Overexpression of Mitochondrial Ferritin Enhances Blood–Brain Barrier Integrity Following Ischemic Stroke in Mice by Maintaining Iron Homeostasis in Endothelial Cells

Wang, Peina; Ren, Qianqian; Shi, Mengtong; Liu, Yuanyuan; Bai, Huiyuan; Chang, Yan‐Zhong

doi:10.3390/antiox11071257

Cited by 12 publications

(3 citation statements)

References 42 publications

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“…In accordance with previously published BMECs isolation protocols [19][20], the brains were perfused with pH 7.4 PBS and swiftly separated into two hemispheres, the ipsilateral cortex was homogenized in ice-cold PBS using a Knote Dounce glass tissue grinder. After centrifugation for 5 minutes (1000×g, 4°C ), discarded the supernatant, then resuspended the deposit with an 18% Dextran solution in PBS.…”

Section: Isolation Of Brain Microvascular Endothelial Cells (Bmecs)mentioning

confidence: 99%

Deferoxamine Reduces Endothelial Ferroptosis and Protects Cerebrovascular Function after Experimental Traumatic Brain Injury

Liang

Wang

Sun

et al. 2023

Preprint

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Cerebrovascular dysfunction resulting from traumatic brain injury (TBI) significantly contributes to poor patient outcomes. Recent studies revealed the involvement of iron metabolism in neuronal survival, yet its effect on vasculature remains unclear. This study aims to explore the impact of endothelial ferroptosis on cerebrovascular function in TBI. A Controlled Cortical Impact (CCI) model was established in mice, resulting in a significant increase in iron-related proteins such as TfR1, FPN1, and FTH, as well as oxidative stress biomarker 4HNE. This was accompanied by a decline in expression of the ferroptosis inhibitor NCOA4. Moreover, Perls' staining and nonhemin iron content assay showed iron overload in brain microvascular endothelial cells (BMECs) and the ipsilateral cortex. Immunofluorescence staining revealed more FTH-positive cerebral endothelial cells, consistent with impaired perfused vessel density and cerebral blood flow. As a specific iron chelator, DFO treatment inhibited such ferroptotic proteins expression and the accumulation of lipid-reactive oxygen species following CCI, enhancing glutathione peroxidase(GPx) activity. DFO treatment significantly reduced iron deposition in endothelial cells and brain tissue, and increased density of the cerebral capillaries as well. Consequently, DFO treatment led to improvements in cerebral blood flow (as measured by laser speckle imaging) and behavioral performance (as measured by the NSS scoring, rotarod test, and Morris water maze test). Taken together, our results indicated that TBI induces remarkable iron disorder and endothelial ferroptosis, and DFO treatment may help maintain iron homeostasis and protect vascular function. This may provide a novel therapeutic strategy to prevent cerebrovascular dysfunction following TBI.

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Section: Isolation Of Brain Microvascular Endothelial Cells (Bmecs)mentioning

confidence: 99%

Deferoxamine Reduces Endothelial Ferroptosis and Protects Cerebrovascular Function after Experimental Traumatic Brain Injury

Liang

Wang

Sun

et al. 2023

Preprint

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“…Mainly expressed in cells with high oxygen demand, mitochondrial ferritin is a protein that stores Fe 3+ , which can limit iron overload and iron-dependent lipid peroxidation induced by cerebral IRI [ 129 ]. Mitochondrial ferritin overexpression attenuates ferroptosis in brain endothelial cells, which prevents disruption of the blood–brain barrier [ 130 ].…”

Section: Mechanisms and Targeted Therapies For Ferroptosis In Irimentioning

confidence: 99%

Ferroptosis—A New Dawn in the Treatment of Organ Ischemia–Reperfusion Injury

Zhou

Han

Guo

et al. 2022

Cells

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Ischemia–reperfusion (I/R) is a common pathological phenomenon that occurs in numerous organs and diseases. It generally results from secondary damage caused by the recovery of blood flow and reoxygenation, followed by ischemia of organ tissues, which is often accompanied by severe cellular damage and death. Currently, effective treatments for I/R injury (IRI) are limited. Ferroptosis, a new type of regulated cell death (RCD), is characterized by iron overload and iron-dependent lipid peroxidation. Mounting evidence has indicated a close relationship between ferroptosis and IRI. Ferroptosis plays a significantly detrimental role in the progression of IRI, and targeting ferroptosis may be a promising approach for treatment of IRI. Considering the substantial progress made in the study of ferroptosis in IRI, in this review, we summarize the pathological mechanisms and therapeutic targets of ferroptosis in IRI.

