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Ryanodine Receptor Mediated Calcium Release Contributes to Ferroptosis Induced in Primary Hippocampal Neurons by GPX4 Inhibition.
- Source :
- Antioxidants; Mar2023, Vol. 12 Issue 3, p705, 18p
- Publication Year :
- 2023
-
Abstract
- Ferroptosis, a newly described form of regulated cell death, is characterized by the iron-dependent accumulation of lipid peroxides, glutathione depletion, mitochondrial alterations, and enhanced lipoxygenase activity. Inhibition of glutathione peroxidase 4 (GPX4), a key intracellular antioxidant regulator, promotes ferroptosis in different cell types. Scant information is available on GPX4-induced ferroptosis in hippocampal neurons. Moreover, the role of calcium (Ca<superscript>2+</superscript>) signaling in ferroptosis remains elusive. Here, we report that RSL3, a selective inhibitor of GPX4, caused dendritic damage, lipid peroxidation, and induced cell death in rat primary hippocampal neurons. Previous incubation with the ferroptosis inhibitors deferoxamine or ferrostatin-1 reduced these effects. Likewise, preincubation with micromolar concentrations of ryanodine, which prevent Ca<superscript>2+</superscript> release mediated by Ryanodine Receptor (RyR) channels, partially protected against RSL3-induced cell death. Incubation with RSL3 for 24 h suppressed the cytoplasmic Ca<superscript>2+</superscript> concentration increase induced by the RyR agonist caffeine or by the SERCA inhibitor thapsigargin and reduced hippocampal RyR2 protein content. The present results add to the current understanding of ferroptosis-induced neuronal cell death in the hippocampus and provide new information both on the role of RyR-mediated Ca<superscript>2+</superscript> signals on this process and on the effects of GPX4 inhibition on endoplasmic reticulum calcium content. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 20763921
- Volume :
- 12
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Antioxidants
- Publication Type :
- Academic Journal
- Accession number :
- 162722930
- Full Text :
- https://doi.org/10.3390/antiox12030705