Primidone blocks RIPK1-driven cell death and inflammation.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
16
09
2020
accepted:
17
11
2020
revised:
16
11
2020
pubmed:
5
12
2020
medline:
8
6
2021
entrez:
4
12
2020
Statut:
ppublish
Résumé
The receptor-interacting serine/threonine protein kinase 1 (RIPK1) is a key mediator of regulated cell death and inflammation. Recent studies suggest that RIPK1 inhibition would fundamentally improve the therapy of RIPK1-dependent organ damage in stroke, myocardial infarction, kidney failure, and systemic inflammatory response syndrome. Additionally, it could ameliorate or prevent multi-organ failure induced by cytokine release in the context of hyperinflammation, as seen in COVID-19 patients. Therefore, we searched for a RIPK1 inhibitor and present the aromatic antiepileptic and FDA-approved drug primidone (Liskantin®) as a potent inhibitor of RIPK1 activation in vitro and in a murine model of TNFα-induced shock, which mimics the hyperinflammatory state of cytokine release syndrome. Furthermore, we detected for the first time RIPK1 activation in the respiratory tract epithelium of hospitalized patients who tested positive for SARS-CoV-2 infection. Our data provide a strong rationale for evaluating the drug primidone in conditions of hyperinflammation in humans.
Identifiants
pubmed: 33273695
doi: 10.1038/s41418-020-00690-y
pii: 10.1038/s41418-020-00690-y
pmc: PMC7712602
doi:
Substances chimiques
Primidone
13AFD7670Q
RIPK1 protein, human
EC 2.7.11.1
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Ripk1 protein, mouse
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1610-1626Subventions
Organisme : Cancer Research UK (CRUK)
ID : CRM089X
Organisme : Worldwide Cancer Research
ID : 14-1328
Pays : United Kingdom
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 400339789
Organisme : Medical Research Council
ID : MR/M019217/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1000089
Pays : United Kingdom
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