scholarly journals Peripheral Administration of Fetuin-A Attenuates Early Cerebral Ischemic Injury in Rats

2009 ◽  
Vol 30 (3) ◽  
pp. 493-504 ◽  
Author(s):  
Haichao Wang ◽  
Wei Li ◽  
Shu Zhu ◽  
Jianhua Li ◽  
Jason D'Amore ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Tissue ◽  
Immune Cells ◽  
Ischemic Injury ◽  
Dependent Manner ◽  
Ischemic Brain ◽  
Fetuin A ◽  
Ischemic Brain Tissue ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Cerebral ischemia-elicited inflammatory responses are driven by inflammatory mediators produced both by central (e.g., neurons and microglia) and infiltrating peripheral immune cells (e.g., macrophage/monocyte), and contribute to the evolution of tissue injury. A ubiquitous molecule, spermine, is released from injured cells, and counter-regulates release of various proinflammatory cytokines. However, the spermine-mediated anti-inflammatory activities are dependent on the availability of fetuin-A, a liver-derived negative acute-phase protein. Using an animal model of focal cerebral ischemia (i.e., permanent middle cerebral artery occlusion, MCAo), we found that levels of fetuin-A in the ischemic brain tissue were elevated in a time-dependent manner, starting between 2 and 6 h, peaking around 24 to 48 h, and returning to baseline 72 h after MCAo. When administered peripherally, exogenous fetuin-A gained entry across the BBB into the ischemic brain tissue, and dose dependently reduced brain infarct volume at 24 h after MCAo. Meanwhile, fetuin-A effectively attenuated (i) ischemia-induced HMGB1 depletion from the ischemic core; (ii) activation of centrally (e.g., microglia) and peripherally derived immune cells (e.g., macrophage/monocytes); and (iii) TNF production in ischemic brain tissue. Taken together, these experimental data suggest that fetuin-A protects against early cerebral ischemic injury partly by attenuating the brain inflammatory response.

scholarly journals Prolonged Fasting Improves Endothelial Progenitor Cell-Mediated Ischemic Angiogenesis in Mice

2016 ◽  
Vol 40 (3-4) ◽  
pp. 693-706 ◽  
Author(s):  
Bao Xin ◽  
Chun-Long Liu ◽  
Hong Yang ◽  
Cheng Peng ◽  
Xiao-Hui Dong ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Endothelial Progenitor Cell ◽  
Progenitor Cell ◽  
Ischemic Injury ◽  
Prolonged Fasting ◽  
Endothelial Progenitor ◽  
Ischemic Brain ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Background/Aims: Prolonged fasting (PF) was shown to be of great potency to promote optimal health and reduce the risk of many chronic diseases. This study sought to determine the effect of PF on the endothelial progenitor cell (EPC)-mediated angiogenesis in the ischemic brain and cerebral ischemic injury in mice. Methods: Mice were subjected to PF or periodic PF after cerebral ischemia, and histological analysis and behavioral tests were performed. Mouse EPCs were isolated and examined, and the effects of EPC transplantation on cerebral ischemic injury were investigated in mice. Results: It was found that PF significantly increased the EPC functions and angiogenesis in the ischemic brain, and attenuated the cerebral ischemic injury in mice that was previously subjected to cerebral ischemia. Periodic PF might reduce cortical atrophy and improve long-term neurobehavioral outcomes after cerebral ischemia in mice. The eNOS and MnSOD expression and intracellular NO level were increased, and TSP-2 expression and intracellular O2- level were reduced in EPCs from PF-treated mice compared to control. In addition, transplanted EPCs might home into ischemic brain, and the EPCs from PF-treated mice had a stronger ability to promote angiogenesis in ischemic brain and reduce cerebral ischemic injury compared to the EPCs from control mice. The EPC-conditioned media from PF-treated mice exerted a stronger effect on cerebral ischemic injury reduction compared to that from control mice. Conclusion: Prolonged fasting promoted EPC-mediated ischemic angiogenesis and improved long-term stroke outcomes in mice. It is implied that prolonged fasting might potentially be an option to treat ischemic vascular diseases.

scholarly journals Curcumin Protects Neuron against Cerebral Ischemia-Induced Inflammation through Improving PPAR-Gamma Function

