Prostanoid Modulators that Reduce Brain Injury After Seizures

描述（由申请人提供）：目前针对神经毒气暴露的医疗对策，如咪达唑仑和阿托品，对平民的普遍效用尚存疑问，因为它们必须在袭击发生后几分钟内服用才能有效。需要在接触化学物质数小时后进行治疗。由毒蕈碱激动剂匹洛卡平或有机磷酸盐氟磷酸二异丙酯（DFP）诱导的延长癫痫持续状态（SE），在大脑中引发类似的一系列细胞事件，其中显著包括大量死亡和选择性神经元变性。我们有证据表明，大脑EP2受体的激活可以在癫痫持续状态后起到神经保护作用。我们的首要目标是开发作用于特定前列腺素受体的小分子，以对抗癫痫诱发的神经变性。我们最近创造了第一个EP2受体的变构增强剂，并在体外证明它们具有神经保护作用。下一个项目期间的目标是将这些化合物开发成实用的神经毒气对策。要实现开发一种可在暴露于神经毒气数小时后使用的新型对策的目标，将需要：a)在脑损伤的匹罗卡品和DFP模型中，对ep2介导的神经保护进行令人信服的原理证明研究；b)优化EP2变构增强剂的脑药代动力学和效价，测试它们对匹洛卡平、DFP和沙林的作用；c)完成fda规定的临床前安全药理学，并提交IND作为神经毒气攻击或意外释放的对策。工作将围绕年度里程碑进行组织。

DESCRIPTION (provided by applicant): Current medical countermeasures to nerve gas exposure such as midazolam and atropine are of doubtful general utility for civilian populations because they must be administered within minutes of an attack to be effective. Therapies that can be administered hours after chemical exposure are needed. Prolonged status epilepticus (SE) induced by the muscarinic agonist, pilocarpine, or the organophosphate, diisopropyl fluorophosphate (DFP), triggers a similar series of cellular events in the brain that prominently includes substantial mortality and selective neuronal degeneration. We have evidence that activation of brain EP2 receptors can be neuroprotective after status epilepticus. Our overarching goal is to develop small molecules that act on specific prostanoid receptors to oppose seizure-induced neurodegeneration. We have recently created the first allosteric potentiators of the EP2 receptor for PGE2 and have shown they are neuroprotective in vitro. The objective of the next project period is to develop these compounds into a practical nerve gas countermeasure. Achieving the objective of developing a novel countermeasure that can be administered hours after exposure to nerve gases will require: a) compelling proof-of-principle studies for EP2-mediated neuroprotection in the pilocarpine and DFP models of brain damage; b) optimizing EP2 allosteric potentiators for brain pharmacokinetics and potency, testing them against pilocarpine, DFP and sarin; c) completing FDA-mandated preclinical safety pharmacology and submitting an IND for use as a countermeasure for nerve gas attack or accidental release. Work will be organized around annual milestones. Public Health Relevance: Injury of the brain is a major target of nerve gases, and is often associated with long-term disability with unusually high accompanying social and medical costs. We intend to create novel drugs that target inflammation pathways to minimize the brain damage and cognitive deficits that accompany prolonged seizures..