Determining a threshold sub-acute dose leading to minimal physiological alterations following prolonged exposure to the nerve agent VX in rats

Abstract

VX, a potent inhibitor of cholinesterase (ChE), is considered as one of the most toxic, persistent and least volatile nerve agents. VX is absorbed in various environmental surfaces and is gradually released long after its initial dispersal. Its toxicity is mainly caused by disrupting central and peripheral cholinergic nervous system activity, leading to potential long-term detrimental effects on health. The primary objective of the present study was to assess the threshold VX dose leading to minimal physiological alterations following prolonged VX exposure. Characterization of such a threshold is crucial for dealing with unresolved operative dilemmas such as when it is safe enough to resettle a population that has been evacuated from a VX-contaminated area. Rats, continuously exposed to various doses of VX (0.225-45 µg/kg/day) for 4 weeks via implanted mini-osmotic pumps, showed a dose-dependent and continuous decrease in ChE activity in whole blood, brain and muscles, ranging between 20 and 100%. Exposure to 13.5 µg/kg/day led to a stable low ChE activity level (~ 20%), accompanied by transient and negligible electrocorticogram spectral power transformations, especially in the theta and alpha brain wave frequencies, and a significant decrease in total brain M2 receptor density. These changes were neither accompanied by observable signs of intoxication nor by changes in motor function, circadian rhythm or TSPO level (a reliable marker of brain damage). Following exposure to lower doses of 2.25 and 0.225 µg/kg/day, the only change measured was a reduction in ChE activity of 60 and 20%, respectively. Based on these results, we delineate ChE inhibition as the physiological measure most susceptible to alterations following prolonged VX exposure, and determine for the first time the threshold sub-acute VX dose for minimal physiological effects (up to 20% reduction in ChE activity) in the rat as 0.225 µg/kg/day.

Acetohydroxamic acid salts: mild, simple and effective degradation reagents to counter Novichok nerve agents

“…Our previous results demonstrated the therapeutic value and dermal and systemic safety of one of our AHA salts as a potential “catch-up therapy” against dermal intoxication by VX in live pigs. 31 Combined, the above suggest that DMSO/H 2 O solutions of AHA salts have a high potential to serve as a generic tool for the decontamination of low-volatility CWAs. Specifically, they may be useful for both skin surface decontamination and within-skin “catch-up therapy” (manuscript in preparation).…”

“…33 Such a high ratio should obviously further accelerate the reactions (see the kinetic equations below). Directly aer mixing, the samples were consecutively examined using 31 P NMR spectroscopy to study the reaction's progress and the resulting kinetic data was analysed via integration using the TOPSPIN soware and GraphPad Prism 5 (Fig. 2 and S1-S48 †), to provide half-life times (t 1/2 ) of these reactions, which are summarized in Table 1.…”

“…It should be noted that a much higher ratio is expected to be used in real-life scenarios. For example in our “catch-up therapy” protocol an excess of ∼10 3 of the AHA salt is used, 31 similar to the skin decontamination protocol using RSDL® (Reactive Skin Decontamination Lotion) where a ∼1 : 10 3 ratio is also desirable. 33 Such a high ratio should obviously further accelerate the reactions (see the kinetic equations below).…”

“…30 Moreover, we also demonstrated the therapeutic value and dermal and systemic safety of one of our lead lotions as a “catch-up therapy” against dermal intoxication by VX in live pigs. 31 Decades ago, these types of nucleophiles were already shown to effectively hydrolyze G-agents like sarin. 32 Herein we report our findings regarding the ability of hydroxamate salts to degrade Novichoks in a relevant time frame, which is applicable for both surface, dermal and transdermal detoxification.…”

Effects of the nerve agent VX on hiPSC-derived motor neurons

“…Unfortunately, these therapeutic approaches show insufficient efficacy in some poisonings and long-term, non-cholinergic effects, such as organophosphorus ester-induced chronic neurotoxicity (OPICN) or organophosphorus ester-induced delayed neurotoxicity (OPIDN), as well as dysfunctions at the neuromuscular synapses could not be addressed so far (Abou-Donia 2003 ; Thiermann et al 2010 , 2013 ). As the conduction of clinical trials is unacceptable from an ethical point of view, most of the results were obtained from animal experiments or cells of animal origin in awareness that translation of findings from animal studies to humans is only possible to a limited extent (Thiermann et al 2016 ; Bloch-Shilderman et al 2018 ; Heppner and Fiekers 1992 ; Tenn et al 2012 ). For the further development and improvement of therapeutic strategies, it is crucial to investigate the mechanisms that occur at the human neuromuscular junction upon nerve agent exposure (Thiermann et al 2010 ).…”