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Magnesium Research (1993) 6, 1, 11-19
ORIGINAL ARTICLE


Audiogenic seizures in magnesium-deficient mice: effects of magnesium pyrrolidone-2-carboxylate, magnesium acetyltaurinate, magnesium chloride and vitamin B-6


Pierre Bac1, Christine Herrenknecht, Pierre Binet1 and Jean Durlach2

1Faculté de Pharmacie, rue J.B. C1ément; 2S.D.R.M. Hôpital Saint-Vincent de Paul, Avenue Denfert-Rochereau, Paris, France


Summary: Magnesium deficiency in mice causes and increases audiogenic seizures. This effect was reversed by oral administration of magnesium acetyltaurinate (ATaMg), magnesium pyrrolidone-2-carboxylate (PCMH), MgCl2. When treatment was discontinued, audiogenic seizures recurred only in the groups treated with PCMH or MgCl2. Following intraperitoneal administration of AtaMg. the mice were protected against audiogenic seizures after 4 h and this protection persisted for up to 72 h after the treatment. With the other magnesium salts (PCMH and MgCl2) maximum protection occurred by 6 h after the injection, but after that time the number of seizures increased sharply. Intraperitoneal taurine alone only reduced the severity of the audiogenic seizures. The length of treatment needed to inhibit audiogenic seizures was reduced by treatment with a combination of vitamin B-6 (a magnesium fixing agent) and PCMH or MgCl2. However this combination of vitamin B-6 and magnesium salts did not prevent the recurrence of audiogenic seizures, which was only achieved by ATaMg.

The results suggest that audiogenic seizures in magnesium-deficient mice form a model of magnesium depletion. This depletion is completely inhibited by the combination of an inhibitory neurotransmitter (taurine) and magnesium, in the form of magnesium acetyltaurinate.

Key words: Dietary magnesium-deficient mice, magnesium depletion, magnesium chloride, magnesium pyrrolidone-2-carboxylate, magnesium acetyltaurine, taurine, vitamin B-6, audiogenic seizures.

Introduction

Sound stimulation of a certain frequency and range triggers generalized convulsions (audiogenic seizures) in mice. There are three successive stages leading to this condition:

(1) Intensive motor excitation expressed by wild running.
(2) Clonic convulsions during which the animal falls on its side accompanied by clonic rhythmical movement of its limbs.
(3) Tonic convulsions during which the animal stretches. During this phase the animal may die from respiratory arrest.

Some strains of mice are naturally susceptible to audiogenic seizures (DBA/2, Fring's O'Grady), These are called audiosusceptible strains. Others are audioresistant (OF1, AKR, C57BL/6) 2-4. The best known form of magnesium deficiency in humans is expressed by neuromuscular hyperexcitability5. Rats, which are most frequently used in studies on experimental magnesium deficiency, may show signs of central nervous hyperexcitability (spontaneous convulsive seizures, audiogenic seizures) when made magnesium-deficient. The beneficial effects of magnesium salts (MgCl2 and MgSO4) on these central manifestations of magnesium deficiency are well known 6-10. However, few experimental studies have been undertaken on magnesium-deficiency-induced audiogenic seizures in mice as a model of central hyperexcitability. Finally, the effects of correcting magnesium deficiency by magnesium salts of acid pyrrolidone-2-carboxylate (PCMH) and acetyltaurinate (ATaMg), and the combination of these two molecules with vitamin B-6, on the central manifestations of magnesium deficiency have never been described. The aims of this study were therefore: (1) to compare the effect of ATaMg and PCMH to that of MgCl2; and (2) to find out whether the combination of vitamin B-6 with magnesium salts will reduce the length of the treatment needed to protect mice from audiogenic seizures.

Methods

Mice were made magnesium-deficient with a low magnesium diet (50 mg of magnesium per kg of food) prepared by U.A.R. (Usine d'Alimentation Rationnelle). Mice on control diet were fed on a normal magnesium intake (U.A.R. dietA.03, containing about 1.70 g of magnesium per kg of food).

