Antiepileptogenic and Antiepileptic Activity of Progesterone in the Rapid Kindling Model in PRKO Mice

Abstract

Presently progesterone is undergoing NIH‐sponsored, multicenter clinical evaluation as treatment for epilepsy in women. Although the anticonvulsant effect of progesterone has long been known, the molecular mechanism underlying its protection in the brain is obscure. Progesterone‐derived GABA‐A receptor‐modulating neurosteroids could be involved in its anticonvulsant actions. However, the role of progesterone receptor (PR) is not clearly defined in the protective effects of progesterone. Here we utilized PR knockout (PRKO) mice to evaluate the antiepileptogenic and antiepileptic activity of progesterone. Progesterone was examined in female PRKO and WT controls in the kindling model under conditions of rapid kindling. Mice were subjected to stimulations via implanted electrode in the hippocampus. Progesterone treatment (100 mg/kg) prior to rapid kindling significantly suppressed subsequent kindling progression indicating antiepileptogenic effect of the steroid. In fully kindled mice, progesterone reduced the occurrence of generalized seizures. In all seizure protocols, the antiepileptogenic and antiepileptic potency of progesterone was undiminished in PRKO mice. These studies provide strong evidence that progesterone exerts both antiepileptogenic and antiepileptic effects in the kindling model, and the PR is not required for these effects of progesterone.