PROGESTERONE‐DERIVED NEUROSTEROID 3ALPHA‐HYDROXY 5ALPHA‐PREGNAN‐20‐ONE INHIBITS SPONTANEOUS RECURRENT SEIZURES IN A RAT MODEL OF TEMPORAL LOBE EPILEPSY

Abstract

Epilepsy affects about 40 million people worldwide, with a proportion of sufferers being women where their symptoms are related to the menstrual cycle and progesterone. Progesterone-derived neurosteroids such as allopregnanolone (3α-hydroxy-5α-pregnan-20-one) are positive allosteric modulators of the GABA-A receptors and thus could play critical role in epilepsy. In this study, we tested the efficacy of allopregnanolone in the rat pilocarpine model of temporal lobe epilepsy (TLE). The TLE was induced in female rats by treatment with pilocarpine and animals were monitored for spontaneous recurrent seizures during 2–6 months post pilocarpine. The efficacy of neurosteroid allopregnanolone (5 mg/kg, sc) was evaluated in rats with TLE. Four key parameters were recorded including: spontaneous seizures; EEG discharges; hippocampal neurodegeneration; and mossy fiber sprouting. Pilocarpine treatment was associated with spontaneous seizures after latency of 60 days post pilocarpine. Allopregnanolone therapy significantly decreased the frequency and duration of spontaneous seizures as well as EEG epileptic spikes. Pilocarpine model of TLE in rats is associated with neurodegeration, spontaneous seizures and EEG epileptic spikes, which are clinical features of human epilepsy. These key parameters were markedly reduced by allopregnanolone treatment, confirming the efficacy of neurosteroid therapy. ∗Supported partly by NIH/NINDS grant NS052158∗