Male mice of the OF1 strain from Ifacredo were placed 20 per cage in an animal house at fixed temperature (22 ± 1° C), under artificial lighting alternating 12 h of daylight and 12 h of darkness (from 7 am to 7 pm). The mice remained under these conditions for at least 3 d and during this time were generously fed a U.A.R. A..03 diet and water containing 40 mg/litre of magnesium in chloride form. After 3 d in the cages, the animals were fed the U.A.R. magnesium-deficient diet for a period of 40 d. This ensures a 100 per cent audiogenic seizure rate. In order to assess the mineral intake more accurately, the mice drank only distilled water during this period. After 40 d of this diet the body weight per animal was 30 ± .5 g.

Audiogenic seizures were triggered by a 10 kHz ± 100 Hz), 1V intensity sinusoid signal at its highest peak, from a low frequency Farnell-MF generator (ref. ESG/1) through a 50 x 60 x 20 cm box. Using a Tektronix RM564 spectrum analyser and a Rochar Electronique frequency metre (ref. A1360C) as a signal check, the signal was then amplified by a Sony TAF 300 system. The noise level of about 100 dB was measured close to the animal's ear by an external decibel meter probe DM 600. A time delay system regulated the length of the sound simulation in 15 s periods. During the audiogenic seizure test only one mouse was in the box at a time. The number of animals completing total audiogenic seizure cycles during each test was recorded. We used the following compounds to correct magnesium-deficiency-induced audiogenic seizures:

We used the Shapiro Wilk test to check for normal distribution among the groups. The Kruskall Wallis test, an analysis of non-parametric variances, was used to compare the different groups.

Results

Correction of audiogenic seizure with magnesium salts

Magnesium intake through an oesophageal probe

For this experiment 40 batches of 20 male OF1 mice were fed a diet deficient in magnesium for 40 d. At the end of this period we checked all the mice in two of the batches of the control animals for audiogenic seizure susceptibility. Later, these two batches of control mice were fed a diet with normal magnesium content, i.e., about 1.7 g of magnesium per kg of food (UARA 03 diet) and 40 mg/litre of water intake (magnesium chloride in drinking water) and for 10 d they were fed distilled water instead of magnesium salts.

The other batches of mice were fed their normal diet with a magnesium supplement (3,5,7,14 or 28 mg) in the form of different magnesium salts. For each type of magnesium salt administered (ATaMg, PCMH, MgCl2) we used three batches of mice per product and per dose.

The product was given in the morning and the audiogenic tests were carried out the next day around 3 pm. Once the treatment was given, the animals were kept under surveillance (a diet of 40 mg/litre with a normal content of magnesium in drinking water) and were once more subjected to audiogenic tests 24, 31, 38, 45, 52 and 60 d later.

Even after 10 d of treatment with different salts and a magnesium supplement of 3.5 mg or 7 mg/d all the animals were not totally protected from audiogenic seizures. On the other hand, an intake of 14 mg/d of magnesium (see Fig. 1) in its different forms helps to protect all the animals from audiogenic seizures after following diets which vary according to the type of salts used. The most effective molecule used was ATaMg, since it took only 6 days of treatment to totally eliminate audiogenic convulsions among all the mice. It is noteworthy that a daily intake of 28 mg of the various magnesium salts brought about no significant change in the length of the treatment required to terminate all audiogenic seizures.


Figure 1.

At the end of the treatment the animals were again subjected to audiogenic seizure tests once a week from the 24th day. The results obtained using PCMH and MgCl2 (Fig. 2) show that a certain percentage of the animals which were fed these compounds did have audiogenic seizures. These results are similar to those obtained in the magnesium-deficient animals and in those reestablished on normal diet. On the other hand, the animals treated with ATaMg were definitely protected from audiogenic seizures.


Figure 2.

After 31 d on a normal diet audiogenic seizures were observed in all the control mice. The normal diet had to be continued for at least 52 d in order to protect the other half of the batch.

Finally, it was observed that at the end of the experiment, i.e., on the 60th day, one third of the control animals were still susceptible to audiogenic seizures.

