Ganaxolone, a selective, high‐affinity steroid modulator of the γ‐aminobutyric acid‐A receptor, exacerbates seizures in animal models of absence

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Abstract
Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) is a novel neurosteroid which has anticonvulsant properties in a number of seizure models as well as the ability to enhance function of the γ-aminobutyric acid-A (GABAA) receptor complex via a neurosteroid binding site. The object of these experiments was to ascertain the efficacy of ganaxolone against absence seizures. Ganaxolone was assessed in the low-dose pentylenetetrazol (PTZ) and the γ-hydroxybutyric acid (GHB) model of absence seizures in rats. Ganaxolone pretreatment resulted in a significant prolongation of absence seizure in both the PTZ and GHB models. Further, ganaxolone in doses above 20 mg/kg alone produced bilaterally synchronous spike wave discharges (SWDs) associated with behavioral arrest. These data suggest that augmentation of GABAA receptor complex function by neurosteroids has the potential to result in or exacerbate absence seizures.