the phenomenon of
sensitization disappeared. In the same conditions, neither
magnesium ion under the form of MgCl 2 , nor taurine or
acetyltaurine were efficient (data not shown).

Within our experimental conditions, ATA Mg among other

commercial magnesium salts (data not shown) was the most
efficient in restoring the habituation capacity.

4
CONCLUSION

ATA Mg is a magnesic analogue of taurine whose N-acetylation

eliminates the zwitterionic character of taurine and improves its
entry into the central nervous system.

The inhibiting properties of ATA Mg on the kainic acid receptor

have been demonstrated in a model of magnesium depletion
(3). Kainic acid is a neurotransmitter involved in NHE which is
present in photosensitive diseases (migraine, convulsion,
epilepsy) (4) (5). Other signs of NHE such as audiogenic
seizures inferred by magnesium depletion and sound
stimulation were significantly inhibited by ATA Mg (6).

Consequently, ATA Mg should be a therapeutic approach of

interest to the treatment of headaches, migraine with reactional
photophobia particularly . Clinical studies should confirm the
results observed in vivo.

References

1. Bac P. et al. A new actimetry-based test of photic

sensitization in a murine photosensitive magnesium
depletion model. Meth. Find Exp. Clin. Pharmacol.
2005; 27 : 681-4.
2. Durlach J. et al. Importance of Magnesium depletion
with hypofunction of the biological clock in the
pathophysiology of headaches with photophobia,
sudden infant death and some clinical forms of multiple
sclerosis. Magnes Res 2004; 17: 314-26.
3. Bac P. et al. Reversible model of magnesium depletion
induced by systemic kainic acid, injection in
magnesium-deficient rats: I -comparative study of
various magnesium salts. Magnes. Res. 1996; 9: 281-
291.
4. El Idrissi A. et al. Prevention of epileptic seizures by
taurine. Adv. Exp. Med. Biol. 2003; 526 : 515-25.

5
5. Baran H. Alterations of taurine in the brain of chronic
Kainic epilepsy model. Amino Acids 2006; 31 : 303-7.
6. Bac P. et al. Audiogenic seizures in magnesium
deficient mice: effect of magnesium pyrrolidone-2-
carboxylate, magnesium acetyl taurinate, magnesium
chloride and vitamin B6. Magnes. Res. 1993; 6: 11-19.

6
MagnesiumResearch2005; 18 (2): 109-22 ORIGINAL ARTICLE

Clirùcal paper

Headache due to photosensitive

magnesium depletion
J. Durlach\ Nicole Pagès2 , Pierre Bac3 , Michel Bara4, Andrée Guiet-Bara4
1
SDRM, SDRM, Université Pierre et Marie Curie, Paris VI, 75252 Paris Cedex 05,
France; 2 Laboratoire de toxicologie, Faculté de pharmacie, Strasbourg, 67400 Illkirch-
Grafenstaden, France ; 3 Laboratoire de physiologie et pathologie, UPMC, 75252 Paris,
Cedex 05, France ; 4 Laboratoire de physiologie et pathologie, UPMC, 75252 Paris,
Cedex 05, France
Correspondence: Dr. Jean Durlach, Président de la SDRM, Rédacteur en Chef de MagnesiumResearch, 64 rue de
Longchamp, 92200 Neuilly-sur-Seine, France. [email protected]

Abstract. Clinical and paraclinical data (visual stress tests, electroencephalogra-

phic and cerebrovascular photic driving, visual evoked potentials) demonstrate that
the concept of photosensitive headache is fully justified. The interictal hallmark of
photosensitive cephalalgic patients is potentiation (or sensitization) instead of
habituation. The aetiopathogenic mechanisms of photosensitive headache associate
hypofunction of the biological dock and magnesium depletion. The new concept of
headache due to photosensitive magnesium depletion seems justified. It appears
logical to add the treatments of magnesium depletion and of photosensitivity to
classical treatment of headache. Prophylactic magnesium treatment relies on atoxic
nutritional magnesium supplementation in case of primary magnesium deficiency.
Pharmacological doses of parenteral magnesium may be used but may induce
toxicity. Therefore it is necessary to know the therapeutic index of magnesium
compound used: the larger its value, the greater the safety margin. Treatment of
photosensitivity uses various types of « darkness therapies »: darkness therapy
through physiologie, psychotherapic, physiotherapic, pharmacologie stimulating
techniques and substitutive darkness therapy through palliative treatment. Melato-
nin is only a partial substitutive treatment of photosensitivity. A new mode! of
photosensitive magnesium depletion with potentiation should be a useful tool for
discriminating the most efficient « darkness-mimicking » agent.
Key words: headache, magnesium, migraine, photosensitivity, visual stimuli

