Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals

Abstract

The continuing horrors of military conflicts and terrorism often involve the use of chemical warfare agents (CWAs) and toxic industrial chemicals (TICs). Many CWA and TIC exposures are difficult to treat due to the danger they pose to first responders and their rapid onset that can produce death shortly after exposure. While the specific mechanism(s) of toxicity of these agents are diverse, many are associated either directly or indirectly with increased oxidative stress in affected tissues. This has led to the exploration of various antioxidants as potential medical countermeasures for CWA/TIC exposures. Studies have been performed across a wide array of agents, model organisms, exposure systems, and antioxidants, looking at an almost equally diverse set of endpoints. Attempts at treating CWAs/TICs with antioxidants have met with mixed results, ranging from no effect to nearly complete protection. The aim of this commentary is to summarize the literature in each category for evidence of oxidative stress and antioxidant efficacy against CWAs and TICs. While there is great disparity in the data concerning methods, models, and remedies, the outlook on antioxidants as medical countermeasures for CWA/TIC management appears promising.

Mustard vesicating agent–induced toxicity in the skin tissue and silibinin as a potential countermeasure

“…The reported molecular events in mustard vesicating agent–induced skin injury largely involve oxidative stress and possible nitrosative stress that can lead to lipid peroxidation, protein oxidation, and DNA damage, which cause cell death and inflammation . Consistent with this, the agents that possess antioxidant and nitric oxide synthase inhibitor properties, such as N ‐acetyl cysteine, superoxide dismutase, glutathione, melatonin, trolox, quercetin, and catalytic antioxidant metalloproteinases, have displayed varying extents of protection against SM‐induced cutaneous effects . Additionally, owing to the fact that mustard vesicants can activate multiple signaling pathways and involve direct DNA damage and inflammatory response, pleiotropic agents or a combination of agents that can target various pathways are likely to be more effective against vesicant‐related skin injury.…”

“…19 Consistent with this, the agents that possess antioxidant and nitric oxide synthase inhibitor properties, such as N-acetyl cysteine, superoxide dismutase, glutathione, melatonin, trolox, quercetin, and catalytic antioxidant metalloproteinases, have displayed varying extents of protection against SMinduced cutaneous effects. 19,22,53,60,61 Additionally, owing to the fact that mustard vesicants can activate multiple signaling pathways and involve direct DNA damage and inflammatory response, pleiotropic agents or a combination of agents that can target various pathways are likely to be more effective against vesicant-related skin injury. On this basis, the therapeutic efficacy of a small-molecule natural flavanone silibinin (3R)-3,5,7-trihydroxy-2-[(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydrobenzo[b] [1,4]dioxin-6-yl]chroman-4-one) has been our major focus in ameliorating CEES-and NM-induced skin injury in established in vitro skin cells and SKH-1 hairless mouse skin injury models.…”

“…Based on some insights into the mechanism of action of vesicating agents so far, many approaches to treat skin injuries have been reported. These treatments include antioxidants and anti‐inflammatory agents, nitric oxide synthase (iNOS) inhibitors, poly (ADP‐ribose) polymerase (PARP) and matrix metalloprotease inhibitors, and regulators of DNA damage repair . However, regardless of extensive research attempts, a comprehensive understanding of the molecular mechanisms and signaling pathways involved in SM‐induced skin injury in an efficient animal model is still lacking.…”

“…These treatments include antioxidants and anti-inflammatory agents, nitric oxide synthase (iNOS) inhibitors, poly (ADP-ribose) polymerase (PARP) and matrix metalloprotease inhibitors, and regulators of DNA damage repair. [17][18][19][20][21][22][23][24] However, regardless of extensive research attempts, a comprehensive understanding of the molecular mechanisms and signaling pathways involved in SM-induced skin injury in an efficient animal model is still lacking. This has been a major caveat in developing effective and targeted medical treatments to rescue vesicant-induced skin injuries, and, hence, an approved treatment against mustard vesicating agent-induced skin injury is not available.…”

N-Acetylcysteine as a treatment for sulphur mustard poisoning

“…Sulphur mustard is a highly reactive bifunctional alkylating agent, and as such is able to react rapidly with a broad range of cellular constituents and molecular targets. This has resulted in numerous hypotheses being proposed and it has been well recognized as causing the production of reactive nitrogen and oxygen species [ [31] , [32] , [33] , [34] , [35] ], as well as disturbing an array of molecular pathways including; intracellular calcium, anion and pH regulation, poly(ADP-ribose polymerase (PARP) activation, DNA damage and repair, apoptosis induction, inflammation, membrane bound receptors, signalling molecules and extracellular matrices [ 2 , 3 , 11 , 14 , 15 , [36] , [37] , [38] , [39] , [40] , [41] , [42] ]. However, the pathways that ultimately lead to toxicity remain elusive and investigators continue their efforts to define the progression of biochemical/molecular events from exposure to the ultimate expression of overt toxicity.…”