scholarly journals The Hsp90 Inhibitor 17-DMAG Attenuates Hyperglycemia-Enhanced Hemorrhagic Transformation in Experimental Stroke

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Jiaming Zhang ◽  
Kai Wang ◽  
Jia Qi ◽  
Xiaodong Cao ◽  
Feng Wang
Keyword(s):  
Ischemic Stroke ◽  
Hsp90 Inhibitor ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Vital Role ◽  
Experimental Stroke ◽  
Acute Hyperglycemia ◽  
Inflammatory Molecules ◽  
Cerebral Artery Occlusion ◽  
The Brain

Introduction. Hemorrhagic transformation (HT) is one of the most common complications of ischemic stroke which is exacerbated by hyperglycemia. Oxidative stress, inflammatory response, and matrix metalloproteinases (MMPs) have been evidenced to play a vital role in the pathophysiology of HT. Our previous study has reported that 17-DMAG, an Hsp90 inhibitor, protects the brain against ischemic injury via inhibiting inflammation and reducing MMP-9 after ischemia. However, whether 17-DMAG would attenuate HT in hyperglycemic middle cerebral artery occlusion (MCAO) rats is still unknown. Methods. Acute hyperglycemia was induced by an injection of 50% dextrose. Rats were pretreated with 17-DMAG before MCAO. Infarction volume, hemorrhagic volume neurological scores, expressions of inflammatory molecules and tight junction proteins, and activity of MMP-2 and MMP-9 were assessed 24 h after MCAO. Results. 17-DMAG was found to reduce HT, improve neurological function, and inhibit expressions of inflammatory molecules and the activation of MMPs at 24 h after MCAO. Conclusion. These results implicated that Hsp90 could be a novel therapeutic target in HT following ischemic stroke.

scholarly journals Improved reperfusion following alternative surgical approach for experimental stroke in mice

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 188
Author(s):  
Melissa Trotman-Lucas ◽  
Raymond Wong ◽  
Stuart M. Allan ◽  
Claire L. Gibson
Keyword(s):  
Ischemic Stroke ◽  
Surgical Approach ◽  
Artery Occlusion ◽  
Laser Speckle ◽  
Experimental Stroke ◽  
Contrast Imaging ◽  
Ipsilateral Hemisphere ◽  
Cerebral Artery Occlusion ◽  
The Brain

Background: Following ischemic stroke, recanalisation and restoration of blood flow to the affected area of the brain is critical and directly correlates with patient recovery.  In vivo models of ischemic stroke show high variability in outcomes, which may be due to variability in reperfusion.  We previously reported that a surgical refinement in the middle cerebral artery occlusion (MCAO) model of stroke, via repair of the common carotid artery (CCA), removes the reliance on the Circle of Willis for reperfusion and reduced infarct variability.  Here we further assess this refined surgical approach on reperfusion characteristics following transient MCAO in mice. Methods: Mice underwent 60 min of MCAO, followed by either CCA repair or ligation at reperfusion.  All mice underwent laser speckle contrast imaging at baseline, 24 h and 48 h post-MCAO. Results: CCA ligation reduced cerebral perfusion in the ipsilateral hemisphere compared to baseline (102.3 ± 4.57%) at 24 h (85.13 ± 16.09%; P < 0.01) and 48 h (75.04 ± 12.954%; P < 0.001) post-MCAO. Repair of the CCA returned perfusion to baseline (94.152 ± 2.44%) levels and perfusion was significantly improved compared to CCA ligation at both 24 h (102.83 ± 8.41%; P < 0.05) and 48 h (102.13 ± 9.34%; P < 0.001) post-MCAO. Conclusions: Our findings show CCA repair, an alternative surgical approach for MCAO, results in improved ischemic hemisphere perfusion during the acute phase.

scholarly journals Improved reperfusion following alternative surgical approach for experimental stroke in mice

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 188
Author(s):  
Melissa Trotman-Lucas ◽  
Raymond Wong ◽  
Stuart M. Allan ◽  
Claire L. Gibson
Keyword(s):  
Ischemic Stroke ◽  
Surgical Approach ◽  
Artery Occlusion ◽  
Laser Speckle ◽  
Experimental Stroke ◽  
Contrast Imaging ◽  
Ipsilateral Hemisphere ◽  
Cerebral Artery Occlusion ◽  
The Brain

