scholarly journals Hypothermia Protects Against Ischemic Stroke Through Peroxisome-proliferator-activated-receptor Gamma

2021 ◽  
Author(s):  
Feng Jia ◽  
Shuai Shao ◽  
Yanlin Chen ◽  
Jiansong Zhang ◽  
Dilimulati Dilirebati ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Infarct Size ◽  
Cell Viability ◽  
Brain Edema ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Neuronal Cells ◽  
Microglial Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Abstract Background: IS (ischemic stroke) remains to be a global public health burden and urgently demands novel strategies. Hypothermia plays a beneficial role in central nervous system diseases. However, the function of hypothermia in IS has not been elucidated. Here we demonstrated the role of hypothermia in IS and explore the mechanism.Methods: IS phenotype was detected by infarct size and infarct volume as well as brain edema in mice. The neuroinflammation was evaluated by activation of microglial cells and expression of inflammatory genes after ischemia/reperfusion (I/R) and oxygen-glucose deprivation/reperfusion (OGD/R). The apoptosis of neuronal cells was assessed by Tunnel staining, expression of Cleaved Caspase-3 and Bax/Bcl-2, cell viability, and LDH release after I/R and OGD/R. Blood-brain-barrier (BBB) permeability was calculated by Evans blue extravasation, the expression of tight junction proteins and MMP-9, cell viability, and LDH release after I/R and OGD/R. The expression of peroxisome-proliferator-activated-receptor gamma (PPARγ) was detected by western blotting after I/R and OGD/R.Results：Hypothermia significantly reduced the infarct size and infarct volume as well as brain edema after ischemia/reperfusion. Consistency, hypothermia induced attenuated neuroinflammation, apoptosis of neuronal cells, and BBB disruption after I/R and OGD/R. Mechanistic studies revealed that hypothermia protected against IS by upregulating the expression of PPARγ in microglial cells, the effect of hypothermia was reversed by GW9662, a PPARγ inhibitor. Conclusions：Our data showed that hypothermia inhibited the activation of microglial cells and microglial cell-mediated neuroinflammation by upregulating the expression of PPARγ in microglial cells. Targeting hypothermia may be a feasible approach for IS treatment.

scholarly journals Remote Limb Ischemic Postconditioning Protects against Ischemic Stroke via Modulating Microglia/Macrophage Polarization in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Dong Han ◽  
Jue Wang ◽  
Lulu Wen ◽  
Miao Sun ◽  
Hang Liu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Ischemic Postconditioning ◽  
Neurological Deficits ◽  
Peroxisome Proliferator ◽  
Clinical Value ◽  
Peroxisome Proliferator Activated Receptor

Aim. The protection against ischemia/reperfusion injury mediated by remote limb ischemic postconditioning (RIPC) shows great clinical value in ischemic stroke therapy, but the particular mechanism of RIPC remains unclear. Methods. We carried out middle cerebral artery occlusion/reperfusion (MCAO/R) surgery on C57BL/6 male mice. RIPC was generated by 10-minute occlusion followed by the same period of reperfusion of the bilateral hind limb femoral artery and repeated for 3 cycles. Infarct size and neurological score were performed to assess stroke outcomes. Ly6Chi monocytes were quantified in the blood and brain by flow cytometry. Real-time PCR, ELISA, and immunofluorescence were utilized to detect phenotype of proinflammatory M1 and anti-inflammatory M2 microglia/macrophage. Nuclear factor κB (NF-κB) and peroxisome proliferator-activated receptor γ (PPARγ) levels were detected using Western blot. Results. At 24 and 72 h after MCAO, RIPC drastically attenuated infarct size and ameliorated the neurological deficits of mice and facilitated transmigration of Ly6Chi monocytes to the brain postischemia reperfusion. Furthermore, RIPC contributed to increased M2 and reduced M1 microglia/macrophage through inhibiting NF-κB and promoting PPARγ activation. Conclusion. Our results reveal pharmacological effect of RIPC in promoting microglia/macrophage transferring from M1 to M2 phenotype after MCAO/R in mice, which provides theoretical support for the therapeutic effect of RIPC in ischemic stroke.

