The unifying goal of the UC Davis CounterACT Center of Excellence is to identify improved medical countermeasures for treating acute intoxication with seizure-inducing chemical threat agents. Research will focus on the organophosphorus (OP) cholinesterase inhibitor diisopropylfluorophosphate (DFP) and the GABA-inhibiting agent tramethylenedisulfotetramine (TETS), which arguably encompass the mechanistic spectrum of seizure inducing chemical threats, with the goal of identifying therapeutic approaches with broad-spectrum efficacy. The specific objectives of the Center are to: (1) identify improved treatments for acute seizures and lethality;and (2) identify therapeutic strategies for mitigating seizure-induced brain damage in patients that survive acute intoxication. This will be accomplished by repositioning marketed drugs and drug combinations for treatment of seizures triggered by chemical threat agents, in parallel with evaluation of new antidotes based on strong preliminary efficacy data. The molecules to be tested for anticonvulsant and neuroprotective efficacy range from compounds approaching readiness for IND enabling studies to early stage chemical probes. In all cases, these efforts in translation of anti-seizure agents are supported by innovative work on diagnostics employing emerging in vivo imaging technologies and analytical chemistry for monitoring pathological effects as well as target engagement and therapeutic efficacy. Additional outcomes from Center research that will benefit the CounterACT community include: (1) a high content in vitro/ex vivo platform for rapid screening of compounds to identify anticonvulsant and neuroprotective potential as well as mechanistically relevant novel drug targets;(2) in vivo models of DFP and TETS-induce seizures for studying neuropathic mechanisms and therapeutic rescue of neurologic sequelae triggered by seizurogenic exposures;(3) innovative in vivo imaging modalities for non-invasive longitudinal monitoring of neurologic damage and response to therapeutic candidates;(4) focused metabolomic profiling to identify biomarkers of seizure damage;and (5) innovative immunoassays for the detection of TETS in biological and environmental matrices. A highly integrated, interdisciplinary (pharmacology, medicinal chemistry, neurotoxicology, analytical chemistry, behavioral neuroscience, imaging, cellular/molecular neuroscience) research team with experience in drug discovery and translational research will work cooperatively and synergistically to achieve the Center's goal of identifying improved medical countermeasures that can be readily deployed during a chemical emergency to stop seizures and mitigate the neurological sequelae of seizures triggered by TETS and OPs.
Current medical countermeasures for acute TETS or OP intoxication can prevent mortality but do not sufficiently protect the CNS from persistent seizures and/or permanent injury. The goal of this research project is to identify improved medical countermeasures that can be readily deployed during a chemical emergency to stop seizures and mitigate the neurological sequelae of seizures triggered by TETS and OPs.
|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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