# Antiglutamatergic Therapy to Protect the Immature Brain Against Nerve Agents

> **NIH NIH U01** · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · 2020 · $449,535

## Abstract

Nerve agents are lethal chemical weapons that have been used in war and in terrorist attacks, with devastating
consequences; the possibility that they will be used again against civilians is presently very high. One of the
clinical manifestations of exposure to nerve agents is seizure activity progressing to status epilepticus (SE)
which can lead to death, or brain damage with long-term neurological and behavioral consequences. The
American Academy of Pediatrics have pointed out the reasons that children may be more vulnerable to nerve
agent toxicity; yet, there is very little information on the appropriate countermeasures to protect the pediatric
population, as data in immature animals are lacking. The FDA has approved diazepam as the anticonvulsant
treatment for nerve agent-induced SE, irrespective of the age of the victim. However, there is sufficient
evidence indicating that diazepam does not have good neuroprotective efficacy, and, in the developing brain, it
may worsen the injury induced by the SE. Animal data are, therefore, needed to provide knowledge on how to
protect the immature brain from damage in the event of nerve agent exposure, taking into account that GABAA
receptor-mediated activity can be excitatory in the developing brain, while glutamatergic activity and
particularly the activity of NMDA receptors, which are well known for their role in excitotoxicity, is very
pronounced. We have already demonstrated the efficacy of LY293558, an AMPA/GluK1 receptor antagonist, in
stopping seizures and significantly reducing neuropathology and long-term deficits in adult rats exposed to
soman. We have also tested the combination of LY293558 with caramiphen, an antimuscarinic with NMDA
receptor antagonistic properties, and found that it terminates soman-induced seizures faster than LY293558
alone, provides full protection from neuronal damage in all brain regions examined, and the recovery of the
animals is swift with no weight loss. In the present application, we propose to test and compare the efficacy of
LY293558+caramiphen with that of LY293558 alone, and with two benzodiazepines, diazepam and
midazolam, against soman, in male and female rats of postnatal age 7, 12, and 21 days; anticonvulsant
treatments will be administered 1 h after soman exposure. We hypothesize that LY293558+caramiphen will
provide more benefits than LY293558 alone, and will prove to be far superior to both diazepam and midazolam
in stopping soman-induced seizures, preventing neuronal degeneration, neuronal loss, GABAergic
interneuronal loss, atrophy and pathophysiological alterations in the amygdala and hippocampus, as well as
cognitive, behavioral, and neurological deficits studied up to 6 months postexposure. The data acquired will
contribute immensely in developing safe and efficacious countermeasures for protecting the lives of infants and
children and prevent long-term morbidities.

## Key facts

- **NIH application ID:** 9960596
- **Project number:** 5U01NS102135-03
- **Recipient organization:** HENRY M. JACKSON FDN FOR THE ADV MIL/MED
- **Principal Investigator:** Maria F. Braga
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $449,535
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960596

## Citation

> US National Institutes of Health, RePORTER application 9960596, Antiglutamatergic Therapy to Protect the Immature Brain Against Nerve Agents (5U01NS102135-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9960596. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*