A 5-HT_1D -receptor agonist protects Dravet syndrome mice from seizure and early death

Mutations in the SCN1A gene encoding the Nav1.1 sodium channel cause several forms of epilepsy, the most severe is Dravet syndrome (DS). DS patients are at high risk for sudden death and seizures are often triggered by fever or hyperthermia. To improve understanding of how serotonergic ligands might influence DS in this study, we tested several drugs for their effect on hyperthermia-induced seizure using a mouse model of DS consisting of a heterozygous loss of function of Scn1A. We found that a mixed 5-HT_2A/2C receptor agonist had no effect while a mixed 5-HT_1B/D receptor agonist had a modest effect reducing the severity of seizures. Hypothesizing selective agonists may be more effective, we tested selective 5-HT_1B and 5-HT_1D receptor agonists, CP-93129 and GR-46611, respectively. Of these GR-46611 significantly increased the threshold of hyperthermia-induced seizure and lowered seizure severity. Given chronically at 1 mg kg^-1  day^-1 , GR-46611 also significantly improved survival of DS mice. Thus, 5-HT_1D -receptors may represent a meaningful target for pharmacotherapy for DS with potential relevance for related forms of epilepsy, particularly those with a known sensory trigger such as heat.