Abstracts

Rationale: Stiripentol (STP, Diacomit^®) is an antiepileptic drug indicated for Dravet syndrome, a rare developmental and epileptic encephalopathy characterized by pleiotropic effects, including absence seizures. STP is known to inhibit generalized tonic-clonic seizures and to reduce the frequency and duration of status epilepticus in patients and to enhance GABAergic function. GABAergic drugs either suppress (benzodiazepines) or aggravate (e.g., tiagabine or vigabatrin) absence epilepsy. The mode of action of STP is still under investigation, and it might interact with voltage-dependent calcium channels involved in abnormal thalamo-cortical oscillations underlying absence seizures. In order to tackle this hypothesis, we have studied the effects of STP on the WAG/Rij rat model of absence seizures. Using in vitro electrophysiological recordings, we evaluated STP activity on T-type calcium and P/Q type channels.

Methods: Adult male WAG/Rij rats were implanted with frontal and parietal electrodes to continuously monitor cortical activity by EEG. Between 16 and 21 weeks of age, the effects of STP (150, 300 mg/kg, i.p.) and THIP (5 mg/kg i.p.) were quantified on three parameters: total duration, mean duration and number of spike-and-wave discharges (SWD). The effects of gaboxadol (THIP), a delta subunits selective GABA(A) agonist, which increases the occurrence of SWD have also been studied in the presence of STP. In vitro, the effect of STP at seven concentrations were analyzed on peak currents recorded with manual patch-clamp, from CHO cells expressing the human isoform for Cav 2.1, Cav 3.1 and Cav3.3, and from HEK393 expressing Cav3.2 channels.

Results: In vivo administration of STP at 300 mg/kg significantly decreased the total duration, number and mean duration of SWD. At 150 mg/kg, mean duration of SWD was significantly decreased. While THIP dramatically increased the cumulated duration of SWD and their occurrence, STP completely blocked THIP effects on SWD. In vitro patch-clamp recordings showed that STP induced an inhibition of the peak current amplitude with IC₅₀ values of respectively 170, 69.2, 64.3, 36.6 µM for Cav2.1, Cav3.1, Cav3.2 or Cav3.2, respectively.

Conclusions: STP had a strong antiepileptic effect in the WAG/Rij rat model of absence seizures. It retained its efficacy despite THIP-induced aggravation of SWD. These results suggest that GABAergic function is not the main target of STP in its anti-absence effects and that an additional mechanism could be implicated. STP inhibition of T-Type calcium channels, in particular the Cav3.3 subtype, could be involved as an additional target. Further studies are warranted to confirm the promising therapeutic effect involving calcium channels of STP against absence seizures.

Funding: Biocodex