# Project 3: Normalization of Neuronal Excitability

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $514,764

## Abstract

Project Summary – Project 3
Both clinical and preclinical data clearly demonstrate that survivors of OP-induced status epilepticus (SE) can
develop persistent neuropathology, spontaneous recurring seizures (SRS) and cognitive dysfunction. Current
standard-of-care (SOC) for acute OP intoxication includes the muscarinic receptor antagonist, atropine,
combined with an oxime, such as pralidoxime chloride (2-PAM) to reactivate acetylcholinesterase and finally a
benzodiazepine to increase inhibitory tone. However, it is now clear that the potential for SOC to prevent SE or
to counteract the downstream consequences of the OP-induced cholinergic storm rapidly diminishes with time.
Specifically, immediate treatment with atropine and 2-PAM can increase viability, but does not prevent a
transition into SE. Once in SE, the potential for benzodiazepines to interrupt seizures and protect against ongoing
cell death quickly declines. It is also clear that as the interval between acute intoxication and treatment increases,
the severity of the corresponding chronic neurological deficits increases as well. It is likely that following a mass
casualty event, treatment of civilians exposed to chemical threat agents is going to fall outside of the optimal
therapeutic window, increasing the likelihood that they will develop persistent SRS and cognitive disorders.
Therefore, there is a clear need to identify biological markers to identify those individuals with the highest risk of
developing long-term morbidity and also to move beyond the management of acute OP intoxication in the field,
and to investigate therapeutic strategies for managing chronic neurological sequelae, including SRS and
cognitive dysfunction. In Project 3, we will first evaluate the natural history of acute DFP intoxication. This will
include a rigorous assessment of neural oscillations recorded from depth and cortical electrodes over the course
of four months following injury, the quantification of SRS and also evaluation of both a standard battery of
cognitive outcomes (Y-maze, novel object recognition and contextual fear conditioning) and also translationally
relevant touchscreen behaviors (that evaluate memory, executive function, and attention). We will then evaluate
four therapeutic candidates for their potential to modulate excitability, restore oscillations, reduce seizures and
improve cognition. These candidates include: (i) FDA-approved lacosamide, which enhances the slow
inactivation of voltage-gated sodium channels (Nav); (ii) FDA-approved riluzole, which blocks Nav, but also
enhances the activity of small-conductance calcium-activated potassium channels (KCa) and also glutamine
transport; (iii) SKA-19, a mixed Nav blocker and KCa activator; and (iv) NS13001, a relatively selective KCa
activator. Finally, we will determine the potential of combinatorial therapy including one of the above therapeutic
candidates with theta frequency deep brain stimulation to further manage the chronic neurol...

## Key facts

- **NIH application ID:** 10911237
- **Project number:** 5U54NS127758-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Gene Gabriel Gurkoff
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $514,764
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911237

## Citation

> US National Institutes of Health, RePORTER application 10911237, Project 3: Normalization of Neuronal Excitability (5U54NS127758-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10911237. Licensed CC0.

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