Authors :
Presenting Author: Alexandre Bacq, PhD – Biocodex
Alexandre Robert, M.S. – Biocodex; Peggy Cloarec, M.S. – Biocodex; Isabelle Heulard, M.S. – Biocodex; Clara Lesueur, M.S. – Biocodex; Emmanuelle Simon O'Brien, PhD – Biocodex; Philippe Girard, PhD – Biocodex; Vincent Castagné, PhD – Biocodex
Rationale:
Stiripentol (STP, Diacomit
©) is an antiseizure medication indicated for Dravet syndrome, a rare developmental and epileptic encephalopathy with pleiotropic effects, including status epilepticus (SE). Dravet syndrome increases the risk of premature death, either unexpectedly (called SUDEP – sudden unexpected death in epilepsy) or following prolonged refractory SE. Here, we evaluated the effect of STP on SUDEP and SE-associated mortality, using 2 preclinical models.Methods:
Two murine models were used: the 'DBA/2 SUDEP model" and the "methionine sulfoximine (MSO)-induced SE" model. For SUDEP assessment, audiogenic seizures were induced in DBA/2 mice, and STP effects were tested on seizure severity and respiratory-arrest induced death, at different concentrations and different timings between administration and stimulation. Then, we used the MSO model and evaluated STP impact on tonic-clonic seizures and death. Electroclinical seizures were assessed by Video-EEG and behavioral characterization (with adapted Racine score) every hour during eight hours after MSO injection.
Results:
In the DBA/2 model, STP prevented tonic-clonic seizures and associated death in a dose-dependent manner, when audiogenic seizures were induced 30 min after STP systemic administration. At optimal concentration (75 mg/kg), STP could prevent tonic seizures from 30 min to 4h and prevent death up to 2h. In the MSO metabolic model of epilepsy, SE started 4h after MSO i.p. administration, with a progressive increase of the Racine score (5.5 ± 0.2) and mortality (84%) at the eighth hour. Single (30 min pre-treatment) administration of 200, 300, and 400 mg/kg STP inhibited MSO-induced seizures with Racine scores of 5.1 ± 0.5, 3.1 ± 0.4 and 1.4 ± 0.6, respectively. Likewise, percentages of death were 70%, 30% and 0%, respectively. MSO also strongly increased ammonia level. STP 300 mg/kg significantly reduced MSO-induced hyperammonemia, while having no effect in the control group with normal ammonemia level.
Conclusions:
In addition to its antiseizure effects, STP has a potent impact against epilepsy-related death, either SUDEP or following prolonged refractory SE. In Dravet syndrome, the effect of STP on SUDEP rates is not described, but its preventive effect against prolonged SE is demonstrated, notably in the youngest patients. Future studies will evaluate the mechanisms of action of STP explaining its effects against epilepsy-related mortality.
Funding: Biocodex