Mechanism of Ferroptosis and Its Relationships With Other Types of Programmed Cell Death: Insights for Potential Interventions After Intracerebral Hemorrhage.

Sheng-Yu Zhou,Xu Wang,Zhen-Ni Guo,Hang Jin,Guo-Zhen Cui,Yang Qu,Xiu-Li Yan

doi:10.3389/fnins.2020.589042

Sheng-Yu Zhou, Xu Wang + Show 5 more

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https://doi.org/10.3389/fnins.2020.589042

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Abstract

Intracerebral hemorrhage (ICH) is a fatal cerebrovascular disease with high morbidity and mortality, for which no effective therapies are currently available. Brain tissue damage caused by ICH is mediated by a newly identified form of non-apoptotic programmed cell death, called ferroptosis. Ferroptosis is characterized by the iron-induced accumulation of lipid reactive oxygen species (ROS), leading to intracellular oxidative stress. Lipid ROS cause damage to nucleic acids, proteins, and cell membranes, eventually resulting in ferroptosis. Numerous biological processes are involved in ferroptosis, including iron metabolism, lipid peroxidation, and glutathione biosynthesis; therefore, iron chelators, lipophilic antioxidants, and other specific inhibitors can suppress ferroptosis, suggesting that these modulators are beneficial for treating brain injury due to ICH. Accumulating evidence indicates that ferroptosis differs from other types of programmed cell death, such as necroptosis, apoptosis, oxytosis, and pyroptosis, in terms of ultrastructural characteristics, signaling pathways, and outcomes. Although several studies have emphasized the importance of ferroptosis due to ICH, the detailed mechanism underlying ferroptosis remains unclear. This review summarizes the available evidence on the mechanism underlying ferroptosis and its relationship with other types of cell death, with the aim to identify therapeutic targets and potential interventions for ICH.

Highlights

Intracerebral hemorrhage (ICH) accounts for 10–15% of all stroke types, which is a catastrophic event associated with high mortality and morbidity rates (Van Asch et al, 2010)
It is known that hemoglobin in a hematoma after ICH can cause lipid peroxidation and form hydroxyl radicals, which are highly neurotoxic, leading to damage to the membranes, DNA, and proteins (Xi et al, 2006; Cao and Dixon, 2016)
Some preclinical and clinical studies about ferroptosis in neurodegeneration and stroke indicate that iron released from the hematoma can lead to a newly identified form of programmed cell death, ferroptosis, which may greatly contribute to secondary brain injury (SBI) after ICH (Zhang Z. et al, 2018; Djulbegovic and Uversky, 2019; Zhang et al, 2020)

Summary

Introduction

Intracerebral hemorrhage (ICH) accounts for 10–15% of all stroke types, which is a catastrophic event associated with high mortality and morbidity rates (Van Asch et al, 2010). Oxytosis is induced by the glutamate-mediated inhibition of system Xc-, which leads to the depletion of GSH; it represents a distinct type of oxidative neuronal cell death after ICH (Landshamer et al, 2008; Grohm et al, 2010). The study further showed that erastin-induced ferroptosis in neuronal cells is accompanied by mitochondrial transactivation of BID, loss of mitochondrial membrane potential, enhanced mitochondrial fragmentation, and reduced ATP levels.

Results

Conclusion