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..
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