Patients complain of headache very often, since Headache patients often exhibit a hypersensitivity to
approximatively 70-75% of men and more than 80% of light, usually with photophobia- its clinical marker
women are concerned. The great majority of head- -, during and between the algie attacks [4-17].
aches are idiopathie in origin. Although they are cur- Headache frequently appears as related to magne-
rently classified as Tension TYPe Headache (ITH) or sium deficit. Cephalalgia represents a symptom of
Migraine (M), this classification does not result in the the nervous form of magnesium deficient balance
delineation of separate headache types. A clinical and magnesium depletion in particular may play a
approach shows a continuum ranging from mild to role in the pathophysiology of migraine (3, 18, 19].
moderate then severe headaches, with clinical symp- The aim of this s tq,d y was to stress the importance of
toms, pathophysiological mechanisms and therapies photosensitivity in headache; to analyze the place of
similar in both M and TIR. Clinicians and research- magnesium deficit in photosensitive cephalalgic
ers alike may find it more logical to use a continuum patients; to hypothesize a causality link between
approach to primary headaches [1-3]. these factors with the clinical and pathophysiologi-

109
J. DURLACH, ET AL.

cal notion of « headache due to photosensitive Physical symptoms

magnesium depletion »; to conclude with the The so-called « tinted glass sign » may be considered
therapeutic consequences of this new concept, as an indirect symptom of light hypersentivity. Pho-
which encompasses a large part of the so-called pri- tophobie patients wear sunglasses in normal day-
mary headaches. light. Frequent wearing of tinted spectacles indoors
is pathological. Though it may be a physical sign of
photosensibility, it may also be recorded as « a
marker of neurotic and hypochondrial personality »
Importance of the light sensitivity or «a valid indicator of psychological distress ». Ali
in headache patients of these various interpretations may be valid: photo-
sensitivity may induce anxiety, anxiety may be a pre-
cipitating factor of photosensitive headache, the
Clinical symptoms symptomatology may be increased by a neurotic per-
sonality and by distress [20-23].
Reported symptoms
In photosensitive headaches - of the migraine type -
Paraclinical examinations
during algie attacks (ictal period) but alsobetween
episodes (interictal period), light stimuli can trigger Objective paraclinical examinations involve: visual
photophobia, the clinical marker of light sensitivity stress tests which evaluate visual stress thresh-
and a common symptom in primary headache. The olds, in order to obtain quantitative assessment of
term photophobia is derived from the Greek photo light induced-discomfort; electrical photic
(light) and phobia (fear or dread ot) -hence « fear of response, studied through EEG tracings; circulat-
light ». This ab normal sensitivity to light may appear ing photic response, studied through either Transc-
as pain on exposure to light or an uncomfortable ranial Doppler, or Magnetic Resonance lmaging;
sense of glare. This symptom is generally self- visual Evoked Potentials.
reported or diagnosed when questioning patients. As
early as the second century, A.D. Aretaei Cappadocis Visual stress tests
Severa! types of exposure to light during interictal
had written (in liber IV) «fugiunt enim quodam
periods may induce visual discomfort in cephalalgic
modo lucem, tenebrae aegritudinem solentur »
patients such as certain geometric patterns such as
(they avoid light by all possible means and the dark
parallel lines of alternate light and dark stripes,
subsides their feeling of sickness). Today light intol-
flicker, colors and fluorescent light.
erance is a well recognized symptom of primary
headache, and the patient may be improved by To sum up: photosensitive headache patients
retreating into a dark room [3-16]. exhibit a hyper-sensitivity to light during and
between the attacks. Pain thresholds are lower than
in controls. Migraineurs are more sensitive interic-
Abbreviations tally to light stimuli than TTH patients during attack
BC = biological dock and than controls [8, 12, 14, 15, 20-24].
M=migraine
CT = cranial tomography ElectroEncephaloGram (EEG) photic response
MRI = Magnetic Resonance Imaging In 1953, Mundy-Castle reported « considerably
MMPI = Minnesota multiphasic personality inventory greater mean response amplitude to photic stimula-
ED50 = median effective dose; MRI, magnetic reso- tion » in headache patients, during routine EEG.
nance imaging Later Galla and Winter (1959) described persis-
EEG = electro encephalogram; MT, melatonin
GABA = gamma-aminobutyric acid tance of photic driving to 20 Hz flashes or above (the
RDA = recommended dietary allowances H response) in headache patients.
Hb = hemoglobin Although many studies considered the H response
SCN = supra chiasmatic nudei as an EEG marker of migraine, it is no longer consid-
hBC = hypofunction of the biological dock ered as valid in routine evaluation since « the sensi-
TA= taurine tivity and specificity of the H response are too low to
HBC = hyperfunction of the biological d ock
TCD = transcranial Doppler change the probabiliey of the presence of migraine in
kO = kappa opioid a clinically significant way... », so « we do not recom-
TTH = tension type headache mend the use of EEG instead of head cranial tomog-
LD50 = median lethal dose raphy or magnetic resonance imaging in evaluating
VEPs = visual evoked potentials headache patients with suspected intracranial

