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.

• Authors: Pascale P Quilichini, Catherine Chiron, Yehezkel Ben-Ari, Henri Gozlan
• Journal: Epilepsia (Epilepsia) Vol. 47 Issue 4 Pg. 704-16 (Apr 2006) ISSN: 0013-9580 [Print] United States
• PMID: 16650136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Chloride Channels
• Dioxolanes
• GABA Plasma Membrane Transport Proteins
• GABA Uptake Inhibitors
• Nipecotic Acids
• Oximes
• Receptors, GABA-A
• NNC 711
• gamma-Aminobutyric Acid
• N-(4,4-diphenyl-3-butenyl)nipecotic acid
• Pentobarbital
• stiripentol

Topics

• Animals
• Animals, Newborn
• Anticonvulsants (pharmacology, therapeutic use)
• Chloride Channels (drug effects, physiology)
• Dioxolanes (pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Interactions
• Epilepsy (drug therapy)
• Excitatory Postsynaptic Potentials (drug effects)
• GABA Plasma Membrane Transport Proteins (pharmacology)
• GABA Uptake Inhibitors
• Hippocampus (drug effects, physiology)
• In Vitro Techniques
• Neural Inhibition (drug effects, physiology)
• Nipecotic Acids (pharmacology)
• Oximes (pharmacology)
• Patch-Clamp Techniques
• Pentobarbital (pharmacology)
• Pyramidal Cells (drug effects, physiology)
• Rats
• Rats, Wistar
• Receptors, GABA-A (drug effects)
• Synaptic Transmission (drug effects)
• gamma-Aminobutyric Acid (pharmacology)