Inhibition of double-stranded RNA-dependent protein kinase prevents oxytosis and ferroptosis in mouse hippocampal HT22 cells

Toxicology
Yoko HirataHiroshi Takemori

Abstract

Double-stranded RNA-dependent protein kinase (PKR) is a component of signal transduction pathways mediating various stress signals including oxidative stress and endoplasmic reticulum (ER) stress and is suggested to be implicated in several neurodegenerative diseases. Cell death in neurodegenerative conditions has been linked to oxidative stress; however, the involvement of PKR in endogenous oxidative stress such as oxytosis and ferroptosis which is quite distinct from classical apoptosis remains unknown. We investigated here the effect of a PKR inhibitor C16 (an imidazole-oxindole derivative) on oxytosis and ferroptosis in cultured HT22 mouse hippocampal cells. C16 prevented glutamate- and erastin-induced cell death, reactive oxygen species accumulation, Ca2+ influx, phosphorylation of inositol-requiring enzyme 1 (IRE1), one of the three branches of ER stress signaling and its downstream signaling components. On the other hand, C16 did not prevent oxidative stress-induced heme oxygenase-1 expression; instead, C16 activated the extracellular signal-regulated kinase pathway. The protective effect of C16 is diminished in PKR knockout HT22 cells. Real time measurements of the oxygen consumption rate and extracellular acidification...Continue Reading

Citations

May 7, 2020·Frontiers in Neuroscience·Xiaohua Song, Dingxin Long
Oct 13, 2020·Frontiers in Cell and Developmental Biology·Feimei KuangRui Kang
Dec 4, 2020·Cell Research·Daolin TangGuido Kroemer
Feb 5, 2021·Signal Transduction and Targeted Therapy·Hong-Fa YanPeng Lei
Oct 30, 2020·Chemical Research in Toxicology·Yoko HirataToshiaki Murai

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