Skip to Main content Skip to Navigation
Journal articles

Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels.

Abstract : 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 gamma-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.
Document type :
Journal articles
Complete list of metadatas

Cited literature [62 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-00483880
Contributor : Roman Tyzio <>
Submitted on : Monday, May 17, 2010 - 2:13:32 PM
Last modification on : Wednesday, April 8, 2020 - 2:00:04 PM
Long-term archiving on: : Thursday, December 1, 2016 - 12:31:19 AM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

Pascale Quilichini, Catherine Chiron, Yehezkel Ben-Ari, Henri Gozlan. Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels.. Epilepsia, Wiley, 2006, 47 (4), pp.704-16. ⟨10.1111/j.1528-1167.2006.00497.x⟩. ⟨inserm-00483880⟩

Share

Metrics

Record views

317