Lipocalin-2 may produce damaging effect after cerebral ischemia by inducing astrocytes classical activation

Zhao, Nan; Xu, Xiaomeng; Jiang, Yongjun; Gao, Jie; Wang, Fang; Xu, Xiaohui; Wen, Zhe; Xie, Yi; Li, Juanji; Li, Rongrong; Lv, Qiushi; Liu, Qian; Dai, Qiliang; Liu, Xinfeng; Xu, Gelin

doi:10.1186/s12974-019-1556-7

Cited by 84 publications

(63 citation statements)

References 43 publications

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“…We also found that the ferritin and ceruloplasmin expressions in the hippocampi of KA-treated mice were reduced by LCN2 deletion. Nitric oxide, produced by iNOS, is known to cause neuronal damage and apoptotic cell death after KA administration [ 50 ], and LCN2 has been shown to produce a damaging effect after cerebral ischemia by inducing high iNOS expression in astrocytes both in vivo and in vitro [ 51 ]. Consistently, we found that iNOS expression increased in a time-dependent manner in KA-treated WT mice, but remained at baseline in LCN2 (−/−) mice.…”

Section: Discussionmentioning

confidence: 99%

Lipocalin-2 Deficiency Reduces Oxidative Stress and Neuroinflammation and Results in Attenuation of Kainic Acid-Induced Hippocampal Cell Death

et al. 2021

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The hippocampal cell death that follows kainic acid (KA)-induced seizures is associated with blood–brain barrier (BBB) leakage and oxidative stress. Lipocalin-2 (LCN2) is an iron-trafficking protein which contributes to both oxidative stress and inflammation. However, LCN2′s role in KA-induced hippocampal cell death is not clear. Here, we examine the effect of blocking LCN2 genetically on neuroinflammation and oxidative stress in KA-induced neuronal death. LCN2 deficiency reduced neuronal cell death and BBB leakage in the KA-treated hippocampus. In addition to LCN2 upregulation in the KA-treated hippocampus, circulating LCN2 levels were significantly increased in KA-treated wild-type (WT) mice. In LCN2 knockout mice, we found that the expressions of neutrophil markers myeloperoxidase and neutrophil elastase were decreased compared to their expressions in WT mice following KA treatment. Furthermore, LCN2 deficiency also attenuated KA-induced iron overload and oxidative stress in the hippocampus. These findings indicate that LCN2 may play an important role in iron-related oxidative stress and neuroinflammation in KA-induced hippocampal cell death.

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Section: Discussionmentioning

confidence: 99%

Lipocalin-2 Deficiency Reduces Oxidative Stress and Neuroinflammation and Results in Attenuation of Kainic Acid-Induced Hippocampal Cell Death

et al. 2021

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“…A neurological behavior assessment was made according to previous methods 24 h after reperfusion. By mNSS scoring standards 20 , mild injury is scored 0 to 6 points, moderate injury 7 to 12 points, and severe injury 13 to 18 points. The mNSS score assessed was 18 points.…”

Section: Evaluation Of Neurologic De Citsmentioning

confidence: 99%

WITHDRAWN: Combination of Paeoniflorin and Calycosin-7-glucoside Promotes Ischemic Stroke Recovery via the PI3K/AKT Signaling Pathway

Wang

Yan

et al. 2020

Preprint

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Background Paeoniflorin (PF) and calycosin-7-glucoside (CG) play a role in protecting against brain damage following cerebral ischemia. However, the mechanism of action of PF in combination with CG (PF + CG) against ischemia/reperfusion injury remains unclear. Methods The aim of this study was to investigate the protective role of PF + CG on ischemia/reperfusion injury in vivo and in vitro, as well as its potential mechanism of action indicating that PF + CG attenuates middle cerebral artery occlusion (MCAO) /oxygen-glucose deprivation reperfusion (OGD/R) injury via the PI3K/AKT pathway. MCAO rat model was prepared by modified suture method, and behavioral scoring, cerebral infarction area, brain tissue water content measurement, using PI3K, p-PI3K, AKT, p-AKT, Bcl-2, Bax, GSK-3β protein expression as indicators, observe the effect of PI3K / AKT signaling pathway inhibitor LY294002 on the anti-ischemia-reperfusion effect of PF + CG. Oxygen deprivation method was used to prepare the OGD/R model, CCK-8 was used to determine the survival rate of HT22 cells, the contents of SOR, ROS, MDA, and LHD were determined, and apoptosis was detected by flow cytometry and mitochondrial membrane potential, using PI3K, p-PI3K, AKT, p-AKT, Bcl-2, Bax, GSK-3β protein expression as indicators, observe the effect of PI3K/AKT signaling pathway inhibitor LY294002 on the anti- oxidative and glucose deprivation effect of PF + CG. Results The animal studies showed that PF + CG significantly decreased neurobehavioral deficits, cerebral infarct volume, and brain edema; ameliorated histopathological damage in model rats; increased levels of PI3K, AKT, p-PI3K, p-AKT, and Bcl-2; and reduced BAX and GSK-3β expression. After treatment with PF + CG, the morphology and number of cells in brain tissue were restored to normal, demonstrating a therapeutic effect in cerebral ischemia-reperfusion injury. Results of further studies revealed that, in vitro, PF + CG has a therapeutic effect to enhance cell vitality; elevate levels of superoxide dismutase (SOD); reduce levels of reactive oxygen species (ROS), lactate dehydrogenase (LDH), and malondialdehyde (MDA); decrease apoptosis rate; increase levels of PI3K, AKT, p-PI3K, p-AKT, and Bcl-2; and reduce BAX and GSK-3β expression. Conclusion These results demonstrate that PF + CG has a positive therapeutic effect on ischemia/reperfusion and OGD/R injury, and the mechanism is attributed to activation of the PI3K/AKT signaling pathway.

