Counter Measures Against Acetylcholine Receptor Activated Status Epilepticus

描述（申请人提供）：该研究项目的总体目标是通过开发新的，安全有效的治疗剂，可作为对抗暴露于抗胆碱酯酶神经毒剂（气体）引起的癫痫持续状态（SE）对大脑损害的措施在RFA中被确定为高度优先的化学品威胁，即可能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化学品。这项研究的重点是开发可以在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并预防或逆转SE的破坏性影响。SE是一种严重的医疗和神经紧急情况，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。本研究中提出的研究将使用啮齿动物毛果芸香碱SE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作为动物模型，以开发可以预防SE的急性死亡率和长期发病率的医学对策，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期间和之后给药时是否可以预防SE后Ca 2+平台的发展。假设：SE期间或之后用氯胺酮和/或丹曲林治疗可预防或逆转SE的Ca 2+平台。目的2：确定氯胺酮和/或丹曲林在SE期间和之后给药时是否可预防神经元丢失并降低死亡率。假设：氯胺酮和/或丹曲林在SE期间或之后给药时可减少或预防SE引起的神经元丢失和死亡。目的3：确定氯胺酮和/或丹曲林在阻断SE后AE发生方面的有效性。假设：SE期间或之后给予氯胺酮和/或丹曲林可预防SE后AE的发生。目的4：确定氯胺酮和/或丹曲林预防SE后认知丧失的有效性。假设：SE期间或之后的氯胺酮和/或丹曲林将显著减少SE后的认知丧失。本研究结果可为神经毒剂暴露后的脑保护提供有效的对策。初步结果表明，SE对脑损伤的预防是可能的。

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.