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Identifying Molecular Targets for the Proconvulsant Activity of TETS

确定 TETS 促惊厥活性的分子靶点

基本信息

批准号：
9905564
负责人：
Pamela J Lein
金额：
$ 18.7万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905564
关键词：
Acute Address Aminobutyric Acids Behavior Behavioral Binding Sites Biological Biophysics Cell Culture Techniques Cell Line Cells Cessation of life Chemicals Chlorides Convulsants Data Dose Electrophysiology (science)Environment Environmental Pollution Exhibits Exposure to Genes Genetic Goals Half-Life Hippocampus (Brain)Human In Vitro Individual Intoxication Larva Lethal Dose 50 Life Maps Mediating Membrane Methods Military Personnel Modeling Molecular Mechanisms of Action Molecular Target Mus Natural Products Neonatal Neurons Orthologous Gene Pattern Pentylenetetrazole Pharmaceutical Preparations Picrotoxin Plants Production Property Recombinants Risk Assessment Rodent Rodenticides Security Seizures Signal Transduction Site Site-Directed Mutagenesis Soil Specificity Status Epilepticus Structure Substance of Abuse Synapses Techniques Testing Toxicology Triazines United States Whole Organism Zebrafish base experimental study extracellular gamma-Aminobutyric Acid ground water in vivo inhibitor/antagonist insight knock-down medical countermeasure molecular modeling molecular site novel patch clamp positive allosteric modulator receptor superior colliculus Corpora quadrigemina tetramethylenedisulfotetramine zebrafish genome

项目摘要

Inhibition of γ-aminobutyric acid type A (GABAA) receptors (GABAAR) is the presumed mechanism of the seizure-inducing activity of the natural product picrotoxin (PTX), the rodenticide tetramethylenedisulfotetramine (TETS) and the high-energy explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). TETS, which has been banned from production worldwide, is still readily available on the black market, and is associated with thousands of human poisonings per year. It is incredibly stable in the environment. RDX is an environmental contaminant found in both groundwater and soil due to its worldwide military and civilian use, and it is an illicit abuse substance. PTX is of toxicological concern, because like TETS and RDX, it is listed as a credible threat agent by the United States Department of Homeland Security. All three compounds can cause seizures that rapidly progress to status epilepticus and death; however, TETS is by far the most potent with a lethal dose of 7 to 10 mg in humans and an LD50 of 0.1 mg/kg in rodents, which makes it roughly ~40x more potent than PTX and ~1000x more potent than RDX. There currently is no approved medical countermeasure for individuals acutely intoxicated with these convulsant chemicals. While some information is available regarding the molecular site of action and the GABAAR subtype selectivity of PTX, practically nothing is known about the molecular mechanism of action of TETS and RDX other than that they are most probably GABAAR inhibitors. We intend to use molecular modeling, whole-cell patch-clamp electrophysiology and gene knockdown techniques in zebrafish to identify the subunit specificity of TETS and RDX interactions with GABAA receptors and to determine whether it differs from that of picrotoxin. Treatment with subtype selective compounds/drugs should allow us to confirm which GABAA receptor subunit combinations are important for the seizure activity of TETS and RDX, and whether they differ from the receptor subunit profile that mediate PTX action. Detailed understanding of the molecular mechanism(s) of action of TETS and RDX will not only provide novel insight as to the biological reasons for the toxicologic differences between these agents, but will also be important for evaluating the validity of “read across” risk assessment approaches for GABAA receptor antagonists, and for developing effective medical countermeasures for terminating SE in intoxicated individuals.

γ-氨基丁酸A型（GABAA）受体（GABAAR）的抑制被认为是其发生的机制