Abstract
Objective
Patients with drug-resistant epilepsy, including Dravet syndrome, are frequently prescribed multiple antiseizure medications. Nevertheless, people with Dravet syndrome often have inadequate seizure control, and there is an ongoing unmet clinical need to identify novel therapeutics. As a proof-of-principle study to further validate and characterize the Scn1a
A1783V/WT
mouse model and identify a drug-testing paradigm with face, construct, and predictive validity, we assessed the efficacy of subchronic administration of stiripentol add-on to clobazam and valproic acid at clinically relevant doses using the Scn1a
A1783V/WT
mouse model.
Methods
Following a 14-day treatment, we evaluated the efficacy of stiripentol add-on to clobazam and valproic acid using hyperthermia-induced (n = 6) and video-electroencephalography (EEG) monitoring of spontaneous seizure tests (n = 13). Valproic acid was delivered via osmotic minipump, whereas stiripentol and clobazam were administered via food pellets delivered through automatic feeders. Bioanalytical assays were performed to evaluate drug concentrations in plasma and brain using liquid chromatography–tandem mass spectrometry.
Results
Stiripentol, clobazam, N-desmethylclobazam, and valproic acid all yielded plasma concentrations within the therapeutic plasma concentration range for humans. Stiripentol added to clobazam and valproic acid significantly elevated the seizing temperatures in the hyperthermia-induced seizure assay (**p = 0.0018; Log-rank test). Clobazam, valproic acid, and stiripentol co-administration significantly reduced spontaneous seizure frequency compared to clobazam and valproic acid combined (***p = 0.0003, Mann–Whitney test).
Significance
This research lays the groundwork for exploring effective add-on compounds to clobazam and valproic acid in treating Dravet syndrome. The study further highlights the utility of the Scn1a
A1783V/WT
mice in discovering therapies for Dravet syndrome–associated pharmacoresistant seizures.
JUL