Estrogen increases latencies to seizures and levels of 5alpha-pregnan-3alpha-ol-20-one in hippocampus of wild-type, but not 5alpha-reductase knockout, mice.

Abstract

Sex steroids can influence seizures. Estrogen (E(2)), progesterone (P(4)), and its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), in particular, have received much attention for exerting these effects. Typically, it is thought that E(2) precipitates seizures, and progestogens, such as P(4) and 3alpha,5alpha-THP, attenuate seizures. However, E(2) may also have antiseizure effects, perhaps in part through its enhancement of the formation of 3alpha,5alpha-THP, which has GABA(A)/benzodiazepine receptor agonist-like actions. To test this hypothesis, male and female, castrated or ovariectomized, wild-type and 5alpha-reductase knockout mice were implanted with Silastic capsules of E(2) or vehicle and then administered pentylenetetrazol (85 mg/kg, ip). Wild-type, but not 5alpha-reductase knockout, mice administered E(2) had significantly longer latencies to myoclonus and increased levels of 3alpha,5alpha-THP in the hippocampus. Thus, some of the anticonvulsive effects of E(2) may involve formation of 3alpha,5alpha-THP in the hippocampus.