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Current Neurovascular Research

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ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

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Research Article

Cerebral Ischemia Induces Iron Deposit, Ferritin Accumulation, Nuclear Receptor Coactivator 4-depletion, and Ferroptosis

Author(s): Nora Hanke and Abdelhaq Rami*

Volume 19, Issue 1, 2022

Published on: 19 April, 2022

Page: [47 - 60] Pages: 14

DOI: 10.2174/1567202619666220321120954

Price: $65

Abstract

Background: The neuronal death upon cerebral ischemia shares not only characteristics of necrosis, apoptosis, and autophagy but also exhibits biochemical and morphological characteristics of ferroptosis. Ferroptosis is a regulated form of cell death that is considered to be an oxidative iron-dependent process. It is now commonly accepted that iron and free radicals are considered to cause lipid peroxidation as well as the oxidation of proteins and nucleic acids, leading to increased membrane and enzymatic dysfunction and finally contributing to cell death. Although ferroptosis was first described in cancer cells, emerging evidence now links mechanisms of ferroptosis to many different diseases, including cerebral ischemia.

Methods: The objective of this study was to identify the key players and underlying biochemical pathways of ferroptosis, leading to cell death upon focal cerebral ischemia in mice by using immunofluorescence, Western blotting, histochemistry, and densitometry.

Results: In this study, we demonstrated that cerebral ischemia induced iron-deposition, downregulated dramatically the expression of the glutathione peroxidase 4 (GPX4), decreased the expression of the nuclear receptor coactivator 4 (NCOA4), and induced inappropriate accumulation of ferritin in the ischemic brain. This supports the hypothesis that an ischemic insult may induce ferroptosis through inhibition of GPX4.

Conclusion: We conclude that iron excess following cerebral ischemia leads to cell death despite activating compensatory mechanisms for iron homeostasis, as illustrated by the accumulation of ferritins. These data emphasized the presence of a cellular mechanism that allows neuronal cells to buffer iron levels.

Keywords: Cerebral ischemia, ferroptosis, ferritin, ferritinophagy, GPX-4, NCOA4.

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