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，对平民群体的一般效用值得怀疑，因为它们必须在攻击后几分钟内施用才能有效。需要在化学品暴露后数小时内进行治疗。由毒蕈碱激动剂毛果芸香碱或有机磷酸盐二异丙基氟磷酸盐（DFP）诱导的延长的癫痫持续状态（SE）在脑中触发类似的一系列细胞事件，其突出地包括大量死亡和选择性神经元变性。我们有证据表明，脑EP 2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，以对抗前列腺素诱导的神经变性。我们最近创造了第一个PGE 2的EP 2受体的变构增效剂，并在体外显示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发展成为一种实用的神经毒气对策。实现开发一种可以在暴露于神经毒气数小时后施用的新对策的目标将需要：a）在毛果芸香碱和DFP脑损伤模型中对EP 2介导的神经保护进行令人信服的原理验证研究; B）优化EP 2变构增效剂的脑药代动力学和效力，测试它们对毛果芸香碱、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用于神经毒气攻击或意外释放的对策。将围绕年度里程碑组织工作。 公共卫生相关性：脑损伤是神经毒气的主要目标，通常与长期残疾有关，伴随着异常高的社会和医疗成本。我们打算创造新的药物，靶向炎症途径，以尽量减少脑损伤和认知缺陷，伴随着长时间的癫痫发作。

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..