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“…First, neurons damage and/or die due to ischemic stroke, followed by reestablishing blood flow to the ischemic zones, aggravating brain damage and further deteriorating the condition [ 23 ]. During C I/R, the blood–brain barrier (BBB) permeability amplifies, which promotes cerebral edema [ 24 ]. As a result of brain volume expanding, the intracranial pressure elevates [ 25 ], and the inflammatory cells and inflammatory factors permit into intensifying inflammatory and apoptosis reactions, which cause further deterioration of the disease [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Anethole Pretreatment Modulates Cerebral Ischemia/Reperfusion: The Role of JNK, p38, MMP-2 and MMP-9 Pathways

Younis

Mohamed

2023

Pharmaceuticals

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Anethole (AN) is one of the major constituents of several plant oils, demonstrating plentiful pharmacological actions. Ischemic stroke is the main cause of morbidity and death worldwide, particularly since ischemic stroke therapeutic choices are inadequate and limited; thus, the development of new therapeutic options is indispensable. This study was planned to explore the preventive actions of AN in ameliorating cerebral ischemia/reperfusion-induced brain damage and BBB permeability leakage, as well as to explore anethole’s potential mechanisms of action. The proposed mechanisms included modulating JNK and p38 as well as MMP-2 and MMP-9 pathways. Sprague–Dawley male rats were randomly assigned into four groups: sham, middle cerebral artery occlusion (MCAO), AN125 + MCAO, and AN250 + MCAO. Animals in the third and fourth groups were pretreated with AN 125 or 250 mg/kg orally, respectively, for two weeks before performing middle cerebral artery occlusion (MCAO)-induced cerebral ischemic/reperfusion surgery. Animals that experienced cerebral ischemia/reperfusion exhibited amplified infarct volume, Evans blue intensity, brain water content, Fluoro-Jade B-positive cells, severe neurological deficits, and numerous histopathological alterations. MCAO animals exhibited elevated MMP-9 and MMP-2 gene expressions, enzyme activities, augmented JNK, and p38 phosphorylation. On the other hand, pretreatment with AN diminished the infarct volume, Evans blue dye intensity, brain water content, and Fluoro-Jade B-positive cells, improved the neurological score and enhanced histopathological examination. AN effectively lowered MMP-9 and MMP-2 gene expression and enzyme activities and diminished phosphorylated JNK, p38. AN decreased MDA content, amplified GSH/GSSG ratio, SOD, and CAT, decreased the serum and brain tissue homogenate inflammatory cytokines (TNF-α, IL-6, IL-1β), NF-κB, and deterred the apoptotic status. This study revealed the neuroprotective ability of AN against cerebral ischemia/reperfusion in rats. AN boosted blood–brain barrier integrity via modulating MMPs and diminished oxidative stress, inflammation, and apoptosis through the JNK/p38 pathway.

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Overexpression of Mitochondrial Ferritin Enhances Blood–Brain Barrier Integrity Following Ischemic Stroke in Mice by Maintaining Iron Homeostasis in Endothelial Cells

Cited by 12 publications

References 42 publications

Deferoxamine Reduces Endothelial Ferroptosis and Protects Cerebrovascular Function after Experimental Traumatic Brain Injury

Deferoxamine Reduces Endothelial Ferroptosis and Protects Cerebrovascular Function after Experimental Traumatic Brain Injury

Ferroptosis—A New Dawn in the Treatment of Organ Ischemia–Reperfusion Injury

Anethole Pretreatment Modulates Cerebral Ischemia/Reperfusion: The Role of JNK, p38, MMP-2 and MMP-9 Pathways

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