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Zun-Jing Liu ◽  
Wei Liu ◽  
Lei Liu ◽  
Cheng Xiao ◽  
Yu Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Damage ◽  
Infarct Volume ◽  
Critical Role ◽  
Ischemic Injury ◽  
Ppar Gamma ◽  
Neurological Deficits ◽  
Protective Effects ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Cerebral ischemia is the most common cerebrovascular disease worldwide. Recent studies have demonstrated that curcumin had beneficial effect to attenuate cerebral ischemic injury. However, it is unclear how curcumin protects against cerebral ischemic injury. In the present study, using rat middle cerebral artery occlusion model, we found that curcumin was a potent PPARγagonist in that it upregulated PPARγexpression and PPARγ-PPRE binding activity. Administration of curcumin markedly decreased the infarct volume, improved neurological deficits, and reduced neuronal damage of rats. In addition, curcumin suppressed neuroinflammatory response by decreasing inflammatory mediators, such as IL-1β, TNF-α, PGE2, NO, COX-2, and iNOS induced by cerebral ischemia of rats. Furthermore, curcumin suppressed IκB degradation that was caused by cerebral ischemia. The present data also showed that PPARγinteracted with NF-κB-p65 and thus inhibited NF-κB activation. All the above protective effects of curcumin on cerebral ischemic injury were markedly attenuated by GW9662, an inhibitor of PPARγ. Our results as described above suggested that PPARγinduced by curcumin may play a critical role in protecting against brain injury through suppression of inflammatory response. It also highlights the potential of curcumin as a therapeutic agent against cerebral ischemia.

N-Myc Downstream-Regulated Gene 2 (Ndrg2): A Critical Mediator of Estrogen-Induced Neuroprotection Against Cerebral Ischemic Injury

2021 ◽  
Author(s):  
Lixia Zhang ◽  
Yulong Ma ◽  
Min Liu ◽  
Miao Sun ◽  
Jin Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuroprotective Effect ◽  
Ischemic Injury ◽  
Artery Occlusion ◽  
Male Mice ◽  
Neuroprotective Effects ◽  
Female Mice ◽  
Ndrg2 Expression ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Abstract Growing evidence indicates that estrogen plays a pivotal role in neuroprotection against cerebral ischemia, but the molecular mechanism of this protection is still elusive. N-myc downstream‐regulated gene 2 (Ndrg2), an estrogen-targeted gene, has been shown to exert neuroprotective effects against cerebral ischemia in male mice. However, the role of Ndrg2 in the neuroprotective effect of estrogen remains unknown. In this study, we first detected NDRG2 expression levels in the cortex and striatum in both female and male mice with western blot analyses. We then detected cerebral ischemic injury by constructing middle cerebral artery occlusion and reperfusion (MCAO-R) models in Ndrg2 knockout or conditional knockdown female mice. We further implemented estrogen, ERα or ERβ agonist replacement in the ovariectomized (OVX) Ndrg2 knockouts or conditional knockdowns female mice, then tested for NDRG2 expression, glial fibrillary acidic protein (GFAP) expression, and extent of cerebral ischemic injury. We found that NDRG2 expression was significantly higher in female than in male mice in both the cortex and striatum. Ndrg2 knockouts and conditional knockdowns showed significantly aggravated cerebral ischemic injury in female mice. Estrogen and ERβ replacement treatment (DPN) led to NDRG2 upregulation in both the cortex and striatum of OVX mice. Estrogen and DPN also led to GFAP upregulation in OVX mice. However, the effect of estrogen and DPN in activating astrocytes was lost in Ndrg2 knockouts OVX mice and primary cultured astrocytes, but partially retained in conditional knockdowns OVX mice. Most importantly, we found that the neuroprotective effects of E2 and DPN against cerebral ischemic injury were lost in Ndrg2 knockouts OVX mice but partially retained in conditional knockdowns OVX mice. These findings demonstrate that estrogen alleviated cerebral ischemic injury via ERβ upregulation of Ndrg2, which could activate astrocytes, indicating that Ndrg2 is a critical mediator of E2-induced neuroprotection against cerebral ischemic injury.

miR-137 alleviates focal cerebral ischemic injury in rats by regulating JAK1/STAT1 signaling pathway

2020 ◽  
Vol 39 (6) ◽  
pp. 816-827
Author(s):  
M Zhang ◽  
DJ Ge ◽  
Z Su ◽  
B Qi
Keyword(s):  
Brain Tissue ◽  
Hippocampal Neurons ◽  
Focal Cerebral Ischemia ◽  
Cell Damage ◽  
Ischemic Injury ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

