Clobazam and Valproate, but Lamotrigine, a Sodium Channel Inhibitor, Reduce the Incidence of Hyperthermia-Induced Clonic Seizures in Dravet Syndrome Mice: Assessment of Anti-Seizure Effects in Mice Using a Stabilized Ambient Temperature System.

BACKGROUND

Dravet syndrome (DS) is a severe and treatment-resistant epileptic encephalopathy, most commonly caused by de novo mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene. Patients with DS often present with febrile seizures. It has been reported that Scn1a mutant mice have the risk for hyperthermia-induced clonic seizures similar to those observed in patients with DS. Using our heating protocol with an incubator, we evaluated the effects of antiseizure medications on the incidence of hyperthermia-induced clonic seizures in mutant Scn1a knock-in (KI)/+ mice.

METHODS

For clonic seizure induction in Scn1a KI/+ mice, each mouse was placed into an incubator (38°C-40°C) and observed for 15 min. Antiseizure medications were administered orally 30 min prior to the experiment. The time to seizure onset and the incidence of clonic seizures were analyzed to evaluate and compare the antiseizure effects among treatment groups.

RESULTS

Our incubation system increased the body temperature of mice and induced clonic seizures in Scn1a KI/+ mice. Clobazam (CLB) and valproate (VPA) significantly reduced the incidence of hyperthermia-induced clonic seizures in Scn1a KI/+ mice, with 50% effective dose (ED50) values of 1.94 mg/kg (95% confidence interval [CI]: 0.93-3.89 mg/kg) and 255.87 mg/kg (95% CI: 188.66-356.85 mg/kg) respectively, and prolonged the time to seizure onset. In contrast, lamotrigine (LTG), a sodium channel blocker, did not reduce the incidence of hyperthermia-induced seizures. CLB and LTG did not affect the body temperature. VPA decreased the body temperature compared to the vehicle-treated mice before and after incubation.

CONCLUSION

These results reflect clinical findings that CLB and VPA suppress, but LTG does not suppress seizures in patients with DS. Our data demonstrate the validity of our test system to induce hyperthermia-induced seizures and to evaluate the efficacy of antiseizure medications in Scn1a KI/+ mice.