A number of characteristics distinguish TETS and organophosphorus (OPs) cholinesterase inhibitors as credible chemical threat agents. 1) These agents can be easily manufactured on a large scale. 2) They are widely available in some countries even though banned in the US. 3) Exposure to either TETS or OPs dose dependently results in lethality or profound and sustained damage to the brain. In rodents, acute TETS or OP intoxication elicits delayed neuronal injury as evidenced by increased apoptosis and oxidative stress in the CNS that persists for up to several days following exposure. In humans, indivuduals that survive acute TETS or OP intoxication often experience significant brain damage. A limited number of therapeutic agents are available to prevent mortality induced by OP threat agents but these do not sufficiently protect against brain injury. Therapeutic approaches for TETS intoxication are less well known. To address these gaps, Core B will synthesize TETS and an inactive analog to be used as a negative control in mechanistic studies, as well as characterize and validate primary standard stocks of TETS, DFP and parathion. This will enable Projects 1-3 to advance applied therapeutic and mechanistic knowledge on these agents. Furthermore we will synthesize, characterize, test and optimize the pharmacokinetic (PK) properties and CNS penetration of two distinct classes of therapeutic agents, sEH inhibitors and KCa2 channel activators. Overall, the successful realization of the proposed aims in Core B is likely to improve therapeutic approaches for the treatment of acute OP and TETS intoxication by providing novel therapeutics for physicians and emergency first-responders to effectively intervene in cases of human intoxication with these seizurogenic chemical threat agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54NS079202-03
Application #
8730735
Study Section
Special Emphasis Panel (ZRG1-MDCN-J)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
$415,777
Indirect Cost
$143,245
Name
University of California Davis
Department
Type
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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

Showing the most recent 10 out of 83 publications