Magnesium salts or taurine by parenteral injection

For this test we used three batches of 10 male OF1 mice after a 40 d magnesium deficiency period. The different compounds were given intraperitoneally at 24 h intervals (from day 1 to day 3). The audiogenic test was carried out 2, 4, 6, 24, 48 and 72 h after the last injection. Injections of magnesium (3 mmol/kg) were given in the form of ATaMg (1070 mg/kg), PCMH (986 mg/kg) and MgCl2 (613 mg/kg). A dose of 1200 mg/kg of taurine was injected. During this experiment we observed the different stages of the audiogenic seizure cycle (wild running, clonic convulsions, tonic convulsions and fatal convulsions). The results are illustrated in Figs 3 to 5.


Figure 3.


Figure 4.


Figure 5.

A qualitative analysis of the results shows that all the compounds injected intraperitoneally (ATaMg, PCMH, MgCl2, and taurine) helped to diminish magnesium-deficiency-induced audiogenic seizures more or less efficiently depending on the compound used. However, there were major differences in quality between compounds.

Two hours after injecting ATaMg, effective protection from audiogenic seizures was observed and persisted for 72 h after the treatment, reaching its maximum level about 4 h after injection. Protection was equally effective during all stages of the audiogenic seizure cycle (particularly in the reduction of the wild running phase). The maximum effect of magnesium chloride and PCMH on audiogenic seizures appeared 6 h after injection but remained well below that of ATaMg. Here too there was equal protection from audiogenic seizure during all the different stages; however, after 24 h, this protection ceased to be effective.

Taurine or magnesium acetyltaurinate have similar effects on magnesium-deficiency-induced audiogenic seizures but only the results for taurine are presented in the figures. The action of taurine or sodium acetyltaurinate on magnesium-deficiency-induced audiogenic seizures is complex and, in contrast to the other compounds used, did not equally affect all stages of the convulsions. Indeed, 2 h after injection there was a decline in the number of clonic and tonic convulsions, whereas the wild running did not diminish significantly in any way. Four hours after the injection, the number of clonic convulsions increased and equaled the number of wild running movements. These two stages of audiogenic seizure develop along the same lines and affected 100 per cent of the mice from 24 h onward. The number of tonic convulsions decreased after 2 h and remained low up to 48 h before increasing again. Thus it seems that the action of taurine or sodium acetyltaurinate is characterised only by the non-occurrence of tonic convulsions among a large number of the mice.

Correction of audiogenic seizures through the combination of magnesium salts and vitamin B-6

The role of vitamin B-6 as a magnesium fixing compound has been fully described and used in therapy. We sought to determine whether the combination of vitamin B-6 with magnesium salts helps to shorten the duration of the treatment required in order to protect our model animal with neuromuscular hyperexcitability from audiogenic seizure.

For this test we used 40 d magnesium-deficient OF1 mice (each weighing about 30-33 g). The mice were in batches of 20. At the end of the magnesium deficiency period the animals were fed a diet with a normal magnesium content and separated into four batches. The first batch was fed 30 mg/kg per day of vitamin B-6 alone for 10 d through an oesophageal probe. The other batches were fed the different magnesium salts and 30 mg/kg per day of vitamin B-6 for 10 d. During the treatment period all the animals were submitted to audiogenic seizure tests on a daily basis. At the end of the treatment period, the animals were once more submitted to audiogenic seizure tests 24, 31, 38, 45, 52 and 60 d later.

After 10 d of treatment complete audiogenic seizure frequency was reduced by 50 per cent through the use of vitamin B-6 alone (see Fig. 6). However, these results show that use of vitamin B-6 does not ensure complete protection against audiogenic seizures, since it only lowered the number of tonic convulsions in the control mice significantly and had no effect on the first two stages of the audiogenic seizure cycle (wild running and clonic convulsions). Thus rather than ensuring guaranteed protection from audiogenic seizures there was in fact only an attenuation of the cycle.


Figure 6.

