Nerve agents are organophosphates with high toxicity, whose primary action is the irreversible inhibition of acetylcholinesterase. Clinical manifestations following nerve-agent exposure include the development of convulsive seizures, which can cause profound brain damage, resulting in death, or long-term cognitive deficits. At present, there are no prophylactic treatments that can effectively protect against nerve agent induced seizures, without causing significant side effects. Currently available post-exposure treatments can prevent death, but their efficacy in preventing seizures and associated brain damage has not been satisfactory. After exposure to a nerve agent, seizures are initiated primarily due to hyper-stimulation of muscarinic receptors. Cholinergic hyper-stimulation triggers glutamatergic hyperactivity, which intensifies and sustains seizures, and is ultimately responsible for neuronal damage. Therefore, anti-glutamatergic agents can be effective against seizures induced by cholinergic hyper-stimulation. Indeed, recent discoveries in the function of GluR5 kainate receptors (GluR5KRs, a kainate subtype of glutamate receptors containing the GluR5 subunit) have revealed that blockade of these receptors blocks epileptic seizures induced by the muscarinic agonist pilocarpine. As there are common mechanisms between pilocarpine-induced seizures and seizures induced by nerve agents, we hypothesize that antagonists of GluR5KRs will also be effective against nerve agent-induced seizures. The animal model we propose to use to test our hypothesis is in vivo exposure of rats to soman, as well as in vitro exposure of rat amygdala and hippocampal slices to soman. The selective GluR5KR antagonists LY293558 and UBP302 will be administered as a prophylactic treatment before exposure to soman, or as a therapy at different time points post-exposure. The efficacy of these antagonists against seizures will be correlated with their efficacy in preventing brain pathology, as well as pathophysiological alterations in the amygdala and hippocampus, studied in vitro after in vivo exposure to soman. The in vitro experiments will be performed in the amygdala and hippocampus because these brain regions play a pivotal role in the generation of brain seizures, including seizures induced by nerve agents. Furthermore, GluR5KRs play an important role in the regulation of neuronal excitability in the hippocampus, as well as in the amygdala, where we have found that strong activation of GluR5KRs inhibits evoked GABA release, and induces epileptiform activity. Because antagonists of GluR5KRs do not affect normal synaptic transmission, and the distribution of GluR5KRs in the brain is relatively limited, treatment with GluR5KR antagonists is likely to produce minimal or no side effects. Thus, the proposed investigations may result in the development of a novel, safe and effective prophylactic and/or therapeutic treatment against nerve agent-induced brain damage that will enhance our treatment response capabilities during an emergency. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZNS1-SRB-R (22))
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Jett, David A
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Henry M. Jackson Fdn for the Adv Mil/Med
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