The anticonvulsive Phenhydan((R)) suppresses extrinsic cell death
- Author(s)
- Moerke, C; Jaco, I; Dewitz, C; Muller, T; Jacobsen, AV; Gautheron, J; Fritsch, J; Schmitz, J; Brasen, JH; Gunther, C; Murphy, JM; Kunzendorf, U; Meier, P; Krautwald, S;
- Journal Title
- Cell Death and Differentiation
- Publication Type
- Journal Article in press
- Abstract
- Different forms of regulated cell death-like apoptosis and necroptosis contribute to the pathophysiology of clinical conditions including ischemia-reperfusion injury, myocardial infarction, sepsis, and multiple sclerosis. In particular, the kinase activity of the receptor-interacting serine/threonine protein kinase 1 (RIPK1) is crucial for cell fate in inflammation and cell death. However, despite its involvement in pathological conditions, no pharmacologic inhibitor of RIPK1-mediated cell death is currently in clinical use. Herein, we screened a collection of clinical compounds to assess their ability to modulate RIPK1-mediated cell death. Our small-scale screen identified the anti-epilepsy drug Phenhydan((R)) as a potent inhibitor of death receptor-induced necroptosis and apoptosis. Accordingly, Phenhydan((R)) blocked activation of necrosome formation/activation as well as death receptor-induced NF-kappaB signaling by influencing the membrane function of cells, such as lipid raft formation, thus exerting an inhibitory effect on pathophysiologic cell death processes. By targeting death receptor signaling, the already FDA-approved Phenhydan((R)) may provide new therapeutic strategies for inflammation-driven diseases caused by aberrant cell death.
- Publisher
- Springer Nature
- Research Division(s)
- Cell Signalling And Cell Death
- PubMed ID
- 30442947
- Publisher's Version
- https://doi.org/10.1038/s41418-018-0232-2
- Open Access at Publisher's Site
https://doi.org/10.1038/s41418-018-0232-2- NHMRC Grants
- NHMRC/1124735, NHMRC/1105754,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-11-20 09:12:53
Last Modified: 2018-11-20 01:07:10