Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a synthetic analog of the endogenous neurosteroid allopregnanolone and a positive allosteric modulator of GABAA receptors, may represent a new treatment approach for epilepsy. Here we demonstrate that pretreatment with ganaxolone (1.25-20 mg/kg, s.c.) causes a dose-dependent suppression of behavioral and electrographic seizures in fully amygdala-kindled female mice, with nearly complete seizure protection at the highest dose tested. The ED50 for suppression of behavioral seizures was 6.6 mg/kg. The seizure suppression produced by ganaxolone was comparable to that of clonazepam (ED50, 0.1 mg/kg, s.c.). To the extent that amygdala kindling represents a model of mesial temporal lobe epilepsy, this study supports the utility of ganaxolone in the treatment of patients with temporal lobe seizures.
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