Combination of Ebselen and Hydrocortisone Substantially Reduces Nitrogen Mustard-induced Cutaneous Injury

Overview

Journal Curr Res Toxicol

Specialty Biology

Date 2021 Nov 22

PMID 34806038

Citations 2

Authors

Hemanta C Rao Tumu

Benedette J Cuffari

Blase Billack

Affiliations

Soon will be listed here.

Abstract

The purpose of the present study was to investigate the vesicant countermeasure effects of hydrocortisone (HC) and ebselen (EB-1), administered as monotherapy or as a combination treatment. The mouse ear vesicant model (MEVM) was utilized and test doses of HC (0.016, 0.023, 0.031, 0.047, 0.063, 0.125 or 0.250 mg/ear), EB-1 (0.125, 0.187, 0.250, 0.375 or 0.500 mg/ear) or the combination of HC + EB-1 were topically applied at 15 min, 4 h and 8 h after nitrogen mustard exposure. Ear punch biopsies were obtained 24 h after mechlorethamine (HN2) exposure. Compared to control ears, ear tissues exposed topically to HN2 (0.500 µmol/ear) presented with an increase in ear thickness, vesication, TUNEL fluorescence and expression of matrix metalloproteinase 9 (MMP-9) and inducible nitric oxide synthase (iNOS). In contrast, HN2 exposed ears treated topically with EB-1 showed a significant decrease in morphometric thickness and vesication vs. HN2 alone. Ear tissues exposed to HN2 and then treated with HC also demonstrated reductions in morphometric thickness and vesication. Combination treatment of HC + EB-1 was found to be the most effective at reducing HN2-induced ear edema and vesication. The combination also dramatically decreased HN2-mediated cutaneous expression of iNOS and MMP-9 and decreased HN2-induced TUNEL staining. Taken together, our study demonstrates that the combination of HC + EB-1 is an efficacious countermeasure to HN2.

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References

Shakarjian M, Bhatt P, Gordon M, Chang Y, Casbohm S, Rudge T . Preferential expression of matrix metalloproteinase-9 in mouse skin after sulfur mustard exposure. J Appl Toxicol. 2006; 26(3):239-46. DOI: 10.1002/jat.1134. View

Aras M, Altas M, Meydan S, Nacar E, Karcioglu M, Ulutas K . Effects of ebselen on ischemia/reperfusion injury in rat brain. Int J Neurosci. 2014; 124(10):771-6. DOI: 10.3109/00207454.2013.879581. View

Hollebeeck S, Raas T, Piront N, Schneider Y, Toussaint O, Larondelle Y . Dimethyl sulfoxide (DMSO) attenuates the inflammatory response in the in vitro intestinal Caco-2 cell model. Toxicol Lett. 2011; 206(3):268-75. DOI: 10.1016/j.toxlet.2011.08.010. View

Kumar D, Tewari-Singh N, Agarwal C, Jain A, Inturi S, Kant R . Nitrogen mustard exposure of murine skin induces DNA damage, oxidative stress and activation of MAPK/Akt-AP1 pathway leading to induction of inflammatory and proteolytic mediators. Toxicol Lett. 2015; 235(3):161-71. PMC: 4430414. DOI: 10.1016/j.toxlet.2015.04.006. View

Kanoh M, Takemura G, Misao J, Hayakawa Y, Aoyama T, Nishigaki K . Significance of myocytes with positive DNA in situ nick end-labeling (TUNEL) in hearts with dilated cardiomyopathy: not apoptosis but DNA repair. Circulation. 1999; 99(21):2757-64. DOI: 10.1161/01.cir.99.21.2757. View

Chan G, Hardej D, Santoro M, Lau-Cam C, Billack B . Evaluation of the antimicrobial activity of ebselen: role of the yeast plasma membrane H+-ATPase. J Biochem Mol Toxicol. 2007; 21(5):252-64. DOI: 10.1002/jbt.20189. View

