The limitations of diazepam as a treatment for nerve agent-induced seizures and neuropathology in rats: comparison with UBP302.

Abstract

Exposure to nerve agents induces prolonged status epilepticus (SE), causing brain damage or death. Diazepam (DZP) is the current US Food and Drug Administration-approved drug for the cessation of nerve agent-induced SE. Here, we compared the efficacy of DZP with that of UBP302 [(S)-3-(2-carboxybenzyl)willardiine; an antagonist of the kainate receptors that contain the GluK1 subunit] against seizures, neuropathology, and behavioral deficits induced by soman in rats. DZP, administered 1 hour or 2 hours postexposure, terminated the SE, but seizures returned; thus, the total duration of SE within 24 hours after soman exposure was similar to (DZP at 1 hour) or longer than (DZP at 2 hours) that in the soman-exposed rats that did not receive the anticonvulsant. Compared with DZP, UBP302 stopped SE with a slower time course, but dramatically reduced the total duration of SE within 24 hours. Neuropathology and behavior were assessed in the groups that received anticonvulsant treatment 1 hour after exposure. UBP302, but not DZP, reduced neuronal degeneration in a number of brain regions, as well as neuronal loss in the basolateral amygdala and the CA1 hippocampal area, and prevented interneuronal loss in the basolateral amygdala. Anxiety-like behavior was assessed in the open field and by the acoustic startle response 30 days after soman exposure. The results showed that anxiety-like behavior was increased in the DZP-treated group and in the group that did not receive anticonvulsant treatment, but not in the UBP302-treated group. The results argue against the use of DZP for the treatment of nerve agent-induced seizures and brain damage and suggest that targeting GluK1-containing receptors is a more effective approach.

• Authors: James P Apland, Vassiliki Aroniadou-Anderjaska, Taiza H Figueiredo, Franco Rossetti, Steven L Miller, Maria F M Braga
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 351 Issue 2 Pg. 359-72 (Nov 2014) ISSN: 1521-0103 [Electronic] United States
• PMID: 25157087 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: U.S. Government work not protected by U.S. copyright.

Chemical References

• 1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl)pyrimidine-2,4-dione
• Anticonvulsants
• Gluk1 kainate receptor
• Receptors, Kainic Acid
• Soman
• Alanine
• Diazepam
• Thymine

Topics

• Alanine (analogs & derivatives, pharmacology)
• Amygdala (drug effects, metabolism)
• Animals
• Anticonvulsants (pharmacology)
• Anxiety (chemically induced, drug therapy, metabolism)
• Diazepam (pharmacology)
• Hippocampus (drug effects, metabolism)
• Male
• Nerve Degeneration (drug therapy, metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Kainic Acid (metabolism)
• Seizures (chemically induced, drug therapy, metabolism)
• Soman (adverse effects)
• Status Epilepticus (chemically induced, drug therapy, metabolism)
• Thymine (analogs & derivatives, pharmacology)