Primidone blocks RIPK1-driven cell death and inflammation

Theresa Riebeling,Eileen Dahlke,Fred Lühder,Rebecca Wilson,Franziska Theilig,Laura Ramos Garcia,Caroline Moerke,Bartosz Tyczynski,Kunzah Jamal,Domagoj Schunk,Philipp Doldi,Ulrich Kunzendorf,Stefan Krautwald,Friederike Michels,Charlotte Flüh,Pascal Meier,Benedikt Kolbrink,Friedrich Alexander Von Samson-Himmelstjerna,Andreas Kribben

doi:10.1038/s41418-020-00690-y

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.

Highlights

The scaffolding function of the receptor-interacting serine/ threonine protein kinase 1 (RIPK1) regulates pro-survival signaling and inflammatory gene expression, while its kinase activity paradoxically mediates caspase-8-dependent apoptosis and RIPK3-mixed-lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis [1]
By using the U937 pro-monocytic human myeloid cells we found that primidone (Fig. S1A shows its chemical structure) protected this cell line from RIPK1mediated necroptosis (Fig. 1A) in a dose-dependent manner (Fig. 1B)
All of these reports revealed that RIPK1 is a major regulator of signaling pathways that lead to inflammation and regulated cell death, which is why RIPK1 has gained considerable interest as a drug target for treating a spectrum of human diseases, including amyotrophic lateral sclerosis (ALS), multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, inflammatory bowel disease (IBD), sepsis, viral infections, hepatitis, myocardial infarction, stroke, and ischemia-reperfusion injury (IRI)

Summary

Introduction

The scaffolding function of the receptor-interacting serine/ threonine protein kinase 1 (RIPK1) regulates pro-survival signaling and inflammatory gene expression, while its kinase activity paradoxically mediates caspase-8-dependent apoptosis and RIPK3-mixed-lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis [1].

Present address

Materials and methods

Results

Discussion

Compliance with ethical standards