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

Autor: Vaddarahally N. Manjuprasanna, Amog P. Urs, Mallanayakanakatte D. Milan Gowda, Gotravalli V. Rudresha, Rajesh Rajaiah, Krishnegowda Jayachandra, Bannikuppe S. Vishwanath
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Necrosis
Neutrophils
Hydrolases
RC955-962
Snake Bites
Venom
Pharmacology
Toxicology
Pathology and Laboratory Medicine
Vascular Medicine
Biochemistry
Extracellular Traps
White Blood Cells
Mice
Medical Conditions
Animal Cells
Arctic medicine. Tropical medicine
Disulfiram
Medicine and Health Sciences
Viperidae
Toxins
Snakebite
Deoxyribonucleases
biology
Antivenins
Eukaryota
Snakes
Squamates
Enzymes
Infectious Diseases
Snake venom
Myeloperoxidase
Toxicity
Vertebrates
Female
medicine.symptom
Cellular Types
Public aspects of medicine
RA1-1270
medicine.drug
Research Article
Neglected Tropical Diseases
Nucleases
Immune Cells
Toxic Agents
Immunology
Hemorrhage
Viper Venoms
03 medical and health sciences
Signs and Symptoms
DNA-binding proteins
medicine
Animals
Humans
Blood Cells
030102 biochemistry & molecular biology
business.industry
Venoms
Public Health
Environmental and Occupational Health
Organisms
Biology and Life Sciences
Proteins
Reptiles
Neutrophil extracellular traps
Cell Biology
biology.organism_classification
Tropical Diseases
030104 developmental biology
Echis carinatus
Amniotes
biology.protein
Enzymology
Metalloproteases
Clinical Medicine
business
Zoology
Zdroj: PLoS Neglected Tropical Diseases, Vol 15, Iss 2, p e0008596 (2021)
PLoS Neglected Tropical Diseases
ISSN: 1935-2735
1935-2727
Popis: 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).
Author summary India has highest incidence of deaths due to snakebite in the world. Echis carinatus (EC) is known as saw-scaled viper and its bite causes major mortality and morbidity in the Indian subcontinent. The abundant presence of zinc (Zn++) metalloproteases in Echis carinatus venom (ECV) is responsible for local tissue necrosis. An earlier report has shown that ECV activates neutrophils and leads to NETosis that blocks blood vessels leading to tissue necrosis. However, the toxin in ECV responsible for NETosis has not addressed. Here we investigated the Echis carinatus venom metalloproteases (ECVMPs) are responsible for NETosis and its associated tissue necrosis using Zn++ specific chelator, Tetraethyl thiuram disulfide (TTD). TTD inhibited ECVMPs-induced skin hemorrhage and footpad tissue necrosis by reduced expression of citrullinated H3 (citH3) and myeloperoxidase (MPO) in mice 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 p-ERK and NETosis markers. Further, we demonstrated that ECV-induced NETosis and tissue necrosis is 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).
Databáze: OpenAIRE
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