# Novel Mechanisms for Seizure Mitigation and Neuroprotection

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $526,787

## Abstract

Project Summary – Project 1
Phenotypic hallmarks of intoxication with seizure-inducing chemical threat agents include: (1) acute
hyperexcitation of neural circuits associated with seizures and status epilepticus (SE); and (2) chronic
neuroinflammation and neuropathology that manifest subsequent to seizures. Project 1 is using in vitro models
essential for elucidating toxicological and therapeutic mechanisms and for discovering intervention strategies
that are more effective and safer than current medical countermeasures (atropine, oxime, high-dose
benzodiazepines) for treating acute intoxication and protecting against persistent neuropathology. Our focus is
on two classes of threat agents: those that block GABAA receptor (GABAAR) function, e.g., tetramethylene-
disulfotetramine (TETS) and picrotoxin (PTX, and organophosphates (OP) that inhibit cholinesterases, e.g.,
diisopropylfluorophosphate (DFP) and paraoxon (PO). Our hypothesis is that in vitro approaches we developed
during the first project period can be used to identify, refine and optimize combinatorial therapies that more
effectively target TETS- and OP-triggered seizure mechanisms and control subsequent neuroinflammation.
This hypothesis will be tested using in vitro and ex vivo rodent models of both sexes. Aim-1 will determine
whether midazolam plus a neurosteroid is more potent than either alone for normalizing TETS and PTX-
triggered neuronal network hyperexcitability. In Aim 2 we will test whether subtype selective nicotinic
cholinergic receptor (nAChR) inhibitors are superior to our standard midazolam ± neurosteroid combination or
synergize with it in mitigating OP-triggered seizure-like activity in adult neuron/glia cocultures. Our reasoning is
based on the known cholinergic mechanisms of seizure initiation. Aim 3 will investigate neuroinflammation by
evaluating astrogliosis, microglial activation, and neuropathology following exposure to seizure-inducing
chemical threat agents and screen for anti-inflammatory compounds that can mitigate these processes. We
have developed two cell-based models (astrocyte/microglia and neuron/glia cocultures) from mouse and rat
models of both sexes to quantitatively measure differences in neuroinflammation (astrogliosis and microglia
activation) and their relationship to neuropathology over acute and prolonged exposures to chemical threat
agents. Results obtained from these three aims will be critical for identifying and prioritizing the most promising
candidate therapeutics for mitigating seizure-like activity, neuroinflammation and neuropathology to be testedin vivo by Projects 2 and 3.

## Key facts

- **NIH application ID:** 9963381
- **Project number:** 5U54NS079202-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Isaac N Pessah
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $526,787
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963381

## Citation

> US National Institutes of Health, RePORTER application 9963381, Novel Mechanisms for Seizure Mitigation and Neuroprotection (5U54NS079202-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963381. Licensed CC0.

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