Tonic Inhibition Therapy for Refractory Status Epilepticus

强效抑制疗法治疗难治性癫痫持续状态

• 批准号: 8066974
• 负责人: Doodipala Samba Reddy
• 金额: $ 17.95万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066974
• 关键词: Acute; Address; Adult; Affect; Agonist; Animal Model; Animals; Anticonvulsants; Behavioral; Benzodiazepines; Brain; Child; Chloride Channels; Chronic; Clinical Trials; Development; Diazepam; Dose; Drug Controls; Drug Formulations; Drug usage; Early treatment; Effectiveness; Electroencephalography; Emergency Situation; Epilepsy; Epileptogenesis; Exhibits; Frequencies; GABA-A Receptor; Goals; Hippocampus (Brain); Histological Techniques; Histology; Hour; Impaired cognition; Investigation; Lead; Left; Life; Limbic System; Lithium; Mediating; Military Personnel; Modeling; Molecular; Monitor; Morbidity - disease rate; Neurological emergencies; Neurons; Outcome; Outcome Measure; Outcome Study; Parvalbumins; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phenytoin; Pilocarpine; Play; Predisposition; Rattus; Refractory; Resistance; Risk; Role; Seizures; Severities; Simulate; Staging; Staining method; Stains; Status Epilepticus; Steroids; Surface; Synapses; Synaptic Receptors; System; Techniques; Testing; Time; Translating; Translations; Traumatic Brain Injury; Treatment Effectiveness; United States; Work; base; clinical practice; design; drug efficacy; drug testing; effective therapy; efficacy testing; gamma-Aminobutyric Acid; ganaxolone; insight; mind control; mortality; mossy fiber; neuropeptide Y; neuroprotection; neurosteroids; novel; novel therapeutics; postsynaptic; public health relevance; receptor; research study; response; therapy development; treatment strategy

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.

描述（由申请人提供）：这种翻译和探索性应用的主要目标是调查补品抑制疗法对癫痫持续状态（SE）的疗效，这是一种神经系统紧急情况，其特征是延长，持续的癫痫发作活性，死亡率显着和发病率。尽管有几种SE药物，但许多患者对当前一线药物表现出抗性。我们提出，促进强直抑制作用的新型药物会产生难治性SE的快速有效终止。这种新型的治疗策略基于神经类固醇的新兴分子机制以及SE中涉及的细胞变化。神经类固醇是在大脑中局部合成的类固醇，通过主要作用于介导阶段性抑制作用的GABA-A受体来控制癫痫发作的易感性。通过在外鼻外受体上作用的环境GABA介导的滋补抑制作用，通过“设定”基线兴奋性来控制癫痫发作。最近的工作表明，SE导致突触（苯二氮卓敏感）的阶段性抑制显着降低，而外肌周围（神经固醇敏感）的强直抑制作用的变化很小。因此，增强对突触外GABA-A受体的敏感性和突触受体的最大刺激功效使神经类固醇使神经固醇理想地用于控制SE。这种旨在增强补品抑制和阶段抑制系统的新型治疗策略尚未进行广泛测试。我们使用增强这些系统的新药在SE的毛果果模型中的初步研究证明了这种疗法可以阻止难治性SE的可行性。我们假设神经类动物和选择性药物可以有效地终止SE，从而增强屈肌和间刺激性的GABA能抑制作用，从而挽救癫痫发生。 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.我们将在大鼠中使用SE的锂锂模型，并在2个时间点进行治疗：发作发作后10分钟或60分钟。行为和脑电图癫痫发作将记录24小时以评估药物疗效。将在72小时评估急性组织学结果，在SE后将研究慢性癫痫发生，组织学> 3个月。意义。这些研究的发现将提供滋补抑制疗法的关键“效率”，并为制造难治性SE的新药物奠定了基础。 公共卫生相关性：地位癫痫病是一种威胁生命的神经系统紧急情况，儿童和成人以及脑损伤的军事人员都有明显的发病率和死亡率。在美国，它每年影响约200,000例，估计死亡率超过25,000例。该项目将实验性SE的最新分子研究转化为使用一种新的药物来促进滋补和质量抑制作用。希望这项研究能够提供新的药物，以成功终止持久性或难治性的SE，并可能在SE后“治愈”癫痫发育。