# Mitigation of Neurological Damage Following Seizures

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $1,019,174

## Abstract

Project Summary – Project 3
Convulsant chemical threat agents, such as the GABAA receptor blocker tetramethylenedisulfotetramine (TETS)
and the organophosphate (OP) cholinesterase inhibitor diisopropylfluorophosphate (DFP), can trigger seizures
that progress to life-threatening status epilepticus (SE). Survivors face significant, long-term morbidity, including
mild-to-severe memory loss, affective disorders and recurrent seizures (epilepsy). Current medical counter-
measures fail to sufficiently protect against these neurological deficits. It is hypothesized that neuroprotection
will be enhanced by: (1) improving seizure control, and (2) combining antiseizure treatment with agents that
mitigate neuroinflammation and/or Ca2+ dysregulation. During the first project period, we developed a mouse
model of TETS-induced SE and refined a rat model of DFP-induced SE for use in neuroprotection studies. Using
these preclinical models, Projects 1 and 2 showed that allopregnanolone, a positive allosteric modulator of
GABAA receptors, was a superior countermeasure for TETS-induced SE, particularly when administered at
delayed times. Allopregnanolone alone or in combination with midazolam did not terminate DFP-induced SE,
but the combined intramuscular administration of midazolam, allopregnanolone and a low dose of perampanel,
a potent AMPA receptor antagonist, was highly effective in terminating DFP-induced behavioral and
electrographic SE without causing significant sedation. We also discovered in a screen of candidate neuro-
protectants that post-exposure treatment with dantrolene, a Ca2+ channel stabilizer, reduced neurodegeneration,
and that a novel small molecule dual inhibitor of soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-
2) attenuated microglial activation. Core A found that sEH inhibitors (sEHI) also normalized the hypotension
associated with high-dose diazepam or midazolam. In the second project period, we will quantify the effects of
antiseizure and neuroprotective treatments on neurodegenerative, neuroinflammatory and functional outcomes
using in vivo imaging to longitudinally monitor brain damage with corroborative histology, 24 h video
electroencephalography to quantify recurrent seizures, and behavioral assessments of cognitive, affective and
motor function. Our goals are to: (1) obtain neuroprotection data to support the advance of our antiseizure lead
allopregnanolone; (2) obtain proof-of-concept neuroprotective efficacy data for perampanel alone or in
combination with allopregnanolone; and (3) identify neuroprotectant leads, with an initial focus on our most
promising candidate compounds: sEHI, the dual sEH-COX-2 inhibitor and dantrolene. We will continue testing
additional antiseizure candidates identified by Project 2 and novel neuroprotective treatments identified in Project
1 using in vitro models. Superior neuroprotective treatments identified in this project will be tested by Project 2
to assess whether they interact with...

## Key facts

- **NIH application ID:** 9963385
- **Project number:** 5U54NS079202-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Pamela J Lein
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,019,174
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963385

## Citation

> US National Institutes of Health, RePORTER application 9963385, Mitigation of Neurological Damage Following Seizures (5U54NS079202-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963385. Licensed CC0.

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