Abstracts

Rationale: In 2007, when stiripentol (STP) was granted its first marketing authorization as Diacomit^® in Europe, its mechanism of action was not fully described. At this time STP was known to be a positive allosteric modulator of GABA_A receptors, and to inhibit GABA transaminase and GABA synaptosomal uptake. Since then, several studies investigated and characterized STP biological properties.

Methods: This work summarizes additional pharmacological activity of STP. Information was extracted from the recent literature and from Biocodex internal reports.

Results: The effect of STP on recombinant GABA receptors containing a variety of different subunit combinations revealed positive modulation by stiripentol was most effective at receptors containing an a3 subunit. As these receptors are expressed with highest levels in the immature brain, this selectivity may explain the clinical efficacy of STP in childhood-onset epilepsies, including Dravet syndrome. Interaction of STP with various benzodiazepines on GABA receptors showed STP activity is potentiated by benzodiazepines. These pharmacodynamic interactions suggest STP and benzodiazepines act independently on GABA-A receptors and polytherapy could be expected to increase the maximum effect beyond the effect of either drug used alone. STP has also been found to inhibit lactate dehydrogenase thereby decreasing ATP production, limiting the activation of K_ATP channels and rendering the neuron less excitable.
_x000D_ In rat neuronal‑glial cells exposed to oxygen-glucose deprivation stiripentol was neuroprotective when used prior the insult. In cells exposed to high glutamate levels, STP at high concentrations was neuroprotective when used both prior to and after exposure. A significantly decreased cell injury after lithium‑pilocarpine-induced status epilepticus was also observed in the CA1 region of the hippocampus in young and adult Wistar rats, and in the dentate gyrus in adult animals. Finally, recent data suggest STP could also interact with voltage-dependent calcium channels involved in abnormal thalamo-cortical oscillations underlying absence seizures. In particular, in vitro manual patch-clamp techniques showed that STP inhibits peak current amplitude of T-type calcium and P/Q type channels.

Conclusions: As with most antiepileptic drugs, STP has multiple mechanisms of action. The efficacy observed in Dravet syndrome as well as other types of epilepsy derives from the sum of its biological properties and pharmacological actions rather than a single action. Further research is necessary to better understand the relation between the different biological properties and beneficial effects observed as well as characterize additional utility for other rare forms of epilepsy.

Funding: None