Abstracts

Rationale: Progesterone (P) is an anticonvulsant hormone. Women with epilepsy are prone to seizures in response to decreased levels of P during perimenstrual periods. P is being evaluated as a treatment for epilepsy, traumatic brain injury and other complex neurological conditions. Preclinical and clinical studies suggest that P may interrupt epileptogenic events. However, the potential disease-modifying effect of P in epileptogenic models is not widely investigated. In this study, we examined the effects of P on the development of hippocampus kindling in female mice. In addition, we determined the role of progesterone receptors (PRs) in P s activity against kindling epileptogenesis utilizing PR knockout (PRKO) mice. Methods: Female adult WT and PRKO mice received kindling stimulations in the hippocampus at the 125% current intensity that evoked afterdischarges (AD) according to standard techniques until they exhibit stage 5 seizures. P was administered at a dose of 25 mg/kg, SC twice daily for 2 weeks. The morning dose of P was injected 30-min prior to kindling stimulation. The epileptogenesis was evaluated by monitoring the progression of behavioral seizure intensity and electrographic AD duration. The rate of kindling was compared between control and treatment groups during P treatment and drug-free stimulation sessions. Results: P, at 25 mg/kg, did not affect seizures and sedative/motor effects in fully-kindled mice. P treatment (25 mg/kg, twice daily for 2 weeks) significantly suppressed the rate of development of behavioral kindled seizure activity evoked by a daily hippocampus stimulation in wild-type mice, indicating antiepileptogenic effect. There was a significant increase in the rate of rebound kindling during drug-free stimulation sessions following abrupt discontinuation of P treatment. P s effects on early kindling progression was partially decreased in PR knockout mice, but the overall (~2-fold) delay in the rate of kindling for induction of stage 5 seizures was undiminished in PR knockout mice. Moreover, the acute anticonvulsant effect of P (50 and 100 mg/kg) was undiminished in fully-kindled PR knockout mice. Conclusions: These studies provide strong evidence that P exerts antiepileptogenic effect in the hippocampus kindling model at doses that do not significantly affect seizure expression and motor performance, and the PRs appear to play a modulatory role in epileptogenesis in this model. ** Supported by NIH grant NS051398 **