Protective Efficacy and Potency of Neuroactive Steroids and Benzodiazepines in the Amygdala Kindling Model of Epilepsy

Abstract

Although neuroactive steroids protects against experimental seizures, the role of GABA‐A receptor‐modulating neuroactive steroids in the development and expression of amygdala kindling remains unclear. In this study, the neuroactive steroid ganaxolone was examined on behavioral and electrographic seizure expression in the amygdala kindling model of epilepsy in mice, and the protective activity was compared with the antiseizure benzodiazepine clonazepam. Mice were kindled by daily stimulation of amygdala until they exhibit consistent behavioral and electrographic seizures. In fully kindled mice showing stage 5 seizures, ganaxolone (1.25‐20 mg/kg, s.c.) significantly reduced both clonic and generalized seizures elicited by amygdala stimulation. The protective effect of ganaxolone was dose‐dependent with an ED50 of 6.6 mg/kg. Ganaxolone treatment was associated with significant reduction in the afterdischarge duration. As expected, there was a substantial suppression of behavioral and electrographic seizures in mice treated with clonazepam. Clonazepam was more potent than ganaxolone, but the overall maximal efficacy of both clonazepam and ganaxolone was similar. These studies provide strong evidence that ganaxolone is highly effective antiseizure agent in the amygdala kindling model, which is a clinically‐relevant model of complex partial epilepsy.