Treatment of Status Epilepticus: A Translational Proposal

癫痫持续状态的治疗：转化建议

• 批准号: 8391124
• 负责人: CLAUDE G WASTERLAIN
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391124
• 关键词: Accident and Emergency department; Acute; Affect; Agonist; Ambulatory Care Facilities; Anticonvulsants; Behavior; Behavioral; Benzodiazepines; Chemical Stimulation; Chronic; Clinical; Computer software; Conscious; Depressed mood; Development; Diagnosis; Dose; Drug Combinations; Drug usage; Early treatment; Electric Stimulation; Electroencephalogram; Epilepsy; Epileptogenesis; FDA approved; Frequencies; Future; Glutamate Receptor; Gold; Histology; Hour; Human; Injury; Intensive Care Units; Investigation; Ketamine; Lead; Left; Length; Lithium; Lorazepam; Mediating; Modeling; Movement; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurological emergencies; Neuronal Injury; Outcome; Patients; Perforant Pathway; Pharmaceutical Preparations; Pharmacopoeias; Pilocarpine; Progress Reports; Role; Seizures; Severities; Status Epilepticus; Synapses; System; Testing; Therapeutic; Time; Toxic effect; Translating; Traumatic Brain Injury; Treatment Effectiveness; Veterans; Work; base; cooperative study; design; dizocilpine; effective therapy; felbamate; improved; indexing; mortality; neuron loss; population based; prevent; public health relevance; receptor; success; trafficking

DESCRIPTION (provided by applicant): Treatment Of Status Epilepticus: A Translational Proposal Epilepsy is the most common diagnosis in VA outpatient clinics, and the large number of traumatic brain injuries in OEF/OIF is expected to result in a significant increase in its frequency among veterans. This study translates our investigations of the role of receptor trafficking in experimental SE into principles of treatment, using drugs available in the US pharmacopeia. Treatment of status epilepticus (SE) remains ineffective, with a mortality of 27% in recent population-based studies. Once seizures have started, they become self-sustaining, independent of their original trigger, and develop time-dependent pharmacoresistance. Our work (Naylor et al J Neurosci 2005) has shown that repeated seizures cause an internalization (and temporary inactivation) of synaptic GABAA receptors and an increase in synaptic NMDA receptors, which both result from seizure-induced, maladaptive receptor trafficking. These changes suggest a mechanism for the development of self-sustaining seizures (fewer GABAA receptors and more NMDA receptors in synapses) and for pharmacoresistance (fewer synaptic targets for GABAergic drugs). They also suggest that, in SE, polytherapy is more likely to be successful than monotherapy (the current gold standard), since treatment should have at least 2 targets: GABAA receptors (either preventing their internalization and/or maximally stimulating those that are left in the synapse), and NMDA receptors (preventing their movement to the synapse, or reducing their activity). Combination treatments aimed at the GABAA and NMDA systems simultaneously have not been tested extensively. Our preliminary studies explored the use of such combinations, using drugs which are currently approved for human use or are close to approval, and were able to stop severe experimental SE with low subanesthetic doses of anticonvulsants. Therapeutic success with this receptor-based approach to drug selection would confirm the importance of receptor trafficking in the pathophysiologiy of SE, and could greatly improve the effectiveness of treatment of SE. We will induce SE chemically with lithium and pilocarpine, or electrically by stimulating the perforant path, and will treat at 3 time points: after the second intense seizure, 30minutes after seizure onset, or 2 hours after seizure onset. Electroencephalogram and behavior will be recorded for 24 hours and analyzed with appropriate software. Acute histological outcome will be assessed at 72 hours, chronic epileptogenesis, behavior and histology will be studied > 3 months after SE. The importance of timing of treatment will be studied. Our preliminary results suggest that combinations of low doses of anticonvulsants which include GABAA agonists and NMDA blockers are far more effective than monotherapy with the same agents in stopping severe experimental SE, and we hope that the principles of treatment established in this study will lead to improvements in the way we treat status epilepticus clinically.

描述（由申请人提供）： 癫痫状态的治疗：转化建议癫痫是VA门诊诊所中最常见的诊断，OEF/OIF中大量的脑损伤有望导致退伍军人的频率显着增加。这项研究将我们对受体运输在实验SE中的作用的研究转化为使用美国药物中可用的药物的治疗原理。癫痫持续状态（SE）的治疗仍然无效，在最近的基于人群的研究中死亡率为27％。一旦癫痫发作开始，它们就会变得自我维持，独立于原始触发因素，并发展时间依赖于时间。我们的工作（Naylor等人2005年）表明，重复的癫痫发作会导致突触GABAA受体的内在化（和暂时灭活）和突触NMDA受体的增加，这两者都是由癫痫发作诱导的不良受体运输引起的。这些变化提出了一种自我维持癫痫发作（加巴受体较少和突触中的NMDA受体更多）和药物耐药性（GABA能药物的突触靶标更少）的机制。他们还表明，在SE中，多疗法比单一疗法（当前的黄金标准）更可能成功，因为治疗应至少具有2个靶标：GABAA受体（可以防止其内在化和/或最大刺激突触中留在突触中的人），以及NMDA受体（防止其运动引起突触，或减少其活动）。针对GABAA和NMDA系统的组合处理尚未进行广泛测试。我们的初步研究探讨了这种组合的使用，使用目前被批准用于人类使用或接近批准的药物，并能够停止使用低下抗惊厥药的抗惊厥药的严重实验性SE。这种基于受体的药物选择方法的治疗成功将证实受体运输在SE的病理生理学中的重要性，并且可以大大提高SE治疗的有效性。我们将用锂和毛果碱化学诱导SE，或通过刺激穿孔路径进行电诱导，并在3个时间点进行处理：第二次强烈癫痫发作后，发作后30分钟后，或在发作发作后2小时。脑电图和行为将记录24小时，并使用适当的软件进行分析。急性组织学结果将在72小时后评估，在SE之后将研究慢性癫痫发生，行为和组织学> 3个月。将研究治疗时间的重要性。我们的初步结果表明，包括GABAA激动剂和NMDA阻滞剂在内的低剂量抗惊厥药的组合远比单一疗法更有效，在停止严重的实验性SE方面，我们希望在这项研究中确定的治疗原理能够在我们的临床上治疗状态的改善。