# Identification of Treatments for Chemical Threat Agent Seizures

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $539,302

## Abstract

Summary – Project 2
There is a need for improved treatments to terminate status epilepticus (SE) and increase survival following
exposure to seizure-inducing chemical threat agents. There are two major classes of convulsant chemical
threat agents: organophosphate (OP) anticholinesterases, including soman and diisopropylfluorophosphate
(DFP), and GABAA receptor antagonists, including tetramethylenedisulfotetramine (TETS) and picrotoxin. The
current standard of care treatment for chemical threat agent seizures is the benzodiazepine diazepam, but the
benzodiazepine midazolam will likely be used in the future. These agents fail to terminate chemical threat
agent induced SE in many situations, particularly when they are administered at delayed times after exposure,
and they are not effective at preventing seizure-induced brain damage. In the initial project period, a mouse
model of TETS-induced SE was developed. In addition, a rat model of DFP-induced SE was adapted to the
laboratory. Diazepam and midazolam at doses equivalent to recommended human doses were partially active
in the TETS SE model. However, allopregnanolone, a positive modulator of GABAA receptors, had superior
activity in terminating TETS-induced behavioral and electrographic SE, particularly when administered at a
delayed time. At effective doses, allopregnanolone did not cause marked sedation, motor impairment or
adverse effects on blood pressure or respiration. Unlike other similar agents, allopregnanolone is uniquely
suited for intramuscular administration via autoinjector. DFP-induced SE was not terminated by
benzodiazepines or allopregnanolone. However, the combination of perampanel, a potent AMPA receptor
antagonist, and allopregnanolone administered intramuscularly was highly effective in terminating DFP-
induced behavioral and electrographic SE. It is hypothesized that a combination of allopregnanolone and
perampanel would represent an effective and safe “universal” treatment for chemical threat agent seizures. In
the proposed research, studies will be conducted that are required for the lead compound allopreganolone to
enter advanced development, including studies in conjunction with standard therapy as well as non-human
primate pharmacokinetic and efficacy testing. Proof-of-concept data will be obtained for perampanel and the
combination of perampanel and allopregnanolone. Testing will also be conducted of additional antiseizure
agents identified in Project 1 to determine if they are superior to the candidate treatments. Efficacy and safety
testing will be conducted in both male and female animals to assess sex differences; and safety tests will be
conducted in young and aged animals. Project 3 will identify candidate anti-inflammatory treatments to mitigate
the long-term consequences of chemical treat agent seizures. Project 2 will assess whether these treatments
interact with the antiseizure treatments. The results from this project will permit the lead compound
allopregna...

## Key facts

- **NIH application ID:** 9963383
- **Project number:** 5U54NS079202-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** MICHAEL A. ROGAWSKI
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $539,302
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963383

## Citation

> US National Institutes of Health, RePORTER application 9963383, Identification of Treatments for Chemical Threat Agent Seizures (5U54NS079202-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9963383. Licensed CC0.

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