Echis carinatus snake venom metalloprotease-induced toxicities in mice: Therapeutic intervention by a repurposed drug, Tetraethyl thiuram disulfide (Disulfiram).

Autor: Rudresha GV; Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore, Karnataka, India., Urs AP; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America., Manjuprasanna VN; Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore, Karnataka, India., Milan Gowda MD; Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore, Karnataka, India., Jayachandra K; Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore, Karnataka, India., Rajaiah R; Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore, Karnataka, India., Vishwanath BS; Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore, Karnataka, India.; Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore, Karnataka, India.
Jazyk: angličtina
Zdroj: PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2021 Feb 02; Vol. 15 (2), pp. e0008596. Date of Electronic Publication: 2021 Feb 02 (Print Publication: 2021).
DOI: 10.1371/journal.pntd.0008596
Abstrakt: Echis carinatus (EC) is known as saw-scaled viper and it is endemic to the Indian subcontinent. Envenoming by EC represents a major cause of snakebite mortality and morbidity in the Indian subcontinent. Zinc (Zn++) dependent snake venom metalloproteases (SVMPs) present in Echis carinatus venom (ECV) is well known to cause systemic hemorrhage and coagulopathy in experimental animals. An earlier report has shown that ECV activates neutrophils and releases neutrophil extracellular traps (NETs) that blocks blood vessels leading to severe tissue necrosis. However, the direct involvement of SVMPs in the release of NETs is not clear. Here, we investigated the direct involvement of EC SVMPs in observed pathological symptoms in a preclinical setup using specific Zn++ metal chelator, Tetraethyl thiuram disulfide (TTD)/disulfiram. TTD potently antagonizes the activity of SVMPs-mediated ECM protein degradation in vitro and skin hemorrhage in mice. In addition, TTD protected mice from ECV-induced footpad tissue necrosis by reduced expression of citrullinated H3 (citH3) and myeloperoxidase (MPO) in footpad tissue. TTD also neutralized ECV-induced systemic hemorrhage and conferred protection against lethality in mice. Moreover, TTD inhibited ECV-induced NETosis in human neutrophils and decreased the expression of peptidyl arginine deiminase (PAD) 4, citH3, MPO, and p-ERK. Further, we demonstrated that ECV-induced NETosis and tissue necrosis are mediated via PAR-1-ERK axis. Overall, our results provide an insight into SVMPs-induced toxicities and the promising protective efficacy of TTD can be extrapolated to treat severe tissue necrosis complementing anti-snake venom (ASV).
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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