Catalytic antioxidant AEOL 10150 treatment ameliorates sulfur mustard analog 2-chloroethyl ethyl sulfide-associated cutaneous toxic effects

Tewari‐Singh, Neera; Inturi, Swetha; Jain, Anil K.; Agarwal, Chapla; Orlicky, David J.; White, Carl W.; Agarwal, Rajesh; Day, Brian J.

doi:10.1016/j.freeradbiomed.2014.04.022

Cited by 37 publications

(40 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results are also in agreement with previous demonstration of efficacy of this compound against expression of inflammatory markers in a rat model of 2-chloroethyl ethyl sulfide (CEES)- induced lung injury (O’Neill et al, 2010), a mouse model of stroke (Bowler et al, 2002) and mouse model of chlorine-induced lung injury (McGovern et al, 2011). Additionally, these studies also demonstrated the efficacy of the antioxidant in inhibiting oxidative stress (Castello et al, 2008; O’Neill et al, 2010; Tewari-Singh et al, 2014). We confirmed its antioxidant action in the pilocarpine model using the tissue samples from the same rats that were utilized for the multiplex cytokine analysis, indicating that the effect of the compound on inflammation is most likely due to its effect on oxidative stress, confirming target engagement by the drug.…”

Section: Discussionmentioning

confidence: 83%

Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation

McElroy

Liang

Day

et al. 2017

Experimental Neurology

Self Cite

View full text Add to dashboard Cite

Inflammation has been identified as an important mediator of seizures and epileptogenesis. Understanding the mechanisms underlying seizure-induced neuroinflammation could lead to the development of novel therapies for the epilepsies. Reactive oxygen species (ROS) are recognized as mediators of seizure-induced neuronal damage and are known to increase in models of epilepsies. ROS are also known to contribute to inflammation in several disease states. We hypothesized that ROS are key modulators of neuroinflammation i.e. pro-inflammatory cytokine production and microglial activation in acquired epilepsy. The role of ROS in modulating seizure-induced neuroinflammation was investigated in the pilocarpine model of temporal lobe epilepsy (TLE). Pilocarpine-induced status epilepticus (SE) resulted in a time-dependent increase in pro-inflammatory cytokine production in the hippocampus and piriform cortex. Scavenging ROS with a small-molecule catalytic antioxidant decreased SE-induced pro-inflammatory cytokine production and microglial activation, suggesting that ROS contribute to SE-induced neuroinflammation. Scavenging ROS also attenuated phosphorylation of ribosomal protein S6, the downstream target of the mammalian target of rapamycin (mTOR) pathway indicating that this pathway might provide one mechanistic link between SE-induced ROS production and inflammation. Together, these results demonstrate that ROS contribute to SE-induced cytokine production and antioxidant treatment may offer a novel approach to control neuroinflammation in epilepsy.

show abstract

Section: Discussionmentioning

confidence: 83%

Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation

McElroy

Liang

Day

et al. 2017

Experimental Neurology

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, one needs to keep in mind that the CEES toxicity depends on specific conditions of the treatment protocol. The studies of CEES induced cytotoxicity in HaCaT cells reported LC50 values differing by at least one order of magnitude within a range of 0.25 to 2 mM depending on treatment time and conditions applied (Paromov et al, 2011a,b;Tewari Singh et al, 2010, 2014a.…”

Section: Mustards Exhibit Substance Specific Cytotoxicity Profilesmentioning

confidence: 99%

Sulfur and nitrogen mustards induce characteristic poly(ADP-ribosyl)ation responses in HaCaT keratinocytes with distinctive cellular consequences

et al. 2016

View full text Add to dashboard Cite

Letters ; 244 (2016). -S. 56-71 https://dx.doi.org/10.1016/j.toxlet.2015In particular, we recorded substance specific as well as dose and time dependent PARylation responses using independent bioanalytical methods based on single cell immuno fluorescence microscopy and quantitative isotope dilution mass spectrometry. Furthermore, we analyzed if and how PARylation contributes to mustard induced toxicity by treating HaCaT cells with CEES, SM, and HN2 in combination with the clinically relevant PARP inhibitor ABT888. As evaluated by a novel immunofluorescence based protocol for the detection of N7 ETE guanine DNA adducts, the excision rate of CEES induced DNA adducts was not affected by PARP inhibition. Furthermore, while CEES induced moderate changes in cellular NAD + levels, annexin V/PI flow cytometry analysis revealed that these changes did not affect CEES induced short term cytotoxicity 24 h after treatment. In contrast, PARP inhibition impaired cell proliferation and clonogenic survival, and potentiated micronuclei formation of HaCaT cells upon CEES treatment. Similarly, PARP inhibition affected clonogenic survival of cells treated with bi functional mustards such as SM and HN2.In conclusion, we demonstrate that PARylation plays a functional role in mustard induced cellular stress response with substance specific differences. Since PARP inhibitors exhibit therapeutic potential to treat SM related pathologies and to sensitize cancer cells for mustard based chemotherapy, potential long term effects of PARP inhibition on genomic stability and carcinogenesis should be carefully considered when pursuing such a strategy.

