Gabapentin potentiation of the antiepileptic efficacy of vigabatrin in an in vitro model of epilepsy

Abstract

1. An enhancement of promoted release of γ-aminobutyric acid (GABA) and a change in GABA-metabolism have been suggested as mechanisms of action of gabapentin. Vigabatrin is supposed to act mainly via inhibition of GABA-transaminase but it also interferes with GABA-release and GABA-uptake. On the basis of these mechanisms of action, a pharmacodynamic interaction of the two antiepileptic drugs could be supposed which might be of relevance in the sense of a rational polypharmacy.

2. To address the aforementioned hypothesis, experiments were carried out on hippocampal slices (n=107) of guinea-pigs (n=70). Epileptiform field potentials (e.f.p.) were induced by omission of magnesium from the bath solution and recorded in the stratum pyramidale of the CA3 region. Gabapentin (30–600 μM; 5.1–102.72 μg ml⁻¹), vigabatrin (50–200 μM, 6.45–25.8 μg ml⁻¹) and the GABA_A-receptor antagonist bicuculline (100 μM) were added to the bath solution for 3 h.

3. Gabapentin, in concentrations up to 600 μM, failed to decrease the repetition rate or duration of e.f.p. (n=19). However, vigabatrin, evoked a dose-dependent reduction of the repetition rate of e.f.p. For a concentration of 100 μM (12.9 μg ml⁻¹) there was a reduction down to 48±5% (mean±s.e.mean) of the initial value within 3 h (n=11). With simultaneous administration of vigabatrin (100 μM) and gabapentin (60 μM) for 3 h (n=15), the repetition rate of e.f.p. decreased down to 8±3%, which is significantly different from the values obtained after administration of 100 μM vigabatrin alone (P<0.0001). Both, the antiepileptic effect of vigabatrin alone and the enhancement by gabapentin were blocked by the GABA_A-receptor antagonist bicuculline (100 μM, n=16).

4. These results demonstrate that gabapentin is able to augment the antiepileptic effects of vigabatrin significantly. It is possible that a change in the GABA-release machinery is induced by vigabatrin which then can be augmented by gabapentin.

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