# Project 1: Reduction of Pro-Inflammatory Signaling

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $491,094

## Abstract

Project Summary – Project 1
Convulsant chemical threat agents, such as the organophosphates (OPs) diisopropylfluorophosphate (DFP) and
soman, can trigger seizures that progress to life-threatening status epilepticus (SE). Survivors face significant,
long-term morbidity, including spontaneous recurrent seizures (SRS) and mild-to-severe memory loss. Current
medical countermeasures fail to sufficiently protect against these long-term neurological deficits. Project 1 will
use a well-established rat model of acute DFP intoxication to test the hypothesis that therapies that promote
resolution of inflammation when administered as adjuncts to standard of care will mitigate the long-term, adverse
neurological consequences of acute OP intoxication. The scientific premise for this hypothesis includes
experimental evidence that: (1) acute OP intoxication triggers a robust neuroinflammatory response in multiple
brain regions that persists for up to 6 months; and (2) pro-inflammatory signaling is causally linked to
epileptogenesis and cognitive dysfunction in non-OP models. We will focus our initial efforts on lipid mediators
of inflammation. Our analyses of the brain lipidome in rats acutely intoxicated with DFP suggests two potential
therapeutic approaches: inhibiting cyclooxygenase-2 (COX-2) to block the formation of prostaglandins, and
inhibiting the enzyme soluble epoxide hydrolase (sEH) to stabilize anti-inflammatory lipid mediators. A small
molecule inhibitor of sEH (sEHI) developed at UC Davis has been shown to significantly attenuate SRS in
preclinical models of pilocarpine-induced epilepsy, improve cognitive function in preclinical models of Alzheimer’s
disease (AD), and reduce pathology in models of AD, stroke and Parkinson’s disease. Our preliminary data
suggest that sEHI also mitigates neuroinflammation and terminates SRS in the rat DFP model. Our goals are to:
(1) Characterize the spatiotemporal profile of neuroinflammation in male and female rats following acute DFP
intoxication in order to identify therapeutic targets, determine therapeutic windows, and develop translatable
biomarkers of inflammation that predict SRS and/or cognitive dysfunction. (2) Evaluate the neuroprotective
efficacy of sEHI and other compounds that target dysregulated inflammatory mediators in male and female rats
acutely intoxicated with DFP. (3) Determine the safety of therapeutic lead(s) and their efficacy in protecting
against adverse neurological consequences in a rat model of acute soman intoxication. If successful, Project 1
will identify novel therapeutic lead(s) that improve long-term neurological outcomes when used as adjuncts to
standard of care, as well as biomarkers that identify individuals at increased risk for developing SRS and/or
cognitive deficits following acute OP intoxication.

## Key facts

- **NIH application ID:** 10684082
- **Project number:** 5U54NS127758-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Pamela J Lein
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $491,094
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10684082

## Citation

> US National Institutes of Health, RePORTER application 10684082, Project 1: Reduction of Pro-Inflammatory Signaling (5U54NS127758-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10684082. Licensed CC0.

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