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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS058162-09
Application #
8914678
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yeung, David
Project Start
2006-09-30
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2017-08-31
Support Year
9
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
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Aroniadou-Anderjaska, Vassiliki; Pidoplichko, Volodymyr I; Figueiredo, Taiza H et al. (2018) Oscillatory Synchronous Inhibition in the Basolateral Amygdala and its Primary Dependence on NR2A-containing NMDA Receptors. Neuroscience 373:145-158
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
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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
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

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