Phenytoin: a new cytoprotective mechanism

An impressive group of scientists from Germany, Spain, USA and France worked on discovering a new cellular mechanism of phenytoin, a mechanism leading to cellular protection [1]. They published the results in March 2018. We have described phenytoin’s protective mechanism on the level of nerve cells before [2,3], but these researchers found a new key for the necroptosis inhibition of phenytoin.

They stipulate that based on their findings phenytoin could be repositioned in kidney ischemia-reperfusion injury (IRI), and phenytoin also appeared to protect cells from TNFα-induced severe inflammatory response syndrome (SIRS).

Via a series of elegant experiments they found out that phenytoin amongst other mechanisms prevents necrosome formation and partially inhibits RIP1 kinase. Necroptosis is the best studied pathway of regulated necrosis and is mediated by receptor-interacting protein kinases 1 and 3 (RIPK1/3). The exact mechanism of phenytoin is still unclear, but it is NF-kB signaling independent.

Their conclusion highligts a new putative indication for phenytoin: With greater than 60 years of clinical experience and low costs alongside with the availability on ICUs and in ambulances, phenytoin may provide a drug to target necroptosis.

Given our own findings we think this mechanism might be related to its analgesic effects in small fiber neuropathic pain.


    1. von Mässenhausen A, Tonnus W, Himmerkus N, Parmentier S, Saleh D, Rodriguez D, Ousingsawat J, Ang RL, Weinberg JM, Sanz AB, Ortiz A, Zierleyn A, Becker JU, Baratte B, Desban N, Bach S, Schiessl IM, Nogusa S, Balachandran S, Anders HJ, Ting AT, Bleich M, Degterev A, Kunzelmann K, Bornstein SR, Green DR, Hugo C, Linkermann A. Phenytoin inhibits necroptosis. Cell Death Dis. 2018 Mar 2;9(3):359. doi: 10.1038/s41419-018-0394-3.
    2. Keppel Hesselink JM, Kopsky DJ. Phenytoin: neuroprotection or neurotoxicity? Neurol Sci. 2017 Jun;38(6):1137-1141. doi: 10.1007/s10072-017-2993-7.
    3. Chiosi F, Keppel Hesselink J, Rinaldi M, Di Staso S, Bartollino S, Costagliola C. Phenytoin: its potential as neuroprotective and retinoprotective drug. Br J Clin Pharmacol. 2018 Jan;84(1):195-196. doi: 10.1111/bcp.13435.