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.

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 #
5U01NS058162-07
Application #
8526578
Study Section
Special Emphasis Panel (ZRG1-MDCN-J (50))
Program Officer
Yeung, David
Project Start
2006-09-30
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
7
Fiscal Year
2013
Total Cost
$533,799
Indirect Cost
$184,911
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
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
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
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
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
Prager, Eric M; Aroniadou-Anderjaska, Vassiliki; Almeida-Suhett, Camila P et al. (2013) Acetylcholinesterase inhibition in the basolateral amygdala plays a key role in the induction of status epilepticus after soman exposure. Neurotoxicology 38:84-90
Williams, Larry R; Aroniadou-Anderjaska, Vassiliki; Qashu, Felicia et al. (2011) RDX binds to the GABA(A) receptor-convulsant site and blocks GABA(A) receptor-mediated currents in the amygdala: a mechanism for RDX-induced seizures. Environ Health Perspect 119:357-63
Figueiredo, Taiza H; Qashu, Felicia; Apland, James P et al. (2011) The GluK1 (GluR5) Kainate/{alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist LY293558 reduces soman-induced seizures and neuropathology. J Pharmacol Exp Ther 336:303-12
Figueiredo, T H; Aroniadou-Anderjaska, V; Qashu, F et al. (2011) Neuroprotective efficacy of caramiphen against soman and mechanisms of its action. Br J Pharmacol 164:1495-505
Qashu, Felicia; Figueiredo, Taiza H; Aroniadou-Anderjaska, Vassiliki et al. (2010) Diazepam administration after prolonged status epilepticus reduces neurodegeneration in the amygdala but not in the hippocampus during epileptogenesis. Amino Acids 38:189-97

Showing the most recent 10 out of 15 publications