llO
 HEADACHE DUE TO PHOTOSENSITIVE MAGNESIUM DEPLETION

pathology ». But a prominent photic driving may Visual evoked potentials

identify clinical subsets of photosensitive headache Classical Visual Evoked Potentials (VEPs) concern
patients [29]. In addition a dynamic notion must be the reactivity of electrocortical activity to visual
stressed since photic driving power decreases stimuli generated by either transient flash Oumi-
(towards normal values) during the headache phase nance stimulus) or checkerboard pattern (contrast
[30, 31]. In any case there is a complete overlap of the stimulus).
H response between the two main primary headache Stimulation produced surprising contradictory
subgroups TIR and M which agrees with the results since an increased amplitude was often found
so-called continuum severity theory: the lower limit in migraine, the typical form of photoreactive head-
of the continuum is TIR which progressively ache.
evolves into migraine and finally into migraine with Habituation has been studied after repetitive
aura[30]. visual stimuli. VISual stimuli were presented for
These various clinical forms of primary headache example, as a checkerboard pattern of 8 min of arc,
with abnormal visual reactivity are compatible with black and white squares (contrast 800Ai), at a reversa!
the concept of « photosensitive headache » [7, 10, frequency of 3.1 Hz. Five consecutive blocks of 50
24-32]. responses averaging a total number of 250 responses
were analyzed separately for latencies, peak to peak
Cerebrovascular photic responses amplitudes and areas under the components. Habitu-
Circulatory responses have been studied through ation was assessed as the amplitude changes in
either TransCranial Doppler (TCD), or Magnetic blocks 2-5 compared to block 1. Habituation was
Resonance Imaging (MRI). observed in healthy subjects. Migraine patients were
Changes in the cerebral perfusion were studied characterized by an amplitude increment (potentia-
during repetitive visual stimulation by functional tion) ofVEPs components which reached their maxi-
TCD in the right posterior cerebral artery and the left mum value in the second to the fourth blocks. Poten-
middle cerebral artery in interictal migraineurs. They tiation instead of habituation characterizes VEPs in
exhibited a steady increase in cerebral blood flow migraine patients between attacks [39]. Electro-
velocity while normal subjects showed habituation. physiologie studies demonstrate that, the hallmark
The lack of habituation of the cerebrovascular of migraine between attack, is a deficient habitu-
response in migraineurs was significantly more pro- ation.
nounced among patients with a high attack fre- Lack of habituation has been observed not only in
quency (at least 4 per month) compared with migraineurs' visual evoked potentials (and in related
migraineurs with a low attack frequency Oess than 4 parents'), but also in many other neurophysiologie
per month) [33]. These cerebrovascular data, in data: other sensory and somato sensory evoked
accordance with neurophysiological findings in potentials, event-evoked potentials (contingent
migraineurs highlight the importance of the lack of negative variation), cerebrovascular responses to
habituation in the pathophysiology of migraine. visual stimuli [3-7, 35-60].
Another study, using functional MRI, examined Habituation is a physiological phenomenon char-
changes in resting perfusion and in activation within acterized by a decrease in the responses to repetitive
the occipital cortex due to photic stimulation in both stimuli. It is considered to be a protective mecha-
controls and true menstrual migraine patients. No nism against overstimulation.
di:fference in resting baseline perfusion was Dishabituation, by contrast, is a process that lib-
observed between the two groups during either erates the nervous system from the habituation pro-
phase of the menstrual cycle. But the results di:ffered cess. Dishabituation stimuli act as sensitization or
after photic stimulation. During the late luteal phase, potentiation processes which rely on a dysfunc-
changes in perfusion within the occipital lobe were tioning of cortical information processing. The dys-
similar for both groups. whereas it decreased in function might result from the high level of cortical
controls, but significantly increased in menstrual arousal with increased energy demands and from
migraine patients during the mid-follicular phase. hypofunction of the subcortico-cortical pathwàys.
A significant di:fference (p < 0.05) was observed in Visual potentiation depends on the type of visual
the mean values for photic activation among the subsystem which is preferentially activated, either
true menstrual migraine patients compared to the magnocellular Ouminance and motion sensitive)
normals, after allowing for effects of di:fferences in or the parvocellular ( contrast and colour sensitive)
cycle Oate luteal phase versus mid-follicular phase) systems. The cortical arousal level depends on the
[34]. effects of various neurotransmitters from the brain-

