Abstracts

11-Beta hydroxylase is involved in final steps of steroid hormone synthesis. Inhibition of this enzyme leads to accumulation of hormone precursors, which may eventually enter an alternative metabolic pathway and become neurosteroids. Neurosteroids are potent anticonvulsants acting via positive modulation of GABAA receptors. We have previously shown that they are particularly effective against 6 Hz seizures in mice. In the present study we investigated whether inhibition of 11-beta hydroxylase protects against 6 Hz seizures and whether this effect is associated with increased neurosteroid synthesis., Male NIH Swiss mice were the experimental subjects. The animals were pretreated with either metyrapone or etomidate, which both are potent inhibitors of 11-beta hydroxylase, and challenged at various time points with corneal 6 Hz electrical stimulation (32 mA, 3 sec.) to induce seizures. Separate groups of animals were additionally treated with finasteride to test whether seizure protection following administration of metyrapone or etomidate is attenuated by inhibition of neurosteroid synthesis., Metyrapone afforded dose-dependent protection against 6 Hz seizures 30 min. after injection (ED50=190.6 mg/kg). However, the potency of metyrapone was much higher (6-fold increase) when the animals were tested 6 hrs. following injection (ED50=30 mg/kg). Etomidate displayed very similar pattern of protection against 6 Hz seizures with respective ED50 values of 4.5 and 1.7 mg/kg. Finasteride partially attenuated the anticonvulsant effects of both 11-beta hydroxylase inhibitors., Inhibition of 11-beta hydroxylase produces prolonged anticonvulsant actions in mice. This effect may be associated with an increased neurosteroid production, which could be responsible for protection from seizures.,