On the other hand, the combination of vitamin B-6 and magnesium salts (Fig. 7) helped to protect the mice from audiogenic seizures by interacting during all stages of the cycle. A comparison of the percentage of audiogenic seizures obtained when combining each type of salt with vitamin B-6 shows that during treatment for a chosen period of time the percentage was significantly lower when using PCMH and MgCl2, and only slightly lower when using AtaMg. However, the combination of vitamin B-6 and MgCl2 or PCMH was far less effective than ATaMg alone or ATaMg in combination with vitamin B-6. Further at the end of the treatment audiogenic seizures recurred only among those mice treated with vitamin B-6 alone or with B-6 in combination with MgCl2 or PCMH. Those animals treated with vitamin B-6 and ATaMg were permanently protected from audiogenic seizures.


Figure 7.

Discussion

Oral magnesium intake

On the basis of quality the correcting effect of the three types of magnesium salts was the same. In fact, pharmacological doses of magnesium (14 mg per day per mouse or about 500 mg/kg per day) suppresses all magnesium-deficiency-induced audiogenic seizure activity. This adds to a previous study11 which shows that MgCl2 suppresses seizures among OF1 mice made magnesium-deficient for 43 days, and confirms other results which show that MgCl2 or MgSO4, when given in pharmacological doses, are capable of suppressing convulsive seizures in the rat 6,7,12 and mouse8,13,14. On the other hand, when magnesium-deficient animals are again fed a normal diet, audiogenic seizures recur. Thus the nature of the deficit is not simply a case of magnesium deficiency but one of magnesium depletion.

In terms of quantity, the correcting effect of the three salts is different. Indeed, processing the results statistically using the Kruskall-Wallis test shows that the action of ATaMg or PCMH is greater than that of MgCl2 in inhibiting audiogenic seizures. Moreover, ATaMg is the more effective salt since, for each equal dose of magnesium administered, this compound suppresses the seizures more quickly than the other salts. This salt is seen to be most effective even when providing a low intake of magnesium (3.5 mg/kg per day of Mg2+), at which level one third of the animals were protected from audiogenic seizures.

The fact that PCMH is more effective in suppressing audiogenic seizures than MgCl2 was expected since it is well knownl5 that among mice that are not magnesium-deficient the intracellular penetration of magnesium is more active with PCMH than with MgCl2. This may well be due to the ion pyrrolidine-2-carboxylate-5, which sensitizes the cellular receptors for the cation Mg2+. Furthermore, other investigators 16 have shown that administering PCMH to magnesium deficient animals produces an increase in the magnesium level equal to that of the magnesium fed control animals after 10 days of treatment, whereas administering MgCl2 is not followed by a return to normal levels of magnesium under the same conditions. However, the difference between these two salts is most striking with regard to skin problems, which heal more quickly and more completely with PCMH than with MgCl2. Thus our research is complementary to these results in showing that PCMH is more effective than magnesium chloride in treating central nervous system problems associated with severe magnesium deficiency.

Magnesium load by parenteral injection

We showed that ATaMg was the most effective compound when given either by injection or orally in protecting magnesium-deficient mice from audiogenic seizures. Indeed, ATaMg injection equivalent to a dose of 3 mmol/kg of magnesium ensured protection throughout all stages of audiogenic seizure from the second hour after the injection. The effect reached its maximum level 4h after the injection and persisted for 72 h. In contrast, injecting the other salts caused a reduction in the number of audiogenic seizures after 6 h, but after 24 h convulsions recurred in all the animals.

