The anticonvulsive Phenhydan® suppresses extrinsic cell death.
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Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2019-09-01
Date Accepted
2018-10-30
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.
Citation
Cell death and differentiation, 2019, 26 (9), pp. 1631 - 1645
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
1350-9047
eISSN
1476-5403
Collections
Research Team
Cell Death and Immunity