Abstract TP98: Genetic Deletion of Kruppel-Like Factor 11 Aggravates Ischemic Brain Injury

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Xuelian Tang ◽  
Kai Liu ◽  
Ke-Jie Yin
Keyword(s):  
Ischemic Stroke ◽  
Protective Factor ◽  
Infarct Volume ◽  
Brain Infarction ◽  
Artery Occlusion ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Neurological Outcomes ◽  
Cerebrovascular Function

Kruppel-like factors (KLFs) are members of the zinc finger family of transcription factors and the function of the KLFs in the central nervous system is largely unexplored. KLF11 is a member of the KLF family and we have previously demonstrated that peroxisome proliferator-activated receptor gamma-mediated cerebral protection during ischemic insults needs recruitment of KLF11 as its critical coactivator. In this study we sought to determine the role of KLF11 itself in cerebrovascular function and the pathogenesis of ischemic stroke. Transient middle cerebral artery occlusion (MCAO) was performed in KLF11 knockout and wild-type control mice, and brain infarction size was analyzed by TTC staining. BBB integrity was assessed by using Evans Blue and TMR-Dextran extravasation assays. KLF11 KO mice exhibited significantly larger brain infarct volume and worse neurological outcomes in response to ischemic insults. Genetic deficiency of KLF11 in mice also significantly aggravated ischemia-induced BBB disruption by increasing cerebrovascular permeability and edema in comparison with wild-type mice. Mechanistically, KLF11 was found to directly regulate several key inflammatory cytokines in the brains of ischemic mice. These findings suggest that KLF11 acts as a novel protective factor in ischemic stroke. Elucidating the functional importance of KLF11 in ischemic process may lead us to discover novel pharmaceutical targets for the development of effective therapies against ischemic stroke.

scholarly journals Neuronal GPR30 Participates in Genistein-Mediated Neuroprotection in Ischemic Stroke by Inhibiting NLRP3 Inflammasome Activation in Ovariectomized Female Mice

2021 ◽  
Author(s):  
Shiquan Wang ◽  
Zhen Zhang ◽  
Jin Wang ◽  
Lina Ma ◽  
Jianshuai Zhao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion ◽  
Underlying Mechanism ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Peroxisome Proliferator ◽  
Neuroprotective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nlrp3 Inflammasome Activation

Abstract Estrogen replacement therapy (ERT) is potentially beneficial for the prevention and treatment of postmenopausal cerebral ischemia but inevitably increases the risk of cerebral hemorrhage and breast cancer when used for a long period of time. Genistein, a natural phytoestrogen, has been reported to contribute to the recovery of postmenopausal ischemic stroke with reduced risks. However, the underlying mechanism of genistein-mediated neuroprotection remains unclear. We reported that genistein exerted significant neuroprotective effects by enhancing the expression of neuronal G protein-coupled receptor 30 (GPR30) in the ischemic penumbra after cerebral reperfusion in ovariectomized (OVX) mice, and this effect was achieved through GPR30-mediated inhibition of nod-like receptor protein 3 (NLRP3) inflammasome activation. In addition, we found that Peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) was the pivotal molecule that participated in GPR30-mediated inhibition of NLRP3 inflammasome activation in OVX mice after ischemia/reperfusion (I/R) injury. Our data suggest that the neuronal GPR30/PGC-1α pathway plays an important role in genistein-mediated neuroprotection against I/R injury in OVX mice.

Abstract WP47: Reperfusion Following Ischemic Stroke is Associated with Reduced Brain Edema

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Hannah J Irvine ◽  
Thomas W Battey ◽  
Ann-Christin Ostwaldt ◽  
Bruce C Campbell ◽  
Stephen M Davis ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Edema ◽  
Infarct Volume ◽  
Brain Magnetic Resonance Imaging ◽  
Lesion Volume ◽  
Stroke Patients ◽  
Early Reperfusion ◽  
Echoplanar Imaging ◽  
Swelling Volume

Introduction: Revascularization is a robust therapy for acute ischemic stroke, but animal studies suggest that reperfusion edema may attenuate its beneficial effects. In stroke patients, early reperfusion consistently reduces infarct volume and improves long-term functional outcome, but there is little clinical data available regarding reperfusion edema. We sought to elucidate the relationship between reperfusion and brain edema in a patient cohort of moderate to severe stroke. Methods: Seventy-one patients enrolled in the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) with serial brain magnetic resonance imaging and perfusion-weighted imaging (PWI) were analyzed. Reperfusion percentage was calculated based on the difference in PWI lesion volume at baseline and follow-up (day 3-5). Midline shift (MLS) was measured on the day 3-5 fluid attenuated inversion recovery (FLAIR) sequence. Swelling volume and infarct growth volume were assessed using region-of-interest analysis on the baseline and follow-up DWI scans based on our prior methods. Results: Greater percentage of reperfusion was associated with less MLS (Spearman ρ = -0.46; P <0.0001) and reduced swelling volume (Spearman ρ = -0.56; P <0.0001). In multivariate analysis, reperfusion was an independent predictor of less MLS ( P <0.006) and decreased swelling volume ( P <0.0054), after adjusting for age, baseline NIHSS, admission blood glucose, baseline DWI volume, and IV tPA treatment. Conclusions: Reperfusion is associated with reduced brain edema as measured by MLS and swelling volume. While our data do not exclude the possibility of reperfusion edema in certain circumstances, in stroke patients, reperfusion following acute stroke is predominantly linked to less brain swelling.