The repairing effect and potential mechanism of miR-137 on cerebral ischemic injury in rats was investigated. The volume of cerebral infarction and calculated brain water content was detected by triphenyltetrazolium chloride staining. The expression of inflammatory factors was detected by enzyme-linked immunosorbent assay. The pathological damage of brain tissue was analyzed by hematoxylin and eosin and Nissl staining. The apoptosis in ischemic brain tissue was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling. The levels of STAT1 and JAK1 proteins were analyzed by Western blot. The expression of miR-137 in primary hippocampal neurons was detected by reverse transcription polymerase chain reaction. miR-137 overexpression significantly improved brain damage in rats. miR-137 overexpression can reduce the expression of TNF-α, IL-1β, and IL-6. miR-137 overexpression can reduce the degree of brain tissue damage and inhibit the expression of JAK1 and STAT1 proteins. miR-137 overexpression can reduce oxygen-glucose deprivation (OGD)/R-induced cell damage, improve cell proliferation, and reduce apoptotic rate. JAK1 and STAT1 protein expression was inhibited in hippocampal neurons after OGD/R treatment after transfection with miR-137 mimic. After the addition of the Filgotinib inhibitor, the levels of JAK1 and STAT1 proteins were significantly reduced. The results suggested that miR-137 overexpression can effectively improve ischemic injury after focal cerebral ischemia and protect against by inhibiting JAK1/STAT1 pathway.

scholarly journals Ghrelin reduces cerebral ischemic injury in rats by reducing M1 microglia/macrophages

2022 ◽  
Vol 66 (1) ◽  
Author(s):  
Rong Tian ◽  
Gengsheng Mao
Keyword(s):  
Cerebral Ischemia ◽  
Brain Tissue ◽  
Infarct Volume ◽  
Neurological Function ◽  
Tunel Staining ◽  
Triphenyltetrazolium Chloride ◽  
Ischemic Brain ◽  
Tnf Α ◽  
Ischemic Brain Tissue ◽  
The Brain

The purpose of this study was to investigate the effect of Ghrelin on the polarization of microglia/ macrophages after cerebral ischemia (CI) in rats. 60 wild-type SD rats were randomly divided into sham group, CI group, CI+Ghrelin group, 20 rats in each group. The modified Longa suture method was used to establish the middle cerebral artery occlusion (MCAO) model in rats. Before surgery, Ghrelin was injected subcutaneously (100μg/kg, twice a day) for 4 consecutive weeks. After modeling, neurological function scores were performed with three behavioral experiments: mNSS score, Corner test, and Rotarod test, to evaluate the recovery of neurological function after Ghrelin treatment. At the same time, the brain tissues were collected and stained with 2,3,5-triphenyltetrazolium chloride (TTC) to detect the cerebral infarct volume. RT-qPCR was used to detect the expression of TNF-α and IL-1β in the ischemic brain tissue, and the TUNEL staining was used to detect the apoptosis of brain tissue. Flow cytometry was used to detect the percentage of M1 type microglia/macrophages which were isolated by trypsin digestion of fresh cerebral cortex. Then, the Western blotting and immunofluorescence method were used to detect the phosphorylation level of AKT (P-AKT) and AKT. Compared with the CI group, the neurological function of the rats in the CI+Ghrelin group was dramatically improved, and the cerebral infarction area was dramatically reduced. At the same time, the expression of TNF-α and IL-1β in the ischemic brain tissue of rats in the CI+Ghrelin group decreased, and the apoptotic cells in the brain tissue also decreased. Compared with the CI treatment group, the activation of M1 microglia/macrophages in the cortex of the ischemic side of the infarct and the peri-infarct area in the CI+Ghrelin group was dramatically inhibited. At the same time, the ratio of P-AKT/AKT of the brain tissue in the CI+Ghrelin group was dramatically higher than that of the CI group. In the rat cerebral ischemia model, Ghrelin can promote the repair of brain damage and the recovery of neurological function after ischemia. Its mechanism may be related to activating AKT to selectively reduce M1 microglia/macrophages, reducing inflammation and cell apoptosis in brain tissue.

