Neuroactive Steroid Therapy of Catamenial Epilepsy

描述(由申请人提供)： 在美国，约有250万人患有癫痫。癫痫的一个特征是癫痫发作的不可预测的发生。然而，患有癫痫的女性经常报告在月经期间癫痫发作增加，这种情况被称为月经性癫痫。人们早就知道，围绝经期癫痫的恶化与黄体酮的突然停用有关，黄体酮是一种抗惊厥的卵巢激素。黄体酮的抗惊厥作用部分是由于它转化为“神经类固醇”别孕酮。尽管月经性癫痫的发病率有所增加，但目前还没有针对月经性癫痫的特效药物治疗。目前，尚无月经性癫痫的动物模型。在这个应用中，我们建议建立一种月经发作加重的大鼠模型，用于评估新的药物治疗。我们的初步研究有力地支持了“神经类固醇停用”与大鼠癫痫敏感性增强有关的概念。我们的结果强调，在癫痫大鼠中，慢性暴露(10天)后“突然”停用别孕酮可以诱发围绝经期癫痫发作。该项目的特定假设是，停用神经类固醇别孕酮会导致慢性癫痫状态下自发性复发性癫痫(SRS)的恶化。我们将使用毛果芸香碱的大鼠癫痫模型对这一假说进行严格的检验。在具体目标1中，我们将严格测试停用神经类固醇是否会增加匹罗卡品诱导的慢性癫痫大鼠SRS的频率或严重程度。为了模拟月经发作加剧，我们将通过假孕-非那雄胺范例在表现频繁SRS的癫痫大鼠中诱导反复神经类固醇停药。我们将评估假孕期间(如黄体期)和戒断期(如月经)的行为和心电图癫痫发作的严重程度。从癫痫大鼠分离的海马区将检测苔藓纤维萌发和GABA能中间神经元作为癫痫发生的指标。在具体目标2中，我们将评估标准和新型抗癫痫药物对匹罗卡品诱导的慢性癫痫大鼠月经性癫痫发作加剧的疗效。为了开发一种治疗月经发作恶化的药物疗法，我们将使用为期两天的脉冲治疗方案，在两个停药周期中检查两种药物，地西潘和“神经活性类固醇”甘纳松酮。SRS频率相对于服药前或服药后两个控制周期的减少将被解释为药物治疗的疗效。意义重大。这些研究将为寻找特定的治疗方法提供合适的月经发作加重的动物模型，并为未来月经癫痫的神经活性类固醇疗法的发展奠定基础。关联性。患有月经性癫痫的女性的癫痫发作集中在她们的月经周期周围。然而，目前还没有针对这种脑部疾病的特效药。本申请中提出的实验将有助于开发一种新的动物模型，用于测试月经性癫痫的特定治疗方法，目前传统的癫痫控制药物无法成功治疗月经性癫痫。

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.