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The limitations of diazepam as a treatment for nerve agent-induced seizures and neuropathology in rats: comparison with UBP302.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2014 Nov; Vol. 351 (2), pp. 359-72. Date of Electronic Publication: 2014 Aug 25. - Publication Year :
- 2014
-
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.<br /> (U.S. Government work not protected by U.S. copyright.)
- Subjects :
- Alanine pharmacology
Amygdala drug effects
Amygdala metabolism
Animals
Anticonvulsants pharmacology
Anxiety chemically induced
Anxiety drug therapy
Anxiety metabolism
Hippocampus drug effects
Hippocampus metabolism
Male
Nerve Degeneration metabolism
Rats
Rats, Sprague-Dawley
Receptors, Kainic Acid metabolism
Seizures chemically induced
Seizures metabolism
Soman adverse effects
Status Epilepticus chemically induced
Status Epilepticus drug therapy
Status Epilepticus metabolism
Thymine pharmacology
Alanine analogs & derivatives
Diazepam pharmacology
Nerve Degeneration drug therapy
Seizures drug therapy
Thymine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0103
- Volume :
- 351
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 25157087
- Full Text :
- https://doi.org/10.1124/jpet.114.217299