# High-Throughput in Vivo Discovery of Novel Countermeasures Against Organophosphate-Induced Seizure and Status Epilepticus Using Zebrafish

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2023 · $3,587

## Abstract

PROJECT SUMMARY
Chemical threats are a major public health concern and CounterACT recognizes the need to identify new
medical countermeasures (MCMs) that improve the public health response to mass casualty events related to
chemical threats. Organophosphate (OP) agents are of particular concern due to their wide availability in
common pesticides (e.g. chlorpyrifos, parathion, phorate, aldibcarb) as well as their use in chemical nerve
agents (e.g. sarin, soman, tabun, VX). OP-induced seizures are a serious consequence of OP-intoxication and
best agents for treating this complication are unclear. Major gaps include limited opportunities for systematic
clinical evaluations in humans prior to mass casualty, drawbacks to existing medication, which may not control
seizures or excitotoxicity, and worsen sedation; and lack of direction in discovering new MCMs. To address
these gaps, we propose to overcome these barriers by harnessing a zebrafish model of OP-induced seizures
and excitotoxicity using paraxon-ethyl (PXN) and to advance its use for high-throughput compound screening
to identify novel MCMs against OP-induced seizures and excitotoxicity.
We hypothesize that zebrafish models of CPO exposure will recapitulate the features of seizures and SE after
human exposure to OP agents, which is partly supported by existing literature. Furthermore, we hypothesize
that a combination of blind and targeted chemical screening will enable the identification of compounds with
novel anti-seizure and/or anti-excitotoxic properties with special efficacy for OP-related seizures. In vivo drug
screening most closely approximates the disease pathophysiology and allows optimization for the clinical
parameters desired by CounterACT, including post-exposure efficacy, improvement over existing standards-of-
care, and minimal sedation for administration without ICU-level monitoring. The following aims will address
these hypotheses:
Aim 1. Characterize a larval zebrafish model of OP-induced seizure and status epilepticus (SE) and
optimize parameters for identification of novel countermeasures.
 1A. Confirm seizure activity and excitotoxicity by invasive and non-invasive measures.
 1B. Optimize assay parameters to identify novel counter-measures with improved efficacy over existing
 medical management.
 1C. Quantify sedation as a function of anti-seizure activity in conventional AEDs.
Aim 2. Whole organism in vivo compound screening for novel countermeasures against OP-induced
seizure and excitotoxicity.
Taken together, this exploratory R21 is responsive to multiple facets of the CounterACT program including
basic mechanistic research to identify molecular mechanisms of acute toxicity of the chemical threat agent
chlorpyrifos; creation of an animal model of seizures related to chemical exposure; creation and validation of
screening assays for therapy development emphasizing real-world applications to mass casualty events; and
identification of candidate therapeutics among FDA-...

## Key facts

- **NIH application ID:** 11294079
- **Project number:** 7R21NS127345-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Christopher McGraw
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $3,587
- **Award type:** 7
- **Project period:** 2022-04-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11294079

## Citation

> US National Institutes of Health, RePORTER application 11294079, High-Throughput in Vivo Discovery of Novel Countermeasures Against Organophosphate-Induced Seizure and Status Epilepticus Using Zebrafish (7R21NS127345-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11294079. Licensed CC0.

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