Stiripentol, a Putative Antiepileptic Drug, Enhances the Duration of Opening of GABA_A‐Receptor Channels

Abstract

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 concentrationdependent 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 GABA A 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.

Audit of use of stiripentol in adults with Dravet syndrome

“…A rodent model of established status epilepticus showed effectiveness of stiripentol when seizures had already become resistant to treatment with benzodiazepines, by potentiating GABAergic inhibition. The action of stiripentol seemed independent of the benzodiazepine binding site on the GABAA receptor 27, 28, 29, 30…”

“…Stiripentol has an inhibitory effect on clobazam metabolism, mostly mediated by CYP3A4 and CYP2C19, leading to increased plasma concentrations of both clobazam and its active metabolite, norclobazam (desmethylclobazam) 17, 31, 32. This pharmacokinetic drug interaction, along with the fact that stiripentol and clobazam/norclobazam act through separate sites on the GABAA receptor,27, 28, 29, 30 may contribute to the effectiveness as well as the adverse effects of stiripentol. Conversely, data collected in two independent multicentre randomized, double‐blind, placebo‐controlled trials in DS patients, STICLO‐France and STICLO‐Italy,17, 32 did not show any significant interaction between stiripentol and sodium valproate.…”

“…Better treatment strategies are required. Stiripentol is an allosteric modulator of the GABAA receptor,29 proven to be effective and well‐tolerated in children with DS 21, 33. There are no data available in the literature on treatment with stiripentol of DS cases older than 24 years.…”

Stiripentol

“…In addition to inhibiting the synaptosomal uptake of GABA, 1 STP was recently shown in patch-clamp studies to enhance central GABAergic transmission in CA3 pyramidal neurons of immature rats. 2 At clinically relevant concentrations, STP increases both the release of GABA and the duration of the activation of GABA A receptors in a concentration-dependent manner and through a barbiturate-like effect.…”

Potentiating the Strength of Extrasynaptic Currents by Neurosteroid Hormones

“…Given the function and the regional location of these receptors, it is not surprising that they have been closely linked with epilepsy: antagonists of GABA A receptors, such as bicuculline, promote seizures, whereas activators of these receptors, such as diazepam and stiripentol (3), are used clini cally as antiseizure agents. In addition, mutations in Gabrd, the gene coding for the δ subunit of the GABA A receptor, appear to contribute to epilepsy susceptibility (4).…”