show abstract

“…Catalytic antioxidants can scavenge multiple reactive oxygen and nitrogen species without being consumed in the reaction (Day, 2004). This antioxidant has shown promising effects in other studies of SM induced toxicity in both in vitro and in vivo models (Gould et al, 2009;O'Neill et al, 2010O'Neill et al, , 2011Tewari-Singh et al, 2014). This catalytic antioxidant has also displayed therapeutic benefits in other models of lung injury such as exposure to fractionated radiation and chlorine gas inhalation (McGovern et al, 2011;Rabbani et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…AEOL 10150 is a metalloporphyrin class of catalytic antioxidants that has shown promising therapeutic potential for suppressing oxidative stress in relevant SM analog, 2-chloroethyl ethyl sulfide (CEES) models (Gould et al, 2009;O'Neill et al, 2010O'Neill et al, , 2011Tewari-Singh et al, 2014). The aim of this study is to characterize the efficacy of this catalytic antioxidant in improving survival by attenuating the progression of oxidative stress, inflammation, and injury following SM inhalation.…”

mentioning

confidence: 99%

From the Cover: Catalytic Antioxidant Rescue of Inhaled Sulfur Mustard Toxicity

et al. 2016

Self Cite

View full text Add to dashboard Cite

Sulfur mustard (bis 2-chloroethyl ethyl sulfide, SM) is a powerful bi-functional vesicating chemical warfare agent. SM tissue injury is partially mediated by the overproduction of reactive oxygen species resulting in oxidative stress. We hypothesized that using a catalytic antioxidant (AEOL 10150) to alleviate oxidative stress and secondary inflammation following exposure to SM would attenuate the toxic effects of SM inhalation. Adult male rats were intubated and exposed to SM (1.4 mg/kg), a dose that produces an LD 50 at approximately 24 h. Rats were randomized and treated via subcutaneous injection with either sterile PBS or AEOL 10150 (5 mg/kg, sc, every 4 h) beginning 1 h post-SM exposure. Rats were euthanized between 6 and 48 h after exposure to SM and survival and markers of injury were determined. Catalytic antioxidant treatment improved survival after SM inhalation in a dose-dependent manner, up to 52% over SM PBS at 48 h post-exposure. This improvement was sustained for at least 72 h after SM exposure when treatments were stopped after 48 h. Non-invasive monitoring throughout the duration of the studies also revealed blood oxygen saturations were improved by 10% and clinical scores were reduced by 57% after SM exposure in the catalytic antioxidant treatment group. Tissue analysis showed catalytic antioxidant therapy was able to decrease airway cast formation by 69% at 48 h post-exposure. To investigate antioxidant induced changes at the peak of injury, several biomarkers of oxidative stress and inflammation were evaluated at 24 h post-exposure. AEOL 10150 attenuated SM-mediated lung lipid oxidation, nitrosative stress and many proinflammatory cytokines. The findings indicate that catalytic antioxidants may be useful medical countermeasure against inhaled SM exposure.Key words: sulfur mustard; chemical weapons; antioxidant.Sulfur mustard (SM) is a chemical warfare agent possessing strong alkylating properties that induces inflammation and tissue necrosis. SM exposure produces delayed and highly incapacitating injuries that can be lethal (Anderson, 2015). SM was used during World War I and is still maintained in the chemical weapons arsenals of several countries (Kehe and Szinicz, 2005). A specific and effective antidote is not available for use after SM exposure despite research conducted for nearly 100 years (Kehe and Szinicz, 2005). The population most at risk for exposure to SM is comprised of soldiers and individuals working or living near storage depots, but SM is also considered to be a potential terrorist threat due to its low cost of production and simple synthesis.Sulfur mustard (SM) vapor adversely affects the skin, eyes, and the respiratory tract. The respiratory tract is highly

show abstract

Catalytic antioxidant AEOL 10150 treatment ameliorates sulfur mustard analog 2-chloroethyl ethyl sulfide-associated cutaneous toxic effects

Cited by 37 publications

References 35 publications

Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation

Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation

Sulfur and nitrogen mustards induce characteristic poly(ADP-ribosyl)ation responses in HaCaT keratinocytes with distinctive cellular consequences

From the Cover: Catalytic Antioxidant Rescue of Inhaled Sulfur Mustard Toxicity

Contact Info

Product

Resources

About