A calcium antagonistic effect of the new antiepileptic drug lamotrigine

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Abstract

The new antiepileptic drug lamotrigine (LTG; 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) has been shown to be effective in the treatment of focal epilepsies with or without secondary generalization. Furthermore, some case reports indicate an efficacy in the treatment of bipolar affective disorders. It has been suggested that the main mechanism of action of LTG is the inhibition of glutamate release through blockade of voltage sensitive sodium channels and stabilisation of the neuronal membrane. Since some antidepressant drugs and the antiepileptic substance carbamazepine have calcium antagonistic properties, which may be of significance in the pathophysiology of epilepsies and affective disorders, the interaction of lamotrigine with carbamazepine and the organic calcium channel blocker verapamil was analyzed in the low Mg2+-induced model epilepsy which has been shown to be suppressed specifically by organic calcium antagonists. Lamotrigine reduced the frequency of occurrence of low-magnesium induced field potentials in CA1 and CA3 areas of the hippocampus slice preparation (guinea pigs) in a dose-dependent manner. The subthreshold concentrations which yielded no effect were 1 μmol/l for lamotrigine, 10 μmol/l for carbamazepine and 2 μmol/l for verapamil. Combinations of these subthreshold concentrations elicited a reduction in the repetition rate of field potentials. The results indicate that lamotrigine behaves additive with verapamil and carbamazepine what can be due to a common action on the same subtype of calcium channels. It can be assumed that lamotrigine may have besides its action on high-frequency sodium dependent action potentials also effects on calcium channels.

Introduction

The new antiepileptic drug lamotrigine (LTG; 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) has been shown to be effective in the treatment of focal epilepsies with or without secondary generalization (cf. Yuen, 1994). Furthermore, some case reports indicate an efficacy in the treatment of bipolar affective disorders (Weisler et al., 1994, Walden et al., 1996). It has been suggested that the main mechanism of action of LTG is the inhibition of glutamate release through blockade of voltage sensitive sodium channels and stabilisation of the neuronal membrane (Leach et al., 1986). Thus, LTG has been shown in voltage-clamp studies on rodent cells to inhibit voltage dependent sodium channels by tonic and use-dependent mechanisms (Lang and Wang, 1991). Moreover, LTG is able to induce a protection against striatal kainate neurotoxicity being dependent on the release of glutamate (McGeer and Zhu, 1990). This pharmacological profile resembles the action of phenytoin and carbamazepine both of which also exert depressive actions on sodium channels (cf. Catteral, 1987).

In the search for basic mechanisms in affective disorders a disturbed intracellular calcium ion homoeostasis is discussed (Dubovsky, 1993, Dubovsky et al., 1994, van Calker et al., 1993). Several clinical studies evaluated antimanic and partly also antidepressive actions of calcium antagonists like verapamil, diltiazem and nimodipine (cf. Brunet et al., 1990, Dubovsky, 1993, Walden et al., 1995). In this context it was found that the antiepileptic drug carbamazepine, which is used in the prophylaxis of affective and schizoaffective disorders, and also the antidepressant imipramine have other actions in addition to calcium antagonistic properties (Choi et al., 1992, Walden et al., 1992, Walden et al., 1993). Since in a recent study an effect of LTG on calcium channels in cultured cortical rat neurones was described (Lees and Leach, 1993), the aim of the present investigation was to test whether LTG may display also calcium antagonistic properties which may contribute to its pharmacological actions in men.

Section snippets

Materials and methods

The experiments were carried out in hippocampal slices of guinea pigs (300–400 μm thick). The brain was removed from the guinea pig under ether anesthesia. The slices were preincubated for 2 h in a 28°C standard saline solution containing (in mmol/l) NaCl 124, KCl 3, CaCl2 0.75, KH2PO4 1.24, MgCl2 1.3, NaHCO3 26 and glucose 10, which was equilibrated with 5% CO2 in O2 (carbogen). After preincubation the slices were transferred to a superfusion recording chamber which was continuously perfused

Results

During perfusion of the slice with a zero Mg2+ solution typical extracellular field potentials (EFP) developed spontaneously without any stimulation within a few minutes (cf. Fig. 1, CTRL-1) being the correlate of intracellularly recorded paroxysmal depolarization shifts (Mody et al., 1987; cf. Walden et al., 1992, Walden et al., 1993). Several investigations have shown that calcium currents essentially contribute to the generation of these EFP (cf. Pohl et al., 1992, Walden et al., 1992). The

Discussion

In the present study it was found that the new antiepileptic drug lamotrigine reduced dose-dependently the repetition rate of extracellular field potentials in the low-magnesium model of epilepsy. Furthermore, an addition of subthreshold concentrations of lamotrigine and the organic calcium antagonist verapamil or the antiepileptic drug carbamazepine, respectively, led also to a reduction of the frequency of occurrence of zero-Mg2+-induced field potentials. The zero-Mg2+ model is thought to

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