The anticonvulsive Phenhydan® suppresses extrinsic cell death

Moerke C, Jaco I, Dewitz C, Müller T, Jacobsen AV, Gautheron J, Fritsch J, Schmitz J, Bräsen JH, Günther C, Murphy JM, Kunzendorf U, Meier P, Krautwald S (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Cell Death and Differentiation Nature Publishing Group: Open Access Hybrid Model Option B

Book Volume: 26

Pages Range: 1631-1645

Journal Issue: 9

DOI: 10.1038/s41418-018-0232-2

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® as a potent inhibitor of death receptor-induced necroptosis and apoptosis. Accordingly, Phenhydan® blocked activation of necrosome formation/activation as well as death receptor-induced NF-κB 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® may provide new therapeutic strategies for inflammation-driven diseases caused by aberrant cell death.

Authors with CRIS profile

Claudia Günther Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Involved external institutions

Walter and Eliza Hall Institute of Medical Research (WEHI) AU Australia (AU) Sorbonne Université FR France (FR) Universität Regensburg DE Germany (DE) Gottfried Wilhelm Leibniz Universität Hannover DE Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE) The Institute of Cancer Research (ICR) GB United Kingdom (GB)

How to cite

APA:

Moerke, C., Jaco, I., Dewitz, C., Müller, T., Jacobsen, A.V., Gautheron, J.,... Krautwald, S. (2019). The anticonvulsive Phenhydan® suppresses extrinsic cell death. Cell Death and Differentiation, 26(9), 1631-1645. https://dx.doi.org/10.1038/s41418-018-0232-2

MLA:

Moerke, Caroline, et al. "The anticonvulsive Phenhydan® suppresses extrinsic cell death." Cell Death and Differentiation 26.9 (2019): 1631-1645.

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