111
 J. DURLACH, ET AL.

stem projecting to the cortex. Serotonin acts as a tional supplementation only, but requests the most
gain control between a noradrenergic, unspecific, specific control of the dysregulation mechanism.
facilitating system and a cholinergie, specific, inhlbi- There exist as many clinical forms of magnesium
tory system. depletion as numerous possibilities of dysregulation
Dishabituation may finally induce generalization of the magnesium status. But in both clinical and
when the nervous alteration involves other stimuli or experimental studies, the dysregulating mechanisms
invades other substrates. Generalization may con- of magnesium depletion associate a reduced magne-
cem various selective or global targets such as hear- sium intake with various types of stress. Among
ing in particular (with phonophobia), smell (with them chronobiological dysrhythmias, such as hypo-
cacosmia), touch (with allodynia), diet (with alimen- function of the biological clock (hBC) are often over-
tary intolerance). looked. Photosensitive Headache is the main clinical
To sum up: there is an adaptative dysfunction to form of photosensitive disorders due to a secondary
environrnental conditions in migraine [3, 9, 16, 24, 30, reactive response of the biological clock (BC) to
41, 46-88]. light neurostimulating effects through hBC [3, 81-83]
Finally, the clinical and paraclinical data on the (figure 1).
importance of light sensitivity in primary headache ln migraine, the typical form of photosensitive
demonstrate that: i) the concept of photoreactive headache, the nature of the magnesium deficit must
headache is fully justified. It may correspond to a be determined.
large number of the so-called primary headaches, - When chronic primary magnesium de:ticiency
M and TrH particularly. Photosensitivity, as well as coexists with migraine, it only constitutes a decom-
its clinical marker photophobia, may be inherited or pensatory factor whose control with simple oral
acquired; ü) the interictal hallmark of such cephalal- nutritional magnesium supplementation should help
gic patients is dishabituation with pathophysi- in migraine therapy as an adjuvant treatment
ologic potentiation (or sensitization) instead of since magnesium deficiency does not constitute
physiologie habituation; this dishabituation is the cause for migraine perse [3, 18, 19];
observed in ail the studied types ofrepetitive stimuli: - Clinical studies on magnesium status in
sensory (i.e. auditory), cognitive (i.e. contingent migraineurs have shown heterogeneous and incon-
negative variation), painful (i.e. laser), sensory stant decreases in extra- or intra-cellular, total or
motor (i.e. blink reflex), cerebrovascular (through ionized magnesium concentrations in serum, saliva,
TCDorMRI). erythrocytes, mononuclear cells, thrombocyte and
even in brain. Positive therapeutic responses to oral
physiological load are unreliable. These data agree
Photosensitive headache with magnesium depletion corresponding to a mag-
and magnesium status nesium deficit with dysregulation of the magnesium
status in migraine [3, 89-106].
Migraine may be considered as the paradigm for The importance of magnesium deficit in the patho-
PhotoSensitive Headache. An oral magnesium load physiology of migraine should be stressed. Optoki-
test was performed to determine whether netic stimulation may aggravate clinical and para-
. ~.
migraineurs had a disorder of magnesium status. clinical symptomatology ofboth primary magnesium
1\vo groups of either migraineurs (n = 20) and to deficit [107] and migraine [108]; their MMPI patterns
healthy volunteers (n =20) were given 3000 mg of (with elevation of neuroticism scales) are similar [19,
magnesium lactate during a 24h period (interictal for 109, 110] and nitric oxide is instrumental in the
migraineurs. The 24h urinary magnesium excretions pathophysiology of these two disorders [19, 31, 109-
were significantly lower (p = 0.0007) in migraineurs 111].
than in controls after loading, suggesting a systemic To sum up: the aetiopathogenic mechanisms of
magnesium deficit [89]. photosensitive headache associate hBC and magne-
A body of evidence has already stressed the differ- sium depletion [3, 81--83, 89-107].
ence between two types of magnesium deficits:
- de:ticiency linked to an insufficient intake which
may be corrected, through physiological nutritional Headache due -:.,
oral magnesium supplementation, over a long period to photosensitive magnesium depletion
oftime;
- depletion due to a dysregulation of the magne- The coexistence of chronobiological stress and of
sium status which cannot be corrected through nutri- magnesium deficit does not necessarily involve a

