# Inhibiting mPGES-1 as a countermeasure to mitigate organophosphate-induced neurotoxicity

> **NIH NIH R21** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2024 · $192,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10837485
- **Project number:** 1R21NS136070-01
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Jianxiong Jiang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $192,500
- **Award type:** 1
- **Project period:** 2024-06-19 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837485

## Citation

> US National Institutes of Health, RePORTER application 10837485, Inhibiting mPGES-1 as a countermeasure to mitigate organophosphate-induced neurotoxicity (1R21NS136070-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10837485. Licensed CC0.

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