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

Sex steroids can influence seizures. Estrogen (E-2), progesterone (P-4), and its metabolite, 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5-alpha 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 3 alpha,5 alpha-THP, attenuate seizures. However, E-2 may also have antiseizure effects, perhaps in part through its enhancement of the formation of 3 alpha,5 alpha-THP, which has GABA(A)/benzodiazepine receptor agonist-like actions. To test this hypothesis, male and female, castrated or ovariectomized, wild-type and 5 alpha-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 5 alpha-reductase knockout, mice administered E-2 had significantly longer latencies to myoclonus and increased levels of 3 alpha,5 alpha-THP in the hippocampus. Thus, some of the anticonvulsive effects of E-2 may involve formation of 3 alpha,5 alpha-THP in the hippocampus. (C) 2009 Elsevier Inc. All rights reserved.