Tonic Inhibition Therapy for Refractory Status Epilepticus

描述(申请人提供)：这项翻译和探索性申请的主要目的是研究紧张性抑制疗法对癫痫持续状态(SE)的疗效，SE是一种神经紧急情况，其特征是持续长时间的癫痫发作活动，具有显著的死亡率和发病率。尽管有几种治疗SE的药物，但许多患者对目前的一线药物表现出抗药性。我们建议，一类促进紧张性抑制的新型药物可以快速有效地终止难治性SE。这一新的治疗策略是基于神经类固醇新出现的分子机制和SE所涉及的细胞变化。神经类固醇是大脑中局部合成的类固醇，通过主要作用于GABA-A受体来控制癫痫的敏感性，GABA-A受体介导相性和紧张性抑制。紧张性抑制由环境中的GABA作用于突触外受体，通过“设定”基线兴奋性，在控制癫痫发作中发挥着独特的作用。最近的工作表明，SE引起突触(苯二氮敏感)时相抑制的显着减少，而对突触外(神经类固醇敏感)的紧张性抑制的影响很小。因此，突触外GABA-A受体的敏感性增强和突触受体的最大刺激效应使神经类固醇成为控制SE的理想新药。这一旨在同时增强紧张性抑制和时相抑制系统的新治疗策略尚未得到广泛测试。我们在匹罗卡品的SE模型中的初步研究，使用了增强这些系统的新药，证明了这种疗法阻止难治性SE的可行性。我们假设神经类固醇和选择性药物加强时相性和突触外强直的GABA能抑制有效地终止SE，从而挽救癫痫的发生。我们建议通过实现两个特定目标来验证这一假说：(1)确定在幼年动物和癫痫动物SE中同时增强突触和紧张性抑制的有效性；(2)在幼稚动物和癫痫动物中确定在SE中选择性增强突触外紧张性抑制的有效性。我们将使用锂-匹罗卡品建立大鼠SE模型，并在癫痫发作后10分钟或60分钟两个时间点进行治疗。将记录24小时的行为和脑电发作，以评估药物疗效。急性组织学结果将在72小时后评估，慢性癫痫的发生和组织学将在SE后3个月进行研究。意义重大。这些研究的结果将为紧张性抑制疗法提供关键的“有效性证明”，并为开发治疗难治性SE的新药奠定基础。 公共卫生相关性：癫痫持续状态是一种危及生命的神经紧急情况，在儿童和成人以及患有创伤性脑损伤的军人中具有显著的发病率和死亡率。在美国，它每年影响大约20万例病例，估计每年有超过2.5万名患者死亡。该项目将最近实验性SE的分子研究转化为使用一类促进强直抑制和时相抑制的新型药物的治疗开发。希望这项研究能为成功终止持续性或难治性癫痫提供新的药物，并可能“治愈”癫痫在SE后的发展。

DESCRIPTION (provided by applicant): The main goal of this translational and exploratory application is to investigate the efficacy of tonic inhibition therapy for status epilepticus (SE), a neurological emergency characterized by a prolonged, continuous seizure activity with significant mortality and morbidity. Despite several drugs for SE, many patients exhibit resistance to current first-line drugs. We propose that a new class of drugs that promote tonic inhibition produce rapid and effective termination of refractory SE. This novel therapeutic strategy is based on the emerging molecular mechanisms of neurosteroids and also cellular changes involved in SE. Neurosteroids are steroids synthesized locally within the brain that control seizure susceptibility by acting principally at GABA-A receptors that mediate phasic and tonic inhibition. Tonic inhibition, mediated by ambient GABA acting at extrasynaptic receptors, plays a unique role in controlling seizures by "setting" the baseline excitability. Recent work has shown that SE cause significant decrease in synaptic (benzodiazepine-sensitive) phasic inhibition with minimal changes in extrasynaptic (neurosteroid-sensitive) tonic inhibition. Therefore, enhanced sensitivity at extrasynaptic GABA-A receptors and maximally stimulating efficacy at synaptic receptors makes neurosteroids ideal new drugs for controlling SE. This novel treatment strategy aimed at augmenting tonic inhibition and phasic inhibition systems simultaneously has not been tested extensively. Our preliminary studies in the pilocarpine model of SE, using new drugs that enhance these systems, demonstrate the feasibility of this therapy to stop refractory SE. We hypothesize that neurosteroids and selective drugs that enhances phasic and extrasynaptic tonic GABAergic inhibition effectively terminate SE, and thereby rescue epileptogenesis. We propose to test this hypothesis by accomplishing 2 specific aims: (Aim 1) To determine the efficacy of simultaneous augmentation of synaptic and tonic inhibition by ganaxolone in SE in naive and epileptic animals, and (Aim 2) To determine the efficacy of selective augmentation of extrasynaptic tonic inhibition by gaboxadol in SE in naive and epileptic animals. We will use lithium-pilocarpine model of SE in rats, and will treat at 2 time points: 10-minutes or 60-minutes after seizure onset. Behavioral and EEG seizures will be recorded for 24 hours for assessment of drug efficacy. Acute histological outcome will be assessed at 72 hours, chronic epileptogenesis and histology will be studied >3 months after SE. Significance. The findings from these studies will provide critical "proof-of-efficacy" of tonic inhibition therapy and set the stage for developing new drugs for refractory SE. PUBLIC HEALTH RELEVANCE: Status epilepticus is a life-threatening neurological emergency with significant morbidity and mortality in children and adults, and also in military persons with traumatic brain injury. It affects approximately 200,000 cases a year in the USA, with an estimated mortality of over 25,000 patients yearly. This project translates recent molecular investigations in experimental SE into therapy development using a new class of drugs that promote tonic and phasic inhibition. It is hoped that this study will offer novel drugs to successfully terminate persistent or refractory SE and possibly "curing" epilepsy development after SE.