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.
|Miller, Steven L; Aroniadou-Anderjaska, Vassiliki; Pidoplichko, Volodymyr I et al. (2017) The M1 Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala. J Pharmacol Exp Ther 360:23-32|
|Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H; Apland, James P et al. (2016) Long-term neuropathological and behavioral impairments after exposure to nerve agents. Ann N Y Acad Sci 1374:17-28|
|Long Ii, Robert P; Aroniadou-Anderjaska, Vassiliki; Prager, Eric M et al. (2016) Repeated Isoflurane Exposures Impair Long-Term Potentiation and Increase Basal GABAergic Activity in the Basolateral Amygdala. Neural Plast 2016:8524560|
|Prager, Eric M; Bergstrom, Hadley C; Wynn, Gary H et al. (2016) The basolateral amygdala ?-aminobutyric acidergic system in health and disease. J Neurosci Res 94:548-67|
|Prager, Eric M; Figueiredo, Taiza H; Long 2nd, Robert P et al. (2015) LY293558 prevents soman-induced pathophysiological alterations in the basolateral amygdala and the development of anxiety. Neuropharmacology 89:11-8|
|Miller, Steven L; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H et al. (2015) A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists. Toxicol Appl Pharmacol 284:204-16|
|Prager, Eric M; Pidoplichko, Volodymyr I; Aroniadou-Anderjaska, Vassiliki et al. (2014) Pathophysiological mechanisms underlying increased anxiety after soman exposure: reduced GABAergic inhibition in the basolateral amygdala. Neurotoxicology 44:335-43|
|Prager, Eric M; Aroniadou-Anderjaska, Vassiliki; Almeida-Suhett, Camila P et al. (2014) The recovery of acetylcholinesterase activity and the progression of neuropathological and pathophysiological alterations in the rat basolateral amygdala after soman-induced status epilepticus: relation to anxiety-like behavior. Neuropharmacology 81:64-74|
|Apland, James P; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H et al. (2014) The limitations of diazepam as a treatment for nerve agent-induced seizures and neuropathology in rats: comparison with UBP302. J Pharmacol Exp Ther 351:359-72|
|Pidoplichko, Volodymyr I; Prager, Eric M; Aroniadou-Anderjaska, Vassiliki et al. (2013) *7-Containing nicotinic acetylcholine receptors on interneurons of the basolateral amygdala and their role in the regulation of the network excitability. J Neurophysiol 110:2358-69|
Showing the most recent 10 out of 22 publications