Moerke, Caroline and Jaco, Isabel and Dewitz, Christin and Mueller, Tammo and Jacobsen, Annette and Gautheron, Jeremie and Fritsch, Juergen and Schmitz, Jessica and Braesen, Jan Hinrich and Guenther, Claudia and Murphy, James M. and Kunzendorf, Ulrich and Meier, Pascal and Krautwald, Stefan (2019) The anticonvulsive Phenhydan (R) suppresses extrinsic cell death. CELL DEATH AND DIFFERENTIATION, 26 (9). pp. 1631-1645. ISSN 1350-9047, 1476-5403
Full text not available from this repository. (Request a copy)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-kappa B 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MIXED LINEAGE KINASE; LIPID RAFTS; PROGRAMMED NECROSIS; NECROPTOSIS; RECEPTOR; PROTEIN; RIP3; DOMAIN; PHOSPHORYLATION; ACTIVATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 31 Mar 2020 07:17 |
| Last Modified: | 31 Mar 2020 07:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26384 |
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