Abstract
The possibility of mass exposure to nerve agents by a terrorist attack necessitates the availability of antidotes that can be effective against nerve agent toxicity even when administered at a relatively long latency after exposure, because medical assistance may not be immediately available. Nerve agents induce status epilepticus (SE), which can cause brain damage or death. Antagonists of kainate receptors that contain the GluK1 (formerly known as GluR5) subunit (GluK1Rs) are emerging as a new potential treatment for SE and epilepsy from animal research, whereas clinical trials to treat pain have shown that the GluK1/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid] is safe and well tolerated. Therefore, we tested whether LY293558 is effective against soman-induced seizures and neuropathology, when administered 1 h after soman exposure, in rats. LY293558 stopped seizures induced by soman and reduced the total duration of SE, monitored by electroencephalographic recordings within a 24 h-period after exposure. In addition, LY293558 prevented neuronal loss in the basolateral amygdala (BLA) and the CA1 hippocampal area on both days 1 and 7 after soman exposure and reduced neuronal degeneration in the CA1, CA3, and hilar hippocampal regions, entorhinal cortex, amygdala, and neocortex on day 1 after exposure and in the CA1, CA3, amygdala, and neocortex on day 7 after exposure. It also prevented the delayed loss of glutamic acid decarboxylase-67 immuno-stained BLA interneurons on day 7 after exposure. LY293558 is a potential new emergency treatment for nerve agent exposure that can be expected to be effective against seizures and brain damage even with late administration.
Footnotes
This work was supported by the CounterACT Program, National Institutes of Health Office of the Director through the National Institute of Neurological Disorders and Stroke [Award U01-NS058162-01], and the Defense Threat Reduction Agency-Joint Science and Technology Office, Medical Science and Technology Division [Grant 1.E0021_07_US_C].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.171835.
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ABBREVIATIONS:
- SE
- status epilepticus
- BLA
- basolateral amygdala
- GluK1R
- GluK1-containing kainate receptor
- FJC
- Fluoro-Jade C
- LY293558
- (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- EEG
- electroencephalogram
- HI-6
- (1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride
- PBS
- phosphate-buffered saline
- GAD-67
- glutamic acid decarboxylase-67
- CE
- coefficient of error
- dH2O
- distilled water
- ANOVA
- analysis of variance
- LSD
- least significant difference
- IQR
- interquartile range.
- Received June 22, 2010.
- Accepted October 19, 2010.
- U.S. Government work not protected by U.S. copyright
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