The possibility of a terrorist attack with chemical or biological toxins/weapons against civilians, or military troops deployed overseas is at present in the minds of both citizens and government officials. Nerve agents are lethal chemical weapons that have been used in war and in terrorist attacks, with devastating consequences. One of the clinical manifestations of exposure to nerve agents is seizure activity and status epilepticus which can lead to death, or brain damage with long-term cognitive/behavioral consequences. The ultimate goal of this application is the development of a medical countermeasure against nerve agents that will effectively stop seizures and protect from brain damage and the resulting behavioral deficits, and do so without significant acute and/or long-term adverse effects. An emerging promising target for anticonvulsant drugs is the type of kainate receptors that contains the GluR5 subunit (GluRSKRs). We have already shown the efficacy of GluRSKR antagonists against soman-induced seizures and neuropathology in adult male rats. In the proposed studies, the efficacy of LY293558, a GluR5KR/AMPA antagonist, and UBP302, a GluRSKR antagonist will be tested against soman-induced seizures, neuropathology, pathophysiology, and the resulting cognitive/behavioral deficits in immature, adult, and aged male and female rats. Safety/toxicity studies of these GluRSKR antagonists are also part of this application. Neuronal loss, using design-based stereology, and neurodegeneration, using Fluoro-Jade-C staining will be studied in the amygdala, hippocampus, and prefrontal cortex, at 24 hours, 1 week, 1 month, and 3 months after soman exposure. Alterations in neuronal excitability and synaptic plasticity (long-term potentiation) in these brain regions, and behavioral deficits will be investigated at 1 and 3 months after soman exposure. The correlation of behavior with neuropathology and pathophysiology in brain regions that play a key role in cognitive and emotional processes will provide valuable information regarding the mechanisms underlying soman-induced cognitive/behavioral deficits, and the effectiveness of LY293S58 and UBP302 in preventing or minimizing these deficits.
These studies will provide the preclinical information necessary to determine if GluRSKR antagonists can be effectively and safely used against nerve agents in an emergency situation to protect the people. Including a section of the particularly vulnerable population, and will result in the development of new compounds that will reduce mortality and morbidity during and after an emergency event involving nerve agents.
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|Apland, James P; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H et al. (2013) Efficacy of the GluK1/AMPA receptor antagonist LY293558 against seizures and neuropathology in a soman-exposure model without pretreatment and its pharmacokinetics after intramuscular administration. J Pharmacol Exp Ther 344:133-40|
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