Inhibiting mPGES-1 as a countermeasure to mitigate organophosphate-induced neurotoxicity - Project Summary Exposure to organophosphate (OP) nerve agents causes substantial mortality and morbidities, particularly in children. Current medical countermeasures (MCMs) are of doubtful utility unless they are administered within minutes of an attack to be effective, and this is especially true in the pediatric population. Inhibition of acetylcholinesterase is the conventional mechanism underlying the acute neurotoxicity of OPs. However, several lines of evidence support essential contributions of uncontrolled inflammation to pathogenic alterations within the brain after OP intoxication, in which prostaglandin E2 (PGE2) is thought to play a pivotal role. Therefore, we focus on the microsomal prostaglandin E synthase-1 (mPGES-1), an inducible enzyme responsible for the final step of PGE2 biosynthesis after various brain insults. To date, most preclinical studies on OP-induced neurotoxicity have been focusing on adult animals. Unfortunately, the neuropathological changes after OP exposure have not been adequately investigated in the immature brain, although the long- term sequelae of acute brain insults in the pediatric population can be very different from the adult population. Thereby, the goal of this project is to assess the feasibility of pharmacologically blocking mPGES-1 to mitigate OPs-triggered brain damage in neonatal mice after exposure to diisopropylfluorophosphate (DFP), the prototypical OP, thereby preventing the long-term behavioral comorbidities when they reach adulthood. Successful completion of this project will provide new insights into the pathogenic mechanisms of OP intoxication in the immature brain and the development of behavioral deficits that occur at adult stage. Anticipated results will justify future studies on lead optimization, PK/PD, safety, efficacy, and combined treatment, aiming to develop MCMs specifically for the pediatric population.