scholarly journals Fenofibrate Protects Cardiomyocytes from Hypoxia/Reperfusion- and High Glucose-Induced Detrimental Effects

PPAR Research ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Fabiola Cortes-Lopez ◽  
Alicia Sanchez-Mendoza ◽  
David Centurion ◽  
Luz G. Cervantes-Perez ◽  
Vicente Castrejon-Tellez ◽  
...  
Keyword(s):  
Cell Viability ◽  
High Glucose ◽  
Cardiac Injury ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Peroxisome Proliferator ◽  
Related Factor ◽  
Irreversible Damage ◽  
Peroxisome Proliferator Activated Receptor ◽  
Subunit Expression ◽  
Endothelial Nitric Oxide

Lesions caused by high glucose (HG), hypoxia/reperfusion (H/R), and the coexistence of both conditions in cardiomyocytes are linked to an overproduction of reactive oxygen species (ROS), causing irreversible damage to macromolecules in the cardiomyocyte as well as its ultrastructure. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, promotes beneficial activities counteracting cardiac injury. Therefore, the objective of this work was to determine the potential protective effect of fenofibrate in cardiomyocytes exposed to HG, H/R, and HG+H/R. Cardiomyocyte cultures were divided into four main groups: (1) control (CT), (2) HG (25 mM), (3) H/R, and (4) HG+H/R. Our results indicate that cell viability decreases in cardiomyocytes undergoing HG, H/R, and both conditions, while fenofibrate improves cell viability in every case. Fenofibrate also decreases ROS production as well as nicotinamide adenine dinucleotide phosphate oxidase (NADPH) subunit expression. Regarding the antioxidant defense, superoxide dismutase (SOD Cu2+/Zn2+ and SOD Mn2+), catalase, and the antioxidant capacity were decreased in HG, H/R, and HG+H/R-exposed cardiomyocytes, while fenofibrate increased those parameters. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) increased significantly in treated cells, while pathologies increased the expression of its inhibitor Keap1. Oxidative stress-induced mitochondrial damage was lower in fenofibrate-exposed cardiomyocytes. Endothelial nitric oxide synthase was also favored in cardiomyocytes treated with fenofibrate. Our results suggest that fenofibrate preserves the antioxidant status and the ultrastructure in cardiomyocytes undergoing HG, H/R, and HG+H/R preventing damage to essential macromolecules involved in the proper functioning of the cardiomyocyte.

scholarly journals KADAR FIBRIN MONOMER DAN UKURAN INFARK DI STROK ISKEMIK AKUT

2016 ◽  
Vol 20 (3) ◽  
pp. 171
Author(s):  
Ani Kartini ◽  
Mansyur Arif ◽  
Hardjoeno Hardjoeno
Keyword(s):  
Ischemic Stroke ◽  
Infarct Size ◽  
Acute Ischemic Stroke ◽  
Thrombus Formation ◽  
Infarct Volume ◽  
Cross Sectional Study ◽  
Cerebral Infarct ◽  
Cross Sectional ◽  
Fibrin Monomer ◽  
Significant Difference

Coagulation activation and thrombosis frequently exist in ischemic stroke, thrombus formation can be detected early by the presence of fibrin monomer. The purpose of this study was to know the correlation of fibrin monomer level with cerebral infarct size in acute ischemic stroke patients. This was a cross sectional study with a total of 39 samples. The fibrin monomer level was determined by immunoturbidimetry method using STA-Compact and the measurement of the infarct size was done by CT scan of the head using Broderick formula. The results of this study showed that the median level of fibrin monomer in acute ischemic stroke with nonlacunar infarct type and lacunar infarct type were 14.46 μg/mL and 4.29 μg/mL, respectively. Mann-Whitney test showed there was a significant difference of fibrin monomer levels between nonlacunar infarct type and the lacunar type, p=0.000. The cut-off point analysis result of the fibrin monomer level was 5.96 μg/mL with a sensitivity of 88.9% and specificity of 76.4%, respectively. Spearman correlation test showed that fibrin monomer level was positively correlated with cerebral infarct volume in acute ischemic stroke (r=0.56, p=0.000). Based on this study, it can be concluded that fibrin monomer level can be used as a marker to predict the type of cerebral infarct and volume of acute ischemic stroke as well.

