Treatment of Status Epilepticus: A Translational Proposal

描述（由申请人提供）： 癫痫持续状态的治疗：癫痫是VA门诊最常见的诊断，OEF/OIF中大量的创伤性脑损伤预计将导致其在退伍军人中的频率显著增加。这项研究将我们对实验性SE中受体转运作用的研究转化为治疗原则，使用美国药典中的药物。癫痫持续状态（SE）的治疗仍然无效，在最近的人群研究中死亡率为27%。一旦癫痫发作开始，它们就会自我维持，独立于其原始触发因素，并产生时间依赖性抗药性。我们的工作（Naylor et al J Neurosci 2005）表明，反复癫痫发作导致突触GABAA受体的内化（和暂时失活）和突触NMDA受体的增加，这两者都是由癫痫诱导的适应不良受体运输引起的。这些变化表明了自我持续性癫痫发作（突触中GABAA受体减少，NMDA受体增加）和药物抗性（GABA能药物的突触靶点减少）的发生机制。他们还表明，在SE中，多药治疗比单药治疗（目前的金标准）更有可能成功，因为治疗至少应该有2个靶点：GABAA受体（阻止它们的内化和/或最大限度地刺激留在突触中的受体）和NMDA受体（阻止它们向突触移动，或降低它们的活性）。同时针对GABAA和NMDA系统的组合治疗尚未进行广泛测试。我们的初步研究探索了这种组合的使用，使用目前批准用于人类使用或接近批准的药物，并且能够用低亚麻醉剂量的抗惊厥药停止严重的实验性SE。这种基于受体的药物选择方法的治疗成功将证实受体转运在SE病理生理学中的重要性，并可大大提高SE治疗的有效性。我们将用锂和毛果芸香碱化学诱导SE，或通过刺激穿支通路电诱导SE，并将在3个时间点进行治疗：第二次强烈癫痫发作后、癫痫发作后30分钟或癫痫发作后2小时。将记录24小时的脑电图和行为，并使用适当的软件进行分析。将在SE后72小时评估急性组织学结果，将在SE后> 3个月研究慢性癫痫发生、行为和组织学。将研究治疗时机的重要性。我们的初步研究结果表明，低剂量的抗惊厥药物，包括GABAA激动剂和NMDA阻滞剂的组合是更有效的比单一疗法与相同的代理人停止严重的实验性SE，我们希望在这项研究中建立的治疗原则将导致我们在临床上治疗癫痫持续状态的方式的改进。

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.