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“…Consistent with these studies, we found that the levels of LCN2 increase dramatically in the stroked brain. Since both NE and LCN2 have been shown to mediate neuroinflammation and BBB damage in stroke (64)(65)(66)(67)(68), reduced levels of NE and LCN2 in COX-2 deficient animals could be a potential mechanism underlying the vasculoprotective effects of COX-2 blockade in stroke.…”

Section: Discussionmentioning

confidence: 99%

Genetic Deletion or Pharmacological Inhibition of Cyclooxygenase-2 Reduces Blood-Brain Barrier Damage in Experimental Ischemic Stroke

Yang

DeMars

et al. 2020

Front. Neurol.

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Cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-9 are two crucial mediators contributing to blood-brain barrier (BBB) damage during cerebral ischemia. However, it is not known whether MMP-9 activation is involved in COX-2-mediated BBB disruption in ischemic stroke. In this study, we hypothesized that genetic deletion or pharmacological inhibition of COX-2 reduces BBB damage by reducing MMP-9 activity in a mouse model of ischemic stroke. Male COX-2 knockout (COX-2 −/−) and wild-type (WT) mice were subjected to 60 min of middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. Genetic deletion of COX-2 or post-ischemic treatment with CAY10404, a highly selective COX-2 inhibitor, significantly reduced BBB damage and hemorrhagic transformation, as assessed by immunoglobulin G (IgG) extravasation and brain hemoglobin (Hb) levels, respectively. Immunoblotting analysis showed that tight junction proteins (TJPs) zonula occludens (ZO)-1 and occludin as well as junctional adhesion molecule-A (JAM-A) and the basal lamina protein collagen IV were dramatically reduced in the ischemic brain. Stroke-induced loss of these BBB structural proteins was significantly attenuated in COX-2 −/− mice. Similarly, stroke-induced loss of ZO-1 and occludin was significantly attenuated by CAY10404 treatment. Ischemia-induced increase in MMP-9 protein levels in the ipsilateral cerebral cortex was significantly reduced in COX-2 −/− mice. Stroke induced a dramatic increase in MMP-9 enzymatic activity in the ischemic cortex, which was markedly reduced by COX-2 gene deficiency or pharmacological inhibition with CAY10404. Levels of myeloperoxidase (MPO, an indicator of neutrophil infiltration into the brain parenchyma), neutrophil elastase (NE), and lipocalin-2 (LCN2, also known as neutrophil gelatinase-associated lipocalin), measured by western blot and specific ELISA kits, respectively, were markedly increased in the ischemic brain. Increased levels of markers for neutrophil infiltration were significantly reduced in COX-2 −/− mice compared with WT controls following stroke. Altogether, neurovascular protective effects of COX-2 blockade are associated with reduced BBB damage, MMP-9 expression/activity and neutrophil infiltration. Our study shows for the first time that MMP-9 is an important downstream effector contributing to Yang et al. Role of Cyclooxygenase-2 in Stroke COX-2-mediated neurovascular damage in ischemic stroke. Targeting the COX-2/MMP-9 pathway could represent a promising strategy to reduce neuroinflammatory events in order to preserve the BBB integrity and ameliorate ischemic stroke injury.

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Lipocalin-2 may produce damaging effect after cerebral ischemia by inducing astrocytes classical activation

Cited by 84 publications

References 43 publications

Lipocalin-2 Deficiency Reduces Oxidative Stress and Neuroinflammation and Results in Attenuation of Kainic Acid-Induced Hippocampal Cell Death

Lipocalin-2 Deficiency Reduces Oxidative Stress and Neuroinflammation and Results in Attenuation of Kainic Acid-Induced Hippocampal Cell Death

WITHDRAWN: Combination of Paeoniflorin and Calycosin-7-glucoside Promotes Ischemic Stroke Recovery via the PI3K/AKT Signaling Pathway

Genetic Deletion or Pharmacological Inhibition of Cyclooxygenase-2 Reduces Blood-Brain Barrier Damage in Experimental Ischemic Stroke

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