Primidone blocks RIPK1-driven cell death and inflammation.
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Embargo End Date
ICR Authors
Authors
Riebeling, T
Jamal, K
Wilson, R
Kolbrink, B
von Samson-Himmelstjerna, FA
Moerke, C
Ramos Garcia, L
Dahlke, E
Michels, F
Lühder, F
Schunk, D
Doldi, P
Tyczynski, B
Kribben, A
Flüh, C
Theilig, F
Kunzendorf, U
Meier, P
Krautwald, S
Jamal, K
Wilson, R
Kolbrink, B
von Samson-Himmelstjerna, FA
Moerke, C
Ramos Garcia, L
Dahlke, E
Michels, F
Lühder, F
Schunk, D
Doldi, P
Tyczynski, B
Kribben, A
Flüh, C
Theilig, F
Kunzendorf, U
Meier, P
Krautwald, S
Document Type
Journal Article
Date
2020-12-03
Date Accepted
2020-11-17
Abstract
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.
Citation
Cell death and differentiation, 2020
Source Title
Publisher
SPRINGERNATURE
ISSN
1350-9047
eISSN
1476-5403
Collections
Research Team
Cell Death and Immunity