The overall goal of Project 2 is to identify effective therapeutic strategies for mitigating the delayed neurological sequelae of acute intoxication with the GABA antagonist tetramethylenedisulfotetramine (TETS) or organophosphorus (OP) cholinesterase inhibitors. In the context of accidental or terrorist release of these nerve poisons, it is likely that emergency medical support will not be available within the first 30-60 min after seizures begin, at which time the neuropathological processes that promote brain damage and ultimately persistent functional deficits have been set in motion. The specific objectives of Project 2 are to: (1) develop in vivo rodent models for assessing persistent neurological damage subsequent to seizures induced by TETS or the OPs diisopropylfluorophosphate (DFP) and parathion, with a focus on developing in vivo imaging modalities that can be used in preclinical and clinical studies to longitudinally monitor progressive neurological effects of intoxication and the efficacy of candidate therapeutics;and (2) identify effective therapeutic strategies for mitigating neurological damage following acute intoxication with these chemical threat agents. Project 2 will test the hypothesis that compounds that are more effective post-exposure anticonvulsants than diazepam will be more effective in mitigating the neurological damage following TETS- and OP-induced seizures than current medical countermeasures and that neuroprotection will be significantly enhanced by combining anticonvulsants with therapeutics that attenuate neuroinflammation and/or stabilize Ca channels. Neurological damage will be assessed up to 28 days post-exposure using: (1) histological and biochemical indices of neuropathology, inflammation/oxidative stress (Core A) and dysregulated calcium signaling (Project 3);(2) behavioral testing of cognitive and emotional behavior and telemetry EEG video monitoring of spontaneous recurrent seizures (conducted in collaboration with Project 1);and (3) in vivo imaging of neuroinflammation by positron emission tomography (PET) and functional connectivity by resting state functional magnetic resonance imaging (fcMRI). Pharmacological tools will include therapeutics already approved for use in humans or currently undergoing clinical trials (referred to as Tier 1 candidates) to facilitate translation of positive findings in rodent models to human studies as well as novel compounds identified in mechanistic screening studies in Core B and Project 3 (referred to as Tier 2 candidates). Anticonvulsants tested in Project 2 will include diazepam and lead compounds identified by Project 1 to terminate TETS- and DFP-induced seizures when administered at times post-exposure when diazepam has lost efficacy. Candidate lead compounds include AMPA receptor (AMPA-R) antagonists. Pharmacological tools for attenuating neuroinflammation and/or stabilizing Ca2+ channels will be the most promising compounds identified in mechanistic screening studies in Core B and Project 3. Lead candidates include the ryanodine receptor (RyR) antagonist dantrolene (Tier 1 therapeutic), inhibitors of soluble epoxide hydrolase (sEH), phosphodiesterase (PDE) and cyclooxygenase (COX) alone or in combination (Tier 2 therapeutics), and the KCa3.1 inhibitor TRAM-34 (Tier 2 therapeutic). Dosing paradigms will be informed by preliminary pharmacokinetic studies in Core B;optimization studies performed in Project 3 to evaluate timing, dose, and drug combinations;and determination by Core A of ADME and brain levels of therapeutic candidates and toxicants. Across all Aims, study design and data analyses will be developed in consultation with Core C. The most effective therapeutic strategies for enhancing neuroprotection in the DFP model will be assessed for neuroprotective efficacy against parathion and live nerve agent (soman). By comparing the efficacy of novel therapeutic approaches across models of acute TETS and OP intoxication, we hope to identify a convergent therapeutic strategy for protecting against diverse classes of chemical threat agents.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZRG1-MDCN-J)
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University of California Davis
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Lee, Kin Sing Stephen; Henriksen, Niel M; Ng, Connie J et al. (2017) Probing the orientation of inhibitor and epoxy-eicosatrienoic acid binding in the active site of soluble epoxide hydrolase. Arch Biochem Biophys 613:1-11
Wagner, Karen; Gilda, Jennifer; Yang, Jun et al. (2017) Soluble epoxide hydrolase inhibition alleviates neuropathy in Akita (Ins2 Akita) mice. Behav Brain Res 326:69-76
Hwang, Sung Hee; Wagner, Karen; Xu, Jian et al. (2017) Chemical synthesis and biological evaluation of ?-hydroxy polyunsaturated fatty acids. Bioorg Med Chem Lett 27:620-625
Nguyen, Hai M; Singh, Vikrant; Pressly, Brandon et al. (2017) Structural Insights into the Atomistic Mechanisms of Action of Small Molecule Inhibitors Targeting the KCa3.1 Channel Pore. Mol Pharmacol 91:392-402
Wagner, K; Lee, K S S; Yang, J et al. (2017) Epoxy fatty acids mediate analgesia in murine diabetic neuropathy. Eur J Pain 21:456-465
Cao, Zhengyu; Xu, Jian; Hulsizer, Susan et al. (2017) Influence of tetramethylenedisulfotetramine on synchronous calcium oscillations at distinct developmental stages of hippocampal neuronal cultures. Neurotoxicology 58:11-22
Chapman, Christopher A R; Wang, Ling; Chen, Hao et al. (2017) Nanoporous Gold Biointerfaces: Modifying Nanostructure to Control Neural Cell Coverage and Enhance Electrophysiological Recording Performance. Adv Funct Mater 27:
Hu, Pingping; Wu, Xiaojuan; Khandelwal, Alok R et al. (2017) Endothelial Nox4-based NADPH oxidase regulates atherosclerosis via soluble epoxide hydrolase. Biochim Biophys Acta 1863:1382-1391
Pressly, Brandon; Nguyen, Hai M; Wulff, Heike (2017) GABAA receptor subtype selectivity of the proconvulsant rodenticide TETS. Arch Toxicol :
Hobson, Brad A; Sisó, Sílvia; Rowland, Douglas J et al. (2017) From the Cover: MagneticResonance Imaging Reveals Progressive Brain Injury in Rats Acutely Intoxicated With Diisopropylfluorophosphate. Toxicol Sci 157:342-353

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