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

Zhou, Shengyu; Cui, Guozhen; Yan, Xiaofeng; Wang, Xu; Qu, Yang; Guo, Zhen‐Ni; Jin, Hang

doi:10.3389/fnins.2020.589042

Cited by 41 publications

(35 citation statements)

References 120 publications

(155 reference statements)

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“…This result is consistent with the hypothesis that 20-HETE induction after ICH can lead to ferroptosis. It has been established that various forms of cell death are not independent but rather intricately interconnected, forming a signaling network that can produce a spectrum of cell death modalities and damage after ICH ( 48 ). Therefore, we applied a combination of cell death inhibitors to 20-HETE mimetic-treated OHSCs.…”

Section: Discussionmentioning

confidence: 99%

20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis

et al. 2021

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Intracerebral hemorrhage (ICH) is a highly fatal type of stroke that leads to various types of neuronal death. Recently, ferroptosis, a form of cell death resulting from iron-dependent lipid peroxide accumulation, was observed in a mouse ICH model. N-hydroxy-N′-(4-n-butyl-2-methylphenyl)-formamidine (HET0016), which inhibits synthesis of the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE), has shown a protective effect after ICH. However, the underlying mechanisms of the neuroprotective effect need further investigation. We explored whether 20-HETE participates in ICH-induced ferroptosis ex vivo by using hemoglobin-treated organotypic hippocampal slice cultures (OHSCs) and in vivo by using a collagenase-induced ICH mouse model. Ex vivo, we found that the 20-HETE synthesis inhibitor HET0016 and antagonist 20-6,15-HEDGE reduced hemoglobin-induced cell death, iron deposition, and lipid reactive oxygen species levels in OHSCs. Furthermore, 20-HETE inhibition in OHSCs increased the expression of glutathione peroxidase (GPX) 4, an antioxidant enzyme that serves as a main regulator of ferroptosis. In contrast, exposure of OHSCs to the 20-HETE stable mimetic 20-5,14-HEDGE induced cell death that was significantly inhibited by the ferroptosis inhibitor ferrostatin-1. In vivo, HET0016 treatment ameliorated focal deficits, reduced lesion volume, and decreased iron accumulation around the lesion at day 3 and 7 after ICH. In addition, lipid peroxidation was decreased and expression of GPX4 was increased in the HET0016-treated ICH group. The mitogen-activated protein kinase pathway also was inhibited by HET0016 in vivo. These results indicate that 20-HETE contributes to ICH-induced acute brain injury in part by activating ferroptosis pathways, thereby providing an upstream target for inhibiting ferroptosis.

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Section: Discussionmentioning

confidence: 99%

20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis

et al. 2021

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“…During the acute phase of ICH immediately following the initial hemorrhage, hemoglobin undergoes rapid degradation which yields large volumes of iron within the extracellular space, together with biliverdin and carbon monoxide. 3 There is evidence that this resultant iron overload can drive consequent edema in the perihematomal region, contributing to the accumulation of peroxide and widespread cellular death. 4 Ferroptosis is a recently identified form of iron-dependent programmed cell death that can be induced in response to lipid peroxidation.…”

Section: Introductionmentioning

confidence: 99%

Curcumin Nanoparticles Inhibiting Ferroptosis for the Enhanced Treatment of Intracerebral Hemorrhage

