Neuroactive Steroid Therapy of Catamenial Epilepsy

描述（由申请人提供）： 在美国，癫痫影响着大约250万人。癫痫的一个特点是癫痫发作的不可预测性。然而，患有癫痫的女性经常报告月经时癫痫发作增加，这种情况被称为“月经性癫痫”。长期以来，人们都知道围绝经期癫痫发作加重与突然停用孕酮（一种抗惊厥的卵巢激素）有关。孕酮的抗惊厥作用部分是由于其转化为“神经类固醇”别孕烯醇酮。尽管月经性癫痫发作的发病率增加，但没有特异性药物治疗月经性癫痫。目前，还没有动物模型，重演月经性癫痫。在本申请中，我们建议开发一种用于评价新型药物治疗的大鼠月经性癫痫发作加重模型。我们的初步研究强烈支持的概念，“神经类固醇戒断”与增强癫痫易感性大鼠。我们的研究结果强调，可以诱导月经期癫痫发作与慢性暴露（10天），然后“突然”撤回的别孕烯醇酮在癫痫大鼠。该项目的具体假设是，神经类固醇别普奈诺龙的戒断导致慢性癫痫状态下自发性复发性癫痫发作（SRS）的加剧。我们将严格测试这一假设使用大鼠匹鲁卡品模型颞叶癫痫SRS。在具体目标1中，我们将严格测试神经类固醇戒断是否会增加匹鲁卡品诱导的慢性癫痫大鼠SRS的频率或严重程度。为了模拟月经性癫痫发作加重，我们将在表现出频繁SRS的癫痫大鼠中通过假性妊娠-终止模式诱导反复的神经类固醇戒断。我们将对假孕（如黄体期）和停药期（如月经期）的行为和电图癫痫发作的严重程度进行评级。在从癫痫大鼠分离的海马中测定苔藓纤维发芽和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期癫痫发作加重的疗效。为了开发一种治疗月经性癫痫发作加重的药物，我们将研究两种药物，地西泮和“神经活性类固醇”加奈索酮，使用为期2天的脉冲治疗方案进行两个戒断周期。SRS频率相对于两个给药前或两个给药后对照周期的降低将被解释为药物治疗的疗效。意义这些研究将提供一个合适的动物模型，以确定具体的治疗方法，并为未来发展的“神经活性类固醇”治疗月经性癫痫发作加重。本案无关月经性癫痫的女性在其月经周期周围聚集发作。然而，目前还没有针对这种脑部疾病的具体治疗方法。在本申请中提出的实验将有助于开发一种新的动物模型，用于测试针对月经性癫痫的特定疗法，目前常规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.