scholarly journals ADAM8 Activates NLRP3 Inflammasome to Promote Cerebral Ischemia-Reperfusion Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Hongwei Lu ◽  
Yaqin Meng ◽  
Xinrui Han ◽  
Wei Zhang
Keyword(s):  
Cerebral Ischemia ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Transmembrane Protein ◽  
Ischemia Reperfusion ◽  
Cortical Cell ◽  
Ischemic Injury ◽  
Neurological Deficits ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Stroke is the leading cause of death and disability in humans. Strokes are classified as either ischemic or hemorrhagic. Ischemic stroke accounts for 70–80% of the cases. Inflammation is a key factor in ischemic brain injury. Studies have shown that inflammatory response induced by NLRP3 inflammasome is one of the root causes of brain damage in mice with cerebral ischemia. However, its specific mechanism in cerebral ischemia is still unclear. ADAM8 (a disintegrin and metalloproteases 8) is a transmembrane protein with different functions. It plays an important role in tumors and neuroinflammation-related diseases. However, the role and molecular mechanism of ADAM8 in cerebral ischemia injury are still unclear. This study aims to evaluate the role of ADAM8 in cerebral ischemic injury and explore its signal transduction mechanism. This experiment shows that ADAM8 can significantly cause neurological deficits in MCAO mice and can substantially cause ipsilateral cerebral edema and cerebral infarction in MCAO mice. In addition, ADAM8 can significantly induce cortical cell apoptosis in MCAO mice, leading to the loss of neurons and the expression of proinflammatory factors COX2, iNOS, TNFα, and IL-6. Importantly, we confirmed that ADAM8 mediates the inflammatory response by promoting the activation of NLRP3 inflammasome, microglia, and astrocytes. These results indicate that ADAM8 may be a candidate drug target for the prevention and treatment of the cerebral ischemic injury.

Abstract TP100: Pharmacological Inhibition of ACC1 Restrains Peripheral T Cell Activation and Protects Against Cerebral Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Peiying Li ◽  
Long Wang ◽  
Yuxi Zhou ◽  
Xing Wang ◽  
Weifeng Yu
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Infarct Volume ◽  
Ischemic Injury ◽  
Ischemic Brain ◽  
Soraphen A ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic ◽  
Adhesive Removal

Background and purpose: T cell activation, which is detrimental to the ischemic brain, requires metabolic reprogramming to meet the increased fuel demanding. ACC1 is an enzyme catalyzing the carboxylation of acetyl-CoA to malonyl CoA, a key substrate in the glycolytic-lipogenic pathway, which is extremely critical for T cell differentiation and phenotype polarization. We tested the hypothesis that pharmacologically inhibiting the enzyme ACC1 early after stroke may restrain T cell activation and protect against cerebral ischemic injury. Methods: Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 60 minutes in C57/B6 mice. Soraphen A, the specific pharmacological inhibitor of ACC1 was administered at 1 hour after reperfusion at the dose of 1mg/kg, 5mg/kg, 10mg/kg and 50mg/kg intraperitoneally. Infarct volume was assess at 3 days after surgery by staining with 2,3,5-triphenyltetrazolium chloride. Behavior assessments, such as body proprioception, climbing, forelimb walking, lateral turning, foot fault and adhesive removal were examined at 3, 5, 7, 14, 21 and 28 days after stroke. T cell infiltration into the ischemic brain was examined by immunofluorescent staining. Results: Mice treated with 5mg/kg or 10mg/kg soraphen A exhibited significantly smaller infarct volume at 3 days after stroke. 5mg/kg was chosen as the dose for further experiments. Soraphen A treatment improved the overall neurological assessment and enhanced the performance of mice in adhesive removal test and grid walking test. Soraphen A treatment significantly attenuated the CD3+ T cell and Gr-1+ neutrophil infiltration in the ischemic mice brain at 3 days after surgery. Conclusion: Pharmacological inhibition of T cell activation by soraphen A is protective against cerebral ischemic injury and may represent a novel strategy for stroke therapy.

scholarly journals Focal cerebral ischemic injury decreases calbindin expression in brain tissue and HT22 cells

2013 ◽  
Vol 29 (3) ◽  
pp. 156 ◽  
Author(s):  
In-Ohk Ouh ◽  
Young-Min Kim ◽  
Sang-A Gim ◽  
Phil-Ok Koh
Keyword(s):  
Brain Tissue ◽  
Ischemic Injury ◽  
Ht22 Cells ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic
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