Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, 24105, Kiel, Germany.
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK.
Cell Death Differ. 2021 May;28(5):1610-1626. doi: 10.1038/s41418-020-00690-y. Epub 2020 Dec 3.
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.
受体相互作用丝氨酸/苏氨酸蛋白激酶 1（RIPK1）是调节细胞死亡和炎症的关键介质。最近的研究表明，抑制 RIPK1 将从根本上改善中风、心肌梗死、肾衰竭和全身炎症反应综合征中依赖 RIPK1 的器官损伤的治疗效果。此外，它可以改善或预防细胞因子释放引起的多器官衰竭高炎症情况下，如 COVID-19 患者。因此，我们寻找了一种 RIPK1 抑制剂，并提出芳香抗癫痫药和 FDA 批准的药物扑米酮（Liskantin®）作为体外和 TNFα 诱导的休克小鼠模型中 RIPK1 激活的有效抑制剂，该模型模拟细胞因子释放综合征的高炎症状态。此外，我们首次检测到在 SARS-CoV-2 感染检测呈阳性的住院患者的呼吸道上皮中存在 RIPK1 激活。我们的数据为评估扑米酮在人类高炎症情况下的应用提供了强有力的依据。
