Primidone blocks RIPK1-driven cell death and inflammation
| Autor: | Theresa Riebeling, Domagoj Schunk, Charlotte Flüh, Rebecca Wilson, Fred Lühder, Bartosz Tyczynski, Laura Ramos Garcia, Philipp M. Doldi, Stefan Krautwald, Friederike Michels, Ulrich Kunzendorf, Kunzah Jamal, Eileen Dahlke, Franziska Theilig, Benedikt Kolbrink, Pascal Meier, Caroline Moerke, Andreas Kribben, Friedrich Alexander von Samson-Himmelstjerna |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Programmed cell death
medicine.medical_treatment Medizin Context (language use) Inflammation Pharmacology Article Jurkat Cells Mice RIPK1 Cell death and immune response Animals Humans Medicine Molecular Biology Cell Death SARS-CoV-2 business.industry COVID-19 U937 Cells Cell Biology Translational research medicine.disease COVID-19 Drug Treatment Systemic inflammatory response syndrome Cytokine release syndrome HEK293 Cells Cytokine Receptor-Interacting Protein Serine-Threonine Kinases NIH 3T3 Cells medicine.symptom business HT29 Cells Primidone medicine.drug |
| Zdroj: | Cell Death & Differentiation Cell Death and Differentiation |
| ISSN: | 1476-5403 1350-9047 |
| DOI: | 10.1038/s41418-020-00690-y |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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