Antiglutamatergic Therapy to Protect the Brain Against Nerve Agents

Nerve agents are lethal chemical weapons that have been used in war and terrorist attacks, with devastating
consequences. The risk for mass exposure to nerve agents is presently very high. One of the clinical
manifestations of acute exposure to nerve agents is seizure activity progressing to status epilepticus (SE),
which can lead to death, or brain damage. It is imperative that medical countermeasures against the toxic
effects of nerve agents are developed and become available, which will not only save lives, but also protect
against brain damage caused by prolonged SE, and the ensuing long-term morbidities. Currently, diazepam
(DZP) is the FDA-approved anticonvulsant for the treatment of nerve agent-induced SE, and its replacement
by midazolam (MDZ) is under consideration. There is ample evidence, however, indicating that neither
benzodiazepine has satisfactory antiseizure and neuroprotective efficacy. Therefore, a more efficacious
therapy is needed to replace DZP and MDZ. We have already completed a significant amount of research in
soman-exposed rats, demonstrating that an AMPA/GluK1 receptor antagonist, LY293558 (tezampanel), exerts
a far superior antiseizure and neuroprotective efficacy in comparison with DZP or MDZ. However, we also
found that 6 months after exposure (a long time for the life span of a rat), even LY293558-treated rats
presented evidence of brain damage, suggesting a progressive nature of the induced neuropathology, and
indicating the importance of long-term studies in evaluating the neuroprotective efficacy of an anticonvulsant.
Therefore, to enhance neuroprotective efficacy, we subsequently tested the combination of LY293558 with an
NMDA receptor antagonist—we used caramiphen, an antimuscarinic with NMDA receptor antagonistic
properties—and found complete protection against brain damage up to 6 months after soman exposure. Most
of these studies have been conducted in young rats (postnatal day 21 or 12). The goal of the present
application is to test LY293558+caramiphen in adult male and female rats, in order to complete all the
preclinical research necessary to lead this highly efficacious combination therapy to the stage of advanced
development. We will include aged rats in the proposed studies, in order to obtain preclinical data pertinent to
the elderly population, which is more difficult to protect. Comparisons will be made with soman-exposed rats
treated with MDZ. The anticonvulsants will be administered at 1 h after soman exposure in order to simulate a
real case scenario of mass exposure, when medical care is unlikely to available immediately. Our central
hypothesis is that LY293558+caramiphen will prove to be far superior to MDZ in controlling soman-induced
seizures, preventing neuronal degeneration, neuronal loss, GABAergic interneuronal loss, atrophy and
pathophysiological alterations in the amygdala and hippocampus, overall brain pathology as revealed by MRI,
as well as neurological (development of spontaneous recurrent seizures – epileptogenesis) and behavioral
(increased anxiety-like behavior) abnormalities, studied up to 6 months postexposure.

Grant Number: 5U01NS123252-04
NIH Institute/Center: NIH
Principal Investigator: Maria Braga