Tonic Inhibition Therapy for Refractory Status Epilepticus

描述（由申请人提供）：这个转化和探索性申请的主要目的是研究强直抑制治疗癫痫持续状态（SE）的疗效，SE是一种神经系统急症，其特征是长时间持续的癫痫发作活动，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耐药性。我们建议一种促进强直抑制的新型药物可以快速有效地终止难治性SE。这种新的治疗策略是基于神经类固醇的新分子机制和参与SE的细胞变化。神经类固醇是脑内局部合成的类固醇，主要作用于GABA-A受体，介导阶段性和强直性抑制，控制癫痫易感性。强直性抑制由作用于突触外受体的环境GABA介导，通过“设定”基线兴奋性在控制癫痫发作中起着独特的作用。最近的研究表明，SE引起突触（苯二氮卓类药物敏感）相位抑制的显著降低，而突触外（神经类固醇敏感）张力抑制的变化很小。因此，神经类固醇对突触外GABA-A受体的敏感性增强和对突触受体的最大刺激作用使其成为控制SE的理想新药。这种旨在同时增强强直抑制和相位抑制系统的新型治疗策略尚未得到广泛的测试。我们在匹罗卡品的SE模型中进行了初步研究，使用了增强这些系统的新药，证明了这种疗法治疗难治性SE的可行性。我们假设神经类固醇和选择性药物可以增强阶段性和突触外强直性gaba能抑制，有效地终止SE，从而挽救癫痫发生。我们提出通过实现两个特定目的来验证这一假设：（目的1）确定加那洛酮同时增强突触和强直抑制在幼年和癫痫动物SE中的作用；（目的2）确定加博沙多选择性增强突触外强直抑制在幼年和癫痫动物SE中的作用。我们将采用锂-匹罗卡品大鼠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。记录24小时的行为和脑电图发作，以评估药物疗效。急性组织学结果将在72小时后评估，慢性癫痫发生和组织学将在SE后3个月进行研究。的意义。这些研究结果将为强直性抑制疗法提供关键的“疗效证明”，并为开发难治性SE新药奠定基础。

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.