Abstracts

Rationale: Steroid hormones play a key role in gender differences in susceptibility to epileptic seizures, but the underlying mechanisms are obscure. Neurosteroids are synthesized within the brain from circulating steroid hormones and they protect against seizures in males and females. However, whether endogenous neurosteroids are involved in gender differences in seizure susceptibility remains unclear. In the present study, we examined the efficacy and potency of two GABAergic neurosteroids (allopregnanolone and androstanediol) against pilocarpine-induced status epilepticus (SE) in male and female mice, and also assessed potential pharmacokinetic factors. Methods: SE was induced by pilocarpine (416 mg/kg, sc) in adult male and female mice. Animals were monitored for intermittent clonic and persistent seizure activity. Protective activity of two distinct neurosteroids allopregnanolone (progesterone-derived) and androstanediol (testosterone-derived) was tested in a dose-dependent fashion. Plasma neurosteroids levels were determined by LC-MS/MS assay. Results: There were no significant gender differences in baseline seizure sensitivity to pilocarpine. Androstanediol has a dose-dependent protection against pilocarpine-induced SE in both male and female mice with an ED50 value of 34-81 mg/kg. However, female mice exhibited significantly enhanced sensitivity to the protective activity of androstanediol as compared to males (female ED50 = 34 mg/kg; male = 81 mg/kg). Like androstanediol, gender differences in the antiseizure potency was observed with allopregnanolone, which is a more potent allosteric modulator of GABA-A receptors (female ED50 = 1.8 mg/kg; male = 8.5 mg/kg). The plasma concentrations of allopregnanolone or androstanediol did not differ significantly in female and male animals; the estimated plasma concentrations of allopregnanolone producing 50% seizure protection were ~200 and ~700 ng/ml in female and male mice, respectively. Conclusions: These results strongly support the emerging notion that endogenous GABAergic neurosteroids play a key role in gender differences in seizure susceptibility. The gender differences in neurosteroid sensitivity are not related to pharmacokinetic factors. ** Supported partly by NIH grant NS051398 **