Abstract 1944: Atorvastatin Reduces Intracerebral Hemorrhage after Experimental Stroke

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hazem F Elewa ◽  
Anna Kozak ◽  
David Rychly ◽  
Adviye Ergul ◽  
Reginald Frye ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Intracerebral Hemorrhage ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Methyl Cellulose ◽  
The United States ◽  
Experimental Stroke ◽  
High Risk Population ◽  
Protective Agent ◽  
Oral Gavage

Ischemic stroke is a leading cause of death and disability in the United States and diabetes mellitus is the fastest growing risk factor for stroke. In addition, hyperglycemia, which is usually associated with diabetes, tends to worsen ischemia/reperfusion injury and to induce more oxidative stress damage. Preliminary data from our laboratory showed that diabetic animals (Goto-Kakizaki rats (GKs) are more susceptible to vascular damage leading to intracerebral hemorrhage. Many studies have indicated that statins possess neuroprotective properties even when administered after the onset of ischemia. However, the acute vascular effects of statins after ischemic stroke have not been studied to date. Objective: to evaluate the efficacy and magnitude of vascular protection of acute statin therapy in both GKs and their normoglycemic controls after experimental ischemic stroke. Methods: Male Wistar (W) and GK rats (270–305 g) underwent 3 hours of middle cerebral artery occlusion (MCAO) followed by reperfusion for 21 hours. Animals were randomized to receive either atorvastatin (15mg/Kg) or methyl cellulose (0.5%), administered by oral gavage, the first dose 5 minutes after reperfusion and the second dose after 12 hours. Brain tissue was analyzed for infarct volume and hemoglobin content. In another set of Wistar rats (n=3), atorvastatin (15mg/Kg) was administered by oral gavage to compare its pharmacokinetic profile with that of humans Results: Atorvastatin-treated groups had significantly lower hemoglobin (p=0.0156) and infarct volume (p=0.0132) compared to their controls. Atorvastatin peak concentration (27–77 ng/ml) in rats’ plasma was found to be similar to that seen after 80mg/day of atorvastatin in humans. Conclusion: Atorvastatin can be a novel vascular protective agent after acute ischemic stroke especially in a high risk population like diabetics. The mechanisms through which these effects are mediated are currently being investigated.

scholarly journals The Role of Astragaloside IV against Cerebral Ischemia/Reperfusion Injury: Suppression of Apoptosis via Promotion of P62-LC3-Autophagy

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1838 ◽  
Author(s):  
Yi Zhang ◽  
Ying Zhang ◽  
Xiao-fei Jin ◽  
Xiao-hong Zhou ◽  
Xian-hui Dong ◽  
...  
Keyword(s):  
Cell Viability ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Sprague Dawley ◽  
Astragaloside Iv ◽  
Ht22 Cells ◽  
Sd Rats ◽  
Neurological Score

Background: Ischemia/reperfusion (I/R) caused by ischemic stroke treatments leads to brain injury, and autophagy plays a role in the pathology. Astragaloside IV is a potential neuroprotectant, but its underlying mechanism on cerebral I/R injury needs to be explored. The objective of this study is to investigate the neuroprotective mechanism of Astragaloside IV against cerebral I/R injury. Methods: Middle cerebral artery occlusion method (MCAO) and oxygen and glucose deprivation/reoxygenation (OGD/R) method were used to simulate cerebral I/R injury in Sprague-Dawley (SD) rats and HT22 cells, respectively. The neurological score, 2,3,5-Triphe-nyltetrazolium chloride (TTC) staining, and transmission electron microscope were used to detect cerebral damage in SD rats. Cell viability and cytotoxicity assay were tested in vitro. Fluorescent staining and flow cytometry were applied to detect the level of apoptosis. Western blotting was conducted to examine the expression of proteins associated with autophagy. Results: This study found that Astragaloside IV could decrease the neurological score, reduce the infarct volume in the brain, and alleviate cerebral I/R injury in MCAO rats. Astragaloside IV promoted cell viability and balanced Bcl-2 and Bax expression in vitro, reduced the rate of apoptosis, decreased the expression of P62, and increased the expression of LC3II/LC3I in HT22 cells after OGD/R. Conclusions: These data suggested that Astragaloside IV plays a neuroprotective role by down-regulating apoptosis by promoting the degree of autophagy.

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