Abstracts

Rationale: Progesterone is an anticonvulsant hormone. Presently progesterone is undergoing NIH-sponsored, multicenter clinical evaluation as adjunct treatment for epilepsy in women. Previously we demonstrated that GABA-A receptor-modulating neurosteroids synthesized from progesterone mediates its protection in the brain. However, in addition to seizure-suppressing activity, progesterone may possess antiepileptogenic or disease-modifying activity. It is possible that progesterone receptor (PR) affects seizure susceptibility. In the present study, we examined the antiepileptogenic effects of progesterone utilizing PR knockout (PRKO) mouse model. Methods: The antiepileptogenic activity of progesterone was examined in adult female wild-type and PRKO mice in the kindling model under conditions of rapid kindling. Mice were subjected to stimulations via implanted electrode in the hippocampus (bipolar 60Hz pulses for 1s every 30-min). Control and progesterone-treated mice were examined for four key indices of epileptogenesis: (i) behavioral seizure progression; (ii) electrographic afterdischarge progression; (iii) rate of rapid kindling; and (iv) retention of kindled seizures. Results: Progesterone treatment (100 mg/kg, sc) prior to rapid kindling protocol significantly suppressed subsequent kindling progression indicating profound antiepileptogenic effect of the steroid. The retention of kindling epileptogenesis was decreased in progesterone-treated animals. In mice expressing fully kindled state, progesterone treatment nearly completely reduced the occurrence of generalized seizures. The stimulation-induced electrographic afterdischarge duration was strikingly reduced in progesterone-treated animals. In all seizure protocols, the antiepileptogenic and antiepileptic potency of progesterone was undiminished in PRKO mice. Conclusions: These studies provide strong evidence that progesterone, in addition to exerting anticonvulsant activity, can exert antiepileptogenic or disease-modifying effects in the rapid kindling model, and the PR is not required for antiepileptogenic activity of progesterone. ** Supported by NIH grant NS051398 **