PROJECT SUMMARY Exposure to organophosphate (OP) nerve agents leads to quick overstimulation of muscarinic and nicotinic acetylcholine receptors, causing substantial mortality and morbidities associated with damages to the brain. Current medical countermeasure drugs, such as midazolam, atropine, diazepam, and 2-PAM, are of doubtful utility for civilian populations as they must be administered within minutes of an attack to be effective. Nor can they prevent the long-term neurotoxicity and behavioral comorbidities due to the persistent neuroinflammation and aggravated brain injury. Although inhibition of acetylcholinesterase is the conventional mechanism underlying the acute neurotoxicity of OPs, several lines of evidence support essential contributions of uncontrolled inflammation to pathogenic changes within the brain after OP intoxication, in which prostaglandin E2 (PGE2) is widely believed to play a pivotal role. As such, blocking cyclooxygenase (COX), the enzyme responsible for the initial step of PGE2 biosynthesis, was previously considered as a promising strategy to reduce pathogenic PGE2 in the injured brain but turned out to be problematic due to side effects related to the reduction in other COX-derived prostanoids that may be beneficial. In this proposal, we focus on the microsomal prostaglandin E synthase-1 (mPGES-1), an inducible enzyme that is responsible for the terminal step of PGE2 biosynthesis in response to various brain insults. The goal of this project is to evaluate the feasibility of pharmacologically blocking mPGES-1 by novel, brain-penetrant, cross-species, small-molecule inhibitors to mitigate OPs-triggered brain damage and long-term behavioral comorbidities in animals following exposure to diisopropylfluorophosphate (DFP), the prototypical OP. Upon successful completion of this project, we will have established a proof of concept for mPGES-1 inhibition as an effective delayed countermeasure against the neurological sequela of cholinergic receptor hyperstimulation caused by OP agents. Anticipated results will justify future studies on the lead optimization, efficacy, safety, and combined treatment, aiming to develop novel therapies for OP-based nerve agents-triggered long-term neurotoxicity and functional deficits.