Background: Following ischemic stroke, recanalisation and restoration of blood flow to the affected area of the brain is critical and directly correlates with patient recovery.  In vivo models of ischemic stroke show high variability in outcomes, which may be due to variability in reperfusion.  We previously reported that a surgical refinement in the middle cerebral artery occlusion (MCAO) model of stroke, via repair of the common carotid artery (CCA), removes the reliance on the Circle of Willis for reperfusion and reduced infarct variability.  Here we further assess this refined surgical approach on reperfusion characteristics following transient MCAO in mice. Methods: Mice underwent 60 min of MCAO, followed by either CCA repair or ligation at reperfusion.  All mice underwent laser speckle contrast imaging at baseline, 24 h and 48 h post-MCAO. Results: CCA ligation reduced cerebral perfusion in the ipsilateral hemisphere compared to baseline (102.3 ± 4.57%) at 24 h (85.13 ± 16.09%; P < 0.01) and 48 h (75.04 ± 12.954%; P < 0.001) post-MCAO. Repair of the CCA returned perfusion to baseline (94.152 ± 2.44%) levels and perfusion was significantly improved compared to CCA ligation at both 24 h (102.83 ± 8.41%; P < 0.05) and 48 h (102.13 ± 9.34%; P < 0.001) post-MCAO. Conclusions: Our findings show CCA repair, an alternative surgical approach for MCAO, results in improved ischemic hemisphere perfusion during the acute phase.

scholarly journals Improved reperfusion following alternative surgical approach for experimental stroke in mice

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 188
Author(s):  
Melissa Trotman-Lucas ◽  
Raymond Wong ◽  
Stuart M. Allan ◽  
Claire L. Gibson
Keyword(s):  
Ischemic Stroke ◽  
Surgical Approach ◽  
Artery Occlusion ◽  
Laser Speckle ◽  
Experimental Stroke ◽  
Contrast Imaging ◽  
Ipsilateral Hemisphere ◽  
Cerebral Artery Occlusion ◽  
The Brain

Background: Following ischemic stroke, recanalisation and restoration of blood flow to the affected area of the brain is critical and directly correlates with patient recovery.  In vivo models of ischemic stroke show high variability in outcomes, which may be due to variability in reperfusion.  We previously reported that a surgical refinement in the middle cerebral artery occlusion (MCAO) model of stroke, via repair of the common carotid artery (CCA), removes the reliance on the Circle of Willis for reperfusion and reduced infarct variability.  Here we further assess this refined surgical approach on reperfusion characteristics following transient MCAO in mice. Methods: Mice underwent 60 min of MCAO, followed by either CCA repair or ligation at reperfusion.  All mice underwent laser speckle contrast imaging at baseline, 24 h and 48 h post-MCAO. Results: CCA ligation reduced cerebral perfusion in the ipsilateral hemisphere compared to baseline (102.3 ± 4.57%) at 24 h (85.13 ± 16.09%; P < 0.01) and 48 h (75.04 ± 12.954%; P < 0.001) post-MCAO. Repair of the CCA returned perfusion to baseline (94.152 ± 2.44%) levels and perfusion was significantly improved compared to CCA ligation at both 24 h (102.83 ± 8.41%; P < 0.05) and 48 h (102.13 ± 9.34%; P < 0.001) post-MCAO. Conclusions: Our findings show CCA repair, an alternative surgical approach for MCAO, results in improved ischemic hemisphere perfusion during the acute phase.

Abstract 166: Endothelial Overexpression of LOX-1 Increases Stroke Size in vivo

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Alexander Akhmedov ◽  
Remo D Spescha ◽  
Francesco Paneni ◽  
Giovani G Camici ◽  
Thomas F Luescher
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Endothelial Dysfunction ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Oxidized Ldl ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion ◽  
The Brain