112

- - - - -- - -- - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - · - - - ---- -
 HEADACHE DUE TO PHOTOSENSITIVE !VIAGNESIUM DEPLETION

Mgoverload Mg deficiency

LIGHT

Figure 1. Possible central regulation of magnesium status and chronobiology. 1) Mg from physiological to
pharmacological concentration is able to directly enhance melatonin secretion by stimulating serotonin
N-acetyltransferase, the magnesium key enzyme for synthesis of melatonin (MT), and to enhance indirectly
the production of MT through an increased activity of the SNC. 2) MT can decrease magnesemia through its
effects on Mg distribution and the SNC may directly increase MT production. 3) The same mechanisms
induce two symmetrical effects. Darkness stimulates and light decreases MT production. Mg overload
stimulates and Mg deficiency decreases MT synthesis and SNC activities. Balanced Mg status might enhance
the effect of darkness treatments and reversely darkness treatments may potentiate the effects of Mg
therapy. Link demonstrated (-); Link probable(........... ).

causality link between these two factors but it does main clinical form is headache with photophobia
not, however, rule it out. (M and TTH particularly). Comorbidity with other
The inductive aetiopathogenic mechanism ofmag- clinical forms of this photosensitive pathology
nesium depletion with hBC may be due to the sum of may concern the psychic, hypnic and neuromuscular
nutritional magnesium deficiency and of a stress: fields. Comorbidity with anxiety (panic attack or
possibly a chronobiological stress such as hBC generalized anxiety disorder) is frequent, but photo-
through photosensitivity. sensitive headache may also be associated with dys-
somnias (i.e. delayed sleep phase syndrome) or
Chronic primary magnesium deficiency is fre-
local or generalized epilepsy.
quent: about 20 percent of the population consumes
less than two-thirds of the RDA for magnesium [112] . To summarize: the\ ew concept of headache due
In nutritionally magnesium deficient patients a pho- to photosensitive magnesium depletion appears
tosensitive chronobiological stress can induce a well founded and may induce various therapeutic
photosensitive magnesium depletion whose consequences [3, 19, 81, 112].

