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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
3U54NS079202-02S1
Application #
8851844
Study Section
Special Emphasis Panel (ZRG1-MDCN-J (54))
Program Officer
Jett, David A
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2014
Total Cost
$77,127
Indirect Cost
$27,327
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Hampe, Alexander E; Li, Zidong; Sethi, Sunjay et al. (2018) A Microfluidic Platform to Study Astrocyte Adhesion on Nanoporous Gold Thin Films. Nanomaterials (Basel) 8:
Hobson, Brad A; Rowland, Douglas J; Supasai, Suangsuda et al. (2018) A magnetic resonance imaging study of early brain injury in a rat model of acute DFP intoxication. Neurotoxicology 66:170-178
Moeller, Benjamin; Espelien, Brenna; Weber, Waylon et al. (2018) The pharmacokinetics of ketamine following intramuscular injection to F344 rats. Drug Test Anal :
Pressly, Brandon; Nguyen, Hai M; Wulff, Heike (2018) GABAA receptor subtype selectivity of the proconvulsant rodenticide TETS. Arch Toxicol 92:833-844
Dhir, Ashish; Rogawski, Michael A (2018) Determination of minimal steady-state plasma level of diazepam causing seizure threshold elevation in rats. Epilepsia 59:935-944
Tu, Ranran; Armstrong, Jillian; Lee, Kin Sing Stephen et al. (2018) Soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia. Sci Rep 8:5279
Nik, Atefeh Mousavi; Pressly, Brandon; Singh, Vikrant et al. (2017) Rapid Throughput Analysis of GABAA Receptor Subtype Modulators and Blockers Using DiSBAC1(3) Membrane Potential Red Dye. Mol Pharmacol 92:88-99
Zhou, Yong; Liu, Tian; Duan, Jia-Xi et al. (2017) Soluble Epoxide Hydrolase Inhibitor Attenuates Lipopolysaccharide-Induced Acute Lung Injury and Improves Survival in Mice. Shock 47:638-645
Barnych, Bogdan; Vasylieva, Natalia; Joseph, Tom et al. (2017) Development of Tetramethylenedisulfotetramine (TETS) Hapten Library: Synthesis, Electrophysiological Studies, and Immune Response in Rabbits. Chemistry 23:8466-8472
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:

Showing the most recent 10 out of 85 publications