Background— Stroke is one of the most common causes of death and long term disability worldwide primarily affecting the elderly population. Lectin-like oxidized LDL receptor 1 (LOX-1) is the receptor for oxidized LDL identified in endothelial cells. Binding of OxLDL to LOX-1 induces several cellular events in endothelial cells, such as activation of transcription factor NF-kB, upregulation of MCP-1, and reduction in intracellular NO. Accumulating evidence suggests that LOX-1 is involved in endothelial dysfunction, inflammation, atherogenesis, myocardial infarction, and intimal thickening after balloon catheter injury. Interestingly, a recent study demonstrated that acetylsalicylic acid (aspirin), which could prevent ischemic stroke, inhibited Ox-LDL-mediated LOX-1 expression in human coronary endothelial cells. The expression of LOX-1 was increased at a transient ischemic core site in the rat middle cerebral artery occlusion model. These data suggest that LOX-1 expression induces atherosclerosis in the brain and is the precipitating cause of ischemic stroke. Therefore, the goal of the present study was to investigate the role of endothelial LOX-1 in stroke using experimental mouse model. Methods and Results— 12-week-old male LOX-1TG generated recently in our group and wild-type (WT) mice were applied for a transient middle cerebral artery occlusion (MCAO) model to induce ischemia/reperfusion (I/R) brain injury. LOX-1TG mice developed 24h post-MCAO significantly larger infarcts in the brain compared to WT (81.51±8.84 vs. 46.41±10.13, n=7, p < 0.05) as assessed morphologically using Triphenyltetrazolium chloride (TTC) staining. Moreover, LOX-1TG showed higher neurological deficit in RotaRod (35.57±8.92 vs. 66.14±10.63, n=7, p < 0.05) and Bederson tests (2.22±0.14 vs. 1.25±0.30, n=9-12, p < 0.05) - two experimental physiological tests for neurological function. Conclusions— Thus, our data suggest that LOX-1 plays a critical role in the ischemic stroke when expressed at unphysiological levels. Such LOX-1 -associated phenotype could be due to the endothelial dysfunction. Therefore, LOX-1 may represent novel therapeutic targets for preventing ischemic stroke.

Abstract T P229: Deletion of Voltage Gated Proton Channel in Microglial Cells is Neurovascular Protective After Ischemic Brain Injury

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
Becca Ward ◽  
Mohammed Abdelsaid ◽  
Tianzheng Yu ◽  
Yisang Yoon ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Ischemia Reperfusion ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Proton Channel ◽  
Ros Generation ◽  
Vascular Integrity ◽  
Voltage Gated ◽  
Underlying Mechanisms ◽  
Cerebral Artery Occlusion

Despite the failure of antioxidant treatments in clinical trials, the undoubted role of reactive oxygen species (ROS) in neurovascular damage after ischemic stroke calls for a more targeted approach. ROS production by microglia, the primary resident immune cells in the brain, is a key event of this process in ischemic stroke. Voltage gated proton channel, Hv1, is localized primarily to microglia and sustains NADPH oxidase activity. Deletion of Hv1 is neuroprotective after permanent middle cerebral artery occlusion (MCAO). We hypothesized that Hv1-mediated microglial ROS generation is also critical for vascular integrity and contributes to reperfusion injury after transient ischemic stroke. The wildtype (WT) and Hv1 knockout (KO) rats (n=4) were subjected to permanent or 3/24 h transient MCAO. The neurological deficiency, infarct, hemorrhagic transformation, and edema ratio were assessed. We found that in both permanent and transient MCAO model, KO rats develop smaller infarct, less vascular injury, edema, and hemorrhagic transformation, resulting in better short-term functional outcome. These results suggest that deletion of microglial Hv1 channel is vasculoprotective after ischemia/reperfusion and the underlying mechanisms need to be further studied.

scholarly journals P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

2019 ◽  
Author(s):  
Ruoxue Wen ◽  
Hui Shen ◽  
Shuxian Huang ◽  
Liping Wang ◽  
Zongwei Li ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Myosin Light Chain ◽  
Artery Occlusion ◽  
Walking Test ◽  
Microglial Phagocytosis ◽  
Tnf Α ◽  
Severity Scores ◽  
P2y6 Receptor ◽  
Cerebral Artery Occlusion ◽  
The Brain