113
J. DURLACH, ET AL.

Treatment of headaches human membrane while MgS04 decreases it, with

due to photosensitive magnesium depletion many deleterious fetal consequences.
It seems therefore necessary to determine the
Classical medications used for the treatment ofhead- therapeutic index (LD 50 / ED 50) of the various
aches: antalgic drugs, anticonvulsivants, ~-blockers, available magnesium salts before pharmacological
ergot derivatives, triptans... although useful, will not use. The selection of one magnesium salt among
to be considered in this study. others should take into account reliable pharmaco-
The following therapeutic approach concerns only logical and toxicological data and the comparative
the treatment of magnesium depletion due to light therapeutic index of the varions salts: the larger
hypersensitivity: i) magnesium depletion treatment, its value, the greater the safety margin [125]. This
il) photosensitivity treatment. logical prerequisite is lacking in most protocols:
MgSO4 is just routinely used without justification.
Treatment of magnesium depletion Magnesium acetyltaurinate appeared as an effi-
Preventive treatment cient treatment in another type of magnesium deple-
Preventive treatment is more efficient than curative tion: kainate magnesium depletion experimen-
treatment. Since magnesium depletion is usually due tally induced by systemic kainic acid ÏI\Ïection in
to both a primary chronic magnesium deficiency and magnesium deficient rats [126]. But it is not possible
of a stress, the prophylactic treatment must rely on a to extrapolate from the previous mode! concerning
balanced magnesium status and the most specific the efficiency of this magnesium salt in photosensi-
possible antistress treatment. tive magnesium depletion [3, 81, 82, 112-126].
To insure a balanced magnesium status, in case of
chronic primary magnesium deficiency, atoxic Treatment of photosensitivity
nutritional magnesium supplementation will be ( « darkness therapy »)
carried out via the diet or with supplemental mag-
The reactive response to photosensitivity induces a
nesium salts [112]. The dietetic supplement should
hBC. But, in case ofphotosensitive headache, hBC is
have a high magnesium density with the greatest
aggravated because the repetitive stimulating effects
availability. Magnesium in drinking water is of par-
of light induce potentiation (sensitization) - some-
ticular interest as it associates a high bioavailability
times with generalization - instead of habituation
with the lowest nutritional density. The magnesium
[3] .
salt used would be hydrosoluble and the properties
of the anion should be considered [112-115] Treatment of photosensitivity - the so-called
« darkness therapy » - mirrors « phototherapy » the
No specific anti-photosensitive drug currently
exists which could be used as a preventive treatment treatment of hyperfunction of the biological clock
Darkness therapy aims either at stimulating the
of photosensitive magnesium depletion.
BC, or at palliating its hypofunction.
Curative treatment Stimulation of the biological clock may be
The aspecific treatments of magnesium depletion obtained through physiologie, psychotherapic, phys-
which are available, such as pharmacological iotherapic or pharmacologie agents.
doses of parenteral magnesium, may be used. Palliative treatments of hBC are dependent on
Severa! studies have shown that 1 gram of intrave- melatonin, its analogs or its precursors.
nous magnesium sulfate may be considered as effi-
cient, safe and well tolerated in migraine headache Stimulating dark:ness therapies
[116-120], butits efficiency as an antalgic drug and as a) Physiologie darkness therapies (Darkness
an anti-migraine treatment remains controversial therapy perse)
[121-124]. The best physiologie stimulation of the BC is induced
Pharmacological doses of magnesium salts by light deprivation.
may induce a toxicity which varies according to It may be obtained by placing the patient in a
the nature of anions. For example, the effects of closed room, in a totally dark environment, with an
MgC12 and MgS04 on the ionic transfer components eyemaskon.
through isolated amniotic membrane were studied This genuine darkness therapy may be used in
and revealed major differences. MgC1 2 interacts with acute indications, but should be of short duration. It
ail the exchangers, whereas the effects ofMgS04 are is not compatible with any activity and is frequently
limited to paracellular components. MgC12 mainly associated with induction of bed rest, inactivity and
increases the ionic flux ratio of this asymmetric sleep [3, 10, 81, 82, 127, 130].

