The therapeutic effect of stiripentol in Gabrg2+/Q390X mice associated with epileptic encephalopathy.

• The Gabrg2+/Q390X knockin mice associated with DS had increased seizures and death. • Stiripentol alone was ineffective in suppressing seizures but increased survival. • Add-on of stiripentol to diazepam was beneficial in Gabrg2+/Q390X mice. • Stiripentol can be used as adjunct therapy in DS with GABRG2 deficiency. • The response to stiripentol may be different based on different genetic mutations. Anti-seizure drugs (ASDs) are widely used and known to increase inhibitory tone on neuro-circuits and reduce aberrant synchronous firing in epilepsy. Some ASDs act as agonist at the GABA A receptor. Stiripentol, known to increase GABA A receptor activity as well as the metabolites of GABA A receptor agonists, is often used in the treatment of an epileptic encephalopathy, Dravet syndrome (DS), which is caused by mutations mainly in SCN1A and in other genes such as GABRG 2. We have recently generated a Gabrg2+/Q390X knockin mouse model associated with DS in humans. The objective of the study was to explore the effects of stiripentol in DS with GABA A receptor functional deficiency because of the etiology heterogeneity in DS. Monotherapy (stiripentol or Diazepam) and polytherapy (stiripentol and diazepam) treatments were tested in Gabrg2+/Q390X mice challenged with pentylenetetrazol (PTZ) seizure induction in conjunction with video-monitoring synchronized electroencephalogram (EEG) recordings. A combination of stiripentol and diazepam greatly reduced seizure-related events in Gabrg2+/Q390X mice following PTZ administration and increased survival. However, the treatment of stiripentol alone was mostly ineffective in alleviating seizure-related events except that it reduced mortality in PTZ challenged Gabrg2+/Q390X mice. The study suggests that stiripentol could be only used as add-on therapy for DS with GABA A receptor functional deficiency, which is consistent with the most established clinical application of stiripentol. The study highlights the importance of mechanism-based precision treatment for DS considering the highly heterogeneous nature of etiology in DS and the fact that mutations in different genes give rise to the same clinical phenotype. [ABSTRACT FROM AUTHOR]