Treatment of early brain injury after subarachnoid hemorrhage in the rat model by inhibiting p53-induced ferroptosis

Kuang, Hong; Wang, Tianhong; Liu, Lei; Tang, Chunhai; Li, Tao; Ming, Lei; Wang, Tianping; Zhong, Weiying; Wang, Yunyan

doi:10.1016/j.neulet.2021.136134

Cited by 32 publications

(19 citation statements)

References 32 publications

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“…The cerebral occurrence of ferroptosis has been observed in Parkinson's disease, and may occur in several types of brain injury [ 36 ], as well as in infection [ 37 ] and cancer [ 38 , 39 ]. Ferroptosis has been found occur in EBI after SAH, lines reported that via reduction of lipid peroxidation and inhibiting p53 could alleviate ferroptosis in EBI after SAH [ 40 ]. Notably, ferroptosis strongly relates to iron metabolism but whether influencing iron metabolism could alleviate ferroptosis and the pathway have not been reported.…”

Section: Discussionmentioning

confidence: 99%

Hepcidin Promoted Ferroptosis through Iron Metabolism which Is Associated with DMT1 Signaling Activation in Early Brain Injury following Subarachnoid Hemorrhage

Zhang

Ostrowski

Jiang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Iron metabolism disturbances play an important role in early brain injury (EBI) after subarachnoid hemorrhage (SAH), and hepcidin largely influences iron metabolism. Importantly, iron metabolism may be associated with ferroptosis, recently a nonapoptotic iron-dependent form of cell death that may have a great impact on brain injury after SAH. We investigated hepcidin on iron metabolism and ferroptosis involving divalent metal transporter 1 (DMT1), and ferroportin-1 (FPN1) in a rat model of SAH. Male Sprague-Dawley rats were subjected to the endovascular perforation to induce SAH, and treated with heparin (inhibitor of hepcidin), or oncostatin M (OSM, inducer of hepcidin), or ebselen (inhibitor of DMT1) by intracerebroventricular injections. Hepcidin, DMT1, FPN1 and glutathione peroxidase 4 (GPX4), were detected by western blot and immunofluorescence. Iron metabolism was detected through Perl’s iron staining and iron content assay. Ferroptosis, the ROS production, lipid peroxidation (LPO) was evaluated by monitoring methane dicarboxylic aldehyde (MDA), glutathione (GSH), glutathione peroxidase 4 (GPX4) activity, and transmission electron microscopy. Neurological deficit scores, Evans blue staining and brain water content were also determined to detect EBI 72 h after SAH. Our results showed that inhibition of DMT1 by ebselen could suppress iron accumulation and lipid peroxidation, and thereby alleviate ferroptosis and EBI in SAH rats. Heparin downregulated the expression of hepcidin and DMT1, increased FPN1, and exerted protective effects that were equivalent to those of ebselen on ferroptosis and EBI. In addition, OSM increased the expression of hepcidin and DMT1, decreased FPN1, and aggravated ferroptosis and EBI, while the effect on ferroptosis was reversed by ebselen. Therefore, the study revealed that hepcidin could regulate iron metabolism and contribute to ferroptosis via DMT1 signaling activation in rats with EBI after SAH.

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Section: Discussionmentioning

confidence: 99%

Hepcidin Promoted Ferroptosis through Iron Metabolism which Is Associated with DMT1 Signaling Activation in Early Brain Injury following Subarachnoid Hemorrhage

Zhang

Ostrowski

Jiang

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Liproxstatin-1 was found with the protection effect on the neural function and neuronal cell death in vivo [ 114 ]. Besides, the p53 inhibitor could block cortical SAH-induced ferroptosis, which provides new insight of ferroptosis in SAH [ 115 ].…”

Section: Ferroptosis In Neurological Diseasesmentioning

confidence: 99%

Role and mechanism of ferroptosis in neurological diseases

Ou¹,

Ji²,

Zhou³

et al. 2022

Molecular Metabolism

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“…Neuronal death is an important component of brain injury after SAH [ 5 ]. An increasing number of studies suggest that SAH triggers neuronal ferroptosis [ 6 – 8 ], and intervention with ferroptosis inhibitors is beneficial for improving early brain injury (EBI) after SAH [ 9 , 10 ]. Mature neurons have a high level of polyunsaturated ether phospholipids (PUFA-EPLS), which makes them sensitive to ferroptosis [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Aquaporin 4 Depolarization-Enhanced Transferrin Infiltration Leads to Neuronal Ferroptosis after Subarachnoid Hemorrhage in Mice

Liu

Wang

Cao

et al. 2022

Oxidative Medicine and Cellular Longevity

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The infiltration of blood components into the brain parenchyma through the lymphoid system is an important cause of subarachnoid hemorrhage injury. AQP4, a water channel protein located at the astrocyte foot, has been reported to regulate blood–brain barrier integrity, and its polarization is disrupted after SAH. Neuronal ferroptosis is involved in subarachnoid hemorrhage- (SAH-) induced brain injury, but the inducing factors are not completely clear. Transferrin is one of the inducing factors of ferroptosis. This study is aimed at researching the role and mechanism of AQP4 in brain injury after subarachnoid hemorrhage in mice. An experimental mouse SAH model was established by endovascular perforation. An AAV vector encoding AQP4 with a GFAP-specific promoter was administered to mice to achieve specific overexpression of AQP4 in astrocytes. PI staining, Fer-1 intervention, and transmission electron microscopy were used to detect neuronal ferroptosis, and dextran (40 kD) leakage was used to detect BBB integrity. Western blot analysis of perfused brain tissue protein samples was used to detect transferrin infiltration. First, neuronal ferroptosis 24 h after SAH was observed by PI staining and Fer-1 intervention. Second, a significant increase in transferrin infiltration was found in the brain parenchyma 24 h after SAH modeling, while transferrin content was positively correlated with neuronal ferroptosis. Then, we observed that AQP4 overexpression effectively improved AQP depolarization and BBB injury induced by SAH and significantly reduced transferrin infiltration and neuronal ferroptosis after SAH. Finally, we found that AQP4 overexpression could effectively improve the neurobehavioral ability of SAH mice, and the neurobehavioral ability was negatively correlated with transferrin brain content. Taken together, these data indicate that overexpression of AQP4 in the mouse brain can effectively improve post-SAH neuronal ferroptosis and brain injury, at least partly by inhibiting transferrin infiltration into the brain parenchyma in the glymphatic system.

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Treatment of early brain injury after subarachnoid hemorrhage in the rat model by inhibiting p53-induced ferroptosis

Cited by 32 publications

References 32 publications

Hepcidin Promoted Ferroptosis through Iron Metabolism which Is Associated with DMT1 Signaling Activation in Early Brain Injury following Subarachnoid Hemorrhage

Hepcidin Promoted Ferroptosis through Iron Metabolism which Is Associated with DMT1 Signaling Activation in Early Brain Injury following Subarachnoid Hemorrhage

Role and mechanism of ferroptosis in neurological diseases

Aquaporin 4 Depolarization-Enhanced Transferrin Infiltration Leads to Neuronal Ferroptosis after Subarachnoid Hemorrhage in Mice

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