114
 HEADACHE DUE TO PHOTOSENSITIVE MAGNESIUM DEPLETION

Relative darkness therapy may be obtained by headache among the indications of psychological
wearing dark goggles or dark sun glasses but the darkness therapies.
number of lux passing through is not negligible. This c) Physiotherapic darkness therapies
relative darkness therapy may be used as an acces-
sory treatment in the restoration of a light dark Magnetic fields may be used to stimulate the biologi-
schedule: a transition before a totally dark environ- cal clock in a variety of treatment methods using
ment. A successful double-blind study demonstrated very weak (picotesla), extremely low frequency (2 to
a significant difference between placebo and salico- 7 Hz) electromagnetic fields. Transcranial treatment
side (salicin) in association with a photoprotective with alternative current pulsed electromagnetic
mask in treating the two main clinical forms of pho- fields of picotesla flux density may stimulate various
tosensitive headaches: M and TIH [128]. The good brain areas (the hypothalamus particularly) and the
results of this controlled clinical trial have not been pineal gland (which functions as a magneto recep-
confirmed [3, 81, 84, 128, 129]. tor). Severa! studies concem its use for treatment of
Chromatotherapy uses a short exposure (4 min) headaches. A double blind placebo controlled trial
to a precise yellow wavelength, once a week for the has shown that this physiotherapy can alleviate
treatment of hBC. This method, even though suc- symptoms of M but not of TIH. Electromagnetic
cessfully used in practice, has not been validated yet fields for at least three weeks may be considered as
[3, 81, 82). an effective, short term intervention for migraine,
Sorne studies have reported benefit from using although the clinical effects were small [136-139].
. /
colored filters in headache patients: in childhood d) Pharmacologie darkness therapies
migraine particularly. A double masked randomized
controlled study with crossover design compared Three agents may stimulate the biological clock:
the effectiveness of precision ophthalmic tints ( opti- magnesium, L-tryptophan and taurine.
mal tint) or glasses that provided a slightly different - Magn.esium To stimulate the BC, it seems well
colour (control tint). Using individually prescribed advised to facilitate the neural function of suprachi-
coloured filters selected by each migraineur seems asmatic nuclei (/' SCN) and the hormonal pineal
more helpful than the conventional practice of using production ( /' MT). The deleterious effects of light
a neutral grey or sometimes brown tint, but the effect and those of magnesium deficiency are often found
is statistically marginal; it is suggestive rather than together and may be partly palliated by a nutritional
conclusive [23, 24, 130). magnesium supply (/' Mg), providing the best pos-
sible link between photoperiod and magnesium sta-
b) Psychotherapic darkness therapies
tus. Palliative nutritional magnesium supplementa-
Cognitive behavioral strategies have been efficient tion is efficient and atoxic when magnesium
for the treatment of photosensitivity. The treatment deficiency is present, but when there is a balanced
was to gradually increase exposure to computer magnesium status, it is illogical and inefficient. Phar-
monitor and television screen photostimulation. macological use of rnagnesium (high oral doses, or
This desensitisation procedure resulted in a com- parenteral administration) is uncertain and suscep-
plete removal of the patient's phobie anxiety of tible of inducing toxicity. Many data remain impre-
photo-stimulation and of avoidant behavior. This cise, such as nature and doses of the magnesium
_,.--- .. behavioral therapy has been used in photo-sensitive salts, oral or parenteral routes, association with rnag-
epilepsy [131] . It is akin to deconditioning tech- nesium fixing agents [3, 81, 82, 113].
niques used as a non-pharmacological approach to -L-tryptophan (or 50H-tryptophan) may stimu-
prevent photosensitive headache. For example: Vari- late the tryptophan pathway [140]. But they are
able Frequency Photostimulation (VFP) goggles i.e. a unspecific as they not only concem melatonin pro-
portable stroboscope using red Light Emitting duction, but also serotonin synthesis .. LTP supple-
Diodes (LED) to illuminate the right and the left eye mentation may induce toxicity, eosinophilia-
altemately were used with limited efficacy. Various myalgia syndrome particularly [141-145].
biofeedback treatments for migraine were disap- - Taurine is a sulphonated aminoacid which is
pointing since a reduction in the number of migraine present in the whole body in high concentrations,
headaches was observed, but with no change in the particularly in the bi:~ . lt has multiple functions in
intensity, duration or disability of the headaches cell homeostasis, such as membrane stabilization,
[132-135] . • buffering, osmoregulation and antioxidant activities
The concept of headache due to photosensitive together with effects on neurotransmitter release
magnesium depletion places this clinical form of and receptor modulation.