That ATaMg should be extremely effective was foreseeable, since taurine is known to have a positive effect on some types of convulsion17,18 (hyperbaric oxygen, cobalt injections) in the rat and the mouse. Furthermore, studies by Batuev et al. 19 have shown that three intraperitoneal injections of taurine stop the convulsions accompanying audiogenic seizures in genetically audiosensitive rats. This is why the fact that ATaMg is more effective than the other magnesium salts (when expressed in equal doses of magnesium) is undoubtedly linked to the taurinergic component in the molecule rather than to the magnesium. In this case, the greater effectiveness of ATaMg may be due to the following:
(1) A purely anticonvulsive action in the taurinergic component of the molecule. However, it is noteworthy that taurine does not have the capacity to suppress all stages of audiogenic seizure in genetically audiosensitive rats19, but only interacts on the severity of the seizure.
(2) The action of taurine on the cellular effects of magnesium deficiency. Indeed, taurine is released in magnesium-deficient rats20 and this is undoubtedly a major compensatory mechanism which restrains the central nervous hyperexcitability of the animal. It can be assumed that the action of the ATaMg is due to an increase in the taurine levels in the brain blocking the intracellular Ca2+, which in so doing increases the rapport AMPc/GMPc21 and induces hyperpolarization of the cell. Under these conditions, central nervous hyperexcitability is contained.

Combination of magnesium salts with vitamin B-6

In therapy5 it is known that the combination of vitamin B-6 and magnesium is beneficial in the treatment of neuromuscular forms of primary magnesium deficiency. Studies by Majumdar & Boylan22 show clearly that a diet supplement of vitamin B-6 administered to a magnesium-deficient rat increases the magnesium level in its different tissues and in particular, in brain tissue. Furthermore, this increase is in relation to the dose of vitamin B-6 given to the animal. Although the precise mechanism of the interaction between vitamin B-6 and magnesium is not completely known, it seems an established fact5,23 that vitamin B-6 speeds up the transport of magnesium through the cellular membranes and is essential for storing magnesium. In vitro it has been established24 that magnesium may form a coordinated compound with pyridoxal phosphate, but the physiological role of this compound is as yet unknown.

The combination of vitamin B-6 with PCMH or MgCl2 helps reduce the length of the treatment period required to protect all the magnesium-deficient mice from developing audiogenic seizures. This reduced treatment period is probably due to a much more active transport of magnesium to the brain. This may more rapidly restore the metabolic processes disrupted by magnesium deficiency and which are responsible for inducing audiogenic seizures. This seems to be the case of the combination of vitamin B-6 and magnesium salts (PCMH and MgCl2). Vitamin B-6 alone does not ensure total protection as it only reduces the severity of the audiogenic seizures (reduction in tonic convulsions) of magnesium-deficient mice. This confirmed by the studies of Schlesinger & Boggan25 and Schlesinger & Lieff26 which show that vitamin B-6 acts only on the severity of the audiogenic seizures by reducing the number of fatal convulsions.

Paradoxically, a comparison of our results obtained from combining vitamin B-6 with ATaMg to those observed with ATaMg alone does not show any major reduction in the length of treatment required to protect all the magnesium-deficient-mice from audiogenic seizures. There are two possible reasons for this:
(1) Vitamin B-6 does not form a compound with the magnesium contained in the AtaMg. A study is under way to determine the complexation constants between these different molecules and magnesium.
(2) The taurinergic component of the molecule is greater than the magnesium component when used to correct audiogenic seizures. Thus it can be assumed that the action of ATaMg in correcting audiogenic seizures is different from that of PCMH and MgCl2. It is conceivable that the combination of vitamin B-6 and ATaMg brings about no change.

Finally, the combination of vitamin B-6 and magnesium salts (except ATaMg) did not stop the recurrence of audiogenic seizures. Thus it is conceivable that audiogenic seizures are a sign of magnesium depletion in which the combination of magnesium salts with vitamin B-6 brings about no change.

Conclusion

The basis of any treatment for magnesium deficiency consists of oral administration of physiological doses (5 mg/kg per day) of a magnesium salt5. In this model of audiogenic seizures in magnesium-deficient mice, (1) pharmacological intakes (about 500 mg/kg per day) of magnesium salts alone combined with a normal dietary intake of magnesium were able to stop all audiogenic seizures; (2) these convulsive seizures recurred on discontinuing treatment. Increasing the length of the treatment period using PCMH or magnesium chloride did not always prevent the recurrence of audiogenic seizures. Finally, vitamin B-6 used as a magnesium fixing compound did not protect the animals permanently from audiogenic seizures.

