# Identification and optimization of verapamil as a novel neuroprotective and anti-inflammatory agent for reducing long-term neurological morbidities following organophosphate-induced status epilepticus

> **NIH NIH UG3** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $526,392

## Abstract

ABSTRACT
Organophosphate (OP) compounds include pesticides and chemical warfare nerve agents. They are highly
toxic and can produce a cholinergic crisis that rapidly progresses into status epilepticus (SE) and even death
without emergency care. The standard-of-care (SOC) treatment with atropine, pralidoxime, and midazolam has
dramatically improved survival after OP intoxication. Yet, many survivors of OP-SE exhibit brain injury,
cognitive impairments, and spontaneous recurrent seizures (SRS). In addition, both acute and protracted
neuro-inflammation and increased expression of pro-inflammatory cytokines have been reported following OP
SE. These persistent neuroinflammatory changes are thought to underlie neurodegeneration, network hyper-
excitability, and maladaptive plasticity, leading to cognitive dysfunction and SRS. Thus, mitigating neuro-
inflammation is a primary target in alleviating neuronal injury and behavioral morbidities following OP SE.
Verapamil (VPM) is a water-soluble calcium-channel blocker for high blood pressure and angina treatment.
Recent findings have also demonstrated the potent neuroprotective and anti-inflammatory action of VPM in
various CNS injuries. Our preliminary results showed that intramuscular VPM (10 mg/kg, i.m.) was safe and
produced significant neuroprotection and decreased neuroinflammation in multiple brain regions when
administered after the termination of DFP SE. It was also associated with decreased pro-inflammatory and
upregulation of anti-inflammatory cytokines. Finally, this effect had a functional outcome since VPM improved
anxiety and cognitive impairment at eight weeks post-DFP SE. Thus, this UG3-UH3 will investigate and
optimize a VPM therapy as a potential countermeasure for treating OP SE that could be rapidly administered in
the field. Studies will employ DFP-SE rat model to conduct the Specific Aims: In Aim 1, the safety of repeated
i.m. injections will be assessed along with an assessment of pharmacokinetic parameters and the stability of
VPM formulation. In Aim 2, the effects of VPM treatment on reducing neuronal death and neuroinflammation
after DFP SE will be evaluated utilizing Fluoro-Jade C along with Glial Fibrillary Acidic Protein and Ionized
calcium-binding adaptor molecule-1 immunohistochemical staining, respectively. We will also assess the effect
of VPM therapy on pro- and anti-inflammatory cytokine expression. In Aim 3, VPM therapy will be optimized by
studying the effects of various VPM doses and treatment durations on neurodegradation and
neuroinflammation. In Aim 4, the functional outcomes of optimized VPM therapy on long-term anxiety,
cognitive impairment, and SRS will be tested using a battery of rodent behavioral assays and EEG techniques.
We will also draft a preliminary target product profile (TPP) by the end of our studies. These studies will
provide further insight into the role of neuroinflammatory mechanisms in mediating OP morbidities and
optimizing a VPM-based anti-inf...

## Key facts

- **NIH application ID:** 10915000
- **Project number:** 5UG3NS133630-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Laxmikant S Deshpande
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $526,392
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915000

## Citation

> US National Institutes of Health, RePORTER application 10915000, Identification and optimization of verapamil as a novel neuroprotective and anti-inflammatory agent for reducing long-term neurological morbidities following organophosphate-induced status epilepticus (5UG3NS133630-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10915000. Licensed CC0.

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