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.