Cell Death and Differentiation
Cell Death and Differentiation
3 years ago

Primidone blocks RIPK1-driven cell death and inflammation

Primidone blocks RIPK1-driven cell death and inflammation
Theresa Riebeling, Kunzah Jamal, Rebecca Wilson, Benedikt Kolbrink, Friedrich Alexander von Samson-Himmelstjerna, Caroline Moerke, Laura Ramos Garcia, Eileen Dahlke, Friederike Michels, Fred Lühder, Domagoj Schunk, Philipp Doldi, Bartosz Tyczynski, Andreas Kribben, Charlotte Flüh, Franziska Theilig, Ulrich Kunzendorf, Pascal Meier, Stefan Krautwald
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.

Publisher URL: http://feeds.nature.com/~r/cdd/rss/current/~3/2a5mcxxlbso/s41418-020-00690-y

Open URL: https://www.nature.com/articles/s41418-020-00690-y.pdf

DOI: 10.1038/s41418-020-00690-y

Open access
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