Abstract Background Clearance of damaged cells is beneficial for the functional recovery after brain injury. Phagocytosis of tissue and cell debris is an important function of microglia during the development and pathological diseases. However, which specific phagocytic receptor mediates microglial phagocytosis after ischemic stroke is obscure. Methods ICR mice (n=59) underwent 90 minutes transient middle cerebral artery occlusion. P2Y6R, Iba1, GFAP and Tuj-1 double immunostainings were performed to determine P2Y6 receptor location. MRS2578 was injected into mice to inhibit P2Y6 receptor activity. Iba1 and TUNEL staining were performed to examine microglia phagocytosis. Modified neurological severity scores and Grid walking test were used to evaluate the neurological function after ischemic stoke. The expression of IL-1 α, IL-1 β, IL-6, IL-10, TNF-α, TGF-β and MPO was used to examine the inflammation response in the brain. Results The expression of P2Y6 receptor in microglia increased within three days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function using modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL-1α, IL-1β, IL-6, IL-10, TNF-α, TGF-β and MPO after ischemic stroke, which suggested that it had no effect on the inflammation in the brain. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in ischemic mice, which suggested that myosin light chain kinase was involved in P2Y6 receptor mediated phagocytosis. Conclusion Our results indicated that the P2Y6 receptor mediated microglial phagocytosis played an important role during the acute stage of ischemic stroke, which was a potential target for ischemic stroke treatment.

scholarly journals Image-based stroke rat brain atrophy volume and infarct volume computation

2020 ◽  
Vol 76 (12) ◽  
pp. 10090-10121
Author(s):  
Yung-Kuan Chan ◽  
Chun-Fu Hong ◽  
Meng-Hsiun Tsai ◽  
Ya-Lan Chang ◽  
Ping-Hsuan Sun
Keyword(s):  
Ischemic Stroke ◽  
Rat Brain ◽  
Brain Slice ◽  
Infarct Volume ◽  
Brain Slices ◽  
Artery Occlusion ◽  
Tetrazolium Chloride ◽  
Rat Brain Slice ◽  
Cerebral Artery Occlusion ◽  
The Brain

Abstract Stroke is one of the leading causes of death as well as results in a massive economic burden for society. Stroke is a cerebrovascular disease mainly divided into two types: ischemic stroke and hemorrhagic stroke, which, respectively, refer to the partial blockage and bleeding inside brain blood vessels. Both stroke types lead to nutrient and oxygen deprivation in the brain, which ultimately cause brain damage or death. This study focuses on ischemic stroke in rats with middle cerebral artery occlusion (MCAO) as experimental subjects, and the volumes of infarct and atrophy are calculated based on the brain slice images of rat brains stained with 2,3,5-triphenyl tetrazolium chloride. In this study, a stroke rat brain infarct and atrophy volumes computation system (SRBIAVC system) is developed to segment the infarcts and atrophies from the rat brain slice images. Based on the segmentation results, the infarct and atrophy volumes of a rat brain can be computed. In this study, 168 images of brain slices cut from 28 rat brains with MCAO are used as the test samples. The experimental results show that the segmentation results obtained by the SRBIAVC system are close to those obtained by experts.

scholarly journals CD28 Superagonist-Mediated Boost of Regulatory T Cells Increases Thrombo-Inflammation and Ischemic Neurodegeneration during the Acute Phase of Experimental Stroke

2014 ◽  
Vol 35 (1) ◽  
pp. 6-10 ◽  
Author(s):  
Michael K Schuhmann ◽  
Peter Kraft ◽  
Guido Stoll ◽  
Kristina Lorenz ◽  
Sven G Meuth ◽  
...  
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Regulatory T Cells ◽  
Thrombus Formation ◽  
Inflammatory Lesion ◽  
Artery Occlusion ◽  
Acute Stage ◽  
Experimental Stroke ◽  
Cerebral Artery Occlusion

While the detrimental role of non-regulatory T cells in ischemic stroke is meanwhile unequivocally recognized, there are controversies about the properties of regulatory T cells (Treg). The aim of this study was to elucidate the role of Treg by applying superagonistic anti-CD28 antibody expansion of Treg. Stroke outcome, thrombus formation, and brain-infiltrating cells were determined on day 1 after transient middle cerebral artery occlusion. Antibody-mediated expansion of Treg enhanced stroke size and worsened functional outcome. Mechanistically, Treg increased thrombus formation in the cerebral microvasculature. These findings confirm that Treg promote thrombo-inflammatory lesion growth during the acute stage of ischemic stroke.

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