Neuroactive Steroid Therapy of Catamenial Epilepsy

描述（由申请人提供）：

DESCRIPTION (provided by applicant): Epilepsy affects about 2.5 million people in the United States. A hallmark of epilepsy is the unpredictable occurrence of seizures. However, women with epilepsy often report an increase in seizures at the time of menstruation, a condition referred to as "catamenial epilepsy". Perimenstrual seizure exacerbation has long been known to be associated with an abrupt withdrawal of progesterone, an anticonvulsant ovarian hormone. The anticonvulsant effect of progesterone is due in part to its conversion to the "neurosteroid" allopregnanolone. Despite the increased incidence of catamenial seizures, there is no specific drug treatment for catamenial epilepsy. Presently, there is no animal model that recapitulates catamenial epilepsy. In this application, we propose to develop a rat model of catamenial seizure exacerbation for use in the evaluation of novel drug therapies. Our preliminary studies strongly support the concept that "neurosteroid withdrawal" is associated with enhanced seizure susceptibility in rats. Our results underscore that perimenstrual catamenial seizures can be induced with chronic exposure (10 days) followed by "abrupt" withdrawal of allopregnanolone in epileptic rats. The specific hypothesis of this project is that withdrawal of the neurosteroid allopreqnanolone leads to the exacerbation of spontaneous recurrent seizures (SRS) in a chronically epileptic state. We will critically test this hypothesis using a rat pilocarpine model of temporal lobe epilepsy with SRS. In Specific Aim 1, we will critically test whether neurosteroid withdrawal increases the frequency or severity of SRS in rats with pilocarpine-induced chronic epilepsy. To model catamenial seizure exacerbation, we will induce repeated neurosteroid withdrawal by a pseudopregnancy-finasteride paradigm in epileptic rats that exhibit frequent SRS. We will rate the severity of behavioral and electrographic seizures during pseudopregnancy (like luteal phase) and the withdrawal period (like menstruation). Mossy fiber sprouting and GABAergic interneurons will be determined in the hippocampus isolated from epileptic rats as indicators of epileptogenesis. In Specific Aim 2, we will evaluate the efficacy of standard and novel antiepileptic drugs against catamenial seizure exacerbation in rats with pilocarpine-induced chronic epilepsy. To develop a drug therapy for catamenial seizure exacerbation, we will examine two drugs, diazepam and the "neuroactive steroid" ganaxolone, using a 2-day pulse-therapy protocol for two withdrawal cycles. The reduction of SRS frequency relative to two predrug or two postdrug control cycles will be interpreted as efficacy of drug therapy. Significance. These studies will provide a suitable animal model of catamenial seizure exacerbation for identifying specific therapies and set the stage for the future development of the "neuroactive steroid" therapy of catamenial epilepsy. Relevance. Women with catamenial epilepsy have seizures clustered around their monthly cycle. However, currently there is no specific treatment for this brain condition. The experiments proposed in this application will help develop a novel animal model for testing specific therapies for catamenial epilepsy, which is not successfully treated currently with conventional seizure control medications.