Anti-seizure effects of progesterone and 3α,5α-THP in kainic acid and perforant pathway models of epilepsy

The mechanism by which progesterone has its anti-seizure effects is unknown. Progesterone has a high affinity for intracellular progestin receptors, but has weak actions at gamma-aminobutyric acid (GABA)(A) receptors complexes. The progesterone metabolite, 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP) is devoid of activity at intracellular progestin receptors but is a highly effective modulator of GABA(A) receptor complexes. Whether progesterones anti-seizure actions are due to effects of progesterone itself or its metabolite 3 alpha,5 alpha-THP was investigated. In experiment 1, 25 ovariectomized Long-Evans rats were subcutaneously (s.c.) injected with 0.0, 3.0 or 8.0 mg/kg progesterone or 3 alpha,5 alpha-THP, 10 min prior to systemic administration of 32 mg/kg kainic acid. Four and 8.0 mg/kg progesterone significantly reduced the duration of partial and full seizures, without influencing the latency to partial or full seizures, or the number of partial or full seizures. 3 alpha,5 alpha-THP (4.0 mg/kg) significantly increased the latency to initial partial seizure, and decreased the number and duration of partial seizures. In experiment 2, 60 ovariectomized Long-Evans rats were stereotaxically implanted with bipolar electrodes into the perforant pathway. Prior to perforant pathway stimulation, rats were s.c. injected with either progesterone (4.0 mg/kg, n = 12), 3 alpha 5 alpha-THP (4.0 mg/kg, n = 13), progesterone (4.0 mg/kg) + 4MA (10.0 mg of a 5 alpha-reductase inhibitor, 17b-N,N-diethylcarbamoyl-4-methyl-4-aza,5 alpha-androstan-3-one, n = 12), 4MA + vehicle (n = 10), or sesame oil vehicle (n = 13). Administration of progesterone or 3 alpha,5 alpha-THP, but not vehicle control, P + 4MA, or 4MA, resulted in significant decreases in partial seizures. In experiment 3, whole brain progesterone and 3 alpha,5 alpha-THP were measured by radioimmunoassay in additional rats (n = 66) administered the hormonal milieu indicated in experiments 1 and 2. Data suggest anti-seizure effects of progesterone may be due, in part, to metabolism to 3 alpha,5 alpha-THP and subsequent actions at GABA(A) receptor complexes. (C) 2000 Elsevier Science Ltd. All rights reserved.