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Nerve Agent Induced Status Epilepticus: From Seizure Onset to Long Lasting Pathology

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Technical Report

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Uniformed Services University Of The Health Sciences Bethesda United States

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The recent use of chemical nerve agents in Syria left countless civilians to deal with possible health consequences, including the development of anxiety disorders. Anxiety disorders were among the most debilitating neuropsychiatric symptoms reported by victims of the Japan sarin attack, more than a decade after exposure. Nerve agents are powerful neurotoxins that irreversibly inhibit acetyl cholinesterase AChE activity. This leads to the generation of seizures, status epilepticus SE, resulting in brain damage and long-term behavioral deficits. Uncovering the neuro-pathophysiological mechanisms underlying the development of seizures and the subsequent anxiety disorders observed after nerve agent exposure is necessary for developing successful treatments. Towards this goal, we examined AChE activity in three brain regions critically involved in nerve agent induced SE after subcutaneous injection of the nerve agent soman. Following the administration of soman, we observed that AChE activity was significantly reduced in the hippocampus, piriform cortex, and basolateral amygdala BLA of rats that developed SE. In addition, animals that developed seizures went on to have significant neuronal loss and neurodegeneration after SE. In marked contrast, AChE activity was not inhibited in the BLA of animals that did not develop SE, even though AChE activity was reduced in the hippocampus and piriform cortex of these same animals. In addition, these animals did not display any neuropathology 7 days after SE. These results indicate that Ache inhibition in the BLA is necessary for the generation of seizures in response to nerve agent exposure and that only in animals that develop seizures will neuropathology and behavioral deficits ensue.


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