Discovery of treatment for nerve agents targeting a new metabolic pathway.

The inhibition of acetylcholinesterase is regarded as the primary toxic mechanism of action for chemical warfare agents. Recently, there have been numerous reports suggesting that metabolic processes could significantly contribute to toxicity. As such, we applied a multi-omics pipeline to generate a detailed cascade of molecular events temporally occurring in guinea pigs exposed to VX.

On-substrate Enzymatic Reaction to Determine Acetylcholinesterase Activity in Whole Blood by Paper Spray Mass Spectrometry.

Currently, all assays measuring acetylcholinesterase (AChE) activity following a suspected nerve agent exposure leverage methodologies that fail to identify the agent. This limits the overall effectiveness and ability to administer proper countermeasures. As such, there is an urgent need to identify novel, rapid, and more comprehensive approaches to establish AChE activity, including identification of the toxicant.

Activity Based Protein Profiling Leads to Identification of Novel Protein Targets for Nerve Agent VX.

Organophosphorus (OP) nerve agents continue to be a threat at home and abroad during the war against terrorism. Human exposure to nerve agents such as VX results in a cascade of toxic effects relative to the exposure level including ocular miosis, excessive secretions, convulsions, seizures, and death. The primary mechanism behind these overt symptoms is the disruption of cholinergic pathways.

Phosphoproteomic analysis reveals compensatory effects in the piriform cortex of VX nerve agent exposed rats.

To gain insights into the toxicity induced by the nerve agent VX, an MS-based phosphoproteomic analysis was carried out on the piriform cortex region of brains from VX-treated rats. Using isobaric tag based TMT labeling followed by titanium dioxide enrichment strategy, we identified 9975 unique phosphosites derived from 3287 phosphoproteins. Temporal changes in the phosphorylation status of peptides were observed over a time period of 24 h in rats exposed to a 1× LD50, intravenous (i.

Determination of threshold adverse effect doses of percutaneous VX exposure in African green monkeys.

Percutaneous exposure to the chemical warfare nerve agent VX was evaluated in African green monkeys (n=9). Doses of VX (7.5-100 μg/kg) were applied to the skin for 60 min and residual agent was quantified (before decontamination) to estimate the absorbed dose.

Evaluation of miosis, behavior and cholinesterase inhibition from low-level, whole-body vapor exposure to soman in African green monkeys (Chlorocebus sabeus).

Background: Relatively little is known about the effects of very low-level exposures to nerve agents where few signs or symptoms are present.

Methods: African green monkeys (Chlorocebus sabeus) (n = 8) were exposed for 10 min, whole-body, to a single concentration of soman (0.028-0.

Assessment of low level whole-body soman vapor exposure in rats.

We evaluated biochemical and behavioral effects of single, low-level exposures to the chemical warfare nerve agent soman (GD). Male Sprague-Dawley rats were trained on a variable-interval, 56-sec schedule of food reinforcement (VI56). The schedule specifies that a single lever press, following an average interval of 56 s, produces food reinforcement (i.

Behavioral evaluation of rats following low-level inhalation exposure to sarin.

We evaluated the effects, in rats, of single and multiple low-level inhalation exposures to sarin. Rats were trained on a variable-interval, 56 s (VI56) schedule of food reinforcement and then exposed to sarin vapor (1.7-4.

Determination of miosis threshold from whole-body vapor exposure to sarin in African green monkeys.

We determined the threshold concentration of sarin vapor exposure producing miosis in African green monkeys (Chlorocebus aethiops). Monkeys (n=8) were exposed to a single concentration of sarin (0.069-0.

Behavioral and biochemical evaluation of sub-lethal inhalation exposure to VX in rats.

We evaluated the effects of low-level inhalation exposures (whole body, 60min duration) to the chemical warfare nerve agent VX (0.016, 0.15, 0.

Effects of low-level inhalation exposure to cyclosarin on learned behaviors in Sprague-Dawley rats.

Behavioral and biochemical effects of low-level whole-body inhalation exposure to the chemical warfare nerve agent cyclosarin (GF) were evaluated. Sprague-Dawley rats were first trained on a variable-interval, 56-s (VI56) schedule of food reinforcement. The VI56 schedule specifies that a single lever press, following an average interval of 56 s, produces food reinforcement (i.

Comparison of low-level sarin and cyclosarin vapor exposure on pupil size of the Gottingen minipig: effects of exposure concentration and duration.

The current studies estimated effective (miosis) concentrations of the nerve agents' sarin (GB) and cyclosarin (GF) as a function of exposure duration in the Gottingen minipig and determined dependency of the median effective dosage (ECT50) over time. Male and female Gottingen minipigs were exposed to various concentrations of vapor GB or GF for 10, 60, or 180 min. Infrared images of the pig's pupil before, during, and after nerve agent exposure were captured digitally and pupil area was quantified.