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

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Abstract
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. 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 GABAA‐receptor antagonist bicuculline (100 μM) were added to the bath solution for 3 h. 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 (PA‐receptor antagonist bicuculline (100 μM, n=16). 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.