115
J. DURLACH, ET AL.

Taurine may act as a protective inhlbitory neuro- 148, 149]. During M, the typical form ofheadache due
modulator which participates in the functional qual- to photosensitive magnesium depletion, taurine
ity of the neural apparatus and in melatonin produc- mobilisation may be considered as a defensive reac-
tion and action. It plays a role in the maintenance of tion but it is less effective than in case of magnesium
homeostasis in the central nervous system, particu- deficiency [155-160] (figure 2).
larly during central nervous hyperexcitability. Tau- To sum up, magnesium, tryptophan and taurine
rine, a volume-regulating aminoacid, is released may be used to stimulate the biological clock, but
upon excitotoxicity-induced cell swelling. It has an their efficiency seems limited.
established function as an osmolyte in the central
Palliative treatments of hypofunction of the bio-
nervous system [3, 18, 81, 82, 109, 122, 146-154] .
logical clock may be necessary.
In the course of magnesium deficit, the organism
« Substitutive darkness therapy »
appears to stimulate taurine mobilisation to play the
role of «a magnesium vicarious agent». Usually, this (darkness mimicking agents)
compensatory action is rather limited. However, it a) Mechanisms of the action of darkness
allows us to observe the latent form of the least The mechanisms of action of darkness appear to be
severe form ofmagnesium deficiency [18, 109, 122, the reverse of those described with bright light,

Photo
Periodic SENSITIVE
Factors LIGHT

Variations
in
PINEAL
Melatonin
and
Taurine
contents

TA mobilization

Normal subject 1 Photosensitive migraineur 1

Figure 2. Photoperiod, pineal, melatonin and taurine. In normal subject, darkness (a) increases the pineal
melatonin synthesis (ÎMT). Since this MT synthesis is taurine-dependant, pineal taurine levels decrease
( J, TA) during darkness. This induces a down reglated compensatory increase in taurine mobolization wich
marker is an increase in platelet taurine content (ÎTApJ· Reversely, light (b) decreases pineal melatonin
synthesis (J,MT). Consequently, by increasing the pineal taurine content, the down regulated compensatory
increase in taurine mobilization is suppressed leading to a major decrase in pineal MT ( J,J,MT) and
correlatively to a major increase in pineal taurine (ÎÎTA). The pathological disabituation induced by iterative
photosensitivity pathologically reverses the taurine mobilization. Platelet tallli:ne levels increase instead of
decraseing (ÎÎTApJ· This important increase in TAPI does not compensate the pathological decrease in
pineal melatonin, but may appear as defense mechanism having osmolyte beneficial effects on extra-pineal
tissues such as central nervous or cardio-vascular systems. MT: pineal melatonin; TA: pineal taurine; MTb:
circulating blood melatonin; TAPI: platelet taurine.

116
 HEADACHE DUE TO PHOTOSENSITIVE MAGNESIUM DEPLETION

where direct cellular effects (membraneous and Conclusion

redox) and neural mediated effects intervene. ---------------------
The treatment of headache due to photosensitive
lncreased production ofmelatonin (/' MT) consti- magnesium depletion must, at present,associate:
tutes the best marker of darkness, but it is only an - the classical treatments of headache (antal-
accessory mechanism in its action. gic drugs, anticonvulsants, ergot derivatives,
~-blockers, triptans ... )
The main central neural mechanisms of darkness
- a balanced magnesium status (through nutri-
therapy associate decreased serotoninergy ( \. 5HT)
tional or careful pharmacological magnesium
-which could account for the antimigraine effect- and
supplementation)
stimulation of inhibitory neuromodulators gamma-
- the control of hBC through physiologie, psy-
aminobutyric acid, taurine, kappa opiods (/' GABA,
chotherapic, physiotherapic or pharmacologie
/" TA, /" kO) and stimulation of anti-inflammatory
stimulation of the BC or through MT: partial
and antioxidative processes. These effects may
darkness mimicking agents.
induce neural-hypoexcitability i.e. sedative and anti-
convulsant effects. Further research must study other agents with
more efficient darkness mimicking properties. A
Humoral transduction may reinforce these last new model of photosensitive magnesium depletion
effects by decreasing neuroactive gases (\. CO, \. with potentiation is currently described [165] . This
NO) through binding of CO with hemoglobin (Hb) test should be a useful tool for discriminating the
and by increasing melatonin, bilirubin and biliverdin, most efficient darkness mimicking agent in photo-
three antioxidants which are able to quench NO. sensitive magnesium depleted mice.

Apart from the exception of decreased seroton-

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