HYPOTHERMIA REDUCES MORTALITY AND MORBIDITY FROM STATUS EPILEPTICUS

 描述(申请人提供)：本项目的目标是证明在癫痫持续状态(SE)和有机磷(OP)杀虫剂和神经毒剂诱导的SE存活后进行的低温是一种安全有效的非药物治疗，可以预防或减少SE导致的死亡率和发病率，包括行为异常和认知障碍、获得性癫痫(AE)和苔藓纤维发芽。在临床实践中，SE是一种重大的医学紧急情况，SE是暴露于有机磷农药、化学威胁、恐怖袭击、意外或自然灾害暴露的主要并发症。治疗SE相关的癫痫和OP暴露所致的胆碱能危象已经取得了进展，但目前还没有有效的治疗方法来预防SE和OP SE相关的死亡率和长期发病率。我们的研究在了解SE和OP SE如何导致死亡方面取得了重大进展。我们的PR表明，SE后前2周的心脏应激性是死亡的主要原因，这可以通过SE后3小时的低温治疗来预防。我们的初步研究取得了突破性进展，发现SE后的低温治疗可以阻止钙平台的发展和神经元的丢失，为低温降低SE相关的慢性发病率提供了机制。本研究将使用匹罗卡品、OP杀虫剂对氧磷(POX)和OP神经毒剂替代物氟磷二异丙酯(DFP)诱导大鼠SE。我们的实验室非常适合进行这些研究，并已开发出必要的技能来实现以下具体目标：目标1：确定不同时间后的影响 SE和低温治疗的持续时间可以减少或预防毛果芸香碱、POX和DFP诱导的SE存活后的死亡率和心脏应激性(QT间期延长)。目的：探讨SE后不同时间和不同时间低温治疗对SE后钙平台的维持和神经元丢失的影响。目的：确定低温能否预防毛果芸香碱、POX和DFP诱导的SE小鼠存活后行为异常(抑郁)的发生。目的：探讨亚低温能否预防毛果芸香碱、POX和DFP诱导的SE大鼠存活后认知功能障碍的发生、AE的发生和苔藓纤维的发芽。公共关系证明了这些研究的可行性，并强调了进行这项研究的潜在意义。亚低温是目前医院广泛应用的心脏骤停和缺氧性脑损伤的常规有效治疗方法。如果这些初步发现被记录在案，这项研究可能会提供开发临床试验和方案所需的实验数据，以便在医院环境中使用低温治疗SE，以及在每一个不断扩大的恐怖主义威胁或意外暴露于杀虫剂和神经毒剂诱发的SE中。

 DESCRIPTION (provided by applicant): The goal of this project is to demonstrate that hypothermia given after survival of the status epilepticus (SE) and organophosphate (OP) pesticide and nerve agent induced SE is a safe and effective non-pharmaceutical treatment to prevent or decrease SE induced mortality and morbidity, including behavioral abnormalities and cognitive impairment and acquired epilepsy (AE) and mossy fiber sprouting. SE is a major medical emergency in clinical practice and SE is a major complication from exposure to OPs from chemical threats from terrorist attacks or from exposure by accident or natural disasters. Advances have been made to treat the seizures associated with SE and the cholinergic crisis from OP exposure, but at present there are no therapies available to prevent mortality and the long term morbidities associated with SE and OP SE. Our research has made a major advance in understanding how SE and OP SE cause mortality. Our PR indicate that cardiac irritability in the first 2 weeks after SE is the major cause of mortality and this can be prevented by treatment up to 3 h after SE with hypothermia. We made a breakthrough in our preliminary research and discovered that hypothermia treatment following SE can prevent the development of the Ca2+ plateau and neuronal loss providing a mechanism for the effect of hypothermia in reducing the chronic morbidity associated with SE. This study will use pilocarpine, the OP pesticide paraoxon (POX), and OP nerve agent surrogate diisopropyl- fluorophosphate (DFP) to induce SE in rats. Our laboratory is ideally suited to conduct these studies and has developed the necessary skills to carry out the following specific aims: Aim 1: Determine whether effects of different times after SE and durations of hypothermia treatment can reduce or prevent mortality and cardiac irritability (prolongation of the QT interval) following survival from pilocarpine, POX and DFP induced SE. Aim 2: Evaluate the effects of different times after SE and durations of hypothermia treatment on the maintenance of the Ca2+ plateau and neuronal loss after SE. Aim 3: Determine whether hypothermia can prevent the development of behavioral abnormalities (depression) after survival from pilocarpine, POX and DFP induced SE. Aim 4: Evaluate whether hypothermia can prevent the development of cognitive impairment and the development of AE and mossy fiber sprouting following survival from pilocarpine, POX and DFP induced SE. The PR demonstrates the feasibility of these studies and underscores the potential significance of conducting this research. Hypothermia is a routine effective treatment for cardiac arrest and anoxic brain injury that is widely used in hospitals. If these preliminary findings are documented, this study may provide the experimental data needed to develop clinical trials and protocols to employ hypothermia in hospital settings to treat SE and in the every expanding terrorist threats or accidental exposures to pesticide and nerve agent induced SE.