The anticonvulsive Phenhydan® suppresses extrinsic cell death.
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Date
2019-09-01ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
HT29 Cells
NIH 3T3 Cells
Animals
Humans
Mice
Sepsis
Multiple Sclerosis
Myocardial Infarction
Reperfusion Injury
Inflammation
Phenytoin
Anticonvulsants
Cell Death
Apoptosis
Receptor-Interacting Protein Serine-Threonine Kinases
Receptors, Death Domain
Necroptosis
Research team
Cell Death and Immunity
Language
eng
Date accepted
2018-10-30
License start date
2019-09
Citation
Cell death and differentiation, 2019, 26 (9), pp. 1631 - 1645
Publisher
NATURE PUBLISHING GROUP