Yang¹,

Han²,

Li³

et al. 2021

IJN

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Background Intracerebral hemorrhage (ICH) is a form of severe stroke, the pathology of which is tied closely to a recently discovered form of programmed cell death known as ferroptosis. Curcumin (Cur) is a common phenolic compound extracted from the rhizome of Curcuma longa capable of hematoma volume and associated neurological damage in the context of ICH. Despite exhibiting therapeutic promise, the efficacy of Cur is challenged by its poor water solubility, limited oral bioavailability and inability to efficiently transit across the physiological barriers. Polymer-based nanoparticles (NPs) have widely been employed to aid in drug delivery efforts owing to their ideal biocompatibility and their ability to improve the bioavailability and pharmacokinetics of specific drugs of interest. Methods In this study, we encapsulated Cur in NPs (Cur-NPs) and explored the effect of these Cur-NPs to enhance Cur delivery both in vitro and in vivo. Furthermore, we evaluated the anti-ferroptosis effect of Cur-NPs in ICH model mice and erastin-treated HT22 murine hippocampal cells. Results The resultant Cur-NPs were spherical and exhibited a particle size of 127.31±2.73 nm, a PDI of 0.21±0.01 and a zeta potential of −0.25±0.02 mV. When applied to Madin Darby canine kidney (MDCK) cells in vitro, these Cur-NPs were nonspecifically internalized via multiple endocytic pathways, with plasma membrane microcapsules and clathrin-mediated uptake being the dominant mechanisms. Within cells, these NPs accumulated in lysosomes, endoplasmic reticulum and mitochondria. Cur-NPs were capable of passing through physiological barriers in a zebrafish model system. When administrated to C57BL/6 mice, they significantly improved Cur delivery to the brain. Most notably, when administered to ICH model mice, Cur-NPs achieved superior therapeutic outcomes relative to other treatments. In a final series of experiments, these Cur-NPs were shown to suppress erastin-induced ferroptosis in HT22 murine hippocampal cells. Conclusion These Cur-NPs represent a promising means of improving Cur delivery to the brain and thereby better treating ICH.

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“…As an iron-dependent programmed cell death, ferroptosis exists in the acute stage of ICH and participates in the progression of ICH [31][32][33]. However, the pathological process of ferroptosis remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Pyridoxal Isonicotinoyl Hydrazone Improves Neurological Recovery by Attenuating Ferroptosis and Inflammation in Cerebral Hemorrhagic Mice

Zhang

Wen

Chen

et al. 2021

BioMed Research International

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Ferroptosis and inflammation induced by cerebral hemorrhage result in an excessive inflammatory response and irreversible neuronal injury. Alleviating ferroptosis might be an effective way to prevent neuroinflammatory injury and promote neural functional recovery. Pyridoxal isonicotinoyl hydrazine (PIH), a lipophilic iron-chelating agent, has been reported to reduce excess iron-induced cytotoxicity. However, whether PIH could ameliorate the effects of hemorrhagic stroke is not completely understood. In the present study, the preventive effects of PIH in an intracerebral hemorrhage (ICH) mouse model were investigated. Neurological score, rotarod test, and immunofluorescence around the hematoma were assessed to evaluate the effects of PIH on hemorrhagic injury. The involvement of ferroptosis and inflammation was also examined in vitro to explore the underlying mechanism. Results showed that administration of PIH prevented neuronal cell death and reduced lipid peroxidation in Erastin-treated PC-12 cells. In vivo, mice treated with PIH after ICH attenuated neurological deficit scores. Additionally, we found PIH reduced ROS production, iron accumulation, and lipid peroxidation around the hematoma peripheral tissue. Meanwhile, ICH mice treated with PIH showed an upregulation of the key ferroptosis enzyme, glutathione peroxidase 4, and downregulation of cyclooxygenase-2. Moreover, PIH administration inhibited proinflammatory polarization and reduced interleukin-1 beta and tumor necrosis factor alpha in ICH mice. Collectively, these results demonstrated that PIH protects mice against hemorrhage stroke, which was associated with mitigation of inflammation and ferroptosis.

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

Cited by 41 publications

References 120 publications

20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis

20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis

Curcumin Nanoparticles Inhibiting Ferroptosis for the Enhanced Treatment of Intracerebral Hemorrhage

Pyridoxal Isonicotinoyl Hydrazone Improves Neurological Recovery by Attenuating Ferroptosis and Inflammation in Cerebral Hemorrhagic Mice

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