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Summary: Purpose: Stiripentol (STP) is currently an efficient drug for add-on therapy in infantile epilepsies because it improves the efficacy of antiepileptic drugs (AEDs) through its potent inhibition of liver cytochromes P450. In addition, STP directly reduces seizures in several animal models of epilepsy, suggesting that it might also have anticonvulsive effects of its own. However, its underlying mechanisms of action are unknown.
Methods: We examined the interactions of STP with γ-aminobutyric acid (GABA) transmission by using patch-clamp methods in CA3 pyramidal neurons in the neonatal rat.
Results: STP markedly increased miniature inhibitory postsynaptic current (mIPSC) decay-time constant in a concentration-dependent manner. The prolongation of mIPSC duration does not result from an interaction with GABA transporters because it persisted in the presence of GAT-1 inhibitors (SKF-89976A and NO-711). An interaction with benzodiazepine or neurosteroid binding sites also was excluded because STP-mediated increase of decay time was still observed when these sites were initially saturated (by clobazam, zolpidem, or pregnanolone) or blocked (by flumazenil or dehydroepiandrosterone sulfate), respectively. In contrast, saturating barbiturate sites with pentobarbital clearly occluded this effect of STP, suggesting that STP and barbiturates interact at the same locus. This was directly confirmed by using outside-out patches, because STP increased the duration and not the frequency of opening of GABAA channels.
Conclusions: At clinically relevant concentrations, STP enhances central GABA transmission through a barbiturate-like effect, suggesting that STP should possess an antiepileptic effect by itself.
A wide range of antiepileptic drugs (AEDs) is presently available. They are differentiated by their mechanism of action and their clinical efficacy in various epileptic syndromes. However, the adverse effects that AEDs exert directly or through their metabolites (1,2) considerably limit their usefulness, particularly in resistant epilepsies that often require a progressive enhancement of AED concentrations. To prevent or to diminish these adverse effects, a useful strategy might be to combine AEDs with drugs that inhibit their oxidative degradation (3,4). In this context, stiripentol (STP) has been shown to reduce efficiently the metabolic degradation of several cytochromes P450 (CYPs)-sensitive AEDs (5–9). Accordingly, clinical studies have highlighted the usefulness of STP as an adjunctive therapy in pediatric epilepsies, notably in the Dravet syndrome (6,10,11). This striking efficiency of STP raised the possibility that it may have a direct antiepileptic action, although clinical trials failed to demonstrate a specific therapeutic action different from that of AEDs given in association (6). In contrast, when administered alone, STP did display anticonvulsant properties in several animal models of epilepsy. STP attenuated seizures induced by pentylenetetrazol (12,13) and partially protected from convulsions induced by electrical stimulation (12). In addition, short- and long-term STP treatments were effective in reducing generalized seizures induced by 4-deoxypyridoxine in monkeys (14). These observations are consistent with a direct antiepileptic action of STP, but the mechanisms by which STP may exert its direct anticonvulsant properties are largely unknown, particularly at the cellular level. Earlier in vitro studies suggested, however, that STP interferes with γ-aminobutyric acid (GABA)ergic transmission (12,15). We have therefore examined the effects of STP on isolated GABA transmission in postnatal rat hippocampal neurons and investigated the underlying mechanisms. We report that at relevant clinical concentrations, STP markedly enhances GABA release and prolongs GABAA receptor–mediated currents. STP increases the mean open duration of GABAA receptor–dependent chloride channels by a barbiturate-like mechanism, suggesting that it has potential antiepileptic properties on its own.