Counter Measures Against Acetylcholine Receptor Activated Status Epilepticus

描述（由申请人提供）：这个研究项目的总体目标是通过开发新的，安全有效的治疗药物，作为对抗因暴露于抗胆碱酯酶神经毒剂（气体）而产生的癫痫持续状态（SE）对大脑造成损害的对抗措施，这些神经毒剂（气体）在RFA中被确定为更高优先级的化学威胁，代表有毒化学物质，可用于针对平民的恐怖袭击或可能在事故或自然灾害中释放出有毒水平。这项研究的重点是开发能够在SE期间和之后稳定和保护大脑的药物，以便有更多的时间来控制癫痫发作，防止或逆转SE的破坏性影响。SE是一种主要的医学和神经系统急症，与显著的发病率和死亡率相关，是暴露于抗胆碱酯酶神经毒剂的常见结果。本研究提出的研究将使用啮齿类动物匹罗卡品SE模型作为动物模型，该模型已被证明以与神经毒剂基本相同的方式产生SE，以制定医学对策，防止SE的急性死亡率和长期发病率，包括神经元死亡、癫痫和认知障碍的发展。目的1：确定氯胺酮和/或丹trolene是否可以在SE期间和之后使用时预防SE后Ca2+平台的发展。假设：通过在SE期间或之后使用氯胺酮和/或丹trolene治疗，可以预防或逆转SE引起的Ca2+平台。目的2：确定氯胺酮和/或丹trolene在SE期间和之后使用时是否可以预防神经元丢失并降低死亡率。假设：氯胺酮和/或丹曲lene在SE期间或之后给予可减少或预防SE引起的神经元丢失和死亡率。目的3：确定氯胺酮和/或丹曲林阻断SE后AE发展的有效性。假设：在SE期间或之后给予氯胺酮和/或丹曲林可以预防SE后AE的发展。目的4：确定氯胺酮和/或丹trolene预防SE后认知丧失的有效性。假设：氯胺酮和/或丹trolene在SE期间或之后会显著减少SE后的认知丧失。本研究结果可为保护大脑免受神经毒剂暴露提供有效的对策。初步结果表明，预防SE引起的脑损伤是可能的。

DESCRIPTION (provided by applicant): The overall goal of this research project is to respond to the CounterACT RFA by developing new, safe and effective therapeutic agents that will act as counter measures against the damage to the brain caused by status epilepticus (SE) produced by result of exposure to the anticholinesterase nerve agents (gases) identified in the RFA as higher priority chemical threats that represent toxic chemicals that could be used in a terrorist attack against civilians or could be released at toxic levels by an accident or natural disaster. This study is focused on developing drugs that can stabilize and protect the brain during and after SE to allow for additional time to control the seizures and to prevent or reverse the devastating effects of SE. SE is a major medical and neurological emergency that is associated with a significant morbidity and mortality and is a common result of exposure to the anticholinesterase nerve agents. The research proposed in this study will use the rodent pilocarpine model of SE that has been shown to produce SE in an essentially identical manner to nerve agents as an animal model to develop medical counter measures that can prevent the acute mortality and long-term morbidity from SE, including the development of neuronal death, epilepsy, and cognitive impairment. Aim 1: Determine whether ketamine and/or dantrolene can prevent the development of the Ca2+ plateau after SE when administered during and after SE. Hypothesis: The Ca2+ plateau from SE can be prevented or reversed by treatment during or after SE with ketamine and/or dantrolene. Aim 2: Determine whether ketamine and/or dantrolene prevent neuronal loss and decrease mortality when administered during and after SE. Hypothesis: Ketamine and/or dantrolene can decrease or prevent neuronal loss and mortality from SE when administered during or after SE. Aim 3: Determine the effectiveness of ketamine and/or dantrolene in blocking the development of AE after SE. Hypothesis: Ketamine and/or dantrolene given during or after SE can prevent the development of AE following SE. Aim 4: Determine the effectiveness of ketamine and/or dantrolene in preventing cognitive loss after SE. Hypothesis: Ketamine and/or dantrolene during or after SE will significantly reduce cognitive loss following SE. The results of this study may provide effective counter measures to protect the brain from nerve agent exposure. The preliminary results indicate that it is possible to prevent brain injury form SE.