Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib.
Proc Natl Acad Sci U S A
; 121(19): e2315597121, 2024 May 07.
Article
em En
| MEDLINE
| ID: mdl-38687786
ABSTRACT
Snakebite envenoming is a neglected tropical disease that causes substantial mortality and morbidity globally. The venom of African spitting cobras often causes permanent injury via tissue-destructive dermonecrosis at the bite site, which is ineffectively treated by current antivenoms. To address this therapeutic gap, we identified the etiological venom toxins in Naja nigricollis venom responsible for causing local dermonecrosis. While cytotoxic three-finger toxins were primarily responsible for causing spitting cobra cytotoxicity in cultured keratinocytes, their potentiation by phospholipases A2 toxins was essential to cause dermonecrosis in vivo. This evidence of probable toxin synergism suggests that a single toxin-family inhibiting drug could prevent local envenoming. We show that local injection with the repurposed phospholipase A2-inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a therapeutic strategy that may effectively prevent life-changing morbidity caused by snakebite in rural Africa.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Mordeduras de Serpentes
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Venenos Elapídicos
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Indóis
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Cetoácidos
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Acetatos
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Necrose
Limite:
Animals
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Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Reino Unido