Malone-Povolny M, Maloney S, Schoenfisch M . Nitric Oxide Therapy for Diabetic Wound Healing. Adv Healthc Mater. 2019; 8(12):e1801210. PMC: 6774257. DOI: 10.1002/adhm.201801210. View

Pino M, Billack B . Reduction of vesicant toxicity by butylated hydroxyanisole in A-431 skin cells. Cutan Ocul Toxicol. 2008; 27(3):161-72. DOI: 10.1080/15569520802092070. View

Kil J, Harruff E, Longenecker R . Development of ebselen for the treatment of sensorineural hearing loss and tinnitus. Hear Res. 2021; 413:108209. DOI: 10.1016/j.heares.2021.108209. View

10.

Young S, Fabio K, Huang M, Saxena J, Harman M, Guillon C . Investigation of anticholinergic and non-steroidal anti-inflammatory prodrugs which reduce chemically induced skin inflammation. J Appl Toxicol. 2011; 32(2):135-41. PMC: 3770525. DOI: 10.1002/jat.1645. View

11.

Casillas R, Kiser R, Truxall J, Singer A, Shumaker S, Niemuth N . Therapeutic approaches to dermatotoxicity by sulfur mustard. I. Modulaton of sulfur mustard-induced cutaneous injury in the mouse ear vesicant model. J Appl Toxicol. 2001; 20 Suppl 1:S145-51. DOI: 10.1002/1099-1263(200012)20:1+<::aid-jat665>3.0.co;2-j. View

12.

Orie N, Warren A, Basaric J, Lau-Cam C, Pietka-Ottlik M, Mlochowski J . In vitro assessment of the growth and plasma membrane H -ATPase inhibitory activity of ebselen and structurally related selenium- and sulfur-containing compounds in Candida albicans. J Biochem Mol Toxicol. 2017; 31(6). DOI: 10.1002/jbt.21892. View

13.

Herrera C, Escalante T, Rucavado A, Fox J, Gutierrez J . Metalloproteinases in disease: identification of biomarkers of tissue damage through proteomics. Expert Rev Proteomics. 2018; 15(12):967-982. DOI: 10.1080/14789450.2018.1538800. View

14.

Tewari-Singh N, Agarwal R . Mustard vesicating agent-induced toxicity in the skin tissue and silibinin as a potential countermeasure. Ann N Y Acad Sci. 2016; 1374(1):184-92. PMC: 4940265. DOI: 10.1111/nyas.13099. View

15.

Tumu H, Cuffari B, Pino M, Palus J, Pietka-Ottlik M, Billack B . Ebselen oxide attenuates mechlorethamine dermatotoxicity in the mouse ear vesicant model. Drug Chem Toxicol. 2018; 43(4):335-346. DOI: 10.1080/01480545.2018.1488858. View

16.

Ener R, Meglathery S, Styler M . Extravasation of systemic hemato-oncological therapies. Ann Oncol. 2004; 15(6):858-62. DOI: 10.1093/annonc/mdh214. View

17.

Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T . Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group. Stroke. 1998; 29(1):12-7. DOI: 10.1161/01.str.29.1.12. View

18.

Ansari B, Coates P, Greenstein B, Hall P . In situ end-labelling detects DNA strand breaks in apoptosis and other physiological and pathological states. J Pathol. 1993; 170(1):1-8. DOI: 10.1002/path.1711700102. View

19.

Wormser U, Brodsky B, Proscura E, Foley J, Jones T, Nyska A . Involvement of tumor necrosis factor-alpha in sulfur mustard-induced skin lesion; effect of topical iodine. Arch Toxicol. 2005; 79(11):660-70. DOI: 10.1007/s00204-005-0681-5. View

20.

Wormser U, Brodsky B, Reich R . Topical treatment with povidone iodine reduces nitrogen mustard-induced skin collagenolytic activity. Arch Toxicol. 2002; 76(2):119-21. DOI: 10.1007/s00204-001-0307-5. View