This proposal proposes to develop novel, mechanism-based therapies for the treatment of organophosphate (OP) nerve agent-induced seizures. OP nerve agents, such as sarin, soman and VX act by central and peripheral cholinesterase inhibition and enhance cholinergic transmission. In experimental animals, all known nerve agents, produce convulsive seizures and status epilepticus within minutes of exposure. Seizures were also observed in humans exposed to nerve agent poisoning during the Iran-Iraq war, and in the Tokyo subway attacks where sarin and VX were used. The mechanism of OP-induced seizures remains uncertain. Preliminary studies in our laboratory have used the OP, paraoxon, as a surrogate agent to study OP-induced seizures. We demonstrate that low doses of paraoxon infused into the hippocampus cause prolonged seizures. Furthermore, we demonstrate that the concentrations of paraoxon that cause seizures in hippocampal slices can enhance excitatory neurotransmission by stimulating glutamate release from presynaptic terminals. These findings lead to the formulation of the central hypothesis guiding this proposal: convulsant concentrations of OP nerve agents enhance glutamatergic neurotransmission. This proposal seeks to confirm preliminary findings regarding the effect of OP agent on excitatory transmission and to test candidate compounds that diminish glutamate release from presynaptic terminals as potential therapy against seizures induced by cholinergic agents. Experiments are proposed within three aims, each group has specific milestones toward therapeutic interventions. We present quantitative outcomes criteria that represent """"""""go-no go"""""""" decision points. Experiments outlined in Aim 1 seek to confirm and extend the observation that OP cholinesterase inhibitors enhance glutamate release from presynaptic terminals in the hippocampus, using patch clamp electrophysiology and FM dye technique. Experiments proposed in Aim 2 seek to test two classes of compounds, somatostatin and its analogs, and adenosine and its analogs, for their ability to diminish glutamate release during control resting conditions and following OP stimulation, using patch clamp technique and FM dye technique. Two classes of compounds, galanin and neuropeptide Y, are held in reserve and will be tested in case either one of the two proposed agents fail to reduce glutamate release by 30%.
Aim 3 : To test anticonvulsant action of two classes of compounds in controlling lithium/pilocarpine and OP paraoxon-induced status epilepticus. Two classes of compounds, neuropeptide Y and galanin are held in reserve and will be tested in case either one of the two proposed agents fail to control diazepam refractory seizures in 50% of experimental animals. By studying the mechanisms of OP-induced seizures, we are proposing to identify novel therapeutic targets for the treatment of OP-induced seizures. Second, we propose to develop therapies based on novel therapeutic targets. Furthermore, we develop a model of OP-induced seizures that can be used in civilian ? ? ?

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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University of Virginia
Schools of Medicine
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Johnson, Sarah E; Hudson, John L; Kapur, Jaideep (2015) Synchronization of action potentials during low-magnesium-induced bursting. J Neurophysiol 113:2461-70
Kozhemyakin, Maxim; Rajasekaran, Karthik; Todorovic, Marko S et al. (2013) Somatostatin type-2 receptor activation inhibits glutamate release and prevents status epilepticus. Neurobiol Dis 54:94-104
Todorovic, Marko S; Cowan, Morgan L; Balint, Corrinee A et al. (2012) Characterization of status epilepticus induced by two organophosphates in rats. Epilepsy Res 101:268-76
Rajasekaran, Karthik; Todorovic, Marko; Kapur, Jaideep (2012) Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus. Ann Neurol 72:91-102
Rusin, Craig G; Johnson, Sarah E; Kapur, Jaideep et al. (2011) Engineering the synchronization of neuron action potentials using global time-delayed feedback stimulation. Phys Rev E Stat Nonlin Soft Matter Phys 84:066202
Rannals, Matthew D; Kapur, Jaideep (2011) Homeostatic strengthening of inhibitory synapses is mediated by the accumulation of GABA(A) receptors. J Neurosci 31:17701-12
Kozhemyakin, Maxim; Rajasekaran, Karthik; Kapur, Jaideep (2010) Central cholinesterase inhibition enhances glutamatergic synaptic transmission. J Neurophysiol 103:1748-57
Joshi, S; Kapur, J (2009) Slow intracellular accumulation of GABA(A) receptor delta subunit is modulated by brain-derived neurotrophic factor. Neuroscience 164:507-19
Rajasekaran, Karthik; Sun, Chengsan; Bertram, Edward H (2009) Altered pharmacology and GABA-A receptor subunit expression in dorsal midline thalamic neurons in limbic epilepsy. Neurobiol Dis 33:119-32
Martin, Brandon S; Kapur, Jaideep (2008) A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by cholinergic stimulation. Epilepsia 49:248-55

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