These unsuccessful results lead us to the conclusion that audiogenic seizures in magnesium-deficient mice are not due simply to magnesium deficiency but rather to magnesium depletion 5. Parenteral injections of MgCl2 or PCMH do not protect the animals permanently from audiogenic seizures, even after 7-15 days of treatment (unpublished results). It can be assumed that the principal mechanism of the depleted animal model is in no way linked to magnesium deficiency. On the other hand, the fact that ATaMg administered orally or by intraperitoneal injection protects the animal permanently from audiogenic seizures leads us to the conclusion that taurine acts in a very significant way on the magnesium-depleted animal model. However, it is noteworthy that taurine or sodium acetyltaurinate do not have a lasting beneficial effect on audiogenic seizures. It seems that the magnesium-depleted animal model is highly sensitive to the combination of an inhibiting neurotransmitter with a taurine component and magnesium in the same molecule.

Acknowledgements

We thank Mr J. Harper for his translation.

References

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4. Fuller, J.L. & Sjursen, F.H.Jr. (1967): Audiogenic seizures in eleven mouse strains. J. Hered. 58, 135-140.

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9. Poenaru, S., Durlach, J., Rouhant, S., Rayssiguier, Y., Gueux, E., Iovino, M. & et Reba, A., (1983): Etude électrophysiologique de la carence magnésique du rat. Magnésium 2, 299-312.

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12. Chutkow, J. G. & Meyers, S. (1968): Chemical changes in the cerebrospinal fluid and brain in magnesium deficiency. Neurology 18, 963-974.

13. Belknap, J.K., Berg, J.H., Cocke, R. & Clancy, A.N. (1977): Induction and reversal of the magnesium deficiency syndrome in inbred mice. Exp. Neurol. 57, 506-515.

14. Belknap, J.K., Berg, J.H., Ondrusek, G. & Waddingham, S. (1978): Barbiturate withdrawal and magnesium deficiency in mice. Psychopharmacology 59, 299-303.

15. Binet, P., Miocque, M. Pechery, C., Roux, M. & Rinjard, P. (1976): Etude expérimentale de quelques propriétés pharmacodynamiques du pyrrolidone-2-carboxylate-5 de magnésium. Thérapie 31, 47 l-481.

16. Binet, P., Miocque, M.. Pechery, C.. Roux, M. & Rinjard, P. (1978): Effet correcteur comparé du pyrrolidone-2 carboxylate de magnésium et du chlorure de magnésium sur les troubles cutanés et hématologiques de la carence magnésique expérimentale due Rat. Thérapie 33, 491-500.

17. Adembri. G., Bartolini, R., Giotti, A. & Zilleti, L. (1974):Anticonvulsive action of homotaurine and taurine. Br. J. Pharmacol. 52, 439-440.

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20. Durlach. J., Poenaru, J., Rouhani, S., Bara, M. & Guiet-Bara, A. (1987): The control of central neural hyperexcitability in magnesium deficiency. In: Nutrients and brain function, ed. W.B. Essman, pp. 49-71. Basel: Karger.

21. Rapin, J.P,, Galiez, V., Le Poncin-Lafitte, M., Durlach, J., Rayssiguier, Y. et Godard, J.P. (1983): Distribution régionale des nucléotides cycliques dans le cerveau de rats adultes carenccés en magnésium. Magnesium-Bull. 2, 87-91.

22. Majumdar, P. & Boylan, L.M. (1989): Alteration of tissue magnesium levels in rats by dietary vitamin B6 supplementation. Int. J. Vitam. Nutr. Res. 59, 300-303.

23. Durlach, J. (1969): Données actuelles sur les mécanismes de synergie entre vitamine B6 et magnésium. J. Méd. Besançon 5, 349-359.

24. Boylan, L.M. & Spallholz. J.E. (1990): in vitro evidence for a relationship between magnesium and vitamin B6. Magnesium Res. 3, 79-85.

25. Schlesinger, K. & Boggan, W. (1968): Genetics of audiogenic seizures: II-Effects of pharmacological manipulation of brain serotonin, norepinephrine and gamma aminobutyric acid. Life Sci. 7, 437-447.

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