Reducing the Amount of M1 Microglia by Inhibiting CXCR4 and iNOS Exerts Neuroprotection in a Rat Model of Subarachnoid Hemorrhage

Abstract Early inflammation is a significant factor in acute pathophysiological events of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Although there have been numerous studies of neuroinflammation and SAH, the effect of M1 microglia on the progressions of neuroinflammation in SAH remains non-elucidated. CXCR4 is thought to be the critical regulator of the migration and recruitment of microglia, and early studies found that iNOS/NO• does represent an effective ferroptosis regulator and leads to the M1 microglia more resistant to the initiator of ferroptosis. Thus, we investigated the effect of AMD3100 (a highly selective antagonist of CXCR4) and L-NIL (an inhibitor of iNOS) on neuroinflammation in a rat SAH model. We found AMD3100 could suppress the migration of M1 microglia through the CXCL12/CXCR4 pathway. Treatment of AMD3100 could decrease the level of related inflammation factors and improved the prognosis within 24 h after SAH. Moreover, L-NIL could inhibit the expression of (i)NOS and promote the expression of ferroptosis-related proteins and the degree of lipid peroxidation. Importantly, the combination of AMD3100 and L-NIL could reduce the quantity of M1 microglia in the injured brain area and reduce the secretion of related inflammatory factors to improve the prognosis. To sum up, these data indicate that inhibiting CXCR4 and iNOS following SAH produces cerebral protection, and its anti-inflammation provides a potential therapeutic target for treating SAH.

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Inhibition of BECN1 Suppresses Lipid Peroxidation by Increasing System Xc− Activity in Early Brain Injury after Subarachnoid Hemorrhage

Journal of Molecular Neuroscience ◽

10.1007/s12031-019-01272-5 ◽

2019 ◽

Vol 67 (4) ◽

pp. 622-631 ◽

Cited By ~ 1

Author(s):

Yazhou Guo ◽

Xiao Liu ◽

Dezhong Liu ◽

Kai Li ◽

Changwei Wang ◽

...

Keyword(s):

Lipid Peroxidation ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Early Brain Injury

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9800794 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Hongxia Zhang ◽

Robert Ostrowski ◽

Dengzhi Jiang ◽

Qing Zhao ◽

Yidan Liang ◽

...

Keyword(s):

Lipid Peroxidation ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Glutathione Peroxidase ◽

Iron Metabolism ◽

Early Brain Injury ◽

Oncostatin M ◽

Blue Staining ◽

Divalent Metal Transporter 1 ◽

Signaling Activation

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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Ethyl Pyruvate Attenuates Early Brain Injury Following Subarachnoid Hemorrhage in the Endovascular Perforation Rabbit Model Possibly Via Anti-inflammation and Inhibition of JNK Signaling Pathway

Neurochemical Research ◽

10.1007/s11064-016-2138-z ◽

2017 ◽

Vol 42 (4) ◽

pp. 1044-1056 ◽

Cited By ~ 7

Author(s):

Tao Lv ◽

Yi-Feng Miao ◽

Yi-Chao Jin ◽

Shao-Feng Yang ◽

Hui Wu ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Signaling Pathway ◽

Ethyl Pyruvate ◽

Rabbit Model ◽

Early Brain Injury ◽

Jnk Signaling ◽

Jnk Signaling Pathway ◽

Anti Inflammation

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Inhibition of Ferroptosis Alleviates Early Brain Injury After Subarachnoid Hemorrhage In Vitro and In Vivo via Reduction of Lipid Peroxidation

Cellular and Molecular Neurobiology ◽

10.1007/s10571-020-00850-1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Yuchen Li ◽

Yao Liu ◽

Pei Wu ◽

Yang Tian ◽

Binbing Liu ◽

...

Keyword(s):

Lipid Peroxidation ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Early Brain Injury

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Atorvastatin ameliorates early brain injury through inhibition of apoptosis and ER stress in a rat model of subarachnoid hemorrhage

Bioscience Reports ◽

10.1042/bsr20171035 ◽

2018 ◽

Vol 38 (3) ◽

Cited By ~ 7

Author(s):

Wentao Qi ◽

Demao Cao ◽

Yucheng Li ◽

Aijun Peng ◽

Youwei Wang ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Water Content ◽

Caspase 3 ◽

Sham Group ◽

Early Brain Injury ◽

Brain Water Content ◽

Atorvastatin Group ◽

Related Proteins ◽

Brain Water

Aneurysmal subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease with very poor prognosis. The aim of the present study was to evaluate the protective effects of atorvastatin on early brain injury (EBI) after SAH using a perforation SAH model. Male Sprague–Dawley rats were randomly divided into four groups: the sham group, the SAH group (model group), SAH + 10 mg.kg−1.day−1 atorvastatin (low atorvastatin group), and SAH + 20 mg.kg−1.day−1 atorvastatin (high atorvastatin group). Atorvastatin was administered orally by gastric gavage for 15 days before operation. At 24 h after SAH, we evaluated the effects of atorvastatin on brain water content, apoptosis by TUNEL assay and scanning electron microscope (SEM), and the expression of apoptosis-related proteins by immunofluorescence and Western blotting analysis. Compared with the sham group, we observed increased brain water content, significant apoptosis, and elevated levels of apoptosis-related proteins including caspase-3, CCAAT enhancer-binding protein homologous protein (CHOP), the 78-kDa glucose-regulated protein (GRP78), and aquaporin-4 (AQP4) in the SAH group. Atorvastatin administration under all doses could significantly reduce brain water content, apoptosis, and the expression levels of caspase-3, CHOP, GRP78, and AQP4 at 24 h after SAH. Our data show that early treatment with atorvastatin effectively ameliorates EBI after SAH through anti-apoptotic effects and the effects might be associated inhibition of caspase-3 and endoplasmic reticulum (ER) stress related proteins CHOP and GRP78.

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TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways

Cell Death and Disease ◽

10.1038/s41419-020-03278-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yan Zhou ◽

Tao Tao ◽

Guangjie Liu ◽

Xuan Gao ◽

Yongyue Gao ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Therapeutic Target ◽

Cortical Neurons ◽

Neuronal Apoptosis ◽

Early Brain Injury ◽

Neurological Deficits ◽

Human Brain Tissue

AbstractNeuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.

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