Counter Measures Against Acetylcholine Receptor Activated Status Epilepticus

描述(申请人提供)：本研究项目的总体目标是通过开发新的、安全和有效的治疗药物来应对RFA，这些药物将作为对抗因接触RFA中确定的更高优先级化学威胁的抗胆碱酯酶神经毒剂(气体)而导致的癫痫状态(SE)对大脑造成的损害的措施，这些气体代表可能被用于针对平民的恐怖袭击的有毒化学品，或者可能因事故或自然灾害而以有毒水平释放的有毒化学品。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是一种重要的内科和神经急症，与显著的发病率和死亡率有关，是暴露于抗胆碱酯酶神经毒剂的常见结果。这项研究中提出的研究将使用SE的啮齿动物匹罗卡品模型作为动物模型，该模型已被证明以与神经毒剂本质上相同的方式产生SE作为动物模型，以开发医学对策来预防SE的急性死亡和长期发病率，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/或丹曲林在SE期间和SE后应用是否能阻止SE后钙平台的形成。假设：在SE期间或之后使用氯胺酮和/或丹曲林治疗，可防止或逆转SE产生的钙平台。目的2：观察氯胺酮和丹曲林在SE中和SE后应用是否能防止神经元丢失和降低死亡率。假设：氯胺酮和/或丹曲林在SE期间或之后应用可减少或预防SE所致的神经元丢失和死亡率。目的3：观察氯胺酮和/或丹曲林对SE后AE的阻断作用。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的发生。目的4：确定氯胺酮和/或丹曲林预防SE后认知功能丧失的有效性。假设：氯胺酮和/或丹曲林在SE期间或之后将显著减少SE后的认知损失。这项研究结果可能为保护大脑免受神经毒剂暴露的影响提供有效的对策。初步结果表明，SE对预防脑损伤是可能的。

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.