title: Catalytic antioxidant AEOL 10150 treatment ameliorates sulfur mustard analog 2-chloroethyl ethyl sulfide-associated cutaneous toxic effects.
abstract: Our previous studies and other published reports on the chemical warfare agent sulfur mustard (SM) and its analog 2-chloroethyl ethyl sulfide (CEES) have indicated a role of oxidative stress in skin injuries caused by these vesicating agents. We examined the effects of the catalytic antioxidant AEOL 10150 in the attenuation of CEES-induced toxicity using our established skin injury models (skin epidermal cells and SKH-1 hairless mice) to validate the role of oxidative stress in the pathophysiology of mustard vesicating agents. Treatment of mouse epidermal JB6 and human HaCaT cells with AEOL 10150 (50μM) 1h post-CEES exposure resulted in significant (p < 0.05) reversal of CEES-induced decreases in both cell viability and DNA synthesis. Similarly, AEOL 10150 treatment 1h after CEES exposure attenuated CEES-induced DNA damage in these cells. Similar AEOL 10150 treatments also caused significant (p < 0.05) reversal of CEES-induced decreases in cell viability in normal human epidermal keratinocytes. Cytoplasmic and mitochondrial reactive oxygen species measurements showed that AEOL 10150 treatment drastically ameliorated the CEES-induced oxidative stress in both JB6 and HaCaT cells. Based on AEOL 10150 pharmacokinetic studies in SKH-1 mouse skin, mice were treated with a topical formulation plus subcutaneous injection (5mg/kg) of AEOL 10150 1h after CEES (4mg/mouse) exposure and every 4h thereafter for 12h. This AEOL 10150 treatment regimen resulted in over 50% (p < 0.05) reversal of CEES-induced skin bi-fold and epidermal thickness, myeloperoxidase activity, and DNA oxidation in mouse skin. Results from this study demonstrate the potential therapeutic efficacy of AEOL 10150 against CEES-mediated cutaneous lesions, supporting AEOL 10150 as a medical countermeasure against SM-induced skin injuries.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado at Denver, Aurora, CO 80045, USA.
authors.forename: Neera
authors.initials: N
authors.lastname: Tewari-Singh
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado at Denver, Aurora, CO 80045, USA.
authors.forename: Swetha
authors.initials: S
authors.lastname: Inturi
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado at Denver, Aurora, CO 80045, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jain
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado at Denver, Aurora, CO 80045, USA.
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.affiliation: Department of Pathology, University of Colorado at Denver, Aurora, CO 80045, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.affiliation: Department of Pediatrics, University of Colorado at Denver, Aurora, CO 80045, USA.
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado at Denver, Aurora, CO 80045, USA. Electronic address: Rajesh.Agarwal@ucdenver.edu.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO 80206, USA. Electronic address: dayb@njhealth.org.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D020552:Comet Assay; D006801:Humans; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008812:Mice, Hairless; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000473:pathology
chemical_list: C472668:AEOL 10150; D000931:Antidotes; D000975:Antioxidants; D002619:Chemical Warfare Agents; D008665:Metalloporphyrins; C031278:2-chloroethyl ethyl sulfide; D009151:Mustard Gas
keywords: Alkylating agents; Antioxidants; Chemical weapons; Free radicals; Medical countermeasure; Oxidative stress; Reactive oxygen species; Skin injury; Vesicating agents